3.01 Pyrroles and their Benzo Derivatives: Structure M. d’Ischia, A. Napolitano, and A. Pezzella University of Naples ‘‘...
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3.01 Pyrroles and their Benzo Derivatives: Structure M. d’Ischia, A. Napolitano, and A. Pezzella University of Naples ‘‘Federico II’’, Naples, Italy ª 2008 Elsevier Ltd. All rights reserved. 3.01.1
Introduction
1
3.01.2
Theoretical Methods
2
3.01.2.1 3.01.2.2 3.01.3
Pyrroles
2
Indoles
4
Molecular Spectroscopy
5
3.01.3.1
X-Ray Crystallography
5
3.01.3.2
Microwave Spectroscopy
7
3.01.3.3
Nuclear Magnetic Resonance Spectroscopy
8
3.01.3.3.1 3.01.3.3.2 3.01.3.3.3
3.01.3.4
Pyrroles Indoles Carbazoles
28
Pyrroles Indoles Carbazoles
28 29 31
Mass Spectrometry
3.01.3.6.1 3.01.3.6.2
19 19 22 26
Infrared Spectroscopy
3.01.3.5.1 3.01.3.5.2 3.01.3.5.3
3.01.3.6
8 12 17
Ultraviolet and Fluorescence Spectroscopy
3.01.3.4.1 3.01.3.4.2 3.01.3.4.3
3.01.3.5
Proton NMR Carbon-13 NMR Nitrogen-15 NMR
31
Pyrroles Indoles
32 33
3.01.3.7
Electron Paramagnetic Resonance Spectroscopy
34
3.01.3.8
Other Structural Methods
35
3.01.4
Structural Properties and Thermodynamic Aspects
35
3.01.4.1
Dipole Moments
35
3.01.4.2
Aromaticity
36
3.01.4.3
Acidity and Basicity
36
3.01.4.4
Tautomerism and Atropisomerism
37
3.01.5
Further Developments
37
3.01.5.1
Theoretical Methods
37
3.01.5.2
Molecular Spectroscopy
38
References
38
3.01.1 Introduction The aims and scope of this chapter remain those set out in CHEC(1984) <1984CHEC(4)155> and CHEC-II(1996) <1996CHEC-II(2)1>. Ring systems considered in this section include pyrroles, indoles, isoindoles, carbazoles, and, where appropriate, their tautomers. Their structures and numbering schemes are illustrated in Figure 1. Literature on the structure of pyrroles and their benzo derivatives has grown steadily since the last update in CHEC-II(1996), as witnessed by the number of reviews and book chapters <1999H(50)1157, 1999AHC(75)2,
1
2
Pyrroles and their Benzo Derivatives: Structure
Figure 1 Numbering schemes of pyrrolic heterocycles.
2001AHC(79)115, 2001AHC(80)1, 2002AHC(82)102>. These and other literature reports reflect a shift in emphasis from traditional spectroscopic techniques (NMR, UV, IR) to other ones, for example, fluorescence spectroscopy, and the burst of theoretical approaches as a means to integrate and strengthen the interpretative value of molecular spectroscopy. The large volume of data that has accumulated during the past decade necessitates that this survey be selective. Coverage of the topics will therefore be dictated by their relevance to structural issues and will not merely reflect the distribution of papers in the various fields of theoretical and spectroscopical structural analysis.
3.01.2 Theoretical Methods Applications of computational methods, especially ab initio and density functional theory (DFT) methods, feature prominently in the literature on the structural investigations of pyrroles and their benzo derivatives. The present coverage of the topic is mainly restricted to theoretical work with a major focus on the basic structural parameters of simple molecules in their ground state, whereas studies in support of spectroscopic investigations are separately dealt with in the relevant sections.
3.01.2.1 Pyrroles Bond orders of pyrrole calculated at the second-order Moller–Plesset (MP2) level and Hartree–Fock (in brackets) level are: N–C(2), 1.07 (1.09); C(2)–C(3), 1.47 (1.64); C(3)–C(4), 1.30 (1.33) <2002IJQ(90)534>. The steric and electronic effects of methyl substitution in pyrrole and bipyrroles have been theoretically investigated. Ab initio calculations indicate that replacement of a hydrogen atom with a methyl group in pyrroles significantly lowers the ionization potential (Table 1) <2000CM1490>. A more pronounced effect is predicted with substitution at C-3 rather than at the nitrogen because of the larger release of p-electron density from the former position. Bipyrroles prefer nonplanar conformations, with the largest angle for N,N9-dimethyl-2,29-bipyrrole ( ¼ 59.6 , RHF/6-31G** ) and the lowest for 2,29-bipyrrole ( ¼ 59.6 , RHF/6-31G** ). Full geometry optimization at the RHF/6-31G** level and as a function of the torsion angle between two adjacent rings demonstrates that the increasing loss of planarity in the 2,29-bipyrrole, 3,39-dimethyl-2,29-bipyrrole, and N,N9-dimethyl-2,29-bipyrrole series adversely affects the positive contributions expected from methyl substitution, and a corresponding increase in the ionization potential is observed. Table 1 Theoretical vertical ionization potentials (eV) in pyrrole and bipyrroles Cmpd.
"HOMO
E(M)ROHF
E(M)UHF
Pyrrole N-Me-pyrrole 3-Me-pyrrole
7.96 7.88 7.84
8.19 6.90 6.85
6.82 7.03 6.57
2,29-Bipyrrole N,N9-Me2-2,29-bipyrrole 3,39-Me2-2,29-bipyrrole
6.98 7.23 7.14
6.33 6.49 6.36
5.94 6.14 6.03
ROHF ¼ restricted open Hartree-Fock, UHF ¼ unrestricted Hartree–Fock. E(M)ROHF ¼ EROHF (Mþ) –E(M)RHF; E(M)UHF ¼ E(Mþ)UHF –E(M)RHF.
Structural parameters of geometry-optimized fluoropyrroles <2003PCA6476> and chloropyrroles <2005PCA8874> are reported in Table 2, selected data for methyl pyrrole-2-carboxylate <2001JST(567)107, 2002NJC165> and N-substituted 2- and 3-nitropyrroles <2003JMT(636)115> are listed in Table 3.
˚ and angles (deg) for substituted pyrroles and their cations (italic, lower row) Table 2 B3LYP/6-31G** optimized values of bond lengths (A) Substituent
N–C(2)
N–C(5)
C(2)–C(3)
C(4)–C(5)
C(3)–C(4)
C(2)–N–C(5)
C(2)–N–H
C(5)–N–H
N–C(2)–C(3)
N–C(2)–X
N–C(5)–X
None
1.375 1.363 1.365 1.363 1.379 1.337 1.369 1.344 1.360 1.379 1.376 1.366 1.376 1.365 1.365 1.359 1.382 1.356 1.377 1.367 1.371 1.374 1.374 1.334 1.372 1.354 1.369 1.392 1.374 1.369 1.372 1.363 1.370 1.374 1.376 1.358 1.374 1.370
1.375 1.363 1.385 1.365 1.371 1.395 1.380 1.387 1.392 1.352 1.376 1.366 1.376 1.364 1.387 1.372 1.370 1.379 1.377 1.367 1.378 1.359 1.373 1.397 1.376 1.380 1.378 1.342 1.374 1.369 1.372 1.364 1.376 1.360 1.373 1.382 1.374 1.370
1.378 1.433 1.368 1.425 1.375 1.455 1.371 1.449 1.372 1.402 1.364 1.421 1.376 1.43 1.372 1.433 1.366 1.441 1.368 1.427 1.375 1.432 1.378 1.396 1.376 1.399 1.376 1.404 1.374 1.427 1.378 1.428 1.380 1.433 1.377 1.448 1.378 1.430
1.378 1.433 1.374 1.431 1.380 1.395 1.377 1.405 1.371 1.447 1.364 1.421 1.376 1.431 1.372 1.426 1.367 1.404 1.368 1.427 1.375 1.432 1.377 1.455 1.379 1.457 1.376 1.444 1.374 1.427 1.378 1.428 1.376 1.423 1.374 1.407 1.378 1.430
1.425 1.374 1.431 1.376 1.416 1.385 1.420 1.380 1.424 1.380 1.440 1.380 1.416 1.379 1.422 1.380 1.431 1.382 1.431 1.384 1.426 1.376 1.421 1.396 1.423 1.390 1.423 1.388 1.428 1.377 1.425 1.391 1.427 1.392 1.426 1.387 1.430 1.392
109.7 109.0 108.3 107.5 110.2 109.6 108.9 107.9 108.9 108.1 106.1 106.1 110.7 109.4 109.5 108.0 107.6 106.7 108.4 107.0 108.9 108.5 110.2 109.8 108.4 109.0 109.3 109.0 108.2 108.1 110.5 109.2 109.8 108.9 108.7 108.6 109.2 108.7
125.1 125.4 124.6 125.3 124.6 125.3 124.2 125.4 124.7 125.0 126.5 126.9 124.6 125.3 124.2 125.3 125.9 126.7 125.7 126.4 124.7 125.2 124.7 125.3 124.2 125.0 124.7 124.8 125.9 125.9 124.8 125.4 124.3 125.0 125.4 125.8 125.4 125.6
125.1 125.4 126.9 127.0 125.1 124.9 126.7 126.5 126.3 126.8 126.5 126.9 124.6 125.3 126.1 126.5 126.4 126.5 125.7 126.4 126.4 126.3 125.1 124.9 126.4 125.9 125.9 126.2 126.9 125.9 124.8 125.4 125.9 126.1 125.9 126.6 125.4 125.6
107.6 108.3 110.2 110.3 105.9 106.0 108.2 108.2 110.6 111.5 110.1 110.4 106.6 108. 108.9 109.8 108.1 108.4 108.7 109.8 109.0 108.6 106.5 106.9 107.8 107.3 109.3 109.3 109.0 108.8 107.2 108.4 108.3 108.5 107.8 107.7 108.3 108.7
121.1 121.7 119.0 120.6 122.8 124.4 120.4 123.3 119.1 119.4 118.6 120.4 122.7 123.2 120.5 122.1 119.9 122.6 120.0 121.6 120.4 122.5 122.5 124.0 121.4 124.0 120.5 121.1 120.3 122.2 122.5 122.7 121.4 122.8 121.2 123.5 121.2 122.6
121.1 121.7 120.9 121.5 121.2 120.6 121.0 120.5 122.5 123.8 118.6 120.4 122.7 123.2 122.4 122.7 118.8 119.4 120.0 121.6 120.9 121.5 121.3 120.7 121.0 120.7 122.1 123.2 120.3 122.2 122.5 122.7 122.2 122.4 120.4 121.3 121.2 122.6
2-F 3-F 2,3-F2 2,4-F2 2,5-F2 3,4-F2 2,3,4-F3 2,3,5-F3 2,3,4,5-F4 2-Cl 3-Cl 2,3-Cl2 2,4-Cl2 2,5-Cl2 3,4-Cl2 2,3,4-Cl3 2,3,5-Cl3 2,3,4,5-Cl4 X ¼ H,F,Cl.
4
Pyrroles and their Benzo Derivatives: Structure
˚ and angles (deg) for methyl pyrrole-2-carboxylate (MPC) (RHF/6-311þG*) Table 3 Selected optimized values of bond lengths (A) <2002NJC165>, 2-nitropyrrole (2NP), 1-methyl-2-nitropyrrole (1Me2NP), 1-hydroxy-2-nitropyrrole (1OH2NP), 3-nitropyrrole (3NP), 1-methyl-3-nitropyrrole (1Me3NP), 1-hydroxy-3-nitropyrrole (1H3NP) (B3LYP/6-311G**) <2003JMT(636)115> Parameter C(5)–C(4) C(3)–C(4) C(2)–C(3) C(5)–N C(2)–N N–X C(2)–CO CTO C–O C(2)–NO2 C(3)–NO2 C(5)–C(4)–C(3) C(4)–C(3)–C(2) C(3)–C(2)–N C(5)–N–C(2) C(4)–C(5)–N N–C(2)–CO
MPC 1.368 1.417 1.365 1.348 1.366 0.992 1.463 1.191 1.318
106.9 107.1 108.1 109.4 108.6 119.3
2NP
1Me2NP
1OH2NP
1.387 1.411 1.382 1.387 1.369 1.009
1.386 1.404 1.385 1.363 1.383 1.464
1.399 1.397 1.395 1.345 1.383 1.371
1.423
1.426
1.407
107.7 106.1 109.3 108.3 108.2
107.2 106.5 109.5 107.0 109.7
108.1 106.5 107.9 109.6 107.8
3NP
1Me3NP
1OH3NP
1.371 1.421 1.380 1.382 1.360 1.007
1.371 1.418 1.382 1.384 1.360 1.457
1.373 1.419 1.383 1.378 1.357 1.380
1.438 106.0 109.3 106.2 110.5 108.1
1.436 105.7 109.1 106.9 109.5 108.8
1.438 106.3 109.5 105.1 112.0 107.0
DF calculations at the B3LYP/6-311G level indicate that among various geometry-optimized N-substituted 2- and 3-nitropyrroles, only 2-nitropyrrole, 1-hydroxy-2-nitropyrrole, 3-nitropyrrole, and 1,3-dinitropyrrole are planar, whereas steric effects contribute to the twist of the substituted group when a neighboring group exists <2002NJC1567, 2003JMT(636)115>. Internal rotational V2 barriers of the nitro group depend on the resonance, inductive, conjugation, hydrogen bonding, and steric effects between the substituted group and the pyrrole ring, with 2-nitropyrrole having the lowest V2 barrier (3.43 kcal mol1) and 1-hydroxy-2-nitro-pyrrole the highest barrier (14.91 kcal mol1). Ab initio HF, MP2, and DFT investigations of 2,29-bipyrrole, 2,29:59,20-terpyrrole, and 2,29:59,20:50,2--quaterpyrrole show that the energetics and conformational behavior of -oligopyrroles are closely related to the torsional potential of the parent 2,29bipyrrole <1998JCF25>. The minimum energy conformations of 2,29:59,20-terpyrrole and 2,29:59,20:50,2--quaterpyrrole are all anti-gauche (helix-like) structures, and there is evidence that the geometrical parameters of the pyrrole ring rapidly converge and the torsional potential around the planar anti-conformation decreases as the -oligomerization increases, suggesting that very conformationally flexible structures are highly probable.
3.01.2.2 Indoles The structural parameters of indole, its radical, and radical cation have been calculated by applying DFT methods (SVWN, BLYP, and B3LYP) and selected data are provided in Table 4 <1996J(P2)2653>. A DFT investigation of the relationship between indole and its constituent fragments for properties such as proton affinity, hydrogenation, and tautomerization has been reported <2004CPH(301)61>. A theoretical refinement of indole ring geometry using a 6-311G** basis set has been focused on the C(2)–D bond direction in site specifically deuterated tryptophan, and shows that the C(2)–D bond forms an angle of about 6 with respect to the normal to the C(3a)–C(7a) bond <2003JA111>. Transition state studies of tautomerization showed that unimolecular conversion of indole to 3H-indole proceeds via 2H-indole with an activation barrier of 51 kcal mol1 <1999JMT(491)211>. Theoretical studies of the four possible conformers of indole-2-carboxylic acid with ab initio (HF and MP2) and DFT (B3LYP) methods have provided bond lengths and angles of the most stable structure that are in good agreement with experimental data from X-ray analysis <2004JST(688)79>. An ab initio 6-31G* study of the effect of small substituents (the isoelectronic series F, OH, NH2, CH3) in positions 5 and 6 of the indole ring indicates that the bond length change with respect to indole is very limited ˚ <1998JMT(433)203>. The pyrrole ring has a more localized charge (0.01 A˚ at most, and on average below 0.005 A) distribution than the benzene ring. While the methyl has no effect on the molecular electrostatic potential outside of the condensed ring plane, the F and OH lone pairs produce a noticeable negative potential, enhancing the polarity of the NH proton. The p-density is increased by the presence of the NH2 group which, however, reduces the positive potential at the proton linked to the ring nitrogen. Comparative analysis shows that Slater–Vosko–Wilk–Nusair (SVWN)
Pyrroles and their Benzo Derivatives: Structure
Table 4 Comparison of computational methods for bond lengths of indole, its radical, and radical cation BLYP Method Bond
SVWN IndH
N–C(2) C(2)–C(3) C(3)–C(3a) C(3a)–C(4) C(4)–C(5) C(5)–C(6) C(6)–C(7) C(7)–C(7a) C(3a)–C(7a) C(7a)–N N–H C(2)–H C(3)–H C(4)–H C(5)–H C(6)–H C(7)–H
1.371 1.369 1.424 1.399 1.384 1.403 1.385 1.391 1.421 1.369 1.017 1.090 1.090 1.096 1.096 1.096 1.096
B3LYP/6-311G(d.p)
Ind ?
IndH ? þ
IndH
Ind ?
IndH ? þ
IndH
Ind ?
IndH ? þ
1.321 1.426 1.415 1.393 1.398 1.390 1.408 1.376 1.428 1.394
1.335 1.414 1.403 1.409 1.393 1.391 1.416 1.373 1.417 1.391 1.024 1.092 1.092 1.096 1.094 1.095 1.096
1.396 1.381 1.444 1.413 1.400 1.419 1.401 1.407 1.438 1.392 1.016 1.089 1.089 1.095 1.094 1.094 1.095
1.338 1.444 1.434 1.409 1.416 1.405 1.426 1.390 1.442 1.425
1.352 1.430 1.420 1.427 1.410 1.406 1.434 1.387 1.435 1.418 1.022 1.089 1.089 1.092 1.092 1.093 1.092
1.382 1.367 1.436 1.404 1.387 1.408 1.387 1.397 1.422 1.379 1.005 1.079 1.079 1.084 1.085 1.084 1.085
1.317 1.436 1.425 1.396 1.402 1.393 1.411 1.377 1.426 1.413
1.333 1.422 1.405 1.417 1.394 1.396 1.421 1.371 1.424 1.407 1.013 1.080 1.080 1.083 1.082 1.083 1.083
1.095 1.094 1.097 1.095 1.096 1.096
1.091 1.091 1.095 1.093 1.094 1.093
1.083 1.082 1.085 1.084 1.084 1.084
methods appear to be superior for optimization of monomer 1H-indole-3-acetic acid geometry, whereas B3LYP and HF can be used equally well for optimization of dimer ring geometry <2003IJQ251>. The standard redox potentials for the oxidation of substituted indoles have been calculated with DFT considering corrections for solvation (COSMO) and for thermal effects (zero-point energy and temperature variations in enthalpy and entropy) using frequency calculations <2000PCP195> Data on indole radical cations indicate that electronwithdrawing 5-substituents show a similar spin-density distribution in the aromatic system, whereas electrondonating substituents show a different distribution, which could explain the observed differences in the oxidative coupling reactions of indole radical cations of the two groups. Theoretical studies on 5,6-dihydroxyindoles and related compounds have been reviewed because of their relevance to the structure of eumelanin polymers <2005AHC(89)1>. The relative stabilities and the excitation energies of tautomers of 5,6-dihydroxyindole have been investigated using B3LYP and PBE0 calculations <2003PCB7162>. DFT calculations on 5,6-dihydroxyindole <2003PCB3061> using both the local VWN functional and the nonlocal BP functional gave calculated properties in good agreement with those of an ab initio study <1999PCB2993> and with experimental data. A carboxyl group on the 2-position significantly affects the physical properties of the 5,6-dihydroxyindole ring system, with special reference to the relative stabilities and the HOMO–LUMO gaps (HOMO – highest occupied molecular orbital and LUMO – lowest occupied molecular orbital) of the various redox forms <2005CPL(402)111>.
3.01.3 Molecular Spectroscopy 3.01.3.1 X-Ray Crystallography Bond lengths and angles of pyrrole-2,5-diacetic acid have been determined by X-ray analysis and are reported in Table 5 <2003NJC1353>. The structural parameters of the pyrrole ring are similar to those of the parent heterocycle, with p-bond orders for C(2)–C(3) and C(4)–C(5) of 0.78 and 0.76, that is, close to those of pyrrole (0.82). The carboxylic groups adopt a mutually trans-conformation with respect to the mean plane of the pyrrole ring. Strong hydrogen bonds are formed between self-complementary carboxylic acid groups of adjacent molecules, and weaker bonds between the N–H bond of one pyrrole unit and the CTO oxygen of a carboxylic group of another chain. Crystal structure determination of 2,29-bipyrroyl revealed supramolecular ribbons that are self-assembled via hydrogen bonding <2000M239>. The pyrrole rings and adjacent carbonyl groups are coplanar (torsion angle c. 0.9 ), with the N–H bond pointing in the same direction as the CTO bond, whereas the two carbonyls have a transoid but not coplanar geometry with a torsion angle of c. 128 . The X-ray crystal structure of 3,4-dichoro-1H-pyrrole-2,5-dicarboxylic acid bis-phenylamide tetrabutylammonium salt reveals the formation of an unusual dimer in the solid state via amide NH N pyrrole hydrogen bonds
5
6
Pyrroles and their Benzo Derivatives: Structure
<2002CC758>. Single-crystal X-ray diffraction data of indole-2-carboxylic acid are reported in Table 6 <2004JST(688)79>. In the crystal, two chains of molecules form a planar ribbon, held together by intermolecular O–H O and N–H O hydrogen bonds, with the O atom of the carboxylic group serving as the acceptor of two hydrogen bonds. Theoretical studies of the four possible conformers using ab initio (HF and MP2) and DFT (B3LYP) methods provide bond length and angle values of the most stable structure in good agreement with the corresponding experimental results <2004JST(688)79>. Table 5 Structural parameters of pyrrole-2,5-diacetic acid (pyrrole ring) as determined by X-ray analysis Bond
˚ Length (A)
Bond
Angle ( )
r(N–C(5)) r(N–C(2)) r(C(2)–C(3)) r(C(2)–CH2) r(C(3)–C(4)) r(C(4)–C(5)) r(C(5)–CH2)
1.372(3) 1.378(3) 1.362(3) 1.495(3) 1.421(3) 1.364(3) 1.502(3)
C(5)–N–C(2) C(3)–C(2)–N C(3)–C(2)–CH2 N–C(2)–CH2 C(2)–C(3)–C(4) C(5)–C(4)–C(3) C(4)–C(5)–N C(4)–C(5)–CH2 N–C(5)–CH2 OC–CH2–C(5) OC–CH2–C(2)
109.18(17) 107.66(18) 130.92(19) 121.38(19) 107.83(19) 107.18(19) 108.14(18) 130.3(2) 121.40(18) 108.88(15) 113.41(15)
Table 6 Structural parameters of indole-2-carboxylic acid as determined by X-ray analysis Bond
˚ Length (A)
Bond
Angle ( )
r(C(2)–CO) r(C(2)–C(3)) r(N–C(2)) r(C(3)–C(3a)) r(C(3)–H(3)) r(C(3a)–C(7a)) r(C(3a)–C(4)) r(C(4)–C(5)) r(C(4)–H(4)) r(C(5)–C(6)) r(C(5)–H(5)) r(C(6)–C(7)) r(C(6)–H(6)) r(C(7)–C(7a)) r(C(7)–H(7)) r(C(7a)–N) r(N–H)
1.439(1) 1.369(1) 1.384(1) 1.416(2) 0.932(9) 1.403(1) 1.409(2) 1.357(2) 0.974(8) 1.404(2) 0.964(8) 1.372(2) 1.026(11) 1.390(2) 1.045(10) 1.383(1) 0.968(11)
HO–CO–C(2) O–CO–C(2) CO–C(2)–N N–C(2)–C(3) C(2)–C(3)–C(3a) C(2)–C(3)–H(3) C(3)–C(3a)–C(7a) C(3)–C(3a)–C(4) C(3a)–C(4)–C(5) C(3a)–C(4)–H(4) C(4)–C(5)–C(6) C(4)–C(5)–H(5) C(5)–C(6)–C(7) C(5)–C(6)–H(6) C(6)–C(7)–C(7a) C(6)–C(7)–H(7) C(7)–C(7a)–C(3a) C(7)–C(7a)–N C(7a)–N–C(2) C(2)–N–H
125.9(1) 112.5(1) 121.8(1) 109.4 (1) 107.6(1) 125.3(6) 106.9(1) 134.2(1) 118.7(1) 117.0(5) 121.4(1) 121.2(5) 121.5(1) 117.7(6) 117.2(1) 122.6(6) 122.2(1) 129.6(1) 107.9(1) 122.9(7)
The structure of dimeric 2-(chloromethylaluminio)-3-(dimethylaluminio)-1-methylindole, a rare example of a crystallographically characterized polyaluminated aromatic compound, consists of a 2,3-dialuminated indole connected by a C4Al2 ring in a chair conformation <1998OM2906>. The C4Al2 ring is composed of two chloromethylaluminio groups bridging between the 2-position of one indole fragment and the 3-position of another. A dimethylaluminio group is bonded to the carbon at the 3-position in each indole ring, and a bridging chloride is situated between the dimethylaluminio and chloromethylaluminio units in each half of the dimeric structure. X-ray analysis of indole-3-acetic acid choline ester, a model compound for molecular recognition between the neurotransmitter acetylcholine and its esterase, shows that the quaternary trimethylammonium group is folded back to make a close contact with the indole ring through the cation–p interaction <1995CC2221>. X-ray crystal structure data of 1,2,7-trimethyl-2,7-dihydro-1H-diindolo[2,3-a:2,3-c]carbazole show that the molecule is not entirely planar, with the central ring displaying a half-boat conformation, while all five-member rings are planar <2000J(P2)2337>.
Pyrroles and their Benzo Derivatives: Structure
3.01.3.2 Microwave Spectroscopy Microwave rotational transitions for pyrrole, indole, and carbazole are given in CHEC-II(1996). The study of N-methylpyrrole is a challenge for rotational spectroscopy because the methyl group has a sixfold internal rotation symmetry axis and internal rotation of the methyl group is hindered by an intermediate sixfold barrier around 45 cm1. The rotational spectra of the lowest internal rotation states of N-methylpyrrole and its van der Waals complexes with one or two argon atoms have been investigated and have been found to be split into A–E doublets because of the internal rotation of the methyl group <1998MP1021>. Rotational transition frequencies for D, 13C, and 15N isotopomers of N-methylpyrrole have been measured <1997JST(413)93>. The 14N quadrupole hyperfine splittings for rotational transitions of N-methylpyrrole in the internal A (m ¼ 0) and E (m 1) states have been analyzed and the observed frequencies are listed in Table 7 <2002JST(612)117>.
Table 7 Observed transitions (MHz) in two internal rotation states of N-methylpyrrole A (m ¼ 0) I
II
E (m ¼ 1)
Transition
F –F
obs
(kHz)
101–000
0–1 2–1 1–1 1–1 1–2 1–0 3–2 2–1 2–2 1–1 3–2 2–1 1–0 2–2 1–0 2–2 3–2 2–1 1–1 2–2 4–3 2–1 3–2 3–3 2–2 4–3 2–1 3–2 3–3 2–1 4–3 3–3 2–2 3–2 2–1 3–3 4–3 3–2 2–2 3–3 2–1 4–3 3–2 2–2
6125.9613 6126.7811 6127.3303 11259.7646 11260.0791 11260.5668 11260.6016 11261.2098 11261.5264 12132.1499 12133.0782 12133.2114 12133.5162 12133.7602 13245.5401 13246.3058 13246.6496 13247.1738 13247.7050 16818.4167 16819.7467 16819.8560 16819.9606 16820.8880 17908.5021 17909.4854 17909.5683 17909.6535 17910.3346 18380.1007 18380.4278
0.6 0.9 1.6 1.4 3.7 4.6 3.1 2.7 0.3 0.7 1.8 0.7 1.2 1.3 0.7 0.4 0.9 1.3 0.2 1.2 2.8 3.4 1.6 0.7 4.1 0.4 0.6 1.0 0.3 2.3 0.6
18381.0151 18851.2208 18851.2789 18851.5160 18851.9599 18852.2851 19789.3251 19789.3611 19789.4928 19789.6661 19789.8923
0.9 2.4 2.8 1.7 1.4 0.4 1.4 0.1 0.4 0.0 1.5
212–111
202–101
211–110
313212
303–202
322–221
321–220
312–211
obs
(kHz)
12196.5290
14.8
12195.8770 12196.4510 12197.0610 12196.7990 12374.0400 12374.8430 12374.7610 12375.4100 12375.3170 12310.4549 12311.2569 12311.0238 12311.5537 12311.1823
3.4 0.2 5.8 0.0 15.7 18.8 20.8 12.5 11.5 1.8 2.1 2.7 4.1 2.9
17941.8028 17941.7766 17942.1079 17942.4349 18831.9904 18832.5752 18832.7183 18832.4394 18832.9056 17827.7029 17828.0668 17828.3962 17828.3962 17828.8448 18480.9863
2.9 12.2 2.4 18.4 4.0 6.1 5.9 5.9 5.3 0.1 0.6 0.7 0.0 2.2 2.7
18481.3038 18481.8605
2.1 6.5
18530.0610 18529.7184 18529.7045 18529.8319 18529.3607
11.6 0.3 7.6 2.7 12.8
7
8
Pyrroles and their Benzo Derivatives: Structure
The data show that the quadrupole hyperfine patterns of the rotational transitions are different between the two states, due to changes of the relative positions of some of the hyperfine components within the multiplet. The rotational spectrum of a pyrrole dimer is consistent with essentially a T-shaped structure, in which the planes of the two pyrrole monomers form an angle of 55.4(4) and the nitrogen side of one ring is directed to the p-electron system of the other ring establishing a weak H bond <1997JCP504>. The rotational spectra of conformers of tryptamine and tryptophol have been determined <2004PCP2806>. Two conformers of tryptamine are stabilized by an intramolecular N–H p bridge, formed between the amino group of the lateral chain in position 3 and the p-system of the pyrrole moiety, whereas the most stable conformer of tryptophol is stabilized by a similar N–H??p bridge, between the hydroxyl hydrogen and the p-system of the pyrrole unit.
3.01.3.3 Nuclear Magnetic Resonance Spectroscopy Basic information on the nuclear magnetic resonance (NMR) properties of pyrroles and their benzo derivatives is collected in CHEC(1984) <1984CHEC(4)155> and CHEC-II(1996) <1996CHEC-II(2)1>. Only recently acquired data or new structurally relevant interpretations of old data based are reported here.
3.01.3.3.1
Proton NMR
1
H chemical shifts for a series of pyrroles and indoles, including the parent heterocycles, have been analyzed in terms of the ring currents and p-electron effects together with a model (CHARGE7h) for the calculation of the two-bond and three-bond electronic effects <2002J(P2)1081>. The results show very good agreement between calculated and observed chemical shifts and demonstrate the concurrent effects of ring currents and p-electron densities.
3.01.3.3.1(i) Pyrroles Proton spectra of 1H-pyrroles are listed in Table 8.
Table 8 Proton NMR data (, ppm) for 1-H-pyrroles Substituent(s) None 1-(pNO2)Ph 1-(mNO2)Ph 1-(p-MeO)Ph 1-(m-MeO)Ph 1-(pNO2)Bn 1-(m-NO2)Bn 1-(p-MeO)Bn 1-(m-MeO)Bn 1-(pNO2)Bz 1-(mNO2)Bz 1-(p-MeO)Bz 1-(m-MeO)Bz 1-(CH2)2(pMeO)Ph 1-(CH2)2(mMeO)Ph 2-Bz 2-(m-NO2)Bz 2-(p-NO2)Bz 2-(m-MeO)Bz 2-(p-MeO)Bz 2-(m-Me)Bz 2-(p-Me)Bz 2-(m-Cl)Bz 2-(p-Cl)Bz 2-CH2CO2H, 3,5-(CO2H)2,
N-H
12.12
2-H
3-H
4-H
5-H
Solvent
Reference
7.19 7.17 7.01 7.10 6.68 6.69 6.64 6.65 7.23 7.25 7.30 7.27 6.59 6.60
6.44 6.42 6.34 6.35 6.23 6.23 6.14 6.17 6.41 6.42 6.35 6.35 6.12 6.12 6.90 6.92 6.87 6.92 6.89 6.89 6.89 6.89 6.87
6.44 6.42 6.34 6.35 6.23 6.23 6.14 6.17 6.41 6.42 6.35 6.35 6.12 6.12 6.34 6.41 6.39 6.34 6.34 6.34 6.33 6.36 6.35 6.96
7.19 7.17 7.01 7.10 6.68 6.69 6.64 6.65 7.23 7.25 7.30 7.27 6.59 6.60 7.16 7.25 7.24 7.15 7.13 7.15 7.14 7.18 7.17
CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 DMSO-d6
2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 1996T8775 (Continued)
Pyrroles and their Benzo Derivatives: Structure
Table 8 (Continued) Substituent(s)
N-H
2-CH2OH, 3,5-(CO2H)2, 2-CHOHCO2H, 3,5-(CO2H)2, 1-Me, 2-F, 5-n-octyl 2-CHO, 5-F 1-Me, 2- F 1-Me, 3- F 1-SnMe3 1-SnEt3 1-SnBut3 1-SnMe3, 2,5-Me2 1-SiMe3, 2,5-Me2 1-PbMe3, 2,5-Me2 1-SnBz3 1-SnPh3 2-NH2, 3-CN,4-Ph 1-C6H11, 2-NH2, 4-CN 1-Bn, 2-NH2, 4-CN, 2-NH2, 3-CN, 4-Ph 1-C6H11, 2-NH2, 4-CN 1-Bn, 2-NH2, 4-CN 2-Ph, 3-NH2, 5-Ph
11.75 12.00
2-H
3-H
5.56 6.96 5.39 6.51 6.62 6.67 6.73
6.21 6.89
6.39 6.43 6.49 5.89 5.83 5.95 6.39 6.50
4-H 6.95 7.00 5.27 5.81 5.85 5.79 6.39 6.43 6.49 5.89 5.83 5.95 6.39 6.50
10.38 5.36 5.23 10.50 6.13 5.88 8.88
7.36
5-H
6.23 6.44 6.62 6.67 6.73
6.21 6.89 6.56 7.15 7.14 6.56 7.64 7.29
Solvent
Reference
DMSO-d6 DMSO-d6 CDCl3 CDCl3 CDCl3 CDCl3 C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA TFA
1996T8775 1996T8775 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161
Within separate series of meta- and parai-substituted 1-phenyl, 1-benzyl, 1-benzoyl, and 1-(2-phenylethyl)pyrroles, -proton chemical shifts of the pyrrole ring show excellent correlation with typical Hammett values, while -proton chemical shifts correlate only poorly. This trend indicates that electronic effects of the substituent on the aryl ring are not only transmitted through bonds. For 1-phenylpyrrole a plausible interpretation involves through-space transmission of the effects of the substituents, which would be made possible by a stacking interaction between the p-orbitals of the -carbons of the pyrrole ring and the meta- and para-carbons of the aryl ring (Figure 2).
Figure 2 Proposed orbital interaction in the intermolecular stacking of 1-phenylpyrroles.
Within a series of m- and p-substituted 2-benzoylpyrroles, a nitro group on the aryl ring causes downfield shifts of 0.05 (m) and 0.07 ( p) ppm of the H-4 proton, and of 0.08 (m) and 0.09 (p) ppm of the H-5 proton, while no effect is seen on the H-3 proton. Conversely, electron-donating groups (e.g., OMe, Me) have no significant influence. Proton NMR data on 2- and 3-fluoro-substituted pyrroles have been reported, including nJHH and nJHF values <2003JFC(124)159>. 2-Aminopyrroles in DMSO/TFA undergo protonation at the amino group <1996JHC161>, with a downfield shift of the NH2 proton signal of 4–6 ppm. The H-3 and NH protons show downfield shifts of c. 0.6–0.8 and 0.1 ppm, respectively, while no effect is experienced by the H-5 proton upon protonation of the 2-amino group.
3.01.3.3.1(ii) Indoles An overview of the proton spectra of indole derivatives that appeared during the past decade is included in Table 9.
9
Table 9 Proton NMR data (, ppm) for 1H-indoles Substituent(s) 1-OH 2-CO2H, 5,6-OH2 1-SnMe3 1-SnMe3, 2-Me 1-SnEt3 1-SnBut3 1-Me, 2-N3 1-Me, 3-N3 3-CO2Me, 6-Br 3-CH2CH(NMe2)CO2H, 5-Br 2-CONHNTC(CH3)C2H5, 3-Ph, 5-Me 2-CONHNTCC5H8, 3-Ph, 5-Me 2H,-2-diazo, 3-Ph 2H, 2-diazo, 3-COMe 2H, 2-diazo, 3-CO2Et 1H, 2-diazonium, 3-Ph 1H, 2-diazonium, 3-COMe 1H, 2-diazonium, 3-CO2Et 2-NH2 2-NH2, 3-Ph 2-NH2, 3-CO2Et 2-NH2, 3-COMe 2-NH2 2-NH2, 3-Ph 2-NH2, 3-CO2Et 2-NH2, 3-COMe 2-CH2(3-indolyl), 3-CH2CH(OH)CO2H 3-CH2(2-(3-CH2CH(OH)CO2H) indolyl)2-N(C2H5)3-3-(39,59(CF3)2)PhNH2, 4,6-(CF3)2 2-N(C2H5)3-3-(39,59(CF3)2)PhNH2, 5-NO2, 7-Br 2-N(C2H5)3-3-(39,59(CF3)2)PhNH2, 5-Cl, 6-CF3 2-N(C2H5)3-3-(39,59(CF3)2)PhNH2, 4,5,6-Cl3 a
Not assigned.
N-H
2-H
3-H
4-H
5-H
6-H
7-H
Solvent
Reference
7.21
6.31 6.81 6.83 6.38 6.81 6.83 6.14
7.56 6.85 7.92 7.66 7.87 7.85 7.46 7.66 7.93 7.77 7.16 7.15 7.74–7.93a 7.61 7.80 7.80–7.82 7.88 7.87 6.89–7.19a 7.54 7.56 7.42 7.39 7.40–7.48a 7.60 7.49 7.55 7.46
7.06
7.20
7.24–7.37a 7.13–7.27a 7.00–7.39a 7.21–7.27a 7.00–7.15a 7.11–7.24a 7.27
7.24–7.37a 7.13–7.27a 7.00–7.39a 7.21–7.27a 7.00–7.15a 7.11–7.24a
7.43 6.76 7.24–7.37a 7.13–7.27a 7.00–7.39a 7.71 7.00–7.15a 7.11–7.24a 7.59 7.28 7.39 7.38 7.74–7.93 7.34 7.58 7.80–7.82 7.64 7.58 6.89–7.19a 7.54 7.11 7.15 7.27 7.40–7.48a 7.14 7.19 7.19 7.32 7.50
CDCl3 DMSO-d6 C6D6 C6D6 C6D6 C6D6 CDCl3 CDCl3 CD3OD CD3OD DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA CD3OD CD3OD DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6
1997H(44)157 1996T7913 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1995G151 1995G151 2005JNP1484 2005JNP1484 2005JST(740)213 2005JST(740)213 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2005HCA1472 2005HCA1472 1998MC242 1998MC242 1998MC242 1998MC242
11.09 7.10 7.10 7.48 6.81 7.93 7.28
10.21 10.53 9.04 10.07 10.28 10.57 10.77 12.41 12.50 10.69 11.19
5.21
4.17 5.62
7.01 8.13 8.26 7.72 7.48
7.90 7.81
6.70–6.90 6.95–7.09a 7.27 7.05–7.15 7.17–7.27a 7.27 6.56–6.79a 6.83 6.87 6.92 7.12 7.08–7.15a 6.89 7.03 6.96 6.96 7.93
7.21 7.08 7.08 6.70–6.90 6.95–7.09a 7.33 7.05–7.15 7.17–7.27a 7.33 6.56–6.79a 6.90 6.95 7.00 7.18 7.08–7.15a 6.97 7.03 6.96 7.06 7.95
7.05 7.88
Pyrroles and their Benzo Derivatives: Structure
Protonation of 2-aminoindoles has been studied by NMR techniques <2000T5177> and has been shown to depend on the substituent at the 3-position. With H or Ph at C-3 protonation in DMSO/TFA occurs at C-3, giving rise to a 2H signal at 4.17 and a 1H signal at 5.62 for 2-aminoindole and 2-amino-3-phenylindole, respectively. The immonium protons appear as two singlets at around 9.9 and 10.1, due to the strong double bond character of the C(2)–N bond. In contrast, 2-aminoindoles bearing electron-withdrawing groups at C-3, for example, CO2Et, COMe, are protonated at the exocyclic nitrogen, as inferred from the 4.3–6.8 ppm downfield shift of the broad signal due to the amino group, with concomitant increase in the integrated area from 2H to 3H. Protonation of 3-aminoindoles 2-substituted with Ph, CO2Et, or 4-ClC6H4 invariably occurs at the amino group, leading to a downfield shift of the relevant resonance. The azido group on the pyrrole moiety of 1-methylindole exerts a shielding effect on the H-3 proton ( ¼ 0.25 ppm in 2-azido-1-methylindole) but causes only a minor opposite influence on the H-2 proton ( ¼ 0.04 ppm in 3-azido-1-methylindole) <1995G151>. In both cases, the methyl protons were shifted downfield, with a larger effect observed in 3-azido-1-methylindole ( ¼ 0.27 vs. 0.05 for 2-azido-1-methylindole). Proton chemical shifts of 1-hydroxyindole have been assigned unambiguously (Table 2) based on NOE effects measured in the NOESY spectrum of the closely related 1-methoxyindole <1997H(44)157>. The H-4 in 1-hydroxyindole is relatively deshielded ( 7.56) and H-3 is the most shielded proton of the series ( 6.31), while the OH proton resonates at 5.56. Indole ring protons in 2-triethylammonium-3-(39,59-bistrifluoromethyl)phenylamino-4,6-bistrifluoromethylindolate <1998MC242> fall within the aromatic resonance signal range at 6.3–8.1. Replacement of the CF3 groups with other electron-withdrawing substituents (NO2, Br, Cl) on the benzo- and phenylamino moieties of 2-triethylammonium-3-phenylaminoindolates does not affect chemical shifts to any significant extent. Diazotization of 2-amino-1H-indoles results in the formation of the corresponding diazonium salts that are converted to 2-diazo-2H-indoles upon subsequent neutralization <2001HCA2212>. 1H NMR data for representative 3-substituted members of both series have been recorded, showing for the 2-diazo-2H-indoles the lack of the indole NH proton. 2-(29-Pyridyl)indole and derivatives are of interest because of the complementary juxtaposition of the p-deficient pyridine and p-rich pyrrole rings. The N-methylated salt 1 undergoes deprotonation at the indole NH to provide the tautomeric (E)-1-methyl-2-(29-indolenylidene)-1,2-dihydropyridine 2, whereas 3-methyl-2-(29-pyridyl)indole and 3,39-bridged derivatives afford (Z)-1-methyl-2-[29-(39-methylindolenylidene)]-1,2-dihydropyridines 3a–d with the opposite Z configuration (Table 10) <1998JOC4055>. The different stereochemistry is apparent from the chemical shift of the H-39 proton of the pyridine moiety in configuration 2 resonating relatively downfield compared to isomer 3 because of the deshielding effect of the lone pair electrons of the indolylidene nitrogen. Furthermore, deviation from coplanarity favors the contribution of a dipolar resonance form accumulating positive charge on the pyridine ring and negative charge on the indole ring. This is seen from the indole protons H-4 and H-7 in 2 which, due to the deviation from coplanarity, are shifted upfield 0.13–0.18 ppm compared to 3. A corresponding upfield shift with increasing dihedral angle between the rings, however, is not seen in derivatives 3b–d.
Table 10 Proton NMR data (, ppm) for 2-(20-pyridyl)indoles <1998JOC4055> Substituent(s)
N-H
1 2 3a 3b 3c 3d
12.13
2-H
3-H
4-H
5-H
6-H
7-H
Solvent
7.38 7.23
7.74 7.54 7.38 7.36 7.42 7.76
7.16 6.81 6.68 6.65 6.69 7.06
7.33 6.99 6.81 6.82 6.85 7.32
7.56 7.41 7.28 7.31 7.33 7.47
DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6
11
12
Pyrroles and their Benzo Derivatives: Structure
1
H NMR data for a variety of 5,6-dihydroxyindoles and their derivatives have been reported <2005AHC(89)1>.
3.01.3.3.1(iii) Carbazoles 1 H NMR spectra of five separate series of mono-, di-, and polysubstituted chloro-, bromo-, iodo-, benzoyl-, and nitrocarbazoles substituted at the 1-, 3-, 6-, and 8-positions have been recorded <2005JHC867> with a view to understanding the factors underlying the transmission of substituent effects in these systems. Data are listed in Table 11. Chlorine shields the ortho-protons (H-2, H-4, H-5, H-7, depending on the pattern of substitution), indicating that resonance effects overwhelm inductive effects. However, in the 1,3,6,8-tetrachloro derivative the same protons experience a modest deshielding influence, suggesting enhanced inductive effects. All other substituents tested deshield the same ortho-protons. Effects on meta-protons (H-1, H-3, H-8) are usually slightly deshielding, whereas the para (H-4) proton is shielded by chlorine and bromine, but is deshielded by the other substituents. Thus, bromine exerts opposite effects on ortho- and para-protons.
3.01.3.3.2
Carbon-13 NMR
3.01.3.3.2(i) Pyrroles 13 C relative shieldings (ppm) have been calculated for pyrrole at the GIAO/B3LYP/6-31G* level <2001H(55)2109> and compared with experimental values: C-2: 107.86 (116.3, CDCl3); C-3: 102.21 (106.1, CDCl3). Protonation of the amino group produces expected opposite shifts of carbon signals of 2-aminopyrroles in DMSO/ TFA <1996JHC161>: C-2 resonances shift upfield by 3–5 ppm (7–11 ppm in the case of N-substituted derivatives), whereas C-3 carbons become deshielded and undergo downfield shifts of 1.5–2.5 ppm (5–9 ppm in N-substituted derivatives) (Table 12). The magnitudes of these effects are smaller than those observed with 3-aminopyrroles, but no explanation has been offered for this difference. Notably, 2- and 3-aminopyrroles in pure TFA are protonated at the 5- and/or 3-positions of the ring, confirming similar behavior. As in the case of protons, -carbon chemical shifts for meta- and para-substituted 1-phenyl, 1-benzyl, 1-benzoyl, and 1-(2-phenylethyl)pyrroles correlate remarkably well with m and p parameters, and much better than -carbon shifts <2000JHC15>. Plots of the same chemical shift data against other substituent correlation parameters, such as Taft’s 13-substituent constant, gave less satisfactory correlations. From comparison of 13C NMR data and theoretical DFT analysis of two 2-fluoropyrroles, F substituent chemical shift (SCS) values (F) have been determined of 26.5/21.2 ppm for C-2 and –23.2/31.3 ppm for C-3, consistent with a strong deshielding effect on the ipso-position and an opposite shielding influence on the adjacent carbon <2003JFC(124)159>. In a representative 3-fluoropyrrole F is 44.0 ppm for C-3, –17.6 ppm for C-2, and –10.5 ppm for C-4. Besides the effects on the chemical shift, the fluoro substituent strongly influences carbon–carbon couplings. Thus, dramatic increases of the 1 JC2C3 couplings (>20 Hz) have been observed in 2-fluoro- and 3-fluoropyrroles in comparison with the parent compounds. These 1JC2C3 constants (83.4–89.1 Hz) are among the largest ever measured for substituted five-membered heterocycles. A smaller increase is observed for 1JC3C4 in the 3-fluoro derivative. DFT calculations satisfactorily reproduce experimental data and show that the Fermi contact is the main factor determining the magnitude of 1J. Electron-withdrawing groups on the N-1 position of benzyl 3,5-dimethylpyrrole-2-carboxylate exert a general deshielding effect on carbon resonances, with more accentuated shifts at C-2 and C-4 caused by the N-triflyl group <2000OL3587>. This effect is a consequence of the decreased aromaticity and electron density distribution within the pyrrole ring subsequent to reduced availability of the nitrogen lone pair. 3.01.3.3.2(ii) Indoles 13 C relative shieldings (ppm) have been calculated for indole at the GIAO/B3LYP/6-31G* level <2001H(55)2109> and have been compared with experimental values (in brackets, CDCl3) tabulated in CHEC-II(1996) <1996CHECII(2)1>: C-2: 114.97 (123.7); C-3: 97.34 (101.8); C-3a: 126.11 (127.0); C-4:114.34 (119.9); C-5: 113.70 (121.1); C-6: 115.63 (119.0); C-7: 103.11 (110.4); C-7a: 121.06 (134.8). 13 C NMR data for substituted indoles are given in Table 13. Protonation of 2-aminoindole and 2-amino-3-phenylindole occurs at C-3 and results in a downfield shift of the C-2 carbon signal in DMSO/TFA of 25.6 and 30.4 ppm, respectively, whereas the C-3 resonance shifts upfield by 39.6 and 42.1 ppm <2000T5177>. With those 2-aminoindoles in which protonation occurs at the amino group the aromaticity of the indole ring is retained and an opposite trend is observed: the C-2 carbon signals shift upfield by 26.5 and 28.7 ppm for 2-amino-3-carboethoxyindole and 2-amino-3-acetylindole, respectively, whereas the C-3 carbons are only slightly deshielded (<2 ppm).
Table 11 Proton NMR data (, ppm) for carbazoles Substituent(s)
1-H
2-H
3-H
4-H
5-H
6-H
7-H
8-H
Solvent
Ref.
None 1-Cl 3-Cl 1,6-Cl2 3,6-Cl2 1,3,6-Cl3 1,3,6,8-Cl4 1-Br 3-Br 3,6-Br2 1,3,6-Br3 1,3,6,8-Br4 1-I 3-I 1,6-I2 3,6-I2 1,3,6-I3 1-Bz 3-Bz 3,6-Bz2 1-NO2 3- NO2 1,6-(NO2)2 3,6- (NO2)2 2-OH, 3-Me, 7-OMe, 8CH2CHC(CH3)(CH2)2CHC(CH3)2, Euchrestine B 1-(3-indolyl), 2-OH, 3-CO2H 3-Me, 6-OMe, 2,6-OMe2, 3-Me Bis 2,29-(1-OH, 3-Me, 6,8-OMe2)
7.16
7.48 7.42 7.36 7.43 7.38 7.45 7.50 7.50 7.50 7.55 7.77 7.70 7.77 7.65 7.80 7.67 8.02 8.17 8.10 8.05 8.24 8.29 8.39 8.38
7.36 7.20
8.10 7.95 7.95 7.95 7.96 7.70 8.17 7.99 8.34 8.30 8.26 8.44 8.13 8.51 8.18 8.57 8.57 8.36 8.54 8.58 8.62 9.15 8.90 9.45 7.67
8.10 8.04 7.85 7.94 7.96 7.81 8.17 8.06 8.09 8.30 8.27 8.44 8.09 8.15 8.50 8.57 8.55 8.11 7.92 8.58 8.31 8.36 9.30 9.45 7.71
7.36 7.58 7.60
7.48 7.42 7.42 7.40 7.38 7.41 7.50 7.42 7.43 7.55 7.54 7.70 7.43 7.43
7.16 7.20 7.19 7.15 7.33 7.35
CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 DMSO-d6 DMSO-d6
2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2001JFA5589
8.40 7.82 7.74 7.81
7.89 7.52 7.44 7.13
7.02
DMSO-d6 CDCl3 CDCl3 DMSO-d6
2005HCA1472 1999P1263 1999P1263 1996TL7819
7.05 7.33
7.40 7.50
7.37 7.36
7.54 7.58 7.65 7.75 6.80
7.27 6.79
7.21
7.21
7.40
6.98 6.99
7.52
7.35 7.49
7.52 7.61
7.20 7.18 7.69
7.40 7.42 7.29 7.51
7.67 7.70 7.38 7.39 8.05 7.51 7.29 8.50 8.38
7.16 7.16 7.50 7.50 7.61 7.52 7.45 7.36 7.43 7.18 7.20 7.58 8.41 7.58 7.88 7.75
6.83
7.13 7.03 6.95 6.45
7.30 7.23 7.23
Table 12 Carbon-13 NMR data (, ppm) for 1H-pyrroles Substituent(s)
2-C
3-C
4-C
5-C
Solvent
References
1-(pNO2)Ph 1-(mNO2)Ph 1-(p-MeO)Ph 1-(m-MeO)Ph 1-(pNO2)Bn 1-(mNO2)Bn 1-(p-MeO)Bn 1-(m-MeO)Bn 1-(pNO2)Bz 1-(mNO2)Bz 1-(p-MeO)Bz 1-(m-MeO)Bz 1-(CH2)2(pMeO)Ph 1-(CH2)2(mMeO)Ph 2-Bz 2-(m-NO2)Bz 2-(p-NO2)Bz 2-(m-MeO)Bz 2-(p-MeO)Bz 2-(m-Me)Bz 2-(p-Me)Bz 2-(m-Cl)Bz 2-(p-Cl)Bz 2-CH2CO2H, 3,5-(CO2H)2, 2-CH2OH, 3,5-(CO2H)2, 2-CHOHCO2H, 3,5-(CO2H)2, 2-BOC, 3,5-Me2 1,2-BOC2, 3,5-Me2 1-Ms, 2-BOC, 3,5-Me2 1-Tf, 2-BOC, 3,5-Me2 1-Me,2-F, 5-n-octyl 1-Me,2-n-octyl 2-CHO, 5-F 2-CHO 1-Si(i-pr)3 1-Si(i-pr)3, 3-F
119.1 119.1 119.4 119.7 121.2 121.1 121.0 121.0 121.0 121.0 121.2 121.1 120.5 120.4 131.1 130.3 130.6 131.1 131.1 131.2 131.2 130.7 130.8 136.1 142.4 140.3 117.5 120.9 122.9 125.0 146.4 132.4 125.9 123.6 123.6 106.0
112.5 111.9 110.3 109.8 109.4 109.4 114.2 114.2 114.2 114.2 112.6 113.0 107.9 107.9 119.5 120.3 120.4 119.5 118.5 119.4 119.0 119.8 119.5 114.5 113.1 113.9 129.6 131.0 131.5 133.2 82.7 104.9 123.5 110.0 110.0 154.0
112.5 111.9 110.3 109.8 109.4 109.4 114.2 114.2 114.2 114.2 112.6 113.0 107.9 107.9 111.0 111.7 111.7 111.0 110.8 110.9 110.9 111.3 111.2 116.2 116.2 116.4 111.6 113.1 115.1 118.3 101.2 105.9 90.9 122.2 110.0 99.5
119.1 119.1 119.4 119.7 121.2 121.1 121.0 121.0 121.0 121.0 121.2 121.1 120.5 120.4 125.3 126.7 126.7 125.3 124.6 125.1 124.9 125.9 125.6 121.8 121.8 122.5 133.3 136.0 137.7 138.4 124.2 119.9 153.7 132.5 123.6 121.3
CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 DMSO-d6 DMSO-d6 DMSO-d6 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3
2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2000JHC15 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 1996T8775 1996T8775 1996T8775 2000OL3587 2000OL3587 2000OL3587 2000OL3587 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 2003JFC(124)159 (Continued)
1-SnMe3 1-SnEt3 1-SnBut3 1-SnMe3, 2,5-Me2 1-SiMe3, 2,5-Me2 1-PbMe3, 2,5-Me2 1-SnBz3 1-SnPh3 2-NH2, 3-CN, 4,5-Me2 2-NH2, 3-CN, 4-Me, 5-Bn 2-NH2, 3-CN, 4-Me, 5-Ph 2-NH2, 3-CN, 4-Ph 2-NH2, 3-Ph, 4-Ac, 5-Me 1-C6H11, 2-NH2, 4-CN 1-Bn, 2-NH2, 4-CN 2-NH2, 3-CN, 4,5-Me2 2-NH2, 3-CN, 4-Me, 5-Bn 2-NH2, 3-CN, 4-Me, 5-Ph 2-NH2, 3-CN, 4-Ph 2-NH2, 3-Ph, 4-Ac, 5-Me 1-C6H11, 2-NH2, 4-CN 1-Bn, 2-NH2, 4-CN 2-Ph, 3-NH2-5-Ph 2-CONHR, 4,5-Br2, Axinellamine A 2-CONHR, 4,5-Br2, Taurodispacamide 1-R, 2-CONHR, 4,5-Br2, Cyclooroid 1-Tips, 2-CO2H, 3,4-Br2 2-CO2Me, 3,4-(pOH)Ph2 Lamellarin Q
124.4 125.0 125.6 133.0 133.0 133.5 124.9 126.3 146.3 146.7 147.8 149.7 133.6 138.8 139.7 141.2 143.2 144.6 146.4 130.2 127.6 132.6 71.8 128.2
109.8 109.8 109.9 108.7 111.1 107.3 109.7 110.2 71.3 71.1 74.0 68.4 103.4 90.6 90.5 73.8 72.6 75.3 70.1 105.7 99.9 95.5 181.3 113.0
109.8 109.8 109.9 108.7 133.0 107.3 109.7 110.2 111.1 112.0 114.6 121.7 119.5 88.4 88.9 112.1 112.7 115.0 121.9 119.6 90.5 89.3 94.8 98.0
124.4 125.0 125.6 133.0 111.1 133.5 124.9 126.3 115.2 118.4 119.3 108.7 127.5 119.3 122.8 116.7 119.4 120.1 108.9 128.4 124.2 124.6 180.5 108.2
C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 CDCl3 CDCl3 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA TFA DMSO-d6
1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1996JHC161 1999JOC731
128.8
114.5
99.9
106.2
CD3OD
2000TL9917
128.5
115.1
93.2
111.4
CD3OD
2000TL9917
121.8 120.7
106.3 126.2
102.7 126.1
122.5 120.5
CDCl3 (CD3)2CO
2004T8659 2004T8659
Table 13 Carbon-13 NMR data (, ppm) for 1H-indoles Substituent(s)
2-C
3-C
3a-C
4-C
5-C
6-C
7-C
7a-C
Solvent
Reference
1-OH 1-SnMe3 1-SnMe3, 2-Me 1-SnEt3 1-SnBut3, 7-Me 2-CO2H, 5,6-OH2 1-Me, 2-N3 1-Me, 3-N3 3-CO2Me, 6-Br 3-CH2CH(NMe2)CO2H, 5-Br 2H,-2-diazo, 3-Ph 2H, 2-diazo, 3-COMe 2H, 2-diazo, 3-CO2Et 1H, 2-diazonium, 3-Ph 1H, 2-diazonium, 3-COMe 1H, 2-diazonium, 3-CO2Et 1-Et, 2,3-Ph2 1-Et, 2,3-Ph2 1-Bz, 2,3-Ph2 2,3-Ph2, 5-Me 2-Ph 2,3-Ph2 2-NH2 2-NH2, 3-Ph 2-NH2, 3-CO2Et 2-NH2, 3-COMe 2-NH2 2-NH2, 3-Ph 2-NH2, 3-CO2Et 2-NH2, 3-COMe 2-CH2(3-indolyl),3CH2CH(OH)CO2H 3-CH2(2-(3CH2CH(OH)CO2H) indolyl)-
125.06 131.6 142.5 132.3 133.9 126.13 135.9 118.5 132.4 125.3 112.9 110.1 115.9 113.1 111.3 113.2 137.2 136.9 137.8 135.2 137.9 135.66 146.3 143.0 153.5 154.1 171.9 173.4 127.0 125.4 137.9
96.51 103.7 103.4 103.9 104.2 107.43 88.3 108.2 107.1 106.6 120.7 117.6 110.0 121.1 115.6 109.6 115.4 115.2 115.7 114.5 98.9 114.7 78.5 92.4 83.5 96.3 36.4 52.8 84.0 98.2 107.4
124.23 131.7 132.3 131.6 131.6 120.22 127.7 129.5 124.8 128.6 126.5 133.2 128.2 127.6 132.9 136.2 128.0 127.8 127.4 127.6 129.0 128.5 130.3 128.1 126.6 126.2 127.0 128.9 133.0 135.0 130.5
120.75 121.1 120.0 121.0 121.0 105.27 121.3 123.1 121.9 120.3 130.4 126.1 126.9 130.3 124.7 127.5 119.7 119.5 119.7 124.2 120.3 119.4 116.2 117.7 199.2 119.6 125.0 125.0 119.7 121.6 119.3
119.21 120.9 119.8 121.0 120.6 142.32 119.7 or 120.6 118.3 or 119.8 124.2 112.0 127.1 123.6 125.7 127.1 123.3 125.5 122.0 121.8 122.3 128.9 121.8 122.4 118.3 119.1 120.3 120.6 128.0 128.8 120.7 121.9 119.8
121.67 119.1 118.9 119.2 119.3 146.46 119.7 or 120.6 118.3 or 119.8 115.6 124.2 126.9 120.4 121.6 126.3 122.3 121.8 120.0 119.8 120.4 119.1 119.6 120.2 115.7 114.9 118.0 117.5 124.1 124.4 118.4 118.9 121.7
108.38 112.8 112.4 112.9 114.7 97.29 109.7 110.0 114.5 112.8 115.6 119.7 121.4 115.2 121.2 121.4 109.7 109.5 110.4 110.5 111.5 110.8 108.8 109.5 109.7 110.0 112.1 112.5 110.0 110.7 111.8
133.73 142.9 144.2 143.5 143.5 132.97 135.6 136.2 137.4 135.2 143.4 147.4 149.2 143.5 143.7 148.4 136.1 135.8 137.0 134.1 137.5 134.9 132.7 132.4 132.6 133.1 143.3 141.9 153.9 156.0 137.5
CDCl3 C6D6 C6D6 C6D6 C6D6 DMSO-d6 CDCl3 CDCl3 CD3OD CD3OD DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 CDCl3 CDCl3 þ Cr(acac)3 CDCl3 CDCl3 DMSO-d6 CDCl3 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6 DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA DMSO-d6-TFA CD3OD
1997H(44)157 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1996T7913 1995G151 1995G151 2005JNP1484 2005JNP1484 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 2001HCA2212 1996M111 1996M111 1996M111 1996M111 1996M111 1996M111 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2000T5177 2005HCA1472
124.3
114.1
129.0
119.8
119.9
122.6
112.4
138.6
CD3OD
2005HCA1472
Pyrroles and their Benzo Derivatives: Structure
Amino group protonation in 2-phenyl-, 2-carboethoxy-, and 2-(4-chlorophenyl)-3-aminoindoles results in an upfield shift of the C-3 carbon of 18.6–28.6 ppm and a downfield shift of the C-2 carbon of 6.9–11.6 ppm. Carbons carrying the azido group in 2-azido-1-methylindole and 3-azido-1-methylindole are deshielded relative to 1-methylindole (6.7 and 7.1 ppm, respectively), whereas an opposite shielding effect is seen on the adjacent carbon ( 12.9 for C-3 in 2-azido-1-methylindole and –10.6 for C-2 in 3-azido-1-methylindole) <1995G151>. The remainder of the carbon signals are virtually unaffected. 13 C chemical shifts of 1-hydroxyindole in (Table 13) reveal a slight deshielding effect at C-2 (<2 ppm) relative to the parent heterocycle <1996CHEC-II(2)1> but an opposite shielding of about 5 ppm at C-3 and 3 ppm at C-3a <1997H(44)157>. In contrast with 3-diazo-3H-indoles, 2-diazo-2H-indoles show 13C NMR spectra similar to those of the corresponding diazonium salts and do not show an appreciable upfield shift at the carbon bound to the diazo function, that is, the C-2 carbon, which resonates at 110–115 <2001HCA2212>. These data support a structure largely zwitterionic in character in which the negative charge is mainly located on the indole nitrogen. 13 C NMR data for a variety of 5,6-dihydroxyindoles and their derivatives have been reported <2005AHC(89)1>. Addition of a paramagnetic relaxation agent enables quantitative determination of carbons by 13C NMR. This technique has been applied to a series of phenylindoles using chromium(III) acetylacetonate (Cr(acac)3) as the relaxation reagent <1996M111>.
3.01.3.3.2(iii) Carbazoles 13 C relative shieldings (ppm) have been calculated for carbazole at the GIAO/B3LYP/6-31G* level <2001H(55)2109> and have been compared with experimental values <1996CHEC-II(2)1> (in brackets, CDCl3): C-1: 102.73 (110.5); C-2: 119.18 (125.8); C-3: 113.16 (119.4); C-4: 114.42 (120.3); C-4a: 117.38 (119.2); C-9a: 130.90 (140.5). 13C NMR data for substituted carbazoles are given in Table 14. 13 C NMR spectra of five separate series of mono-, di-, and polysubstituted chloro-, bromo-, iodo-, benzoyl-, and nitrocarbazoles substituted at the 1-,3-, 6-, and 8-positions have been recorded <2005JHC867>. 13C chemical shifts of carbons ipso, ortho, and para show good linear correlations with net atomic charge density values, suggesting that charge density nicely predicts the substituent effects.
3.01.3.3.3
Nitrogen-15 NMR
Nitrogen-15 NMR, in combination with other NMR techniques and theoretical methods, has become a valuable tool for investigating structural properties of nitrogen heterocycles, including pyrroles, indoles, and carbazoles. 15N relative shieldings (ppm) relative to CH3NO2 have been calculated for pyrrole, indole, and carbazole at the GIAO/ B3LYP/6-31G* level <2001H(55)2109> and have been compared with experimental values (in brackets): pyrrole: 232.60 (224.6, DMSO, 232.0, CD3OD); indole: 250.84 (245.5, DMSO, 253.1, CD3OD); carbazole: 263.97 (264.1, DMSO, 269.7, CD3OD). Although electron-withdrawing groups on the nitrogen atom (N-EWG) of pyrroles significantly deshield ring carbons, the effect on 15N chemical shifts shows no straightforward correlation with the N-EWG strength <2005MP1113>. A DFT study on a series of substituted pyrroles shows that a correlation exists between the paramagnetic shift and the 15N chemical shift, indicating that the trend for the pyrroles arises entirely from variations of the paramagnetic shift contribution. However, a general correlation between 15N chemical shifts and the EWG strength has not been observed. Natural chemical shielding (NCS) analysis shows that the changes in the (N(5)–R)–p* transitions and changes in the sum of the (C(1)–N(5))–p* and (C(4)–N(5))–p* transitions account for the nitrogen chemical shift trend observed in the pyrrole series. A detailed investigation of N-triorganostannyl (R3Sn)-substituted pyrroles, indoles, and a carbazole derivative, and of the corresponding silicon and lead derivatives has been reported, including absolute signs of coupling constants 1 119 J( Sn,15N) <1998MRC39>. 15N Chemical shift values relative to external CH3NO2 indicate an upfield shift on passing from –SnMe3 to –SnEt3 in both the pyrrole and indole series with the effect being much more evident in the pyrrole series (15 ppm) compared to the indole series (3 ppm). Little or no effect is seen with –SnBut3, –SnBz3 and –SnPh3. Methyl groups at the 2- and 5-positions do not affect the 15N chemical shift in the –SnMe3 derivative. Within the –XBut3 series (X ¼ metal), silicon causes a 6 ppm upfield shift of the nitrogen resonance relative to tin, while lead induces an opposite deshielding effect of c. 10 ppm (Table 15). The effects of different types of hydrogen bonds in 2-substituted pyrroles and 1-vinyl pyrroles have been measured by 15N NMR spectroscopy and ab initio calculations <2006MRC59>. N–H O intramolecular hydrogen bonding in 2-(2-acylethenyl)pyrroles decreases the absolute size of the 1J(N,H) coupling constant by 2 Hz in CDCl3 and by 4.5 Hz in DMSO-d6, and deshields the nitrogen by 15 ppm in CDCl3 and by 9 ppm in DMSO-d6. N–H N
17
Table 14 Carbon-13 NMR data (, ppm) for carbazoles Substituent(s) C-1
C-2
C-3
C-4
C-4a
C-4b
C-5
C-6
C-7
C-8
C-8a
C-9a
Solvent
Reference
None 1-Cl 3-Cl 1,6-Cl2 3,6-Cl2 1,3,6-Cl3 1,3,6,8-Cl4 1-Br 3-Br 3,6-Br2 1,3,6-Br3 1,3,6,8-Br4 1-I 3-I 1,6-I2 3,6-I2 1,3,6-I3 1-Bz 3-Bz 3,6-Bz2 1-NO2 3-NO2 1,6-(NO2)2 3,6-(NO2)2 9-SnMe3 2-OH, 3-Me, 7-OMe, 8-CH2CHC (CH3)(CH2)2CHC(CH3)2, 1-(3-indolyl), 2-OH, 3-CO2H 3-Me, 6-OMe, 2,6-OMe2, 3-Me Bis 2,29-(1-OH, 3-Me, 6,8-OMe2)
110.8 116.5 113.0 112.3 112.5 116.0 116.8 102.5 112.8 112.9 105.2 105.1 72.5 113.3 73.0 113.5 77.9 120.1 118.8 110.6 140.6 111.7 132.4 112.4 112.6 96.1
125.3 126.5 126.2 126.3 125.9 126.9 126.0 127.8 127.8 128.5 131.1 131.5 134.0 133.3 134.8 134.0 140.9 125.6 129.6 127.9 121.6 121.1 119.9 122.7 125.4 152.1
118.4 120.2 123.4 119.7 123.0 123.2 124.0 120.6 110.8 110.8 112.2 111.9 120.0 81.2 120.8 81.7 82.0 119.3 128.5 130.0 127.9 143.1 123.2 149.8 118.7 115.8
119.5 118.7 120.0 118.8 120.1 119.4 119.5 118.9 122.6 123.1 123.3 123.1 120.4 128.6 120.5 129.1 128.9 126.5 120.9 123.9 132.8 116.9 129.2 128.8 120.8 121.1
122.4 122.4 122.8 122.9 122.6 124.1 124.1 124.3 124.4 123.4 123.9 124.4 123.0 125.1 125.5 123.8 124.2 124.6 123.3 122.8 127.1 122.2 124.6 141 126.3 117.8
122.4 125.0 122.9 121.6 122.6 124.0 124.1 122.4 121.4 123.4 122.0 124.4 122.6 121.1 121.7 123.8 123.8 122.1 123.7 122.8 121.4 121.9 121.4 141 126.3 117.9
119.5 120.8 119.8 120.6 120.1 120.7 119.5 122.4 120.6 123.1 124.4 123.1 120.6 120.5 129.1 129.1 129.6 117.5 120.3 123.9 120.5 120.9 116.5 128.8 120.8 117.1
118.4 120.0 117.8 123.7 123.0 120.7 124.0 119.6 118.9 110.8 114.3 111.9 119.2 118.9 82.0 81.7 82.7 118.3 118.2 130.0 118.2 120.0 140.0 149.8 118.7 104.6
125.3 125.1 125.6 125.3 125.9 124.9 126.0 126.2 126.2 128.5 130.5 131.5 126.1 126.2 134.0 134.0 134.7 125.8 124.6 127.9 127.1 127.3 122.6 122.7 125.4 154.7
110.8 111.0 110.7 111.2 112.5 113.2 116.8 111.1 111.1 112.9 113.2 105.1 111.7 111.0 114.1 113.5 114.2 110.3 111.0 110.6 112.6 110.9 112.9 112.4 112.6 111.2
139.4 139.3 139.4 138.2 138.5 138.9 136.1 138.2 140.1 138.6 140.1 138.6 139.5 138.7 138.6 138.8 138.7 143.0 141.2 138.3 131.6 140.8 132.1 141 147.4 140.3
139.4 CDCl3 140.3 CDCl3 138.9 CDCl3 140.4 CDCl3 138.5 CDCl3 135.8 CDCl3 136.1 CDCl3 139.6 CDCl3 138.4 CDCl3 138.6 CDCl3 139.5 CDCl3 138.6 CDCl3 141.4 CDCl3 139.7 CDCl3 139.6 CDCl3 138.8 CDCl3 141.2 CDCl3 138.2 CDCl3 139.4 CDCl3 138.3 CDCl3 130.9 CDCl3 139.6 CDCl3 129.1 DMSO-d6 141 DMSO-d6 147.4 C6D6 139.6
2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 O5JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 2005JHC867 97MRC39 2001JFA5589
104.9 110.4 92.5 152.2
160.3 127.7 157.5 117.5
104.9 128.3 119.0 104.7
122.8 120.1 121.4 120.3
112.7 123.6a 116.3 116.4
124.3 123.5a 124.0 124.4
118.4 103.0 102.6 94.0
118.4 153.7 153.9 154.1
122.9 114.9 113.0 95.7
110.8 111.3 110.9 145.8
140.3 134.7 134.2 124.3
142.5 DMSO-d6 138.5 CDCl3 140.1 CDCl3 139.5 DMSO-d6
2005HCA1472 1999P1263 1999P1263 1996TL7819
a
Interchangeable.
Pyrroles and their Benzo Derivatives: Structure
Table 15 Nitrogen-15 NMR data (, ppm) for 1H-pyrroles Substituent(s) 216.2 231.0 222.9 216.1 220.1 206.0 219.7 222.5 222.9 238.6 220.7 220.7 236.4 238.4 237.7 240.4 195.6
1-SnMe3 1-SnEt3 1-SnBut3 1-SnMe3, 2,5-Me2 1-SiMe3, 2,5-Me2 1-PbMe3, 2,5-Me2 1-SnBz3 1-SnPh3 Z 2-CHTCHCOPh, 4,5-(CH2)4 E 2-CHTCHCOPh, 4,5-(CH2)4 Z 2-CPhTCHCOPh, 4,5-(CH2)4 Z 2-CPhTCHCO(2-thienyl), 4,5-(CH2)4 2-(2-pyridyl) 2-(3-pyridyl) 2-(4-pyridyl) 2-Ph 1-But
Solvent
Reference
C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 C6D6 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 CDCl3
1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 1998MRC39 2006MRC59 2006MRC59 2006MRC59 2006MRC59 2006MRC59 2006MRC59 2006MRC59 2006MRC59 1998ZN411
intramolecular hydrogen bond in 2(29-pyridyl)pyrrole increases the 1J(N,H) coupling constant by 3 Hz. These effects depend on the covalent or electrostatic nature of the hydrogen bonding, which depends in turn on the geometry of the hydrogen bridge. The Fermi-contact mechanism is only responsible for the increase of the coupling constant in the case of the predominantly electrostatic hydrogen bonding, whereas both Fermi-contact and paramagnetic spin– orbital mechanisms decrease coupling constants in the case of predominantly covalent hydrogen bonding. An ultrahigh resolution 15N NMR spectrum was measured for N-tert-butylpyrrole in CDCl3 at 300 or 500 MHz to determine coupling constants and isotope-induced chemical shifts at the natural abundance of the isotopes <1998ZN411>. The 15N resonates at 195.6 and 1J(15N,13C) with C-2 and C-5 carbons is 13.21 Hz. Isotopeinduced chemical shifts 114/15N(13C(2,5)) have been measured for N-substituted pyrrole derivatives and are listed in Table 16 against 1J(15N,13C) coupling constants. At variance with other nitrogenous compounds, 114/15N(13C) values do not show any straightforward relationship with 1J(15N,13C). Table 16 Coupling constants 1J(15N,13C) (Hz) and isotope-induced shift 1 14/15 13 N( C(2,5)) (ppb) of N-substituted pyrrole derivatives in CDCl3 <1998ZN411> Substituent
1
14/15N(13C(2,5))
None 1-Me 1-But 1-SiMe3 1-SnMe3 1-Nme2 1-PMe2
22.0 24.0 16.0 19.0 18.0 22.0 19.5
1
J(15N,13C)
12.7 13.7 13.2 8.8 6.9 14.8 10.3
3.01.3.4 Ultraviolet and Fluorescence Spectroscopy 3.01.3.4.1
Pyrroles
Theoretical approaches have been extensively used to investigate the electronic states of pyrrole. Ab initio calculations in the ground and lowest excited-singlet states were performed on pyrrole and pyrrole-H2O clusters <2000CPL(321)479>. Full geometry optimization in the 1p* state revealed the formation of a charge transfer-tosolvent state, and underscore the potential of pyrrole-H2O clusters as models for studying the electron solvation process occurring upon ultraviolet (UV) photoexcitation of organic chromophores in water. The excited states and electronic spectrum of pyrrole have been investigated by several theoretical approaches <1996JCP2312, 1998CPH(238)179, 1999JCP525, 2002JCP7526, 2003MP2391> and the results have led to a reassignment of some excitations.
19
20
Pyrroles and their Benzo Derivatives: Structure
The absorbance photoabsorption cross-section of pyrrole has been measured between the ionization threshold and 35 eV and an interpretation has been offered for some of the observed structures in terms of Rydberg series converging onto the A 2B1 state threshold <1999CPH217>. Theoretical fine spectroscopy has been performed for the valence ionization spectrum of pyrrole and other heterocycles with the symmetry-adapted-cluster CI general-R method <2005JCP234319/1>. It has been shown that the p1 state interacts with the p–123p* , p–22p* , and p–12p–13p* shake-up states providing the split peaks and the outervalence satellites, both of which are in agreement with experiment. Transitions to and from the lower excited state of N-methylpyrrole have been shown to give rise to the structured bands observed around 240 nm <1996JCP867>. Absorption and emission data for N-phenylpyrrole in different solvents are provided in Table 17 <1995CPL(235)195>. Table 17 Absorption and emission data for N-phenylpyrrole in different solvents <1995CPL(235)195>
Solvent
Absorption max (103 cm1)
Emission max (103 cm1)
Excitation max (103 cm1)
Vapor n-Heptane Methylcyclohexane Ethanol Acetonitrile Water 0.1 N NaOH 6 N H2SO4
40.6 39.2 39.2 39.5 40.2 40.2 40.2 40.0
32.9 32.9 32.7, 29.4 32.7, 29.4 25.6 24.7 27.0
37.3 36.4 37.0, 33.3 37.0, 33.3 37.0 37.0 30.3
0.27 0.20 0.21 0.33 0.03 0.01 0.13
This compound exhibits two emission bands in polar solvents, A ((30.3–26.7) 103 cm1) and B (32.7 103 cm1). Addition of water causes a decrease in fluorescence intensity of band A and the appearance of a new band at 25.6 103 cm1 attributed to the formation of aggregates, which are disrupted by the addition of -cyclodextrin. Similarly, 2-(29-hydroxy-59-methylbenzoyl)-1,5-diphenylpyrrole gives a single emission in aqueous solution but addition of -cyclodextrin results in the development of another emission band at higher energy attributed to the change in the polarity of the microenvironment within the supramolecular structural environment <2001JST(570)145>. Fluorescence excitation and single vibronic level dispersed fluorescence spectra indicated that in jet-cooled N-phenylpyrrole the S0 state is in a twisted form with a dihedral angle of 38.7 , whereas the S1 state is also in a twisted form but with a smaller dihedral angle of 19.8 , indicating that electronic excitation causes N-phenylpyrrole to be more rigid <1998JCP7185>. 2-Phenylpyrrole exhibits solvatochromism of the long-wave absorption band and with strong H-bond acceptors complex formation causes polarization of the electronic system of the donor, whereby p ! p* transition no longer produces electron density redistribution <2000RJC596>. Nanosecond laser flash photolysis showed that pyrrole-2-carboxyaldehyde does not exhibit fluorescence emission, but undergoes intersystem crossing to the triplet state with an efficiency of 0.80 in benzene <2003PPS418>. 3,5Dimethyl-2-(29-pyridyl)pyrrole forms weak 1:1 H-bonded complexes with methanol and tert-butanol in the ground state, while 3,5-di-tert-butyl-2-(29-pyridyl)pyrrole forms both 1:1 and 1:2 complexes with the same alcohols, but no excited state proton transfer appears to occur in such complexes <2004MI3948>. Absorption maxima of 2-(29-hydroxybenzoyl)pyrrole (HBP) and 2-(29-methoxybenzoyl)pyrrole (MBP) in different solvents have been determined and compared with the results of theoretical calculations using TDDFT <2004JMT(709)183> and multiconfigurational perturbation theory (CASPT2) <2005JPO1099> methods (Table 18). Table 18 Experimental and computed UV spectra of 2-(20-hydroxybenzoyl)pyrrole (HBP) and 2-(20-methoxybenzoyl)pyrrole (MBP) Cmpd.
Solvent
max (nm)
TDDFT (nm)
Reference
ZINDO (nm) (lowest conformer)
Reference
HBP HBP MBP MBP
C6H12 MeOH C6H12 MeOH
346, 311, 259 339, 312, 258 290, 248 (sh) 300, 254 (sh)
346, 300, 254
2004JMT(709)183
308, 284
2004JMT(709)183
353, 312, 320, 292, 274 352, 306, 321, 291, 275 321, 291, 289, 281, 255 314, 294, 290, 281, 258
2005JPO1099 2005JPO1099 2005JPO1099 2005JPO1099
Pyrroles and their Benzo Derivatives: Structure
In the MBP conformers the methyl hinders coplanarity of the phenyl moiety with the carbonyl group increasing the character of the pBz–pBz* component of the relevant transition, while in HBP the coplanarity of the moieties, due to H-bonding, lowers the energy of the pCO* orbital with consequent red shift for all transitions. The UV–Vis absorption and fluorescence properties of a series of substituted pyrroles are reported in Table 19 <1999TL2157, 1999JPO392, 2005NJC1258>.
Table 19 UV-visible absorption and fluorescence properties of substituted pyrroles Substituent(s)
Solvent
max (nm)
Emission (nm)
Reference
None 2-CO2Et, 3-Ph, 5-Ph 2-CO2Et, 3-Ph, 5-Ph 2-CO2Et, 3-(4-Me2N-C6H4), 5-Ph 2-CO2Et, 3-(4-Me2N-C6H4), 5-Ph 2-CO2Et, 3-(2,6-Me2-4-Me2N-C6H2), 5-Ph 2-CO2Et, 3-(2,6-Me2-4-Me2N-C6H2), 5-Ph 2-PhSO2, 5-CHTN-p-C6H4-N(Me)2 2-MeSO2, 5-CHTN-p-C6H4-N(Me)2 2-PhSO2, 5-CHTN-p-C6H4-N(Et)2 2-MeSO2, 5-CHTN-C6H4-N(Et)2 1-Me, 2-PhSO2, 5-CHTN-C6H4-N(Me)2 1-Me, 2-MeSO2, 5-CHTN-C6H4-N(Me)2 1-Me, 2-PhSO2, 5-CHTN-C6H4-N(Et)2 1-Me, 2-MeSO2, 5-CHTN-C6H4-N(Et)2 1-Me, 2-CHO 1-Me, 2-CHO, 5-Me 1-Me, 2-CHO, 5-Cl 1-Me, 2-CHO, 5-CN 1-Me, 2-CHO, 5-COMe 1-Me, 2-CHO, 5-NO2 1-Me, 2-CHO, 5-CO2H 1-Me, 2-CHO, 5-SMe 1-Me, 2-CHO, 5-CO2Me 1-Me, 2-CHO, 5-Si(Me)3 1-Me, 2-CHO, 5-Br 1-Me, 2-CHO, 5-OMe 1-Me, 2-CHTN-NH-C6H5 1-Me, 2-CHTN-NH-C6H5, 5-Me 1-Me, 2-CHTN-NH-C6H5, 5-Cl 1-Me, 2-CHTN-NH-C6H5, 5-CN 1-Me, 2-CHTN-NH-C6H5, 5-COMe 1-Me, 2-CHTN-NH-C6H5, 5-NO2 1-Me, 2-CHTN-NH-C6H5, 5-CO2H 1-Me, 2-CHTN-NH-C6H5, 5-SMe 1-Me, 2-CHTN-NH-C6H5, 5-CO2Me 1-Me, 2-CHTN-NH-C6H5, 5-Si(Me)3 1-Me, 2-CHTN-NH-C6H5, 5-Br 1-Me, 2-CHTN-NH-C6H5, 5-OMe 1-Me, 2- CHTN-NH-p-C6H4-NO2 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-Me 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-Cl 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-CN 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-COMe 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-NO2 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-CO2H 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-SMe 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-CO2Me 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-Si(Me)3 1-Me, 2-CHTN-NH-p-C6H4-NO2, 5-Br 1-Me, 2- CHTN-NH-p-C6H4-NO2, 5-OMe
C6H12 MeCN C6H12 MeCN C6H12 MeCN dioxane dioxane dioxane dioxane dioxane dioxane dioxane dioxane 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH 95% EtOH
262/306 263/300 296 295 306 304 392 386 400 393 394 387 402 396 288.0 297.0 292.0 289.2 306.0 331.2 299.0 319.0 297.6 296.4 294.0 307.2 336.0 343.2 344.4 377.5 388.8 451.2 363.6 369.8 368.4 348.0 345.6 337.4 429.6 439.2 424.8 413.2 426.0 450.0 426.0 439.6 421.2 432.0 426.0 450.0
350 356 400 492 417 524
2005NJC1258 2005NJC1258 2005NJC1258 2005NJC1258 2005NJC1258 2005NJC1258 1999TL2157 1999TL2157 1999TL2157 1999TL2157 1999TL2157 1999TL2157 1999TL2157 1999TL2157 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392 1999JPO392
21
22
Pyrroles and their Benzo Derivatives: Structure
A comparison of the absorption and fluorescence properties of 3,5-diaryl-1H-pyrrole-2-carboxylic acid ethyl esters reveals marked effects of p-dimethylamino and o-methyl substituents on the phenyl group at C-3 and suggests that in the presence of these substituents emission occurs either from a charge transfer state or from a combination of charge transfer and locally excited states <2005NJC1258>. The chromophores of sulfonyl-substituted pyrroles display maxima falling below 402 nm in dioxane, with N-methyl derivatives absorbing at slightly higher wavelengths compared to their parent pyrroles <1999TL2157>. Correlation analysis of K-band max values for several 1-methyl-2-formyl-5-substituted pyrroles and their phenylhydrazones indicates concurrent polar and spin delocalization effects for most members of the series whereas for the 4-nitrophenylhydrazones polar effects are dominant <1999JPO392>. The photodissociation dynamics of pyrrole and 2,5-dimethylpyrrole have been investigated using H Rydberg atom photofragment translational spectroscopy and, at the longest excitation wavelengths, one photon resonant multiphoton ionization spectroscopy and N–H bond fission channels have been rationalized <2004MI5031, 2006PCP599>. Other spectroscopic studies have been focused on the UV–Vis absorption properties of rhodium and iridium complexes of N-(29-hydroxyphenyl)pyrrole-2-aldimine <2005MI167>, and of 1,19,5,59-tetraaryl-2,29-bipyrroles <2005H(66)319>. The spectrophotometric properties of calix[4]pyrroles as potential sensors and receptors are also the focus of much ongoing work <1998PAC2401, 2004JA16296, 2005JA8270>.
3.01.3.4.2
Indoles
The electronic absorption spectra of indoles usually display three main bands, one very intense at about 215–235 nm, corresponding to the pp* (1B) transition, and the other two at 270–330 nm, due to the pp* 1La and 1Lb transitions. Electrondonating groups cause a red shift of the latter which depends on the nature of the substituent and its position on the indole ring <1996SAA69>. The electronic and fluorescence spectroscopy of indole and its derivatives have been investigated as a means for gaining information about the near-UV fluorescence of tryptophan residues in proteins. The closely lying excited states 1La and 1Lb are responsible for the UV emission of tryptophan, and the sensitivity of the UV emission spectrum and fluorescence lifetime to the local environment makes it a useful internal fluorescent probe of protein structure and solvent accessibility <2004PCB4248>. However, the presence in solution of multiple interconverting conformations of tryptophan in a dynamic, locally heterogeneous solvent environment complicates simple interpretations of the observed fluorescence properties and hampers molecular scale intepretation of these effects, whereby investigation of the parent heterocycle and simple analogues has turned out to be more proficuous. High-resolution UV spectroscopy has been used to investigate the intermolecular bonding in the indole water complex <1998PCA3268>. A hydrogen bond is formed between the indole N–H group and the oxygen atom of the water molecule, and upon electronic excitation to S1 this bond length remains nearly constant. The hydrogen-bonding topologies of indole-(water)1,2, 1-methylindole-(water)1-3, and 3-methylindole-(water)1 clusters formed and cooled in a supersonic expansion have been characterized by UV and IR spectroscopy techniques <1999PCA9943>. In indole-(water)2, the two water molecules form a water dimer bridge between the N–H–H-bond donor site and the indole p-cloud acceptor site. For 1-methylindole-(water)n clusters, the N–H–H-bonding site is blocked, favoring structures in which water acts as an H-bond donor to the indole p-cloud. The UV spectroscopy of indole-(water)n and methylindole-(water)n clusters near their S1 S0 origins can be explained entirely as 1Lb spectroscopy <1998JCP10189>, while 1La mixing may be responsible for the unusual vibronic features observed for 3-methylindole-(water) clusters and the decreased excited-state lifetimes of larger water-containing clusters. In the gas phase, rotationally resolved S1 S0 fluorescence excitation experiments performed on a solute–solvent complex of indole and water indicated a 1:1 complex, with the water molecule linked to the indole frame via a quasi-linear N–H???OH2 H bond <1998PCA7211>. In n-hexane N-methylindole interacts with trifluoroethanol leading to a ground state fluorescent hydrogen bonded complex and a red shifted and weakly fluorescent exciplex <2004CPL(393)217>. The mechanism for the exciplex formation can serve as a model to explain the anomalous large Stokes shift and quenching of indole fluorescence in highly polar protic solvents. A quantitative model has been developed that describes the continuous time-dependent red shift in the fluorescence spectrum of indole due to relaxation of polar solvents around the excited fluorescent solute <2000CPL(322)496>. The fluorescence emission of L-tryptophan, N-acetyl-L-tryptophanamide and indole is affected by hydrostatic pressure, with reversible red shifts of the emission of the three fluorophores of about 170 cm1 at 2.4 kbar <1996MI231>. This effect appears related to changes in Stokes shift of the fluorophores caused by pressure effects on the dieletric constant and/or refractive index of the medium. S1 S0 UV spectra of each of seven conformational isomers of tryptamine free from interference from one another have been recorded <2000PCA8677>. Unlike indole, the fluorescence emission maximum of 5-hydroxyindole is relatively insensitive to solvent polarity, suggesting the lack of appreciable solvent dipolar relaxation <2000SAA1213>. UV spectroscopy studies have proved valuable to elucidate the protolytic equilibria of indole and its derivatives in sulfuric acid, perchloric acid, and in micellar systems.
Pyrroles and their Benzo Derivatives: Structure
The electronic absorption and fluorescence properties of 2-(29-pyridyl)indoles 4 and 5a–e, and their methylated salts 6a–e are listed in Table 20 <1998JOC4055>.
Table 20 Absorption and fluorescence properties of 2-(20-pyridyl)indoles and their methylated salts <1998JOC4055> Cmpd.
max (nm) (log ")a
Emission (nm)a
4 5a 5b 5c 5d 6a 6b 6c 6d 6e
321 328 337 328 339 360 389 374 383 364
376 399 404 389 423 419 543 541 551 506
(4.36) (4.24) (4.36) (4.39) (3.67) (3.82) (4.39) (4.10) (3.98) (4.10)
a
All values are determined in MeCN as the solvent.
The parent 2-(29-pyridyl)indole members absorb at shorter wavelengths and are strongly emitting. The methylated tautomers also show a strong bathochromic shift but emit weakly (data not shown), whereas their methylated salts exhibit intermediate behavior <1998JOC4055>. 2-(29-Pyridyl)indoles and related compounds can exist as two rotamers, and only the syn conformers, which prevail in aprotic solvents, are able to form cyclic, doubly H-bonded complexes with protic solvents <2000JA2818>. These cyclic solvates undergo efficient fluorescence quenching due to photoinduced double proton transfer and internal conversion. Efficient fluorescence quenching caused by rapid internal conversion from the first excited singlet state is observed in alcoholic solutions of 2-(29-pyridyl)indoles <1996JA3508>. Alcohols form 1:1 complexes in the ground state, and hydrogen bonding occurs to the indole NH group. 7-(Pyridyl)indoles reveal solvent-dependent photophysical properties that are quite different from those of 2-pyridylindoles <2004CPL(400)379>. 7-(29-Pyridyl)indole is practically nonfluorescent at room temperature, in nonpolar and polar aprotic solvents. 7-(39-Pyridyl)indole and 7-(49-pyridyl)indole fluoresce strongly, but the emission is quenched in alcohols, and syn and anti rotameric forms of 7-(39-pyridyl)indole are detected with each quenched to a different degree. UV–Vis and fluorescence properties of p-nitrophenyl-substituted ethenylindoles are listed in Table 21 <2006JPO43>.The absorption maxima undergo a moderate red shift with solvent polarity, though the fluorescence maxima become highly red-shifted with increasing solvent polarity <2006JPO43>. Three types of excited state are suggested, namely the locally excited state, the intramolecular charge-transfer excited state and the conformationally relaxed intramolecular charge-transfer excited state. Selected UV–Vis and fluorescence properties of representative indole-3-acetic acids are listed in Table 22. <2004MI247>. With the exception of chloro-, bromo-, and 4- or 7-fluoro-derivatives, these compounds fluoresce at 345–370 nm when excited at 275–280 nm.
23
24
Pyrroles and their Benzo Derivatives: Structure
Table 21 UV–Vis absorption and fluorescence properties of substituted p-nitrophenyl-substituted ethenylindoles <2005JPO1099> Substituent(s)
Solvent
abs max (nm)
Emission (nm)
Excitation (nm)
3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-Et, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2 1-C6H5SO2, 3-CHTCH-p-C6H5-NO2
n-Heptane CCl4 Dioxane THF EtOAc MeOH DMF MeCN n-Heptane CCl4 Dioxane THF EtOAc MeOH DMF MeCN n-Heptane CCl4 Dioxane THF EtOAc MeOH DMF MeCN
393 403 404 414 409 413 428 410 403 413 416 423 414 418 432 419 357 366 369 386 367 367 376 369
511 543 554 581 583 567 638 642 509 531 565 592 592 558 642 650 403, 424, 520 407, 428, 522 418, 529 542 547 417, 546 585 593
402 402 403 407 403 416 425 405 398 406 404 421 413 418 426 410 356 364 371 372 371 372 374 369
Table 22 UV–Vis and fluorescence properties of substituted indole-3-acetic acids <2004MI247> Substituent(s)
max (nm) (log ")a
Emissiona(nm)
Excitationa(nm)
None
275.0 (3.70), 280.0 (3.72), 287.6 (3.66) 271.8 (3.76), 278.8 (3.74), 287.7 (3.69) 274.2 (3.70), 279.1 (3.70), 289.9 (3.60) 274.1 (3.67), 285.5 (3.50) 276.6 (3.77), 281.9 (3.80), 290.7 (3.74) 279.1 (3.67), 285.4 (3.68), 295.2 (3.57) 280.2 (3.75), 285.1 (3.76), 293.0 (3.68) 282.9 (3.67), 288.7 (3.69), 297.0 (3.61) 277.7 (3.75), 291.6 (3.69), 302.8 (3.57) 277.7 (3.75), 295.0 (3.68), 302.5 (3.59) 276.5 (3.71), 281.1 (3.72), 290.4 (3.65) 279.1 (3.69), 281.6 (3.69), 285.6 (3.67) 279.4 (3.67), 285.0 (3.69), 292.9 (3.63) 274.0 (3.75), 278.9 (3.76), 288.4 (3.66)
367
280
370
278
355
278
368
276
368
278
363
276
352
278
370
278
372
276
356
278
2-Me 4-Me 4-F 4-Cl 5-Me 5-F 5-Br 5-OMe 5-OH 6-Me 6-F 6-Cl 7-Me
(Continued)
Pyrroles and their Benzo Derivatives: Structure
Table 22 (Continued) Substituent(s)
max (nm) (log ")a
7-F 7-Cl
274.3 (3.65), 286.2 (3.51) 276.5 (3.72), 283.8 (3.74), 292.1 (3.68) 281.5 (3.75), 286.6 (3.78), 292.8 (3.74) 286.8 (3.67), 293.5 (3.71), 302.8 (3.66) 285.9 (3.69), 293.0 (3.71), 302.5 (3.63) 280.8 (3.76), 286.8 (3.79), 294.4 (3.75) 282.2 (3.80), 288.2 (3.82), 297.3 (3.77) 283.0 (3.74), 289.0 (3.76), 299.0 (3.67)
4,6-Cl2 5,6-Cl2 5,7-Cl2 6,7-Cl2 4,7-Cl2 4,5-Cl2 a
Emissiona(nm)
Excitationa(nm)
In aqueous buffer, pH 7.2.
The absorption maxima of 2,3-bis(4-hydroxyphenyl)indole derivatives are reported in Table 23. <2001EJO1723>. Absorption maxima are shifted bathochromically in the presence of an OH group at C-6 and show limited solvatochromicity in acidic and neutral solvents <2001EJO1723>. The fluorescence emission of these compounds is solvent and pH dependent.
Table 23 UV-visible and fluorescence properties of 2,3-bis(4-hydroxyphenyl)indoles <2001EJO1723> Substituent(s)
Solvent
max (nm) (")a
Emissiona (nm)
1-Me, 2,3-(4-OHC6H4)2
THF MeCN EtOH EtOH (basic) H2O 0.1 N HCl 0.1 N KOH
240 (12100), 313 (16000) 250 (29300), 313 (15800) 255 (25100), 307 (15200) 267 (25600), 335 (8200) 250 (16400), 315 (8200) 248 (15500), 310 (7500) 268 (20400), 313 (13000)
440 441 440 490 448 461 496
1-Et, 2,3-(4-OHC6H4)2
THF MeCN EtOH EtOH (basic) H2O 0.1 N HCl 0.1 N KOH
238 (12600), 313 (22500) 245 (24100), 315 (12400) 253 (31300), 289 (14500), 307 (14500) 269 (56100), 309 (35200) 251 (25200), 305 (13900) 245 (26100), 309 (11200) 269 (32700), 312 (17600)
437 447 438 495 466 456 496
1-Me, 2,3-(4-OHC6H4)2, 6-OH
THF MeCN EtOH EtOH (basic) H2O 0.1 N HCl 0.1 N KOH
241 (10300), 323 (14300) 250 (11000), 322 (6300) 253 (24300), 311 (12200) 261 (50400), 309 (28900), 344 (22600) 250 (29600), 312 (16300) 254 (29600), 275 (20100), 308 (14200) 268 (23700), 322 (9800)
438 438 437 459 458 476 460
1-Et, 2,3-(4-OHC6H4)2, 6-OH
THF MeCN EtOH EtOH (basic) H2O 0.1 N HCl 0.1 N KOH
242 (10100), 325 (14700) 242 (11600), 315 (5300) 258 (33300), 296 (20500), 330 (9600) 267 (69100), 309 (37700), 351 (24300) 244 (25400), 311 (11200) 245 (23800), 314 (9700) 264 (26600), 307 (16200), 345 (15100)
435 (460sh) 407(sh), 445 427 460 444 477 455
25
26
Pyrroles and their Benzo Derivatives: Structure
Other indole derivatives for which absorption and fluorescence properties have been reported include 2,3-dimethylindole, 2,5-dimethylindole, 1,2-dimethylindole <2003PCA10243>, 1-[[2-[7-(diethylamino)-2-oxo-2H-1-benzopyran-3yl]-4-thiazolyl]methyl]-1H-indole-2,3-dione and an acetone adduct <2004H(63)1083>, diarylethenes having a fluorescent indole ring as the aryl group <2003BCJ1625>, benz[ f ]indole, and 3-methylbenz[ f ]indole <2000PCB1837>. The absorption and fluorescence emission spectra of the latter are red-shifted approximately 75 nm compared to the spectra of indole and 3-methylindole. The absorption spectrum of 3-methyl-4-(39-methylindol-29yl)indole-6,7-dione, a model compound for the bacterial methylamine dehydrogenases cofactor tryptophan tryptophylquinone, shows a maximum at 434 nm (" 9200 M1 cm1) shifting to 469 nm (" 12 100 M1 cm1) at alkaline pH, whereas in acetonitrile its absorption is shifted toward shorter wavelengths ( max ¼ 407 nm, " 10 700 M1 cm1) <1995JA1485>. Absorption and fluorescence properties have been described for 3H-indoles <1996CSI143>.
3.01.3.4.3
Carbazoles
Considerable effort has been expended upon investigating the electronic absorption and fluorescence properties of carbazole derivatives or molecules containing a carbazole moiety/substructure, due to the interest of these compounds for application as nonlinear optical chromophores and as photoconducting materials. In the following, selection of papers is guided mainly by criteria of structural relevance, omitting very bulky molecules in which the carbazole unit is not prominent, or studies of luminescence properties. An overview of the electronic absorption spectra of carbazole derivatives is provided in Table 24. Table 24 Electronic absorption spectra of substituted carbazoles Substituent(s)
Solvent
max (nm) (log ") or (", L mol1 cm1)
Reference
None 3-Cl 3,6-Cl2 3-Br 3,6-Br2 1,3,6-Br3 1,3,6,8-Br4 3-I 3-Cl, 9-CH2CO2H 3,6-Cl2, 9-CH2CO2H 3-Br, 9-CH2CO2H 3,6-Br2, 9-CH2CO2H 1,3,6-Br3, 9-CH2CO2H 1,3,6,8-Br4, 9-CH2CO2H 3-I, 9-CH2CO2H 2-OMe, 7-CO2Me, 9-Me 7-CO2Me, 9-Me 2-OMe, 3-NO2, 7-CO2Me, 9-Me
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN CH2Cl2 CH2Cl2 CH2Cl2 MeOH DMSO DMSO CH2Cl2 MeOH DMSO CH2Cl2 MeOH DMSO CH2Cl2 MeOH DMSO CH2Cl2 MeOH DMSO DMF DMF DMF DMF
344 (3.44), 322 (3.52), 290 (4.44), 254 (4.38) 341 (3.67), 326 (3.80), 294 (4.46), 258 (4.57) 350 (3.59), 337 (3.67), 299 (4.39), 264 (4.47) 341 (3.58), 328 (3.66), 295 (4.34), 259 (4.48) 349 (3.46), 333 (3.58), 297 (4.32), 263 (4.46) 352 (3.67), 336 (3.68), 298 (4.35), 266 (4.45) 354 (3.63), 337 (3.68), 299 (4.20), 268 (4.23) 340 (3.48), 328 (3.59), 296 (4.27), 260 (4.50) 344 (3.76), 333 (3.83), 295 (4.47), 259 (4.59) 352 (3.71), 337 (3.72), 299 (4.41), 264 (4.55) 345 (3.70), 332 (3.70), 2.95 (4.37), 262 (4.72) 352 (3.59), 337 (3.63), 299 (4.33), 266 (4.45) 362 (3.58), 342 (3.67), 300 (4.47), 268 (4.43) 364 (3.65), 352 (370), 298 (4.02) 345 (3.54), 332 (3.58), 296 (4.20), 264 (4.39) 322 (28233) 357 (4405) 374 (12170) 373 381 381 (18500) 402 (16666) 404 421 424 (31395) 421 422 475 (20570) 466 476 479 (70700) 465 474 499 530 472 582
2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2000SAA2049 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2001CM2528 2006DP(71)109 2006DP(71)109 2006DP(71)109 2006DP(71)109
2-OMe, 3-NO2, 7-CH2OH, 9-Me 2-OMe, 3-CHTCH-NO2, 7-CO2Me, 9-Me
2-OMe, 3-CHTC(CN)2, 7-CO2Me, 9-Me
2-OMe, 3-C(CN)TC(CN)2, 7-CO2Me, 9-Me
3-C(CN)TC(CN)2, 7-CO2Me, 9-Me
3,6-(6-NO2-benzothiazol-2-yl-NTN-)2, 9-Et 3,6-(5-NO2-thiazol-2-yl-NTN-)2, 9-Et 3,6-(2,4-(NO2)2C6H3)2, 9-Et 3,6-(4-NO2C6H4), 9-Et
Pyrroles and their Benzo Derivatives: Structure
The first band of the absorption spectra at long wavelengths, which is designated 1Lb 1A, shows considerable vibrational structure; the bands around 290 and 260 nm are 1La 1A and 1Ba 1A, respectively, while the other bands at low wavelengths are 1Ca 1A <2000SAA2049>. A study of the UV spectrum of carbazole using linearly polarised light illustrates the potential of this method to gain information that is not available from ordinary spectroscopy. This information relates for example to the anisotropic optical properties of the molecules, which may be useful for molecular structure determination, and the molecular organization within the sample <1996MI273>. Halogen substituents and replacement of the N–H hydrogen by the carboxylic group cause red shifts. The UV absorption spectrum of carbazole has been simulated using the atom monopole–dipole interaction (AMDI) model and atomic dipolar polarizabilities and effective charge given by Fraga <2001SAA1111>. Within a series of push–pull carbazole derivatives substituted with nitro or cyano electron-withdrawing groups <2001CM2528>, those bearing tricyanovinyl groups absorb at relatively longer wavelengths, indicating the stronger electron-withdrawing effect of that group. However, increasing solvent polarity results in a marked shift of the nitrobut not of the cyano-substituted chromophores, indicating that the dielectric constant of the solvent does not affect intramolecular charge transfer. Within a series of 9-ethyl-3,6-bis(arylazo)carbazoles featuring nonlinear optical A-p-D-p-A type chromophores, absorption bands shifting with the degree of conjugation can be observed in DMF at 225–350 nm (due to the carbazole moiety) and at 350–700 nm (due to the p–p* transition of the azo conjugated unit ) <2006DP(71)109>. The absorption and fluorescence properties of a number of substituted carbazoles and derivatives are reported in Table 25. Table 25 UV–Vis absorption and fluorescence properties of substituted carbazoles Substituent(s)
Solvent
abs max (nm) (log ")
Emission (nm)
Reference
9-(99-acridyl)
n-Hexane Cyclohexane Toluene Dioxane AcOEt EtOH MeCN DMSO
360.5, 407.7 361.2, 409.5 361.6 361.0 360.6 360.8 360.8 361.8
424.2 426.8 471.9 481.2 511.8 542.1 532.2 545.0
1998EJO1697 1998EJO1697 1998EJO1697 1998EJO1697 1998EJO1697 1998EJO1697 1998EJO1697 1998EJO1697
1-CO2H, 2-OH
Cyclohexane Dioxane MeCN(Hþ) MeOH (Hþ) H2O (pH 2)
278, 284, 322, 353, 367 278 (4.42), 283 (4.43), 320 (3.83), 359 (3.99) 277 (4.23), 283 (4.45), 320 (3.83), 358 (4.01) 278 (4.41), 283 (4.43), 320 (3.81), 358 (4.01) 289 (4.41), 320 (3.85), 355 (4.04)
401, 461 404, 473 408, 480 415, 482 432, 495
2005SAA1247 2005SAA1247 2005SAA1247 2005SAA1247 2005SAA1247
9-Bn
THF
243
347, 363
2005TL6883
The UV absorption and fluorescence properties of 9-(99-acridyl)carbazole have been investigated in 50 different solvents, and only representative examples are reported <1998EJO1697>. The carbazole unit serves as an electron donor and analysis of the solvatochromic behavior revealed that twisted intramolecular charge transfer emission prevails only in more polar solvents. 9-Benzylcarbazole shows three absorption maxima which are slightly red-shifted within a series of linear 3,9-linked oligomers, with a linear increase in intensity with the number of monomer units, indicating the lack of intramolecular p-interactions for the oligomers <2005TL6883>. It shows however two isolated emission bands which are significantly red-shifted in the oligomers, suggesting that the degree of conjugation of linear oligomers is saturated when the number of carbazole units reaches 4. The absorption spectrum of 2-hydroxy-9H-carbazole-1-carboxylic acid can be divided into three main regions: long wavelength (>340 nm), medium wavelength (300–340 nm), and short wavelength (<300 nm). Compared to carbazole, the maximum red shift is observed in the long wavelength band, which is structured only in cyclohexane <2005SAA1247>. This compound shows dual fluorescence in most solvents except cyclohexane and water (pH 5), and both emission band systems originate from the same ground state species. N-Alkylated 2,7-linked carbazole trimers exhibit a bright blue fluorescence at 394 nm and show absorption characteristics similar to those of analogue fluorene derivatives (maximum around 354 nm) <2004CM4736> while a related 3,6-linked trimer has an absorption maximum at 307 nm, which is c. 45 nm lower <2003MI1706>.
27
28
Pyrroles and their Benzo Derivatives: Structure
Carbazole-containing stilbene analogues have been shown to be efficient two-photon absorbing chromophores <2000TL8573>. Isomeric benzopyranocarbazole derivatives exhibit four absorption maxima in the range 315–390 nm <2005T1681>: their photochromic properties have been investigated under flash photolysis and continuous irradiation. The absorption spectrum of a carbazole-acceptor cyclophane shows transannular p–p electronic interaction and little charge transfer interaction, while the fluorescence spectrum exhibits intramolecular exciplex emission around 525 nm <2003CL910>. 6,13-Bis(9-ethyl-9H-carbazol-3-yl)pentacene (a pentacene derivative bearing two carbazole moieties) displays an absorption spectrum that consists of the bands due to the carbazole (352 nm) and the pentacene moieties (483, 523, 561, 605 nm), indicating that the electronic transition level of pentacene is not affected by the carbazole chromophore <2006MI185>. The electron absorption properties of N,N9-diethyl-3,39-bicarbazyl and N,N9-diphenyl-3,39-bicarbazyl, have been described <2004MCL153>.
3.01.3.5 Infrared Spectroscopy 3.01.3.5.1
Pyrroles
Pyrrole belongs to the C2v symmetry point group and exhibits 24 normal modes of vibration. Selected fundamental vibrations of pyrrole, 1-deuteropyrrole, and pentadeuteropyrrole are reported in Table 26, and have been reassigned based on high-level quantum-chemical calculations <2000JMT(507)75>. Table 26 Experimental and calculated fundamentals of pyrrole, 1-deuteropyrrole, and pentadeuteropyrrole <2000JMT(507)75> Symmetry
max (cm1) (neat liquid)
B3P86
B3LYP
Pyrrole N–H stretch C–H stretch C–H stretch C–H stretch C–H stretch C–H deformation N–H wag
A1 A1 B1 A1 B1 B1 B2
3530 3134 3127 3114 3103 1286 480
3530 3134 3127 3114 3103 1281 483
3530 3134 3128 3113 3102 1281 477
Pyrrole-1d N–D stretch C–H stretch C–H stretch C–H stretch C–H stretch C–H deformation N–D wag
A1 A1 B1 A1 B1 B1 B2
2607 3134 3127 3114 3103 1286 364
2593 3134 3127 3114 3103 1261 375
2593 3134 3128 3113 3102 1262 372
Pentadeutero pyrrole N–D stretch C–D stretch C–D stretch C–D stretch C–D stretch C–D deformation N–D wag
A1 A1 B1 A1 B1 B1 B2
2610 2368 2349 2320 2306 1023 353
2593 2339 2326 2304 2290 1014 375
2593 2339 2326 2303 2290 1015 371
Because pyrrole has four C–H bonds, four C–H stretches are expected in two pairs, one pair of oscillators adjacent to the nitrogen and the other pair on the 3- and 4-positions. The origin of the fundamental C–H stretch vibrations in the gas phase has been intensively investigated <1995CPH(190)407>. The fundamental N–H stretch band has its origin at 3530.811343(82) cm1 and has been rotationally analyzed <1997CPH(220)311>. In low-temperature, solid inert matrixes (argon, xenon; T ¼ 9 K) pyrrole forms hydrogen-bonded aggregates that are predicted to be mainly cyclic trimers and tetramers, based on DFT analysis, with a significant cooperativity effect <2004PCA6953>.
Pyrroles and their Benzo Derivatives: Structure
FTIR measurements and ab initio calculations show that N-methylpyrrole interacts with hexafluoroisopropanol, trifluoroethanol, 2-chloroethanol, and 1-butanol to form 1:1 stoichiometric hydrogen-bonded complexes in which the OH group acts as H-donor and the aromatic p-system as acceptor <2003CPH(290)69>. Experimental and theoretical vibrational spectra for a series of pyrrole derivatives are listed in Table 27. Table 27 IR data of substituted pyrroles Substituent(s)
Vibration
max (cm1)
Method
References
2-CO2H
O–H, N–H stretch C–H stretch CTO stretch N–H stretch C–H stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch
3550, 3465 3132, 3124, 3108 1744 (w), 1671 3465 3098, 3070, 2994 1701 1615 1628 1610 1605 1612 1615 1624 1614 1605 1602 1614
CCl4 CCl4 CCl4 CCl4 CCl4 CCl4
2002PCA10613 2002PCA10613 2002PCA10613 2001JST(562)107, 2002NJC165 2001JST(562)107, 2002NJC165 2001JST(562)107, 2002NJC165 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763 2003JHC763
2-CO2Me
2-CO-m-C6H4NO2 2-CO-m-C6H4Br 2-CO-m-C6H4Cl 2-CO-m-C6H4OMe 2-CO-m-C6H4Me 2-CO-p-C6H4NO2 2-CO-p-C6H4Br 2-CO-p-C6H4Cl 2-CO-p-C6H4OMe 2-CO-p-C6H4Me 2-CO-C6H5
sol. sol. sol. sol. sol. sol.
Pyrrole-2-carboxylic acid exists in solution and in the solid state mainly as the s-cis conformer and in the solid state forms cyclic dimer species that are stabilized through O–H- - -O bonds <2002PCA10613>. Methyl pyrrole-2-carboxylate in CCl4 solution exists as a single main conformer in which the acyl group is located on the same side as the NH group, and this favors formation of N–H- - -O hydrogen bonds <2001JST(562)107, 2002NJC165>. The CTO stretching frequencies of benzoyl derivatives of pyrrole are affected by the nature of substituents on the benzoyl moiety <2003JHC763>. Calculated vibrational spectra of fluorinated pyrrole derivatives show that, of the two monofluoro and four difluoro compounds, 3-fluoropyrrole and 3,4-difluoropyrrole have relatively higher vibrational bending mode frequencies below 1000 cm1, meaning that they have the largest force constants for their modes of vibration <2003PCA6476>.
3.01.3.5.2
Indoles
The indole molecule is a planar asymmetric rotor with Cs symmetry and 29 planar and 13 nonplanar fundamentals. Selected fundamental vibrations of indole in the gas and liquid phase have been re-examined <1995SAA1291>. The IR overtone/combination region from 1600 to 2000 cm1 was used to establish the wave numbers of nonplanar, hydrogenicwagging modes for which the active IR and Raman fundamental is weak. A complete assignment of vibrational modes for indole by application of DFT and a hybrid Hartree–Fock/ DFT method has been provided <1996J(P2)2653>. Investigation of the CH, NH, or OH stretching vibrations of indoleþ and the indole(H2O)1þ cluster cation has shown that the frequency of the NH stretching vibration of the cation is shifted by 300 cm1 to lower frequencies compared to the neutral cluster and, for indole(H2O)1þ, a hydrogen-bonded structure with a nearly linear hydrogen bond can be deduced <2000JCP7945>. In CCl4 solution, even at low concentrations indole forms molecularly associated pairs through N–H p H bonding <2000JST(555)363>. In the same solvent it forms 1:1 or 1:2 complexes with benzene, naphthalene, phenanthrene, toluene, m-xylene, and mesitylene, in which the NH bond interacts with the p-system <2004SAA193>. The NH frequency shifts are independent of the number of rings, but they progressively increase as the electron density is enhanced by methylation. Hybrid NH–p and van der Waals interactions occur between one indole ring and two benzene acceptor molecules. In the electronically excited singlet state, the indole NH stretch fundamental at the S1 origin is shifted from its ground-state value (3525 cm1) to 3478 cm1, as determined by excited-state fluorescence-dip IR spectroscopy <2003JCP2696>. The corresponding band in the indole–H2O complex appears at 3387 cm1, shifted by a similar amount from its ground-state position (3436 cm1). The corresponding spectra in 3-methylindole, 3-methylindole-H2O,
29
30
Pyrroles and their Benzo Derivatives: Structure
tryptamine, and some conformers of tryptophan amide derivatives all miss the indole NH stretch absorption. These are replaced by a broad background absorption spread over the entire 2800–3800 cm1 region, while conformations that possess an intramolecular H bond in the dipeptide backbone have all IR transitions replaced by a stronger broad background absorption. An excited 1p* state which is dissociative along the indole NH stretch coordinate is apparently involved, whereas in the weak coupling case (indole, indole-H2O), the gap between the 1p* state and the S1 origin is too large to be reached by IR excitation. Single-crystal X-ray diffraction, infrared (IR) spectroscopy, and theoretical investigations of indole-2-carboxylic acid in the solid state show two chains of indole molecules forming a planar ribbon held together by intermolecular O–H O and N–H O hydrogen bonds <2004JST(688)79>. In the gas phase, UV, IR, and theoretical analysis shows that the most strongly populated, and lowest-energy conformer of tryptophan presents a folded alanyl side chain that is stabilized by hydrogen-bonded interactions linking the acidic proton, the amino group, and the indole ring, with a further interaction between the carbonyl oxygen and the neighbouring CH group on the pyrrole ring <2001PCP1819>. Resonant ion-dip IR spectroscopy of each of seven conformational isomers of tryptamine has shown that conformers possess unique spectral signatures in the alkyl CH stretch region of the IR, which are affected by the orientation of the amino group <2000PCA8677>. The rotational spectra of two tryptamine conformers have been assigned by free jet millimeter-wave absorption spectroscopy. Both of them are stabilized by an intramolecular N–H p bridge, formed between the amino group of the lateral chain in position 3 and the p-system of the pyrrole unit <2004PCP2806>. A theoretical determination of vibrational absorption and Raman spectra of 3-methylindole radicals has been carried out in comparison to experimentally measured spectra for 3-methylindole (Table 28) to provide specific spectroscopic markers for the detection of neutral or cationic tryptophan radicals in biological systems <2001CPH(265)13>. Among isatin derivatives, substitution at C-5 has relatively greater influence on the electron density and the force constant of the amide than of the ketone carbonyl group (Table 29) <2001SAA469>.
Table 28 IR data of 3-methylindole<2001CPH(265)13> Vibration
max (cm1)
B3LYP
N–H stretch C–H stretch C–H stretch CH3 C–H stretch CH3 C–H stretch CH3 C–H stretch C(2)–H in-plane bend Benzene ring vibration Benzene/pyrrole ring vibration, Benzene/pyrrole ring vibration Benzene ring vibration
3493 3060 3039 2923 2889 2860 1455 1334 1080 1070 731
3682 3192 3181 3097 3062 3021 1485 1366 1107 1091 748
Table 29 IR data of substituted isatins Substituent
Vibration
max (cm1)
Method
Reference
None
N–H stretch
3244, 3187, 3116
2001SAA469
CTO stretch CTO stretch CTO stretch N–H stretch CTO stretch CTO stretch N–H stretch CTO stretch CTO stretch N–H stretch CTO stretch
1748, 1736, 1727 1761, 1744 1769, 1748 3440, 3205, 3187, 3172, 3104, 3069 1762, 1748, 1739 1763, 1744 3091, 3066, 3049, 3031, 3008, 2917, 2848 1760, 1749, 1703 1763, 1751 3203, 2919, 2850 1762, 1750, 1712
Liquid nitrogen temperature (LNT) solid state LNT solid state CHCl3 CCl4 LNT solid state LNT solid state CHCl3 LNT solid state LNT solid state CHCl3 LNT solid state LNT solid state
5-F
5-Cl
5-Br
2001SAA469 2001HCO387 2001HCO387 2001SAA469 2001SAA469 2001HCO387 2001SAA469 2001SAA469 2001HCO387 2001SAA469 2001SAA469 (Continued)
Pyrroles and their Benzo Derivatives: Structure
Table 29 (Continued) Substituent
5-I 5-NO2
5-Me
5-OMe 5-COMe 6-Me 6-OMe 6-Cl 6-Br
Vibration
max (cm1)
Method
Reference
CTO stretch N–H stretch CTO stretch N–H stretch CTO stretch CTO stretch NO2 stretch N–H stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch CTO stretch
1767, 1750 3426, 3381, 3226, 3095, 2917, 2848 1756 (sh), 1745, 1734, 1708 (sh) 3388, 3330, 3097 1770, 1752, 1735 1763, 1749 1337 3193, 3171, 3109 1757 (sh), 1745, 1735 1760, 1740 1769, 1748 1761, 1744 1769, 1748 1765, 1754 1762, 1740 1770, 1745 1760, 1734 1740 1768, 1744 1766, 1746 1770
CHCl3 LNT solid state LNT solid state LNT solid state LNT solid state CHCl3 LNT solid state LNT solid state LNT solid state CHCl3 CCl4 CHCl3 CCl4 CHCl3 CHCl3 CCl4 CHCl3 CCl4 CHCl3 CHCl3 CCl4
2001HCO387 2001SAA469 2001SAA469 2001SAA469 2001SAA469 2001HCO387 2001SAA469 2001SAA469 2001SAA469 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387 2001HCO387
Considerable differences are seen in the N–H stretching values among the five-substituted derivatives examined. Strong electron donors shorten and stabilize the unusually long -dicarbonyl CC bond, while electron-accepting groups tend to stretch this bond further. As an alternative to a previous assignment, the two (CTO) absorption bands of indole-2,3-diones (isatins) can be interpreted as the symmetrical and asymmetrical stretching vibrational modes in the mechanically coupled cyclic -dicarbonyl system <2001HCO387>. The aliphatic–CH2 group in indoleacetic acids acts as an insulator between the conjugated p-system of indole and the carboxylic group, hindering a direct effect on the CTO vibration <1996JST(382)177>. The N–H stretching vibrations are influenced by halogenation and hydrogen bonding. In indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1Hindole-3-acetic acid], the N-linked benzoyl CTO stretching frequency is 1604 and 1614 cm1 at 300 K <2005MI161>.
3.01.3.5.3
Carbazoles
NH-Stretching modes of unsubstituted carbazole- and halogen-substituted derivatives appear at 3417–3403 cm1. Halogen substituents shift the NH stretching bands to lower wave numbers compared to the parent heterocycle due to the conjugation of the halogen that increases electron density around the nitrogen and enhances acidity of the N–H group <2000SAA2049>. Bands in the 1400–1650 cm1 region are the ring-stretching vibration modes mixed with the N–H bending mode and are also affected by substituents. The bands at 1270–1286 cm1 are typical of the substituent. The ring vibration band at 1493 cm1 is shifted at lower wave numbers by halogen substituents. The C–halogen bands are at 1043–1068 cm1 and shift to lower wave numbers on passing from Cl to I. The IR spectra of carbazole and carbazole-(H2O)n (n ¼ 1–3) clusters in a supersonic jet, measured by IR dip spectroscopy, show vibrational structures of both the monomer and the clusters in the 2900–3800 cm1 frequency region, assigned to the NH stretch of carbazole and the OH stretches of H2O molecules in the clusters <2001PCA8651>. In the first excited singlet and triplet states N-(4-cyanophenyl)carbazole gives rise to transient bands at 2090 cm1 and 2060 cm1 detected by time-resolved infrared absorption spectroscopy and attributed to the CN stretch modes of the molecule <2002CL340>.
3.01.3.6 Mass Spectrometry The early use of mass spectrometry as a tool for structural elucidation based on analysis of fragmentation patterns has gradually evolved to its present significance in natural product chemistry and biochemistry. This relies largely on soft ionization techniques, for example, matrix-assisted laser desorption ionization (MALDI) and electrospray ionization
31
32
Pyrroles and their Benzo Derivatives: Structure
(ESI), which provide information about molecular weights and supramolecular associations without causing extensive breakdown of the molecule <2002JAM1254>. In the present survey the focus will be on those papers of structural relevance dealing with the fragmentation behavior of pyrroles and their benzo derivatives, in line with the previous chapter in CHEC-II(1996) <1996CHEC-II(2)1>.
3.01.3.6.1
Pyrroles
A detailed mass spectrometric (TOF) study of pyrrole (11.8–27.5 eV) has allowed estimates of the appearance energy of 17 fragment ions and the doubly charged parent ion <1999CPH(250)217>. 3,4-Dicarboethoxy-2,5-dimethylpyrrole derivatives undergo fragmentation mainly with loss of EtOH (base peak) or of EtO. to give distinct series of fragments (Figure 3) <1998RCM580>.
Figure 3 Fragmentation mechanisms of substituted pyrrole compounds.
Pyrroles and their Benzo Derivatives: Structure
Carbon dioxide protected pyrroles and indole (carbamates), generated by treatment of the N-lithiated heterocycles with gaseous CO2, can be easily tracked by negative ion electrospray ionization mass spectrometry (ESI-MS) revealing invariable loss of CO2 from the anion <2002JMP541>.
3.01.3.6.2
Indoles
The gas-phase ion chemistry of simple indoles by using several mass spectrometric methods has been reviewed <2003MI174, 2004MI398>. The origin of main fragments from cycloalkan[b]indoles, 3-cyanoalkylindoles, and 29-nitrovinylindoles has been extensively discussed <1996IJM97>. Melatonin (N-acetyl-5-methoxytryptamine) isomers have been distinguished by their fragmentation patterns and the relative abundance of generated ions, which have been assigned with the aid of metastable ion studies <1998RCM1538>. Main fragment peaks at m/z 173 and 160 originate from the molecular ion through cleavage of the amide substituent (Figures 4 and 5).
Figure 4 Fragmentation pattern of melatonin isomers accounting for the base peak at m/z 173.
Figure 5 Fragmentation route of melatonin isomers leading to the intense peak at m/z 160.
33
34
Pyrroles and their Benzo Derivatives: Structure
4-Benzyloxyindole-2-carboxylic acid hydrazide and arylidene hydrazides undergo fragmentation with significant loss of hydrazine and arylidenehydrazine radicals as well as of neutral isocyanates <2005JHC985>. The position of the chain substituent on the indole ring is critical in determining the gas-phase reactions of isomeric -cyanoethylindoles <2005JAM397>. When the -cyanoethyl substituent is linked to the indole nitrogen, or to a quaternary 3-position bearing a methyl group, its elimination is a distinctive and regiospecific reaction that can be detected as a metastable ion process (Figure 6).
Figure 6 Origin of the intense ion at m/z 130 from 1- cyanoethyl-3-methylindole.
3.01.3.7 Electron Paramagnetic Resonance Spectroscopy The EPR spectra of the radical cations derived from pyrrole solutions can all be simulated by electronic structures in which the unpaired electron is located in an orbital with the nodal plane on the nitrogen and (2) showing large coupling constant values at the 2- and 5-positions and small values at the 3- and 4-positions <2000J(P2)905>. The EPR parameters of the radical cations from 2,5-dimethyl-1-phenylpyrroles and 3,4-bis(alkylthio)-2,5-dimethyl-1phenylpyrroles (Table 30) denote a marked stabilization of the radical cations by the sulfanyl groups through mesomeric effects.
Table 30 EPR parameters for radical cations derived from substituted pyrroles <2000J(P2)905> Substituents
g
a()/G
a(N)/G
a()/G
1-Ph, 2,5-Me2 1-Ph, 2,5-Me2, 3,4-(MeS)2 1-Ph, 2,5-Me2, 3,4-(n-BuS)2
2.0023 2.0055 2.0055
16.6 (6H) 9.4 (6H) 9.12 (6H)
4.40 1.62 1.37
3.60 (2H) 3.12 (6H) 2.87 (4H)
Trapping of 2-pyrrolylcarbonyl radicals by fluorinated nitrosoalkanes results in the formation of fluorinated nitroxides <1999T2263>. Electron pair accepting groups, such as CN, COCH3, and NO2, on the pyrrole ring decrease the aN value from 7.82 G (YTH) to 7.21 (YTNO2), 7.31 (YTCN) and 7.49 G (YTCOCH3), and increase the stability of the final fluorinated nitroxide. Conversely, electron-donating groups, such as Si(CH3)3 and OCH3, exert opposite effects (aN ¼ 7.95 and 8.45 G, respectively) and decrease stability of nitroxides.
Pyrroles and their Benzo Derivatives: Structure
One-electron reduction of 3-methyl-4-(39-methylindol-29-yl)indole-6,7-dione leads to the semiquinone radical anion with a g value of 2.0044 0.0002 indicating the contribution of spin–orbit coupling due to electron spin at the oxygen nuclei <1995JA1485>. The limited resolution of the hyperfine structure suggests a nonrigid conformation with a partial p-conjugation between the two indole rings. In contrast to the EPR behavior of alkyl nitroxides, 3,6dimethylcarbazole-9-oxyl shows resolved hyperfine coupling for all the ring protons, indicating delocalization of spin density from the N–O group to the whole ring system <2003JOC2209>.
3.01.3.8 Other Structural Methods The revised structural parameters of N-methylpyrrole, as determined by gas electron diffraction using rotational constants and liquid crystal NMR, are listed in Table 31 <2001JST(567)107>.
Table 31 Structural parameters of N-methylpyrrole as determined by gas electron diffraction <2001JST(567)107> Bond
˚ Length (A)
Bond
Angle (degrees)
r(N–C(2)) r(N–CMe) r(C(2)–C(3)) r(C(3)–C(4)) r(H(2)–C(2)) r(H(3)–C(3)) r(HMe–CMe)
1.372 1.452 1.383 1.425 1.079 1.081 1.100
C(2)–N–C(5) N–C(2)–C(3) C(2)–C(3)–C(4) H(2)–C(2)–N H(2)–C(2)–C(3) H(3)–C(3)–C(2) H(3)–C(3)–C(4)
109.3(9) 108.2(7) 107.1(4) 117.7(29) 134.2(32) 124.0(42) 128.9(44)
The adiabatic ionization energies of indole, N-methylindole, 3-methylindole, and 5-methylindole, determined by zero kinetic energy photoelectron spectroscopy and mass-analyzed threshold ionization spectroscopy, are 62592 4, 60749 5, 60679 5, and 61696 5 cm1, respectively <1997PCA2384, 2004JCP5057>. This data indicate that N-Me substitution lowers the zero energy level of the cationic ground state to a greater extent than that of the neutral ground state. Moreover, methyl substitution on the pyrrole moiety leads to a greater red shift in the ionization energy than on the benzene moiety. Ionization energies of indole-Ar (62 505 cm1), indole-H2O (59 433 cm1), and the indole–benzene (59 833 cm1) complexes, as well as ionic and neutral dissociation energies of the complexes in the ground state, indicate a van der Waals character of the indole–Ar complex and hydrogen bonding in indole–water and indole benzene, with the benzene p-cloud serving as electron donor <1998PCA3273>.
3.01.4 Structural Properties and Thermodynamic Aspects Basic structural properties and thermodynamic aspects of pyrroles, indoles, and carbazoles have been covered in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)155, 1996CHEC-II(2)1>. In view of the difficulty of including an effective critique of the various contributions within the allotted space, the following coverage of the topic is restricted to literature data of the past decade that highlight aspects relating to induced and excited state dipole moments, aromaticity, acidity and basicity, tautomerism and atropisomerism.
3.01.4.1 Dipole Moments Dipole moments have been calculated for pyrrole and a series of azoles at the MP2/6-31G* level <1995JPC12790>. Values of best calculations (MP2/C ¼ 1.89 D vs. 1.74 D except for pyrrole) are larger than experimental values, due to vibrational effects and the small differences between the experimental and the MP2/6-31G* geometry. CM2 gasphase dipoles of 3,5-dimethyl-2-(29-pyridyl)pyrrole and 3,5-di-tert-butyl-2-(29-pyridyl)pyrrole are 0.6 and 0.8 D, respectively, whereas liquid-phase values (hexane and methanol) are 0.8 and 1.0 D for the former and 1.0 and 1.3 D for the latter pyrrole <2004PCP3938>.
35
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Pyrroles and their Benzo Derivatives: Structure
Excited state dipole moments have been determined by different methodologies for pyrrole, indole, and carbazole derivatives. Solvatochromic and thermochromic measurements were used to measure the excited state dipole moments e(ICT) (intramolecular charge transfer) and e(LE) (locally excited) of the dual fluorescent molecules N-phenylpyrrole, N-(4-cyanophenyl)pyrrole, and N-(3-cyanophenyl)pyrrole <2003MI342>. The dipole moments of the excited singlet states of some indoles were estimated from solvent-dependent Stokes shift data obtained from electronic absorption and fluorescence spectra recorded in solvents of different polarities and using a solvatochromic method based on a microscopic solvent polarity parameter <2003BCJ1741>. All indoles show a substantial increase in the dipole moment upon excitation to the emitting state. Laser-induced changes in microwave dielectric loss of benzene solutions have been measured for N-(4-cyanophenyl)carbazole and N-(1-naphthyl)carbazole, to determine the dipole moments and hence the nature of the fluorescent states of these electron donor–acceptor systems <2001PCA5438>. Dipole moment determinations give values of 10.4 and 8.6 D, respectively, which are much lower than those expected for a twisted intramolecular charge transfer state. It is concluded that these donor–acceptor systems emit from a state that has predominantly a locally excited character. The magnitude of the induced dipole moment that is produced when an indole molecule in its ground S0 and electronically excited S1 states is polarized by the attachment of a hydrogen-bonded water molecule in the gas-phase complex indole–H2O have been determined as * I(S0) ¼ 0.7 D and * I(S1) ¼ 0.5 D <2005JCP1743011>. The permanent dipole moment values for the complex ( IW(S0) ¼ 4.4 D and IW(S1) ¼ 4.0 D) are substantially different from calculated values based on vector sums of the dipole moments of the component parts. The orientation of the induced moment is also significantly different in the two electronic states.
3.01.4.2 Aromaticity Experimental methods and criteria for quantifying aromaticity in heterocyclic compounds have been covered in CHEC-II(1996) <1996CHEC-II(2)1> and continue to be the subject of a lively debate. Evaluation of aromaticity is currently based on structural-, magnetic-, or energetic-based indices, and reliable comparisons require use of several aromaticity descriptors. Indeed, discrepancies have been observed between three criteria for evaluation of local aromaticity of carbazole derivatives, that is, structurally (HOMA) and magnetically (NICS) based measures, as well as a new electronically based indicator of aromaticity, the para-delocalization index (PDI), which is defined as the average of all Bader delocalization indexes between para-related C atoms in a six-membered ring <2004PCP314>. Polarizabilities have been suggested to provide useful information about aromaticity, and have been calculated for pyrrole and a series of azoles at the MP2/6-31G* level <1995JPC12790>. However, the actual value of polarizabilitybased indices of aromaticity has been questioned following comparative analyses of pyrrole and other heterocycles <2004MI427>. Resonance energies have been calculated for 41 aromatic compounds including pyrrole with good results via the direct-interaction method, which assumes that the resonance energy of a compound is the sum of the directinteraction energies resulting from the interactions between directly bonded functional groups in the compound <2000JMT(528)255>.
3.01.4.3 Acidity and Basicity Ab initio MO and DFT calculations at several levels of theory revealed a marked effect of the medium on the ionization sites of pyrrole- and indolecarboxylic acids, showing that (1) pyrrole- and indole-3-carboxylic acids behave as NH acids in the gas phase, (2) in the gas phase, pyrrole- and indole-2-carboxylic acids are deprotonated at the COOH group, although competing ionizations may take place, and (3) all these acids behave in aqueous solution as OH acids <1998JA13224>. High-level ab initio and DFT calculations indicate that although pyrrole behaves as a carbon base in the gas phase, its 2- and 3-nitro derivatives protonate preferentially on the nitro group <2002NJC1567>. Indole-2- and indole-4carboxylic acids on the one hand, and indole-3- and indole-5-carboxylic acid, on the other hand, show similar values of pKCOOH in hexadecyltrimethylammonium bromide and benzyldimethylhexadecylammonium chloride micelles <1995SAA1691>. In the excited state, all the compounds show equilibria associated with protonation of the heterocyclic ring and deprotonation of pyrrolidine nitrogen. The pKa1* and pKa3* values of indole and carboxylic acid derivatives are influenced by the nature of the medium, the position of the carboxyl group, and the nature of the hydrocarbon chain of the surfactant. Binding energies of metal cations with indole in the gas phase are approximately
Pyrroles and their Benzo Derivatives: Structure
5–10 kcal mol1 greater relative to benzene, as determined by radiative association kinetics analysis in the Fourier transform ICR mass spectrometer, supplemented by DFT calculations <1999JA2259>. The acidity constants of carbazole, 2-nitrocarbazole, 2-methoxycarbazole, and 3-methylcarbazole in the ground as well as in the lowest excited singlet state have been measured <2000JML33>. A good linear correlation exists between the acidity constants and the charge densities on the deprotonation centers in the respective electronic states.
3.01.4.4 Tautomerism and Atropisomerism Tautomerism has been investigated in 3,5-dimethyl-2-(29-pyridyl)pyrrole and 3,5-di-tert-butyl-2-(29-pyridyl)pyrroles in the gas phase, in their alcohol complexes, and as dimers <2004PCP3938>. The compounds exist preferentially in the normal syn-conformation, which in the dimethyl compound is energetically favored over the anti-conformation by 4.3 kcal mol1, with a rotational barrier of 11.3 kcal mol1, and are more stable than their tautomers in the gas phase. Tautomerism is observed in pyrrole-2,5-diacetic acid and its diethyl ester with the pyrrole form being favored for the free acid and the pyrrolidinediylidene tautomer for the diester <2003NJC1353>. Tautomerism has been observed for 2-(29-pyridyl)indoles using NMR and UV-fluorescence techniques <1998JOC4055>. Molecular orbital calculations indicate that the indole is about 40 kcal mol1 more stable than its tautomer. Atropisomerism is relatively rare among pyrrole derivatives. Restricted rotation about the C(4)–C(19) bond, due to the bulky tert-butyl group and an ortho-effect has been described in ethyl and methyl 3,5-dimethyl-4-[((19-iodo-29,29dimethyl)propyl]pyrrole-2-carboxylate) and a variety of related derivatives in which iodine is replaced by methoxy, thiomethyl, acetic acid esters, propionic acid ester, or malonic esters <2002TA1721>. Dynamic NMR studies allowed the determination of kinetic and thermodynamic parameters associated with the atropisomerism, including G values in the range 22–25 kcal mol1 in C2D2Cl4 solvent. Similarly, malonic ester derivatives of ethyl and methyl 3,5-dimethyl-4-(19-iodoneopentyl)-1H-pyrrole-2-carboxylate exhibit restricted rotation about the pyrrole bond C(4)– C(19), with G values of about 32 kcal mol1 <2002M1469>. Finally, bilirubin and biliverdin congeners with propionic acids replaced by o-carboxyphenyl groups exhibit diastereomerism due to axial chirality about the carbon–carbon single bond linking the o-carboxyphenyl group to a pyrrole ring <2002T7411>.
3.01.5 Further Developments From June 2006 to September 2007 further papers appeared dealing with the structural characterization of pyrroles and their benzo derivatives. Only a brief selection is reported here, highlighting those structural studies that focus on simple derivatives of pyrrole and indole.
3.01.5.1 Theoretical Methods A DFT/B3LYP method has been used for analysis of the vibrational spectra and geometric structure of pyrrole and other heterocyclic compounds in the anharmonic approximation <2007MI169>. The B3LYP/6-31þG(d) molecular geometry-optimized structures of 17 five-membered heterocycles were employed together with the gauge including AOs (GIAO) DFT method at the B3LYP/6-31þG(d,p), B3LYP/6-311þþG(d,p) and B3LYP/6-311þG(2d,p) levels of theory for the calculation of proton and carbon chemical shifts and coupling constants <2007MRC532>. Ab initio and DFT methods have been employed to study the molecular structures and thermochemical properties of pyrrole and related nitrogen-containing heterocyclic compounds, their anions and radicals <2006JPC(A)13979>. Using the CBSAPNO, G3, and G3B3 methods, a formation enthalpy of 26.5 kcal mol1 was calculated for pyrrole. Bond dissociation enthalpies for N–H are weaker than for C–H, suggesting that abstraction of the N–H hydrogen atom is more likely. Deprotonation enthalpies and free energies reveal moreover that the C–H protons are less acidic than N–H protons by ca. 49 kcal mol1, or ca. 35 kcal mol1 when adjacent to the NH group. Theoretical studies of two key eumelanin precursors 5,6-dihydroxyindole and 5,6-dihydroxyindole-2-carboxylic acid have been reported, addressing excitedstate reaction paths and energy profiles of the former <2007CPC756> and electronic and structural properties of the latter <2006MI743>.
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3.01.5.2 Molecular Spectroscopy The structure of liquid pyrrole has been investigated by an integrated experimental and theoretical approach involving energy dispersive X-ray diffraction and molecular dynamics <2006CPL200>. The crystal and molecular structure of pyrrole-2-carboxamide has been analyzed by single crystal X-ray diffraction, FT-IR and NMR techniques <2006JPC(B)5875>. The crystal structure of 4-(2-methoxycarbonyl-ethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid benzyl ester has been solved by X-ray diffraction <2006JST32>. 5,59-Diethoxy-3,39-methanediyl-bis-indole was synthesized by a novel protocol and its solid state structure was analyzed using X-ray diffraction and 13C CP/MAS NMR methods <2007JST174>. Isomeric 7-pyridylindoles in which the pyridine ring is attached through the 2-, 3-, or 4-position have been prepared and structurally investigated by NMR and X-ray crystallography <2006JOC7611>. The compounds exist in different states of aggregation dictated by the formation of intra- and intermolecular H-bonds. X-ray analyses of various pyrrole and indole derivatives have been reported in Acta Crystallographica, Section E: Structure Reports Online, and are not mentioned here in detail. 15 N NMR chemical shifts have been measured for a variety of dipyrromethanes and dipyrromethenes by twodimensional correlation to 1H NMR signals <2006JOC2964>. Nitrogen atom resonances in dipyrromethanes were around 230 ppm relative to nitromethane, whereas hydrobromide salts of in meso-unsubstituted dipyrromethenes were around 210 ppm, shifting to about 170 ppm in their corresponding zinc(II) complexes. A complete spectral characterization, comprising 1H and 13C NMR data, has been provided for the first 5,6-dihydroxyindole tetramer <2007OL1411> and for novel 5,6-dihydroxyindole derivatives bearing a mercapto group on the 3-position <2007TL3883>. A systematic study of the anharmonic vibration frequencies has been performed for pyrrole and other fivemembered heterocycles <2007JST113>. FT-IR spectroscopy of pyrrole-2-carboxaldehyde and its dimer in the N–H and CTO stretching range has been used to investigate intermolecular interactions in a model system relevant for antiparallel -sheet formation between peptide strands <2007JCP13431>. The mid-IR absorption spectrum of 5,6-dihydroxyindole-2-carboxylic acid solid samples has been investigated in the region ranging from 1000 cm1 to 4000 cm1 and vibrational modes for dominant absorption bands were successfully assigned with ab initio DFT methods <2007CPL355>. In addition, absorption and emission spectra of the same indole have been investigated and shown to violate mirror symmetry, due to convergent excited-state intramolecular proton-transfer photocycles <2007JA6672>. Collision-induced dissociation of protonated indole with Xe has been studied as a function of kinetic energy using guided ion beam tandem mass spectrometry techniques <2007MI388>.
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Pyrroles and their Benzo Derivatives: Structure
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Pyrroles and their Benzo Derivatives: Structure
Biographical Sketch
Marco d’Ischia was born in 1958 and studied chemistry at the University of Naples Federico II, Italy, where he was appointed assistant professor in 1983. He was then made associate professor in 1992 and full professor of organic chemistry in 2001. His main research interests focus on the chemistry of natural products and heterocyclic compounds. Specific interests include the melanins and melanogenesis, the oxidative chemistry of catecholamines in relation to neuronal degeneration and other oxidative stress diseases; the chemistry of nitric oxide and biological nitrations; lipid peroxidation; the mechanism of action of phenolic antioxidants and antinitrosating agents. He has been a member of the Scientific Board of the European Society for Pigment Cell Research and the Board of Editors of the Journal Pigment Cell Research.
Alessandra Napolitano graduated in chemistry in 1984 at the University of Naples Federico II under the guidance of Prof. G. Prota. In 2001 she was made associate professor of organic chemistry. Her main research interests lie in the field of heterocyclic compounds, with special reference to hydroxyindoles and benzothiazines, oxidative chemistry of phenolic natural products, food chemistry, lipid peroxidation, and analytical chemistry. Currently, she is involved in several research projects dealing with the chemistry of natural pigments, including pheomelanins, and the chemical basis of diseases.
Pyrroles and their Benzo Derivatives: Structure
Alessandro Pezzella received his Ph.D. in 1997 under the direction of Prof. G. Prota at Naples University Federico II. Since 1999 he holds a permament position as researcher in the Department of Organic Chemistry and Biochemistry of Naples University. He has carried out research mainly in the field of 5,6-dihydroxyindole polymerization and oxidative behavior of phenolic compounds.
43
3.02 Pyrroles and their Benzo Derivatives: Reactivity B. A. Trofimov and N. A. Nedolya Russian Academy of Sciences – Siberian Branch, Irkutsk, Russia ª 2008 Elsevier Ltd. All rights reserved. 3.02.1
Introduction
3.02.2
Reactivity of Fully Conjugated Rings
46 46
3.02.2.1
Thermal and Photochemical Reactions
46
3.02.2.2
Electrophilic Attack at Nitrogen
56
3.02.2.2.1 3.02.2.2.2 3.02.2.2.3 3.02.2.2.4 3.02.2.2.5 3.02.2.2.6 3.02.2.2.7
3.02.2.3
N-Acylation and N-sulfonylation N-Alkylation N-Arylation N-Vinylation N-Reactions with heterocumulenes N-Nitrosation N-Miscellaneous reactions
56 58 71 76 81 83 85
Electrophilic Attack at Carbon
3.02.2.3.1 3.02.2.3.2 3.02.2.3.3 3.02.2.3.4 3.02.2.3.5 3.02.2.3.6 3.02.2.3.7 3.02.2.3.8 3.02.2.3.9 3.02.2.3.10 3.02.2.3.11
88
C-Protonation C-Nitration and C-nitrosation C-Halogenation C-Acylation and C-sulfonylation C-Alkylation C-Arylation C-Vinylation C-Ethynylation C-Reactions with carbonyl compounds C-Reactions with heterocumulenes C-Reactions with miscellaneous electrophiles
89 92 94 101 110 134 140 149 151 157 162
3.02.2.4
Reactions with Nucleophiles
168
3.02.2.5
Oxidation of the Heterocyclic Ring
172
3.02.2.6
Reduction of the Heterocyclic Ring
178
3.02.2.7
Reactions with Radicals, Carbenes, Nitrenes, and Silylenes
182
Cycloaddition Reactions
199
3.02.2.8 3.02.3
Reactivity of Nonconjugated Rings
3.02.3.1
Pyrrolenines and Indolenines
3.02.3.2
Dihydro Derivatives
3.02.4
211 211 212
Reactivity of Substituents Attached to Ring Carbon Atoms
214
3.02.4.1
Fused Benzene Rings and Aryl Groups
214
3.02.4.2
Alkyl and Substituted Alkyl Groups
218
3.02.4.3
Alkenyl and Alkynyl Groups
219
3.02.4.4
Carboxylic Acids and Their Derivatives
222
3.02.4.5
Aldehydes and Ketones
224
3.02.4.6
N-Linked Substituents
233
3.02.4.7
Hydroxy and Alkoxy Groups
237
3.02.4.8
S-Linked Substituents
239
3.02.4.9
Halogeno Groups
241
45
46
Pyrroles and their Benzo Derivatives: Reactivity
3.02.5
Reactivity of Substituents Attached to Ring Nitrogen Atom
244
3.02.5.1
N-Alkyl and Substituted N-Alkyl Groups
244
3.02.5.2
Carboxylic Acids and Their Derivatives
250
3.02.5.3
Hydroxy and Alkoxy Groups
253
3.02.6
Further Developments
References
254 255
3.02.1 Introduction The decade passed since the mid-1990s has again shown a sustainable interest in the reactivity of pyrroles and their benzo derivatives <2002CRV4303>; the research interest owes it to their important role in the living matter, drug design, and advanced materials. Since the publication of the corresponding chapter in the previous edition <1996CHEC-II(2)40>, thousands of papers concerning, or just touching in one or other ways, the reactivity of pyrroles and their benzo derivatives have appeared. It is not the goal of this chapter to cover equally all the publications, and it is hardly possible. The authors, to the best of their capacity and understanding, have focused on major trends in this area and their illustration by most meaningful and prospective examples. As in previous decades, the main body of publications relates to diverse versions of electrophilic substitution in the pyrrole (indole) ring, both neutral and deprotonated. Leading these reactions are various types of alkylation and acylation. Most of them, as well as other kinds of reactivities, were modifications of known classic procedure to better fit a task of a total synthesis or to solve a special synthetic problem. Noteworthy as more frequent than previously are applications of transition metal catalyzed cross-couplings in their numerous modifications to functionalize the pyrrole ring, which often can be formally classified as aromatic nucleophilic substitutions <2006EJO3043>. A new efficient C-carbothioation of pyrroles with carbon disulfide in the KOH/DMSO system (Section 3.02.2.3.7) paves the way to richly functionalized C-vinyl pyrroles (Section 3.02.4.8) and further to a variety of pyrrole–azole assemblies and fused pyrrolic systems. Relatively more attention was paid to direct N- and C-vinylation of the pyrrole moiety by acetylene and its electron-deficient derivatives; in the latter case a single electron transfer step has been detected. Attractive for further development and understanding is the palladium- and copper-free ethynylation of the pyrrole and indole rings with haloacetylenes on alumina at room temperature (Section 3.02.2.3.8). This promises to become an alternative to the Sonogashira coupling, particularly due to inaccessibility and low stability of halopyrroles and indoles. The authors hope to be excused for not covering the material in detail it deserves due to lack of room, for omitting many excellent papers and that the chapter is not free from the inevitable influence of authors’ personal visions, interests, tastes, and understanding.
3.02.2 Reactivity of Fully Conjugated Rings 3.02.2.1 Thermal and Photochemical Reactions The thermal reactions (unimolecular isomerization, decomposition, and annulation) of pyrrole and its benzoannulated derivatives, indole and carbazole, have been extensively studied both experimentally (by shock-wave technique over the temperature range of 1050–1800 K <1989JPC5802, 1991IJK733, 1997PCA7787, 2003MI231>, continuous-flow pyrolysis (CFP) <2000ARK576>, infrared laser powered homogeneous pyrolysis (IR LPHP) <2004NJC606>, laser-induced thermal desorption with Fourier-transform mass spectrometry <1997POL3197>, and flash vacuum pyrolysis <1997J(P1)2195, 1997J(P1)2203, 1999J(P1)2047, 2006ARK89, and references therein>) and theoretically <1998PCA10880, 1999CPL(300)321, 1999PCA3917, 1999PCA3923, 1999JMT(461)569, 2001PCA3605, 2001PCP2467, 2003PCA5427>, and also because of the important role that pyrrolic systems play as sources of precursors of the oxides of nitrogen (NOx), atmospheric pollutants, in the combustion of coals and other heavy fuels <1995MI507, 2002MI2317>. Understanding the mechanism and kinetics of pyrolytic reactions of the compounds containing a pyrrole moiety is of considerable interest to the control of NOx formation as well as in the understanding of combustion processes.
Pyrroles and their Benzo Derivatives: Reactivity
In both pyrrole <1989JPC5802> and indole <1997PCA7787>, isomerizations are the main primary thermal reactions. In the case of pyrrole, three isomerization products, (Z)- and (E)-1-cyanoprop-1-ene 3 and 1-cyanoprop2-ene 4 had the highest yields (Scheme 1). 2H-Pyrrole (pyrrolenine) 2, though never established experimentally, was proposed as a precursor to the isomerization products <1989JPC5802, 1991IJK733>. The initial step of pyrolysis mechanism is a concerted N–C(5) bond cleavage (Scheme 1, pathway a) and [1,2]-hydrogen migration from the nitrogen to C-5 <1989JPC5802>. The biradical 1 thus formed can undergo a [1,4]-H migration from C-2 to C-5 to yield (Z)-compound 3. The biradical 1 can also undergo a [1,2]-H migration from C-2 to C-3, leading to compound 4, or a C(2)–C(3) bond cleavage to form HCN and cyclopropene. The latter can rearrange to yield propyne and/or allene. Since a direct C–N bond cleavage is unfavorable because the C–N bond is quite strong due to the aromatic nature of the pyrrole ring, it was also suggested that the first step of pyrrole thermal reactions is a [1,2]-H shift from the nitrogen to C-2 to form 2H-pyrrole 2, followed by C–N bond cleavage to yield a biradical as an important intermediate for the formation of the observed major products (Scheme 1, pathway b) <1991IJK733>.
Scheme 1
A detailed theoretical study by density functional theory (DFT) calculations including configuration interaction supports a biradical mechanism of the isomerizations described in Scheme 1 <1998PCA10880>. There is no direct route that leads from 2H-pyrrole to (E)- compound 3. The latter is formed from the (Z)-isomer by (Z) ! (E) isomerization. Kinetic modeling, which uses the calculated rate constants, gives a very good agreement between the calculated and the experimental yields of the isomerization products. In the opinion of other authors <1999PCA3917>, the biradical 1 seems unlikely to play such an important role under experimental conditions. Alternative isomerization and decomposition mechanisms supported with DFT and ab initio calculations are proposed. A key finding of ab initio quantum chemical and kinetic modeling studies of the thermal decomposition of pyrrole was the fact that the dominant pyrolysis products, namely hydrogen cyanide plus propyne (or allene), were found to be the result of a series of molecular rearrangements of the reactant involving a cyclic carbene intermediate 5 and lowenergy [1,5]-sigmatropic hydrogen shift in 6 (Scheme 2) <1999CPL(300)321, 1999PCA3923>. An indirect support of this pathway can be considered by the Brandsma–Nedolya strategy of pyrrole ring construction (from lithiated allenes or alkynes and isothiocyanates <1996CHE781, 1997TL2409, 1999EJO2663, 1999MI1, 2001EJO4569, 2004S0735,
47
48
Pyrroles and their Benzo Derivatives: Reactivity
2006RJO607>) based on one-pot synthesis and unknown intramolecular cyclization of 1-aza-1,3,4-trienic systems of type 6 (via a cyclic carbene intermediate of type 5 as one of the most probable channels of noncatalytic nucleophilic [1,5]cyclization of allenylimidates that is supported with quantum chemical calculations <1997RJO76, 2004RJO775, 2007RJO576>).
Scheme 2
Recently the thermal decomposition of pyrrole 1 was carried out using the method of infrared laser powered homogeneous pyrolysis (IR LPHP) in a cylindrical Pyrex cell fitted with ZnSe windows <2004NJC606>. The results obtained confirm the dominant step of [1,2]-H shift yielding initially cyclic carbenes 5 and 7 or 2H-pyrrole 2, followed by ring opening and rearrangement (Scheme 3). IR LPHP of pyrrole at temperatures between 1000 and 1050 K confirmed (Z)- and (E)-compound 3 (20% and 9%, respectively) and compound 4 (11%) as the major low-temperature pyrolysis products. In addition, significant amounts of acrylonitrile (16%), acetylene, HCN, and allene or propyne (38%) were also produced, together with benzene and other C6H6 isomers in smaller quantities (5% total); no pyrrole oligomers were detected. Copyrolysis with H2 suppressed the formation of benzene. The IR LPHP results are entirely consistent with earlier investigations and the results of high-level calculations and thus a little additional insight into the decomposition mechanism for pyrrole is afforded.
Scheme 3
In the temperature range of 1050–1700 K, similar to pyrrole, the main thermal reactions of indole are isomerization to produce 2-phenylacetonitrile 8, and 2-methyl- 9 and 3-methyl- 10 benzenecarbonitriles as a result of the pyrrole ring opening under shock heating (Scheme 4) <1997PCA7787>. The major decomposition products that were found in the post-shock samples in decreasing order of abundance were C2H2, HCN, HCUCCN, C4H2, PhCN, MeCN, and C6H6. Small quantities of PhMe, CH4, C5H5CN, H2CTCHCN, C5H6, HCUCPh, and traces of C2H4, H2CTCTCH2, HCUCMe, C4H4, C6H4, and HCUCC5H5
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 4
were also found in the post-shock mixtures. It is suggested that indole to 2-phenylacetonitrile 8 isomerization starts with cleavage of the N–C(7a) bond followed by two [1,2]-H atom migrations. The thermal decomposition of indole is initiated by H-atom ejection from the reactant (by breaking either an N–H bond in indole or a C–H bond in 3Hindole). A reaction scheme containing 48 species and 109 elementary reactions accounts for the observed product distribution. The proposed mechanisms of thermal reactions of indole have been verified by quantum chemical calculations <1999JMT(461)569, 2001PCA3605>. CFP and annulation reactions of pyrrole and its benzo-annulated derivatives, indole and carbazole, have been investigated at 900 C in an argon stream at atmospheric pressure <2000ARK576>. While for pyrrole and indole between 15 and 17 products were identified by gas chromatography–mass spectroscopy (GC-MS), carbazole is rather stable under the reaction conditions and naphthalene was found as the only substantial product. Except for carbazole, about 10 compounds were always present in the pyrolysate, benzenecarbonitrile (13–24%) and naphthalene (2–21%) being the most prominent products. Apart from small amounts of quinoline (5.9%) and indole (3.4%), only traces (<0.1%) of pyridine, isoquinoline, acridine and carbazole were found as nitrogen-containing heterocycles in pyrolysate of pyrrole at 900 C (Scheme 5). Many more nitrogen compounds were found, in which the nitrogen atom is part of a cyanide substituent. Such products are benzonitrile (24.1%), 1-naphthonitrile (15.8%), 9-anthracenecarbonitrile 14 (<0.1%), 3-fluoranthenecarbonitrile 15 (<0.1%) and their isomers. Formation of these cyano compounds may proceed via either benzonitrile or polycyclic aromatic hydrocarbons, generated from volatile pyrolysis products 3, 11–13 (Scheme 5).
Scheme 5
49
50
Pyrroles and their Benzo Derivatives: Reactivity
In the flow pyrolysis of indole, only small amounts of nitrogen heterocycles, such as quinoline (4.4%), isoquinoline (1.0%), and carbazole (2.5%), were generated. Benzonitrile (13.1%) and 9-anthracenecarbonitrile (5.2%) as well as their isomers were found in larger amounts. The larger amount of phenanthrene (9.1%) and anthracene (3.5%) compared with that of naphthalene (2.2%) is remarkable (Scheme 6). In the pyrolysis of pyrrole it was much lower, and this indicates that different reaction paths are followed.
Scheme 6
The absorption and thermal reaction of pyrrole on Si(100)-2 1 has been studied using X-ray and UV-photoelectron spectroscopies (XPS and UPS) and high-resolution electron energy loss spectroscopy (HREELS) <2000CPL(325)508, 2003MI285>. At low exposure, pyrrole chemisorbs molecularly at 120 K with its ring parallel to the surface via the p interaction. The increase in coverage causes tilting of chemisorbed molecules toward the surface normal, attributable to the adsorbate–adsorbate interactions. At ca. 350 K, the N–H bond scission of the p-bonded species occurs, resulting in Si–H and vertically N-bonded pyrrolyl on the surface. The pyrrolyl species is thermally stable to 700 K. Further annealing to 900 K results in the formation of silicon carbide and silicon nitride on the substrate. The organic functionalization or modification of Si(100) is of great technological importance for developing new Si-based microelectronics <1998SCI335>. On Pd(111) decomposition of pyrrole occurs at around 230 K <1997POL3197>. The only reaction product observed in both LITD (laser-induced thermal desorption) with Fourier-transform mass spectrometry and TDS is HCN. The data cannot be readily explained by a pathway involving either a C-4 or a C-3 species; however, results obtained indicate the presence of some intermediate species that decomposes above 325 K yielding hydrogen and above 500 K to give HCN. The thermal rearrangement of 1-substituted pyrroles to 2- (and 3-) substituted isomers by sequential [1,5]-shifts has been known and studied extensively <1966JA3671, 1976S0281, 1988J(P1)339>. It was also shown that 3-(1Hpyrrol-2-yl)acrylate 16 and related compounds undergo concerted elimination of alcohols under flash vacuum pyrolysis (FVP) conditions to give pyrrolizin-3-one 18 by electrocyclization of an intermediate 17 (Scheme 7) <1997J(P1)2195>.
Scheme 7
FVP of 1-(2-methoxycarbonylphenyl)pyrrole 19 at 925 C (0.001 Torr) gives the unusual 5H-pyrrolo[2,1-a]isoindol5-one system 21 (79%) by a novel three-step cascade process involving rate-determining [1,5]-aryl migration,
Pyrroles and their Benzo Derivatives: Reactivity
elimination of methanol, and electrocyclization of the resulting ketene intermediate 20 (Scheme 8) <1999J(P1)2047>. Pyrolysis of the 2-arylpyrrole 22 (obtained by methanolysis of the pyrroloisoindolone 21 in the presence of Hu¨nig’s base) gives product 21 under much milder conditions than required for its isomer 19 (total conversion at 800 C and 0.01 Torr). The remarkable thermal stability of compound 21 (and its ketene valence isomer 20) should be noted.
Scheme 8
The commercially available 1-thienylpyrrole 23 gives the new ring system 24 (79%) in one step at 925 C (0.01 Torr) (Equation 1) showing that the presence of the benzene ring is not required for the process to be successful.
ð1Þ
Gas-phase pyrolysis of 3-(1H-pyrrol-2-yl)prop-2-en-1-ol 25 (R ¼ H) (650 C, 102–103 Torr) and [2-(1H-pyrrol-2yl)phenyl]methanol 27 (700 C, 102 Torr) causes loss of water and cyclization to give 3H-pyrrolizines 26 (Equation 2) and 28 (Scheme 9) in 66–95% yield <1999J(P1)2049>. At 650 C, a number of unidentified by-products were present in the pyrolysate from the tertiary alcohol 25 (R ¼ Me), but 3,3-dimethyl-3H-pyrrolizine 26 was obtained in satisfactory yield and purity (64% after distillation) when pyrolysis was carried out at 550 C.
ð2Þ
At higher temperature (e.g., 900 C) 5H-pyrrolo[2,1-a]isoindole 28 decomposes by loss of HCN to give 1-methylene-1H-indene 29 and naphthalene <1999J(P1)2049>. Flash vacuum pyrolysis of the 3-[2-(1H-pyrrol-1-yl)phenyl]acrylate 30 (at 850 C) gives the pyrrolo[1,2-a]quinoline 31, the pyrrolo[2,1-a]isoindole 32 (R ¼ Me) and the benzoindoles 33 and 34 (Scheme 10), all in low yield <2007ARK85>. These data serve to exclude the isomeric pyrrolo[2,1-a]isoquinoline 36, which might have been formed by loss of CO from the anticipated pyrroloazepinone product 35.
51
52
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 9
Scheme 10
The isomeric precursor 37 cyclizes efficiently under the same conditions to give the pyrrolizin-3-one 39 (via [1,5]sigmatropic shift of the phenyl group, regiospecifically to the 5-position, followed by elimination of methanol to generate the ketene 38 and its electrocyclization to product 39) (Scheme 11) <2007ARK85>.
Scheme 11
It was found that the cheletropic extrusion of SO2 from 3-phenyl-1H-pyrrolo[1,2-c][1,3]thiazole 2,2-dioxides 40 could be carried out in a sealed tube leading to styryl-1H-pyrroles 43 (Scheme 12) <2006ARK89>. The formation of compounds 43 can be explained considering the generation of azafulvenium methides 41 followed by an [1,7]-electrocyclic reaction giving intermediates 42, which rearrange to the final products. Sulfone 40 (R ¼ Me) is converted into benzo[4,5]cyclohepta[1,2-b]pyrrol-4(1H)-one 44 (R ¼ Me) on FVP. Under these reaction conditions, styryl-1H-pyrrole 43 is formed and converted into a pyrrole fused to a 5H-benzo[7]annulen-5one ring system that was confirmed by performing the FVP of pyrrole 43, which also gave compound 44 (31%).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 12
5-Phenyl-derivative 40 and pyrrole 43 (R ¼ Ph) showed similar chemical behavior when compared with 5-methyl analogs 40 and 43 and corresponding tricycle 44 could be obtained on FVP, although in low yield. Some other illustrative examples of extruding SO2 from 1H-pyrrolo[1,2-c][1,3]thiazole 2,2-dioxides both thermally and photochemically giving N- or C-vinylpyrroles and their derivatives <2000CC675, 2001J(P1)1795> are presented in <2006ARK89>. Vacuum-thermal fragmentation and ring cleavage of 2-{3-[(4-methylphenyl)sulfonyl]-1-triazenyl}pyrrole tetraalkylammonium salts 45 leads to azabutadienes 46 (Equation 3) that were of interest as straightforward synthons for heterocyclic synthesis <1997J(P1)1003>.
ð3Þ
Heating of isoindole 47 in diphenyl ether at 250 C led via benzotriazole thermolysis to phenylimine 48, which was further hydrolyzed to 1-isoindolinone 49 (Scheme 13) <2000ARK471>.
Scheme 13
The thermolysis of isoindole 50 in diphenyl ether under similar conditions gave the unusual benzotriazole migration products 53 (benzotriazol-1-yl) and 54 (benzotriazol-2-yl) in the ratio of 1:2, which is postulated to proceed through intermediate 51, along with minor tricyclic lactam product 52 (Scheme 14) <2000ARK471>.
53
54
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 14
1,2-Diheteroarylethenes undergo isomerization from an open 55 to a closed 56 form upon irradiation with UV light (Equation 4) <2000CRV1685, 2005ARK268>. Visible light converts the closed form back into the original open form. Symmetric indole- or pyrrole-containing 1,2-diheteroarylethenes give rise to thermally unstable closed form isomers. By replacing one indole with a furan, thiophene, or benzothiophene group, the asymmetric 1,2-diheteroarylethene becomes thermally stable in the closed form. A number of methylindole derivatives have been introduced <2003BCJ1625> and the resulting photochromic compounds display optical properties which make them suitable as acceptors for energy transfer for a variety of fluorophore donors.
ð4Þ
Indole-containing 1,2-diheteroarylethenes 57 (Figure 1) underwent reversible photochromic reaction in cyclohexane upon alternating exposure to UV (340 nm) and visible (546 nm) light <2005ARK268>. The effect of substituent groups on the nitrogen atom was evaluated by comparison of the optical properties of the BOC, TBDMS, Me, and RCO2CH2 derivatives. The closed form displayed an absorption maximum at ca. 560 nm for the TBDMS, Me and RCO2CH2 substituents. The maximum was shifted to 511 nm for the less electron-rich BOC group.
Figure 1
Pyrroles and their Benzo Derivatives: Reactivity
UV irradiation of 1,2-diaryl-1-sulfonylethenes in the presence of an oxidant produces heterocyclic phenanthrenoids (Equations 5–7) <1996JOC1188>. Thus, UV irradiation of tosylstilbenoids 58 and 60 in EtOH containing catalytic iodine (i) led to the corresponding tosylphenanthrenoids 59 and 61, respectively, in 46–89% yields. Alternatively, the cyclization conditions involving the addition of iodine (1 equiv) and excess 2-methyloxirane in benzene (ii), gave consistently good yields (82–90%) of the corresponding tosylphenanthrenoids. While irradiation of stilbenoid 62 under these conditions (ii) afforded a 90% yield of the desired phenanthrenoid 63, no sizeable amount of compounds 63 using O2/catalytic I2 (i) as oxidants was isolated. Finally, the tosyl group was removed either simply with magnesium in MeOH (iii) or, generally with better, less erratic yields, with sodium dihydronaphthalenide at 78 C (iv).
ð5Þ
ð6Þ
ð7Þ
Photochemically induced ( 280 nm) dehydrocyclization of 2,3-diphenylpyrrole 64 (rt, 30–90 h) gives 2-substituted 1H-dibenzo[e,g]indoles 65 (Equation 8) <2000JPR281>.
ð8Þ
The UV irradiation of 4-(2-nitrophenyl)-1H-pyrrole 66, which is an antibiotic clinically useful against dermatophytosis and possesses a unique 2-(pyrrol-3-yl)nitrobenzene moiety in the molecule, in an anhydrous aprotic solvent (THF, CHCl3, Et2O) resulted in the exclusive formation of the transient the 1H-spiro[2,1-benzisoxazole-3,39-pyrrol]29(19H)-one 67 (in 47–72% yields after a 10-min irradiation) via the intramolecular oxidation of the juxtaposed pyrrole ring by the triplet-excited nitro group (cf. A) followed by collapse (Scheme 15) <2002JOC668>. In an aqueous aprotic solvent, the UV irradiation of pyrrole 66 allowed the occurrence of an intramolecular cyclization by the neighboring singlet-excited nitro group (cf. B) and the concurrent photochemical hydroxylation by water at the
55
56
Pyrroles and their Benzo Derivatives: Reactivity
2-position of the pyrrole ring giving intermediate C to afford the 8-hydroxy-8,8a-dihydropyrrolo[2,3-b]indol-2(1H)-one 68 (in 20% yield), accompanied by the formation of compound 67 (24%). Elongation of the irradiation time in these photoreactions caused rapid consumption of the products, 67 and 68, to give undetermined polar polymeric products. These photoreactions were widely observed in the 2,5-unsubstituted pyrrolnitrins.
Scheme 15
3.02.2.2 Electrophilic Attack at Nitrogen Alkali metal pyrrolides as derivatives of pyrrole, with the hydrogen in the N–H bond being replaced by the metal atom, are widely used as reactants in a variety of chemical and biochemical reactions <1996JOM(514)281, 1996JOM(524)203, 1999JFC(100)21, 1999SM(102)1792>. As is well known, sodium and potassium are more important, compared to lithium, in biological systems <1997CRV1303, 1999JA8864, 2001PCA769>. The remarkable difference between Li pyrrolide, on the one hand, and those of Na and K, on the other, is demonstrated in the work aimed to study the potential energy surfaces of the interaction of Li, Na, and K with the pyrrolyl radical via ab initio quantum chemical methods <2003PCA5427>. If lithium derivative exists as two conformers, s and p, with a significant preference to the p (by 9.9 kcal mol1 over the in-plane s-alternative) <1997OM5032>, at least in the gas phase, Na and K pyrrolides, which have not been reported so far and are examined to a much lesser extent, only show the stable p structure. A key factor of its higher stabilization is the formation of the MþdNs ionic pair (M ¼ Li, Na, and K) where the alkali metal atom behaves as a cation interacting with the pyrrole ring via a typical p-cation interaction. The formation of alkali metal pyrrolides is related to the reactions of the N–H bond-breaking H abstraction and further hydrogen ‘walk’ along the pyrrole ring resulting in nH–pyrrole. Both reactions are thoroughly studied, and four novel pathways for the pyrolysis of pyrrole starting, by means of the [1,2]-H migration, from pyrrolenine (2H-pyrrole), and exiting along the HCN/propyne channel, are proposed. The X-ray crystal structures of lithium and sodium indolides <1990OM1485>, potassium and cesium carbazolides <1989AG1261, 1989AGE1224> point to an increasing preference for alkali metal p interactions with increasing ion size.
3.02.2.2.1
N-Acylation and N-sulfonylation
The importance and the necessity of protecting the nitrogen atom on the pyrrole and indole rings is well established. Two different kinds of protecting groups have been used on the nitrogen of pyrrole and indole: electron-releasing groups (e.g., methyl and benzyl moieties) and, more commonly, electron-withdrawing groups (e.g., acyl and sulfonyl moieties). Moreover, the presence of alkyl and acyl groups as substituents on the nitrogen of the pyrrolic systems is often necessary for different applications <2002TL135, 2005EJO4670>. Traditionally, most of the methodologies used to introduce protecting groups and substituents require very strong bases such as BunLi <1997JOC7447, 2002JME2160>, NaH, or KH <1996JOC7664, 1998JOC4510, 1998OM1134, 2000ARK486, 2003JME417>, or phase-transfer conditions <1998T13915, 2004JOC8668> in order to generate the pyrrole or indole anion, which reacts as a nucleophile with alkyl, acyl, and sulfonyl halides. It was shown that weaker bases such as NaOH, KOH, and Et3N can be substituted for
Pyrroles and their Benzo Derivatives: Reactivity
those strong bases and offer several advantages for N-alkylations <1997CM644, 1997J(P1)2639, 2000TL5211>, N-acylations <1998T13915> and N-sulfonylations <1998T13915, 2004S1951>. The models examined were 3-acylindole, tetrahydro-b-carbolines, tryptamine, and tryptophan derivatives and indole itself (Scheme 16) <1998T13915>. For N-benzenesulfonylation the NaOH process is more general than the other methods, leading to products in very good yields (88–96%). The KOH method works well for pyrrole and indole derivatives with low pKa. The use of triethylamine led to disulfonylated products when tetrahydro-b-carbolines and tryptophan derivatives were used as substrates, these products being isolated in excellent yields. For N-acetylation the most general methods were those that employed NaOH/CH2Cl2 and KOH/Na2SO4. The addition of anhydrous Na2SO4 to the acetone solution permitted the removal of water from the reaction medium, thus avoiding the hydrolysis of acid chloride and making N-acetylation possible.
Scheme 16
Treatment of indole with 2,2-dichloroacetyl chloride in refluxing DCE yielded 2,2-dichloro-1-(1H-indol-1-yl)-1ethanone 69 in 88% yield (Equation 9) <1997TL7813>. Deprotection of compound 69 was carried out under mild nonnucleophilic basic condition using Et3N in CH2Cl2 at room temperature.
ð9Þ
Reaction of unsubstituted pyrrole with acyl and sulfonyl chlorides in ionic liquids, [Bmim][PF6] or [Bmim][PF4], leads to N-substituted pyrroles in excellent yields (Equation 10) <2004S1951>.
ð10Þ
Iridium pyrrolyl complex 73, obtained from pyrrolyl sodium salt 71 and Ir(CO)Cl(PPh3)2 72 in high yield (87%), reacts with acetyl and 4-methylbenzoyl chlorides to give N-acylated pyrroles 74 and 75, respectively, in low yields (Scheme 17) <1998OM1134>. Earlier, stable iridium(I) complexes containing the Z1-N-bonded indolyl ligands, which have potential for further modification of the indolyl molecule, were formed by the reaction of compound 72 with indolyllithium reagents (toluene, reflux, 1–3 days) <1997OM1089>. Pyrrolemagnesium chloride 76 reacted as a N-nucleophile with the lactone (S)-77 (1 equiv) at 0 C to afford the hydroxyamide (S)-78 (59%) (Scheme 18) <2004T1197>. Employing an excess of the organometallic reagent (2 equiv) at 100 C resulted in the formation of ketopyrrole (S)-79 in 87% yield. Obviously, compound (S)-79 is produced by successive N-acylation, o-directed metallation and N,C-acyl migration. Nucleophilic ring-opening reaction of the lactone (S)-77 with N-methylpyrrole lithiated in 2-position (with BunLi/TMEDA) proceeded smoothly furnishing the ketone (S)-79 in 62% yield. Neutral acylation of the indole nitrogen as a simple way to indole-1-carboxylates, indole-1-thiocarboxylates and indole-1-carboxamides 82 is described (Scheme 19) <1999TL2733>.
57
58
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 17
Scheme 18
When intermediate 81 is formed from indole 80 and 1,19-carbonyldiimidazole (CDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with CDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with CDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics.
3.02.2.2.2
N-Alkylation
Compared to C–C bond forming reaction, the C–N bond formation is still immature. Moreover, new amination methodologies will have a direct impact on pharmaceutical and fine chemical industries for the synthesis of a variety of commercially interesting compounds. Since the pyrrolyl anion exhibits ambident behavior as a nucleophile, alkylation can occur at carbon as well as at nitrogen (Scheme 20).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 19
Scheme 20
N-Alkyl chain substituted pyrroles 85 and 86, synthesized by the reaction of the corresponding alkyl halides with 1H-pyrrole under phase-transfer conditions, were condensed with 3,4-dihydroxy-3-cyclobutene-1,2-dione (squaric acid) to form polysquaraine dyes 87, soluble donor–acceptor type conjugated copolymers with interesting optoelectronic properties, in 60–65% yields (Scheme 21) <1997CM644>. A few squaraine dyes, containing 1-octadecylpyrrole units, have been synthesized and studied as Langmuir–Blodgett monolayers <1997J(P2)827, 1998J(P2)779>.
Scheme 21
59
60
Pyrroles and their Benzo Derivatives: Reactivity
In ionic liquids 1H-pyrrole replaced the halogen atom of an alkyl halide to give the corresponding N-substituted pyrroles in excellent yields (Equation 11) <2004S1951>.
ð11Þ
N-Alkylation of 1H-pyrrole, indole and carbazole can be accomplished with benzyl halides (chloride and bromide) in acetonitrile and cesium fluoride/Celite employed as a solid base (Equation 12) <2001T9951>. The procedure is convenient and efficient, and generally gives rise to the N-alkylated products exclusively, in high yields (78–93%).
ð12Þ
Starting from the known inhibitory activity of (2- and 3-benzoylpyrrol-1-yl)acetic acids, a series of 3-aroyl and 2,4bisaroyl N-acetate derivatives 88 were synthesized using phase-transfer catalysis conditions (Equation 13) <1995JPS79, 2003JME417>.
ð13Þ
Solutions of 4H-furo- and 4H-thieno[3,2-b]pyrrole derivatives 89 in dioxane were alkylated with chloroacetone or bromoacetophenone under phase-transfer conditions, in the presence of potassium carbonate and 18-crown-6, to afford the keto esters 90 in good yields (60–85%) (Equation 14) <2005EJO4670>.
ð14Þ
The presence of an electron-releasing group, instead of a withdrawing protective group, on the indole nucleus is sometimes necessary. Moreover, several indole alkaloids have a methyl group as a substituent on the nitrogen of the indole nucleus. Through the treatment of indole 91 (R ¼ H) with KOH (EtOH) and followed by the addition of dimethyl sulfate (the use of MeI gave poorer yields) or benzyl bromide (acetone, rt), both N-methyl- 92 and N-benzyl- 93 indoles were obtained in 90% yield (Scheme 22) <1998T13915>. Using the same method, 3-acetylN-methylindole and 3-acetyl-N-benzylindole were prepared in 93–95% yields. Similar results were also reached by the employment of NaOH/CH2Cl2/RX (rt, 0.5 h). The phase-transfer method was also used (NaOH/H2O, CH2Cl2, Aliquot 336R, rt, 15 min) and proved that all three methods gave essentially the same yields of N-alkylated products.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 22
1-(o-Iodoalkyl)indole-3-carbaldehydes 96, the substrates for radical cyclization (see Section 3.02.2.7), were prepared from indole-3-carbaldehyde 94 (R1, R2 ¼ H) or its derivative 94 (R1 ¼ BnO, R2 ¼ MeO) as shown in Scheme 23 <1997J(P1)2639>. Thus, alkylation of the indole with the appropriate 1-bromo-o-chloroalkane using the Heaney– Ley method (KOH/DMSO) gave the corresponding 1-(o-chloroalkyl)indoles 95 in good yields (74–97%). Reaction of the chlorides 95 with sodium iodide in acetonitrile gave the iodides 96. The iodopentyl derivative 96 (R1 ¼ BnO, R2 ¼ MeO, n ¼ 4) was prepared in 70% yield by direct alkylation of the indole 94 with 1,5-diiodopentane.
Scheme 23
N-Alkylation of 3-aroylindole 97 carried out at 80 C with alkyl halides from ethyl through n-hexyl, gives mixtures of products 98 and 99 in yields of 41–90% (Equation 15) <1998JOC4510>. In addition to the expected N-alkylated indoles 98, a substantial fraction of the product was formed by additional replacement of the methoxy group by an alkoxy group. The reaction is very temperature dependent, since a decrease of only 5 C completely suppresses the formation of the O-alkylation products with the ethyl or n-propyl halide. However, n-hexyl bromide provided a 75% yield of hexyl ether 99 under these conditions.
ð15Þ
Alkylation of pyrroles 100 with the appropriate alkyl halide in alkaline medium (anhydrous K2CO3) gave N-alkylpyrrolylmethanones 101 in moderate to excellent yields (Scheme 24) <2005JME5140>. This procedure was not successful for pyrrole derivative 102, which was achieved in high yields by reaction of 1-bromo-3-methyl-2butene with compound 100 (R1 ¼ Cl, R2, R3, R4, R5 ¼ H), in the presence of NaH (60% in white oil). The products obtained were used as a key intermediates in the synthesis of a series of 1-[(aryl)(4-aryl-1H-pyrrol-3-yl)methyl]-1Himidazoles bearing different substituents (in particular, small alkyl, alkenyl groups) on the nitrogen of pyrrole ring with potent anti-Candida activity. 2-Substituted 3,4-diarylpyrrole 103 was alkylated with 4-(2-bromoethyl)-1,2-dimethoxybenzene 104 using potassium carbonate in DMF but the reaction would not go to completion even after heating at 70 C for 24 h. Substituting cesium carbonate for K2CO3 allowed the reaction to proceed easily to compound 105 (92%) a precursor of Ningalin B 106, a marine natural product (Scheme 25) <2002JOC9439>.
61
62
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 24
Scheme 25
The key synthetic step in a highly convergent and stereoselective synthesis of macrocyclic bisindolylmaleimides of high importance for medicine involves intermolecular alkylation of symmetrical bisindolylmaleimide 107 with chiral bisalkylating agent 108 (DMF, 1.2 equiv of 108, 6 equiv of Cs2CO3, 50 C, 60–72 h) and is amenable to the preparation of multikilogram quantities of this compound (Equation 16) <1998JOC1961>. To prevent undesirable oligomerizations, the reaction was performed at high dilution (8.3 103 M). Alternative solvents (DMF, CH2Cl2, THF, MeCN, toluene, H2O) and bases (Cs2CO3, K2CO3, KOH, NaOH, NaH) were examined in the intermolecular alkylation reaction, although the yields of compound 109 were significantly lower (0–40%) than those obtained using Cs2CO3/DMF.
Pyrroles and their Benzo Derivatives: Reactivity
ð16Þ
When the 73:27 mixture of crude carboxylic acid 110 and the monocyclic diacid 111 was treated with isobutyl iodide/Cs2CO3 in hot DMF, only N-isobutyl isobutyl ester 112 was obtained (Equation 17) <2005JOC688>. Apparently the C(7)-CO2H of 111 is esterified, along with the C(9)-CO2H, and the C(7)-ester is recycled through the intramolecular cyclization.
ð17Þ
The new 1-b-D-ribofuranosylpyrroles 115 were prepared in good yield via alkylation of the sodium salts (obtained with NaH in MeCN) of pyrroles 113 with 1-chloro-2,3,5-tri-O-acetyl-D-ribose 114 (Equation 18) <2000ARK486>. Removal of the protecting group was easily achieved by treatment with sodium alkoxide. This reaction represents a convenient method for the stereoselective glycosylation of pyrroles leading only to the single b-anomer as judged by 1H NMR.
ð18Þ
A naturally occurring L-tryptophan N-glucoside was synthesized using 2-O-pivaloylated glucosyl trichloroacetimidate, which gave b-NIn-glucosides <2004TL295>. The preparation of 3,6-dibromo-N-substituted carbazoles was carried out utilizing either NaH or LiH for hydrogen abstraction in anhydrous DMF, followed by addition of the appropriate alkylating agent (alkyl halogenide or tosylate) <1997CM1578>. A number of methods for glycosylation of indoles and indolocarbazoles via Mannich cyclizations have been reported <1996JA5500, 1997T585, 1999JOC2465, 2000BML419, 2000JOC7541, 2001T8917>. The synthesis of a new series of indolo[2,3-a]carbazole glycosides, potent antitumor antibiotics, analogs of Rebeccamycin, currently undergoing clinical trials for the treatment of numerous types of cancer, derived from the natural sugars (D-glucose, L-fucose, D-maltose, D-xylose, L-rhamnose, and D-galactose), is depicted in Scheme 26 <2004TL1095>. Indole-indoline 117 was obtained in 80% yield by Mannich dimerization of Arcyriarubin A 116. Heating an EtOH solution of product 117 with excess of sugar (5 equiv) and ammonium sulfate (5 equiv) until the reaction was complete followed by removal of EtOH in vacuo and addition of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) in THF gave indolo[2,3-a]carbazole glycosides 118 in 49–97% yields. N-Aminoalkylation of 1H-pyrrole was achieved with 2-chloroethylamine under phase-transfer conditions (TBAS, NaOH, MeCN) <2004JOC8668>. Synthesis of N-alkylated indoles 121 (e.g., RO 60-0175, R ¼ 5-F-6-Cl), that are selective 5HT2C agonists with potential therapeutic utility in the treatment of obsessive compulsive disorder
63
64
Pyrroles and their Benzo Derivatives: Reactivity
<1997JME2762>, includes a key step involving the reaction of indole 119 with the N-protected alaninyl mesylate 120 (Equation 19) <1997WO19979747598, 2000WO20000012475, 2003OPD22>.
Scheme 26
ð19Þ
Higher reaction temperature or replacement of KOH with ButOK increased the loss of the BOC group to give amine 121. Changing both the N-BOC protecting group to N-Ts, N-benzylidine imine, or N-Cbz and the leaving group in compound 120 with O-Ts, O-nosyl, and iodo resulted in no improvement in the overall alkylation. N-Alkylation with a regioisomer of compound 120 did not give the desired alkylation product 122, but the unexpected regioisomer 124, derived from the ring-opening of the intermediate aziridine 123 (Scheme 27) <2003OPD22>.
Scheme 27
Pyrroles and their Benzo Derivatives: Reactivity
Various N-protected aziridines have been reacted with N-lithiated indoles to afford N-alkylated and 3-alkylated products, the exact ratios depending on the reaction solvent and the nature of the N-protecting group <1989CB2397>. Indoles and N-alkyl indoles afford tryptamine derivatives on reaction of aziridines under Lewis acid catalysis <1998SL754>. An improved technical process for the efficient N-alkylation of indoles 119 using the N-protected homochiral aziridine 123 has been developed (Equation 20) <2003OPD22>.
ð20Þ
Indole 125 was alkylated with the triflate 126 giving N-substituted indole 127, intermediate in the synthesis of the antitumor agent FR-900482, in 44% yield (Equation 21) <1997JOC1083>.
ð21Þ
Deprotonation of indoles 128 followed by alkylation with 2-methyloxirane led to the secondary alcohols 129 that were used as starting compounds in the preparation of substituted 2-(1H-indol-1-yl)-1-methylethylamines 130, novel agonists of 5HT2C receptors. SN2 reaction of the corresponding mesylates with sodium azide and reduction of the azides with either hydrogen or LiAlH4 produced amines 130 in excellent yields (Scheme 28) <1997JME2762>.
Scheme 28
The alkylation of pyrroles 131 with epichlorohydrin using potassium carbonate as a catalyst affords 1-(2-oxiranylmethyl)-1H-pyrroles 132 in modest to high yields (Equation 22) <2002BMC2511>. A similar synthetic route led to indole derivatives 133 (Equation 23). Both compounds 132 and 133 are precursors of isopropanolamines, potential anti-HIV-1-PR agents.
ð22Þ
65
66
Pyrroles and their Benzo Derivatives: Reactivity
ð23Þ
Reaction of indole with 1,3-dioxolan-2-one leads to 2-(1H-indol-1-yl)-1-ethanol 134 (Equation 24) <2001PLM3023>. Indole 134 was used in the synthesis of a photoconducting nonlinear optical chromophore, 2-[3-(6-nitro-1,3-benzoxazol-2-yl)-1H-indol-1-yl]-1-ethanol.
ð24Þ
4-(3-Methyl-1H-indol-1-yl)butanoic acid 135 easily prepared from 3-methylindole and dihydro-2(3H)-furanone, was used in the synthesis of natural 12H-pyrido[1,2-a:3,4-b9]diindoles which have antimicrobial activity and are cytotoxic against L-1210 mouse leukemia (Equation 25) <1996TL5207>.
ð25Þ
The novel fused heterocyclic bicycle 137 (R1 ¼ R2 ¼ Me), a rare representative of the pyrrolo[1,2-c]oxazole ring system, was formed in low yield when readily available and stable benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 136 was treated with a stoichiometric amount of Et3N or guanidine hydrochloride in refluxing acetone. Efficient conversion to the product 137 (R1 ¼ R2 ¼ Me) in 80% yield occurred when methanone 136 was refluxed with acetone in the presence of a strong, non-nucleophilic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Equation 26) <2004JOC9313>. These reaction conditions were applied to the reactions of methanone 136 with various (both enolizable and nonenolizable) ketones and aldehydes to give pyrrolo[1,2-c]oxazoles 137 in high yields (47–98%).
ð26Þ
In contrast to pyrrole 136, benzotriazol-1-yl(1H-indol-2-yl)methanone 138, under the same reaction conditions, reacted sluggishly with ketones and aldehydes to afford compounds 139 in lower yields (16–83%) sometimes together with side products (Scheme 29) <2004JOC9313>. For example, reaction of indole 138 with p-tolualdehyde produced compounds 140 and 141 in 30% and 23% yields, respectively. Substoichiometric loadings of DBU catalyze the efficient 1,4-addition of nonnucleophilic amines such as pyrrole to activated alkenes. A novel and efficient nucleophile-catalyzed N-cyanoethylation of pyrrole (pKa 16.5) gives 3-(1Hpyrrol-1-yl)propanenitrile 142 in good yield (Scheme 30) <2005CC227>. To demonstrate the potential synthetic utility of these catalytic processes a DBU-catalyzed cyanoethylation reaction was used as a key step in a novel one-pot synthesis of the Monarch butterfly pheromone Danaidone 144 <1986N17, 2001NPR361, 2005CC227>. Addition of 3-methylpyrrole to acrylonitrile catalyzed by DBU gave intermediate 143, which underwent subsequent electrophilic cyclization in the presence of added HCl/ZnCl2. The resultant iminohydrochloride was hydrolyzed to give the natural product 144 in 30% yield after chromatography.
Pyrroles and their Benzo Derivatives: Reactivity
KF/Al2O3 catalyzed hetero-Michael addition of ethyl acrylate with pyrrole as weakly nucleophile gives ethyl 3-(1Hpyrrol-1-yl)propanoate 145 in moderate yield <2005TL3279>.
Scheme 29
Scheme 30
Indole-2-carboxamides 146 underwent palladium-catalyzed intramolecular cyclization reactions to afford b-carbolin-1-ones 147 or pyrazino[1,2-a]indol-1(2H)-ones 148, according to different reaction pathways (Scheme 31) <2003JOC7625>. Complete regioselectivity of the reactions was obtained in different reaction conditions.
Scheme 31
The intramolecular Michael addition of ()-pyrrole 149 to give compound ()-150, an intermediate in the asymmetric synthesis of an unique cytotoxic tetracyclic alkaloid ()-Agelastatin A, was effected using Cs2CO3 (Equation 27) <1998JOC7594, 1999JA9574, 2006ARK120>.
67
68
Pyrroles and their Benzo Derivatives: Reactivity
ð27Þ
Compounds 155 were apparently obtained from initial addition of triphenylphosphine as a good nucleophile to acetylenic ester as a Michael acceptor and concomitant protonation of the intermediate 152 by the NH acid 151. Then the positively charged ion 153 is attacked by the nitrogen of the conjugated base of the NH acid 154 to form phosphoranes 155 containing several functional groups (Scheme 32) <2006ARK55>.
Scheme 32
A convenient synthesis of indoles bearing allyl, ethynyl, and/or propargyl moieties starting from indole or indole-2carboxylic acid is described <2002S1810>. N-Alkylation of 2-vinylindole by a phase-transfer method using NaOH (30% solution)/toluene and Bu4NI gave 1,3-dipropargylated compound 156 in 50% yield (Scheme 33). Treatment with propargyl bromide using Cs2CO3 as the base affords 1-(2-propynyl)-2-vinyl-1H-indole 157 in 70% yield.
Scheme 33
Pyrroles and their Benzo Derivatives: Reactivity
Some 2-carbonyl-1-propargyl-1H-indoles 159 are prepared by means of Suzuki- and Negishi-type reactions <2006OL4839>. 2-Carbonyl-1H-indoles 158 were converted into the corresponding N-propargyl derivatives in good to excellent yield by means of PTC nucleophilic substitution in toluene/aqueous NaOH and Bu4NBr as the catalyst (Equation 28). 1-[1-(2-Propyn-1-yl)-1H-pyrrol-2-yl]ethanone was obtained in 86% yield by similar route.
ð28Þ
Allylation of indole 160 (obtained from indole in 85% overall yield, five steps) with allyl bromide in the presence of Cs2CO3 led directly to 1-allyl-2-ethynyl-1H-indole 161 with loss of the trimethylsilyl group in the same reaction (Equation 29) <2002S1810>.
ð29Þ
Radical precursors with a five-membered heteroarene for ring D of the important anticancer and antiviral alkaloids (Camptothecin, Mappicine, Nothapodytine B, and Nothapodytine A), 1-(2-halo-3-phenylprop-2-en-1-yl]-1H-pyrrole2-carbonitriles 163, (E)/(Z) mixture, were synthesized in high yields (87–96%) by alkylation of 1H-pyrrole-2carbonitrile with the cinnamyl bromides 162 using KOH in DMF (Equation 30) <2002J(P1)58>.
ð30Þ
Dimethyl 3,39-dithiopropionate 164 can generate, in basic medium, methyl acrylate, which serves in situ as a source of a propionate moiety. This method was applied to the N-alkylation of indoles, pyrido[3,4-b]indole (Norharman) and carbazoles leading to a series of 3-(heteroaryl)propionates 165 (Scheme 34) <2000JOC3123>. KH affords slightly superior results than NaH, while other bases such as LDA, Cs2CO3, or NaHMDS are generally less efficient.
Scheme 34
69
70
Pyrroles and their Benzo Derivatives: Reactivity
Various dialkyl- and diaryl(vinyl)sulfonium salts react with 1H-indole-2-carbaldehyde in the presence of NaH to form a tetracyclic oxirane, for example, 167; these upon treatment with sodium azide form tricyclic azido alcohols analogous to compound 168 in 72% yield (Scheme 35) <1999T10659>. This annulation was a key step in total synthesis of Mitomycin K <1996TL6049>.
Scheme 35
The formation of a minor side product 172 was observed which, if moisture was not rigorously excluded, could become a major product in this reaction (Scheme 36). The formation of compound 172 can be rationalized by protonation of the sulfur ylide 166, followed by deprotonation of one of the readily accessible methyl hydrogens to give the ylide 169, which then reacts at the carbonyl center to give the seven-membered ring intermediate 170. The methyl sulfide is then displaced by the alkoxide to give the oxirane 171, which upon addition of sodium azide, opens up to the azido alcohol 172 <1999T10659>.
Scheme 36
With 1H-pyrrole-2-carbaldehyde, [2,3]-sigmatropic and other rearrangements occur except in the case of diphenyl(vinyl)sulfonium trifluoromethanesulfonate where the annulation reaction does take place to give a low yield of 1-(2-hydroxy-2,3-dihydro-1H-pyrrolizin-1-yl)-1H-pyrrole-2-carbaldehyde 173 (Scheme 37) <1999T10659>. The benzene sulfonyl group is used as a ‘transfer of activation’ reagent to alkylate selectively the N–H of both 7H-pyrrolo[2,3-d]pyrimidines 174 and 5-aminoindole substituted on thienopyrimidines 175 (Equations 31 and 32). A variety of primary and secondary alcohols are utilized as alkylating substrates <1998TL5685>.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 37
ð31Þ
ð32Þ
3.02.2.2.3
N-Arylation
N-Aryl azoles have attracted much attention since they display a broad spectrum of applications as biologically active compounds (agrochemicals, pharmaceuticals, or useful intermediates for their synthesis) and transition metal ligands <1989JME683, 1992JME1092, 1994IJB255, 1999T12757, 2004JOC7914, 2005JME5140>. N-Aryl indoles and carbazoles with axial chirality have been receiving increasing attention for use as chiral ligands <2001TA2435> and in such natural products as Murrastifoline-F <2001JA2703>. Stereoselective nucleophilic aromatic substitution reactions of a variety of indoles with planar chiral fluoroarene chromium complexes 176 in the presence of 18-crown-6 in toluene solution proceeded smoothly to give N-aryl indole chromium complexes 177 or 178a with an axially chiral N–Caryl bond (Equation 33) <2006OL1097>.
71
72
Pyrroles and their Benzo Derivatives: Reactivity
ð33Þ
Stereoselective chromium tricarbonyl migration was achieved in the sterically hindered N-aryl indole chromium complex 178b by refluxing in toluene (Equation 34) <2006OL1097>.
ð34Þ
Hexapyrrolylbenzene 179 and octapyrrolylnaphthalene 180 were obtained in high yields by the reaction of sodium pyrrolide with a stoichiometric amounts of hexafluorobenzene or octafluoronaphthalene, respectively, at room temperature in DMF (Scheme 38) <1996JOC9012>. Six new monosubstituted hexapyrrolylbenzene derivatives have been synthesized (in 6–55% yields) based on the multiple nucleophilic substitution reaction (SNAr) of appropriate 2- or 3-substituted 1-pentafluorophenyl-1H-pyrroles with the sodium salt of pyrrole (7 equiv) in dry DMF at room temperature <2006ARK124>. The products obtained due to their sterically congested structures may be regarded as building blocks for larger p-conjugated systems possessing propeller-shaped molecules with interesting optoelectronic properties.
Scheme 38
Pyrroles and their Benzo Derivatives: Reactivity
Catalytic N-arylation of indoles is mainly limited to aryl iodides and bromides <1998JA827, 2000OL1403>. The combination of Pd(OAc)2 and DPPF catalyzed the formation of N-aryl azoles 181 in the presence of Cs2CO3 or ButONa with electron-rich, electron-neutral, or electron-poor aryl halides (Equation 35) <1998JA827>.
ð35Þ
Only a few examples of an aryl chloride as partner in this coupling were reported <1999JOC5575, 2000OL1403>. The catalytic system involving But3 P as ligand allows for arylation of azoles such as indole and pyrrole to provide N-aryl azoles 182 in high yields (Equation 36). The reaction between indole or pyrrole and unhindered aryl halides (including aryl chlorides), either activated or inactivated, occurred at 100 C after 12 h. The use of Cs2CO3 as base, rather than ButONa, was crucial to the success of this reaction. When reacted with simple indoles, hindered aryl halides such as 2-bromotoluene generated two isomeric products and one product from the addition of two aryl groups that were assigned to the products of arylation at the nitrogen, at the C(3)-position, and at both sites.
ð36Þ
Following the Buchwald–Hartwig reaction conditions, the pyrroloquinoxalines, indoloquinoxalines, pyridopyrrolopyrazines, and pyridoindolopyrazines 185 were obtained in high yields (66–98%) from pyrrole- or indole-2-carboxamides, bearing a suitable o-halosubstituted aryl or heteroaryl group at the amide nitrogen, via the palladium-catalyzed intramolecular N-arylation forming a C–N bond on the oxo-piperazine ring (Scheme 39) <2005S2881>. The best conditions were Pd(OAc)2 (5 mol%) in the presence of BINAP (10 mol%) and Cs2CO3 as base in toluene, heating the mixture at 110 C for 24 h. The possible concomitant Heck pathway involving cyclization on the 3-position of the pyrrole nucleus was never observed. Starting from pyrrole- or indole-2-carboxylic acids 183 and 2-haloanilines or halopyridines the amides 184 were prepared via unisolable acyl chlorides in the presence of Et3N.
Scheme 39
73
74
Pyrroles and their Benzo Derivatives: Reactivity
As an excellent complement to the Pd-catalyzed methodology that has been utilized in a number of applications, in general experimentally simple and inexpensive catalyst system for the N-arylation of a wide variety of azoles (pyrrole, indoles, 7-azaindole, carbazole) has been developed (Equation 37) <2001JA7727>. In particular, it was shown that the combination of air stable CuI and racemic (E)-1,2-cyclohexanediamine 186a in the presence of K3PO4 is an extremely efficient and general catalyst system for the N-arylation of a number of azoles. Competitive C-arylation under these conditions is not observed.
ð37Þ
N-Arylation of a wide range of pyrrole substrates utilizing either aryl iodides or aryl bromides was successfully performed in good yield with catalysts derived from diamine ligands ((E)-1,2-cyclohexanediamine 186a or N1,N2dimethyl-1,2-cyclohexanediamine 186b) and CuI (Equation 38) <2004JOC5578>. General conditions were found that tolerate functional groups such as aldehydes, ketones, alcohols, primary amines, and nitriles on the aryl halide or pyrrole. Hindered aryl halides or pyrrole were also found to be suitable substrates.
ð38Þ
The Ullmann coupling of (S)-1-(3-bromophenyl)ethanamine 187 with pyrrole and indole using microwave heating leads to corresponding pyrrole 188 and indole 189 derivatives in 66% and 76% yield, respectively (Scheme 40) <2003TL4217>.
Scheme 40
The Pd(OAc)2/SIPr?HCl/NaOH system (where SIPr ¼ 1,3-bus(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene) is efficient for the N-arylation of diverse indoles with aryl bromides (Equation 39) but not effective for the reaction with aryl chlorides <2001JOC7729>. Pd(dba)2 or PdCl2/SIPr?HCl/NaOH systems did not effect the arylation of indole.
Pyrroles and their Benzo Derivatives: Reactivity
ð39Þ
N-Arylation of ethyl 1H-pyrrole-2-carboxylate under Chan and Lam conditions <1998TL2933, 1998TL2941>, by reaction with 4-methoxyphenylboronic acid in the presence of cupric acetate and either triethylamine or pyridine at room temperature, gave the pyrrole ester 190 in good yield (Equation 40) <1999T12757>.
ð40Þ
In the indole series this procedure offers a flexible entry into the synthesis of different 1,3-diaryl-2-carboxindoles (Schemes 41 and 42) <1999T12757>. Thus, compound 191 could easily be coupled under Suzuki-type conditions with boronic acid 192 (R2 ¼ MeO) to give 3-aryl derivative 193 in good yield. In contrast, when the reaction conditions described by Chan and Lam employing cupric acetate as the catalyst were used the N-arylated products 194 were observed (Scheme 41). Treatment of substrate 195 (R1 ¼ H) with 3-cyanophenylboronic acid led to the corresponding N-arylation product 197 (R1 ¼ H) only in moderate yield (Scheme 42). However, starting from compound 195 (R1 ¼ I) the corresponding iodo compound 197 was obtained in better yield under the same reaction conditions (ii, see Scheme 41). The results obtained indicate that both the halogen at C-3 and the carboxylic function at C-2 contributed to the positive outcome of this arylation process. The Suzuki-type reaction of the substrate 195 (R1 ¼ I) led exclusively to 3-aryl compound 196 in good yield. 3-Iodoindole 197 was converted to the corresponding 1,3-diaryl compounds 198 under palladium catalysis in good to excellent yield. Arylated pyrroles and indoles obtained were used in the design of factor Xa antagonists.
Scheme 41
75
76
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 42
N-Arylation of phenylpyrrolylmethanone 199 to afford N-aryl derivative 200 was performed in Suzuki reaction conditions using phenylboronic acid, Cu(II) acetate, and pyridine (Scheme 43) <2005JME5140>. The best yields were obtained in the presence of N-methylpyrrolidone (NMP) by microwave-assisted heating (60 W, 120 C, 3 50 s). Reduction of methanone 200 with LiAlH4 gave methanols 201, which were then treated with CDI to afford imidazoles 202, potent anti-Candida agents.
Scheme 43
3.02.2.2.4
N-Vinylation
N-Vinylpyrroles are extensively studied synthetic intermediates <1996JOM(506)337, 1996RCB407, 1997HAC495, 1997JOM(548)279, 2001ARK2, 2003TL2629, 2005JOC6629, 2006ARK89, 2006EJO4021, 2006TL3693> and
Pyrroles and their Benzo Derivatives: Reactivity
monomers for the preparation of diverse polymeric materials <1994SM(66)165, 1995MI90, 1997PAC143, 1998JEC(454)99, 2001PSA253>. General routes to N-vinylpyrroles and their derivatives are: addition of pyrroles and their derivatives to alkynes <1998JOC10022, 1999TL6193, 2000S1585, 2002COR1121, 2003MI27, 2003RJO408, 2003S1272, 2005JME5140> including in situ vinylation of pyrroles resulted from the cyclization of ketoximes and alkynes in a strong base/DMSO system (Trofimov’s reaction) <1998JOC10022, 1998RJO1691, 1998ZOR967, 1999RCR459, 2000S1585, 2002COR1121, B-2004MI121>; Pd-catalyzed vinylic substitution with vinyl bromides <2002OL623> and vinyl triflates <2005JOC8638> and indirect vinylation (substitution–elimination) with dihaloalkanes <1998JOC10022, 2002CHE682, 2005JME5140>. Ketoximes react with acetylene in the presence of superbase systems of the type KOH/DMSO to form pyrroles. When there is an excess of acetylene, one can directly obtain N-vinylpyrroles (Scheme 44) <1998RJO1691, 1998ZOR967, 1999RCR459, 2002COR1121, B-2004MI121>.
Scheme 44
The reaction has been successfully extended to a propyne–allene mixture: the corresponding N-isopropenylpyrroles were isolated as mixtures (Scheme 45) <2000S1585>.
Scheme 45
Using the same base system a new expedient method of vinylation of azoles including carbazole was developed. In its traditional version, the reaction is carried out under pressure of about 15 atm and at a temperature as high as 180 C. The yield of purified N-vinylcarbazole does not exceed 75%. In the superbase promoted vinylation of carbazole, no pressure is required and the optimal temperature is within 90–95 C, that is, half as much as in the classic version. The yield of N-vinylcarbazole is near to quantitative and its purity exceeds 99% (Equation 41) <2002COR1121, 2003MI27>.
ð41Þ
The propyne–allene/KOH/DMSO system was successfully employed for direct isopropenylation of diverse azoles (Equation 42) <2000S1585, 2003RJO408>.
77
78
Pyrroles and their Benzo Derivatives: Reactivity
ð42Þ
1,3-Divinylpyrroles 204 were prepared by direct N-vinylation with acetylene of the corresponding 3-vinylpyrroles 203 according to the Trofimov’s superbasic conditions (Equation 43) <1998JOC10022>. 3-(2-Phenylvinyl)-1-vinylpyrrole 204 (R ¼ Ph) has been also obtained directly from the corresponding 3-(2-phenylvinyl)-1-tosylpyrrole, by its treatment with acetylene in KOH/DMSO, the N-detosylation and the N-vinylation occurring in one-pot.
ð43Þ
Reaction of pyrroles 205 with 3-phenylprop-2-ynenitrile and 1-aroyl-2-phenylethynes proceeds smoothly and selectively in the KOH/DMSO system to furnish functionalized N-vinylpyrroles 206 in 32–88% yield (Equation 44) <2003S1272>.
ð44Þ
Unlike pyrroles 205 (R1 ¼ R2 ¼ H and R1 ¼ Ph, R2 ¼ H), which add in full to the 3-phenylprop-2-ynenitrile (yields of adducts 206 are 85–88%), the conversion of 4,5,6,7-tetrahydroindole 205 (R1–R2 ¼ (CH2)4) under the conditions studied is only 55%. Under analogous conditions, pyrroles 205 (R1 ¼ R2 ¼ H and R1 ¼ Ph, R2 ¼ H) react with 1-aroyl-2phenylethynes as N-nucleophiles to form, depending on the structure of the starting pyrrole, either predominantly (E)-isomers or exclusively (Z)-isomers of functionalized N-vinylpyrroles 206 (R1 ¼ R2 ¼ H and R1 ¼ Ph, R2 ¼ H) in 32–69% yield. The major route of addition of 4,5,6,7-tetrahydroindole 205 (R1–R2 ¼ (CH2)4) to the 1-aroyl-2-phenylethyne (R3 ¼ PhC(O)) is C-vinylation (Equation 45). In this case, N-vinylation is a secondary reaction <2003S1272>.
ð45Þ
Nucleophilic additions to alkynes were commonly considered as typical anionic reactions, the possibility of the single electron transfer normally being unconsidered. The appearance of radicals upon vinylation of 4,5,6,7-tetrahydroindole in KOH/DMSO was detected by spin trapping, seemingly for the first time <2002COR1121>. In the nucleophilic addition of pyrrole to 3-phenylprop-2-ynenitrile and 1-aroyl-2-phenylethynes in the KOH/DMSO system, the formation of radicals was detected directly in the ESR spectrometer <1998RJO1667, 2002COR1121, 2003DOC137>. One of the signals observed was assigned to the adducts of the pyrrolyl radical to alkynes (Figure 2).
Pyrroles and their Benzo Derivatives: Reactivity
Figure 2
In the presence of catalytic amounts of cesium hydroxide (CsOH?H2O) pyrrole and indole add to ethynylbenzene to give N-vinylpyrrole and N-vinylindole in 79% and 65% yield, respectively (Equation 46) <1999TL6193>.
ð46Þ
An intermediate in the synthesis of potent anti-Candida agents N-vinylpyrrole 208 was obtained by addition of pyrrole 207 to methyl propiolate in the presence of tetrabutylammonium fluoride (Equation 47) <2005JME5140>.
ð47Þ
The pyrroles 209 react with 2-(alkylsulfanyl)-1-chloroacetylenes in the KOH/DMSO system to give 1-ethynyl-1Hpyrroles 210 (yield up to 58%) as a substitution product along with 1,19-(1,1-ethenediyl)bis-1H-pyrroles 211 and 1,19-(1,2-ethenediyl)bis-1H-pyrroles 212. These compounds resulted from further nucleophilic addition of excess pyrrole to the triple bond of the initial product (Equation 48) <1999RJO916, 2002COR1121>.
ð48Þ
Vinylation of various azoles (pyrrole, indole, carbazole, and their derivatives) with vinyl bromides catalyzed by palladium/phosphine complexes results in the N-vinylazoles in 30–99% yields (Equation 49) <2002OL623>. This reaction with cis- and trans-b-bromostyrenes is stereospecific giving the respective products with full retention of configuration.
79
80
Pyrroles and their Benzo Derivatives: Reactivity
ð49Þ
The combination of palladium dibenzylidenacetone and 2-dicyclohexylphosphino-29,49,69-triisopropyl-1,19-biphenyl (XPhos) in the presence of potassium phosphate (toluene or toluene/dioxane, 3:1) provides a highly active catalyst system for the efficient and selective synthesis of the N-vinylpyrroles 213 (N-vinylindoles 214) from pyrroles (indoles) and cyclic and acyclic vinyl triflates (Equations 50 and 51) <2005JOC8638>.
ð50Þ
ð51Þ
The reaction of pyrrole 199 with 1,2-dichloroethane under phase-transfer catalysis conditions gave the expected N-vinylpyrrole 215, with concomitant formation of dimeric product 216 (Equation 52) <2005JME5140>.
ð52Þ
N-Vinylpyrroles 217 were also obtained via indirect N-vinylation with 1,2-dichloroethane from 2-formyl- and 3-acetylpyrroles (Scheme 46) <1998JOC10022>.
Scheme 46
Pyrroles and their Benzo Derivatives: Reactivity
In the phase-transfer catalyst system (ClCH2CH2Br/KOH/18-crown-6, toluene) indoles 218 form N-vinylindoles 219 in 42–68% yields (Equation 53) via intermediate chloroethyl derivatives. In a similar reaction the substituted oxime 220 was obtained as the only product (Equation 54) <2002CHE682>.
ð53Þ
ð54Þ
Under analogous conditions 1H-indole-3-thiol reacts with 1-bromo-2-chloroethane to give N,S-divinylindole 221 in 43% yield (Equation 55) <2002CHE682>.
ð55Þ
3.02.2.2.5
N-Reactions with heterocumulenes
2-(1H-Indol-2-yl)ethyl heterocumulenes 222 (isothiocyanates, carbodiimides and ketenimines) undergo ring closure under acidic, basic, and thermal conditions to give either tetrahydro-1H-pyrido[4,3-b]indole-1-thione 223 and dihydro-3H-pyrido[4,3-b]indole 224 or dihydropyrimido[1,6-a]indoles 225–227 in a completely regiospecific fashion (Scheme 47) <1995TL953>. The mode of cyclization strongly depends on the cyclizating agent as well as the nature of the heterocumulene. All attempts to promote the thermal cyclization of the isothiocyanate 222 (Y ¼ S) were unsuccessful, but when it was treated with SnCl4 in CCl4 at room temperature, cyclization took place across the 3-position of the indole ring to give 1H-pyrido[4,3-b]indole 223 as the only reaction product in moderate yield (45%). However, when isothiocyanate 222 was treated with potassium bis(trimethylsilyl)amide (KHMDS) in toluene at room temperature it underwent cyclization in a completely regiospecific fashion to give pyrimido[1,6-a]indole-1(2H)thione 225 in 50% yield. Regioselective cyclization of carbodiimides 222 (Y ¼ NAr) to give compound 227 was achieved either by the action of SnCl4 (32–38%), KHMDS (66–80%) or thermal treatment at 160 C (43–67%). This behavior is in sharp contrast with that observed for the closely related 2-(2-indolyl)phenyl, aryl carbodiimides, which undergo cyclization across the 3-position of the indole ring to give indolo[3,2-c]quinolines <1990T1063>. Ketenimines 222 (Y ¼ CAr2) were cyclized either by the action of SnCl4, or thermal treatment, to give 3H-pyrido[4,3-b]indole 224 albeit in low yield (20–25%), whereas treatment with KHMDS provided pyrimido[1,6-a]indole 226 in modest yields (38–47%). 1H-Imidazo[1,5-a]indole 229 (R1 ¼ R2 ¼ H, Y ¼ S) has been prepared in moderate yield by reaction of 1H-indole-2carbonyl isothiocyanate 228 with sodium methanethiolate (Scheme 48) <1999CCC348, 2000CCC1163>. Condensation of the appropriate 1H-indole-2-carboxylic acid 230 (X ¼ OH; R1 ¼ alkyl, alkoxy) or its methyl ester 230 (X ¼ MeO) with isocyanate or isothiocyanate in the presence of Et3N at high temperatures gives compound 229 (R2 ¼ alkyl, allyl) in moderate to low yields <2003BML533>. Treatment of pyrrole 231 and indole 233, bearing the benzotriazol-1-yl moiety (Bt) as leaving group, with isocyanates (Ar, THF, DBU, reflux, 5–7 h) gives high yields of 2,3-dihydro-1H-pyrrolo[1,2-c]imidazoles 232 (71–95%) (Equation 56) and 1H-imidazo[1,5-a]indoles 234 (79–87%) (Equation 57), respectively <2004JOC9313>. The same conditions when
81
82
Pyrroles and their Benzo Derivatives: Reactivity
applied to the reactions of pyrrole 231 or indole 233 with isothiocyanates gave low yields of compounds 232 and 234. Optimally, the preparation of corresponding isothiocyanate derivatives (in yields of 26–77% for product 232 and of 21–62% for product 234) was achieved in the presence of triethylamine in a sealed tube at 130 C for 10 h.
Scheme 47
Scheme 48
ð56Þ
ð57Þ
Pyrroles and their Benzo Derivatives: Reactivity
Simple amines can rapidly add to ketenes in the absence of a catalyst, but less reactive nitrogen nucleophiles such as the pyrroles do not react at room temperature with ketenes such as phenyl ethyl ketene <2002JA10006>. In contrast, additions can proceed swiftly when planar chiral 4-(pyrrolidino)pyridine (PPY) derivative 235 is employed as a catalyst (Equation 58). In the presence of enantiopure PPY derivative 235 and an appropriate pyrrole, the N-acylpyrroles 236 and 237 can be generated in high enantiomeric excess (Equations 58 and 59) <2002JA10006>. With pyrrole itself as the nucleophile, the new stereocenter is produced in moderate ee (42%). It was discovered that 1-acyl-1H-pyrrole-2-carbonitriles 236 can be converted into a wide array of useful compounds with essentially no erosion in enantiomeric excess.
ð58Þ
ð59Þ
3.02.2.2.6
N-Nitrosation
While nitroxyl (HNO) has been shown to engage in oxidation and hydroxylation reactions, little is known about its nitrosation potential. Very recently it was shown that in buffered aqueous solution (at physiological pH) under aerobic conditions (in the presence of oxygen) the major (the primary) reaction products of the classical nitroxyl donor Angeli’s salt (AS, Na2N2O3) with three representative tryptophan derivatives (melatonin 238, indole-3-acetic acid, and N-acetyl-L-tryptophan) are the corresponding N-nitrosoindoles with negligible formation of oxidation and nitration products <2006CRT58>. A direct comparison of the effects of AS, nitrite, peroxynitrite, aqueous NO? solution, and the NO-donor DEA–NO (2-(N,N-diethylamino)diazen-1-ium-1,2-diolate diethylammonium salt) toward melatonin revealed that nitrite does not participate in the reaction and that peroxynitrile is not an intermediate. Rather, N-nitrosoindole 240 formation appears to proceed via a mechanism that involves electrophilic attack of HNO on the indole nitrogen, followed by a reaction of the intermediate hydroxylamine derivative 239 with oxygen (Scheme 49). Further in vivo experiments demonstrated that AS exhibits a unique nitrosation signature which differs from that of DEA–NO inasmuch as substantial amounts of a mercury-resistant nitroso species are generated in the heart, whereas S-nitrosothiols are the major reaction products in plasma. These data are consistent with the notion that the generation of nitroxyl in vivo gives rise to formation of nitrosative post-translational protein modifications in the form of either S- or N-nitroso products, depending on the redox environment. N-Nitrosation (in sodium nitrite solution in HCl) of copolymers from pyrrole and 2-ethylaniline, easily prepared by oxidative copolymerization, has been done for the improvement of their solubility (Equation 60) <2004PLM385>.
83
84
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 49
ð60Þ
Reduction of pyrrole 241 with zinc dust and ammonium chloride in aqueous ethanol from 0 C to room temperature gave a mixture consisting of pyrrolo[1,2-b]cinnolin-10(5H)-one 242 (45%) and [2-(hydroxyamino)phenyl](1H-pyrrol-2yl)methanone 243 (29%) (Scheme 50) <2000T9675>. Refluxing pyrrole 241 in aqueous ethanol containing zinc dust and NaOH gave cinnoline 242 in 68% yield. A plausible mechanism for the reductive cyclization of compound 241 into cinnoline 242 is via deoxygenation and deprotonation to nitroso intermediate 244, intramolecular cyclization to N-oxide 245, protonation to N-hydroxy compound 246 and reduction to cinnoline 242. The formation of hydroxylamine 243 together with cinnoline 242 is probably due to the relatively weak basic conditions of the redox reaction with ammonium chloride. The concentration of ammonia released may be insufficient to produce stoichiometrically deprotonated intermediate 244, so that further reduction of protonated intermediate 244 leads to hydroxylamine 243.
Scheme 50
Pyrroles and their Benzo Derivatives: Reactivity
3.02.2.2.7
N-Miscellaneous reactions
Iridium pyrrolyl complex 247, derived from sodium pyrrolide and Ir(CO)Cl(PPh3)2 248 (see also Section 3.02.2.2.1), reacts with a variety of Si-, Sn-, B-containing substrates ultimately to produce N-substituted pyrroles 249–252 (Scheme 51) <1998OM1134>.
Scheme 51
In the reaction of lithium pyrrolide <1996JOM(514)281> and dialkyl(fluoro)silylamines 253 (R ¼ Pri or But) the dialkyl(1H-pyrrol-1-yl)silylamines 254 are formed (Scheme 52) <1996JOM(524)203>.
Scheme 52
Another member of this class of substances can be synthesized via the reaction of lithium pyrrolide and N,Nbis[fluoro(diisopropyl)silyl]amine. The monosubstitution product 255 is formed (Equation 61).
ð61Þ
In the reaction of 1H-indol-1-ylsilylamine 256 and lithium amide the latter acts as the lithiation reagent for the more basic nitrogen atom of the heteroaromatic system. The products are 1-lithium indolide and amine 253 (R ¼ But). For this reason a reverse synthetic strategy is necessary to obtain compound 256 (Scheme 53) <1996JOM(524)203>. Trichlorosilanes react with lithium indolide under formation of the mono- and bis(1H-indol-1-yl)silanes 257 and 258 (Scheme 54) <1996JOM(514)281>. In the reaction of lithium pyrrolide and silane 257 (R ¼ Ph) the mono- and bis(1H-pyrrol-1-yl)silanes 259 and 260 are obtained (Equation 62).
85
86
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 53
Scheme 54
ð62Þ
2H-Pyrrole/B(C6F5)3 complex 262 has been synthesized by protonation of the Li salt 261 of the [B(1-pyrrolyl)B(C6F5)3] borate (Scheme 55) <2001EJI535>. The reaction of pyrroles and indoles with B(C6F5)3 (in pentane, toluene, Et2O or CH2Cl2) and BCl3 gives quantitative and instantaneous conversion to the 1:1 B–N complexes containing highly acidic sp3-carbons, for example, 2H-pyrrole/B(C6F5)3 262 and 3H-indole/B(C6F5)3 265, that are formed by a new formal N- to C-hydrogen shift (Schemes 55 and 56) <2003JOC5445>. Several other pyrrole/ and indole/borane complexes were synthesized in nearly quantitative yields. BCl3, which has Lewis acidity comparable to that of B(C6F5)3, reacts with indole to give 3H-indole/BCl3 266. The acidity of the sp3 carbons in complexes 262 and 265 is shown by their ability to protonate triethyl amine to give quantitatively salts 263 and 267, respectively <2003JOC5445>. Pyridine removes the borane from the complexes 2H-pyrrole/B(C6F5)3 262 and 3H-indole/B(C6F5)3 265, with formation of free pyrrole or indole, giving the more stable adduct pyridine/B(C6F5)3 264 <2006IC1683>.
Scheme 55
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 56
Reaction between 7-azaindole 268 and B(C6F5)3 quantitatively yields 7-azaindole/7-B(C6F5)3 269, in which B(C6F5)3 coordinates to the pyridine nitrogen of azaindole 268, leaving the pyrrole ring unreacted even in the presence of a second equivalent of B(C6F5)3 (Scheme 57) <2006IC1683>.
Scheme 57
Reaction of 7-azaindole with H2O/B(C6F5)3 initially produces [7-azaindolium]þ[HOB(C6F5)3] 270 which slowly converts to compound 269 releasing a water molecule (Scheme 58).
Scheme 58
The successive substitution of the fluoro atoms of PF3 by lithium indolide leads to the mono-, bis- and tris(indol-1yl)phosphanes 271–273 (Scheme 59) <1996JOM(514)281>. Reactions of dialkyl or diaryl chlorophosphines with pyrroles 274 give 1-(phosphino)-1H-pyrroles 275 (Equation 63) <2001ASC450>.
87
88
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 59
ð63Þ
The addition of indole to bis(trimethylsilyl)amino(trimethylsilylimino)phosphine leads to the mono(indol-1-yl)phosphine 276 (Equation 64) <1996JOM(514)281>.
ð64Þ
3.02.2.3 Electrophilic Attack at Carbon Based on the results of quantum chemical calculations of model NR-pyrroles (R ¼ H, Me, Et, Pri, But, H2CTCH, HCUC, Ph, 4-O2NC6H4, PhSO2) and their a- or b-protonated s-complexes, carried out using ab initio methods (RHF/631G(d), MP2/6-31G(d)//RHF/6-32G(d)), and in the within the framework of density functional theory (B3LYP/6-31G(d)), it has been shown that the predominant a- or b-position is determined by steric factors and charges on the atoms b-C, a-C, N, and on the substituents at the N atom (Scheme 60) <2003ARK59>. It was concluded that it is not determined by
Scheme 60
Pyrroles and their Benzo Derivatives: Reactivity
differences in the relative stabilities of the onium state Nþ depending on the nature of a substituent at the N atom, or reflecting the role of the heteroatom in the stabilization of s-complexes formed by b-substitution.
3.02.2.3.1
C-Protonation
Unlike the thoroughly studied arenium ions, pyrrolium and indolium ions remain relatively neglected, in spite of the fact that protonated pyrroles and indoles are key intermediates of important reactions. These include the synthesis of tetrapyrrolic ‘life pigments’ like chlorophylls, hemoglobin, cytochromes, and vitamin B12, tripyrrolic antibiotics and fungicides of the prodigiosin series as well as the acid-catalyzed oxidative polycondensation of pyrroles producing conducting polypyrroles, popular among the ‘organic metals’. Protonation of N-vinylpyrroles was systematically studied and documented in a review <1998MI30>. Depending on the conditions, N-vinylpyrroles 277 are protonated either at the pyrrole ring a-position 278, or at the vinyl group b-position 279 or simultaneously at both the sites 280 (Scheme 61) <1996MI1, 1998MI30>.
Scheme 61
Comparison (Equation 65) of the 13C chemical shifts of the vinyl group b-carbon in the cations (Cþ b ) and in the initial N-vinylpyrroles 277 (Cb ) confirms the large deshielding of this position in the cations (up to 15 ppm). It is noteworthy that the vinyl group b-carbon in the cations is still considerably more shielded than the carbon atom in ethylene (by ca. 10 ppm), thus unexpectedly indicating that the protonated pyrrole nucleus still behaves as a p-donor towards the N-vinyl group <1996MI1, 1998MI30>.
ð65Þ
At 80 to 0 C, 2-(2-furyl)-1-vinylpyrroles 281 are protonated by acids at the pyrrole 5-position with the vinyl group remaining intact, whereas with hydrogen halides at 30 C, the (unexpected) formation of furanium ions, along with pyrrolinium ions occurs (Scheme 62) <1998MI30>. Simultaneously, addition of hydrogen halides to the vinyl group takes place. The ratio of the pyrrolinium 282 and furanium 283 ions is within 1:1 to 2:1 depending on the substitution and the halide. In the case of 3-substituted pyrroles and hydrogen bromide, protonation of the pyrrole nucleus is favored. When the a-position of the furan nucleus is occupied by a methyl group, hydrogen halides add only to the vinyl group <1998MI30>. This successful competition between the pyrrole and furan nuclei for a proton is surprising and unpredictable, since in electrophilic reactions pyrrole is known to be more reactive than furan by several orders of magnitude. Also surprising is the stability of the furanium ions, because only a few representatives of them were reported as short-lived species in gas phase or in superacids at high dilutions <1998MI30>. From the pyrrolinium–furanium ion equilibrium (Scheme 62) one can assume, in agreement with sþ p values (1.7 and 0.86 for 2-pyrrolyl and 2-furyl, respectively), that the pyrrole ring stabilizes the adjacent furanium cation better than vice versa. Thus, the selective pyrrole ring protonation at low temperature (80 C) is most likely a kinetic result leading to the thermodynamically nonequilibrium state with the predominance of pyrrolium ions.
89
90
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 62
At 0 C, with HBr 4-bromo-4,5-dihydro-2-(2-pyrrolyl)furanium bromides 284 are seen in the 1H NMR spectra, resulting from the addition of HBr to the protonated furan moiety (Scheme 63) <1998MI30>. Thus, it is demonstrated that under certain conditions pyrrole compounds can undergo electrophilic addition like nonaromatic unsaturated systems.
Scheme 63
The interaction of 2-furyl-1-vinylpyrrole 285 with superacid (Scheme 64) affords the equilibrium mixture of dications: 2-(2-furyl)-5H-1-(1-ethanium)/pyrrolium 286 and 2-(2-furyl)-3H-1-(1-ethanium)/pyrrolium 287 in the 3:1 ratio. Apart from the dication formation, it is the b-protonation that is a remarkable feature of the reaction <1995ZOR801>.
Scheme 64
b-Protonated pyrroles are currently believed to be kinetic intermediates, precursors of a-protonated species. However, it has been found that some N-vinylpyrroles in superacids afford exclusively b-protonated species (Scheme 65) <1998MI30>. For example, 2-t-butyl-1-vinylpyrrole 288 in the superacid at 70 C gives a stable cation 289 having the proton attached to the position 3 and the double bond intact. It requires several hours at 0 C to rearrange this ion, via a [1,2]-hydride shift, to the a-protonated isomer 290 with an unexpected structure (with a proton at the position where the highly branched substituent is attached).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 65
1,4-Bis(1-vinylpyrrolyl)benzene 291 is protonated by the superacid to the dication of unsymmetrical structure with one a- and another b-protonated pyrrole moieties (Scheme 66) <1998MI30>. The rationalization for this is that after the first normal a-protonation, the system readily delocalizes the positive charge over the three aromatic systems up to the remaining a-position, thus preventing its attack by the next proton. This is why the b-position becomes a more favorable site for the second protonation.
Scheme 66
At 0 C with excess hydrogen bromide, N-vinylpyrroles 292 are transformed to 4-bromo-4,5-dihydro-3H-pyrrolium bromides 294 via the covalent bonding of the Br– anion to the position 4 of the initial cation (thus actually representing a completed electrophilic addition) followed by the subsequent protonation of the intermediate enamine 293 (Scheme 67) <1994BCJ1872, 1998MI30>. In the case of 2-methyl-1-vinylpyrrole, two diastereomers are detected (1H NMR) in a 9:1 ratio, each existing as a racemic mixture due to the chiral centers present in the molecule. From the 1H NMR spectroscopic data, including NOE and decoupling, relative configuration have been assigned to the major isomer R* S* , and to the minor one R* R* <1994BCJ1872, 1996MI1, 1998MI30>.
Scheme 67
Topomerization for the isopropyl methyls in the 1-(1-haloethyl)pyrrolium cations has been discovered and thoroughly investigated using total line shape analysis of their NMR spectra (Scheme 67). The deprotonation of the pyrrolium counterpart was proved to be an independent step preceding the enantiomerization, the latter resulting from dissociation of the 1-(1-haloethyl) substituent (Scheme 68) <1994BCJ1161, 1996MI1, 1998MI30>.
91
92
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 68
MNDO, AM1, and PM3 study (with full geometry optimization, in the gas and aqueous phases) of the protonation tautomerization and valence tautomerization equilibria of some pyrrole macromolecules is described in the work <2002JMT(589)43>.
3.02.2.3.2
C-Nitration and C-nitrosation
Nitration of pyrroles has usually been carried out using a mixture of concentrated nitric acid and acetic anhydride . The key starting material for the synthesis of linear polypyrrole–peptide conjugates (novel sequence-specific DNA binders), 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid, was obtained in ca. 40% yield by nitration of corresponding pyrrole (Equation 66) <1999TL3621, 2002EJO3604> by procedure adapted, after suitable modification, from the literature. These modifications helped in avoiding the use of column chromatography for the isolation of the desired 4-nitro isomer from the 3-nitro and 3,4-dinitro isomers formed during the nitration step.
ð66Þ
Addition of fuming nitric acid (over 30 min at 40 C) to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-1-ethanone in acetic anhydride, followed by stirring for 6 h at room temperature, gives 2,2,2-trichloro-1-(4-nitro-1H-pyrrol-2-yl)-1ethanone in 70% yield <2003OBC3327>. Direct nitration of pyrroles 295 with nitric acid/trifluoroacetic anhydride affords mononitro derivatives 296 in 78–81% yield (Equation 67) <2005ARK179>.
ð67Þ
Nitration of Melatonin derivatives 297 using nitric acid in acetic anhydride led to the formation of the two isomers, the 4-nitro 298 and the 6-nitro 299 (Equation 68) <2002JME1853>, which were separated by column chromatography. Analysis by 1H NMR indicated that the resulting mixtures were composed of 66:33% of isomers 298:299 (R2 ¼ PhSO2) and 50:50% (R2 ¼ BOC). Isolated yields for compounds 298 and 299 were 58% and 30%, respectively (when R2 ¼ PhSO2) or 43% and 45%, respectively (when R2 ¼ BOC). The N-deprotection was then realized in MeOH/THF using basic conditions (K2CO3 (when R ¼ PhSO2) and MeONa (when R ¼ BOC)) and afforded the 4and 6-nitro derivatives of Melatonin.
Pyrroles and their Benzo Derivatives: Reactivity
ð68Þ
Sterically controlled N2O4 nitrations of a meso-2,3-unsubstituted porphyrin or bis-a-unsubstituted pyrroloporphyrin affords coplanar conjugated b-nitroporphyrins displaying strong electronic interactions <2000TL3583>. Nitrations of a series of zinc(II) and nickel(II) complexes of 5,12,13,17,18-pentasubstituted porphyrins with dinitrogen tetroxide is reported <2001T4261>. b-Nitration takes place on porphyrins bearing a meso-electron-withdrawing group. Unhindered b-nitro groups are shown to exert stronger electronic effects relatively to meso-nitro groups by conjugating effectively with the porphyrin macrocycle. Introduction of 12 nitro substituents on Zn(II) and Ni(II) mesotetrakis(2,6-dichlorophenyl)porphyrin (TDCPP) 300 was performed by adapting a recently described method for polynitration of metalloporphyrins (by using a very powerful nitrating system based on red fuming HNO3 and the superacid CF3SO3H in the presence of (CF3SO2)2O) <2000CC1907>, allowing the one-pot synthesis of metallododecanitroporphyrins 301 from commercially available compounds (Scheme 69) <2002JOM(643)522>.
Scheme 69
Reactions of the ubiquitously occurring tetrahydro-b-carbolines (unsubstituted and 3-carboxylic acids) under acidic conditions (pH 3) in the presence of nitrosating agents (1 M aqueous of NaNO2, KNO2, or nitrite pickling salt, EtOH, HCl; in the dark at 37 C up to 1 h) yield N2-nitrosotetrahydro-b-carbolines 302, potential mutagens (Scheme 70) <2001JFA5993 and references therein>. It was found that freshly isolated nitroso precursors spontaneously decomposed (incubation time less than 5 min) to yield harman alkaloids 303 (R1 ¼ Me).
Scheme 70
93
94
Pyrroles and their Benzo Derivatives: Reactivity
3.02.2.3.3
C-Halogenation
Halogenated pyrroles and indoles play a central role as intermediates in the synthesis of important biologically active natural products bearing pyrrole nuclei <1998JA2817, 1999JOC2361, 1999T10871, 1999TL5519, 2000T4491, 2001TL6961, 2001TL9281, 2003TL3927, 2004H(62)191, 2004T11283, 2005JOC4542>, including alkaloids <2002T6373, 2002TL4935, 2003BML4515, 2003T207>, as well as in the construction of a variety of mono-, oligo<1995SM(69)467, 2003T9255> and macrocyclic structures <1997J(P1)1443, 2004T11283>. Hence, new and efficient methods for the elaboration of these species could find sustained utility. Much effort has been directed toward synthesis of fluorine-containing heterocycles, owing to their biological activity <2004MI357>. A 2-fluoro-substituted pyrrole 304 has been synthesized (ca. 40%) by a treatment of the 5-lithiated 1-methyl-2-octyl-1H-pyrrole with N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (Equation 69) <2003JFC(124)159>. At room temperature pyrrole 304 slowly undergoes a dimerization process.
ð69Þ
Direct anodic fluorination of substituted N-methyl pyrroles, for example, 1H-pyrrole-2-carbonitrile 305 using Et3N?nHF (n ¼ 2–5) in an individual cell (platinum plate electrodes, MeCN, under N2, rt) provided four fluorinated products 306–309, of which the distribution is found to depend on the value of n in Et3N?nHF as well as the solvents (Equation 70) <2001MI467, 2001TL4857, 2002S2597>. In no cases was the N-methyl group fluorinated. In the presence of an equimolar amount of water, the yield of trifluorinated product 309 decreased drastically (from 65% to 34%) while that of 2H-pyrrol-2-one 308 increased (from 3% to 7%). In this case, a considerable amount (38%) of N-methylmaleimide was formed. It was found that compound 309 is a precursor to pyrrolone 308. When, after the electrolysis of compound 305 in Et3N?3HF/MeCN, excess water was added to the electrolytic solution and then the reaction mixture was stirred for 4 h, pyrrolone 308 was obtained in 54% yield. The use of Et3N?5HF also provided preferentially pyrrolone 308, which has both a biologically interesting gem-difluoromethylene unit and an activated olefin in the heterocyclic ring. The Diels– Alder reactions of pyrrolone 308 as the dienophile with various (open-chain or cyclic) dienes were successfully carried out to provide gem-difluorinated heterocyclic compounds in excellent yields <2002S2597>. In sharp contrast to the case of cyanide 305, the anodic fluorination of 1H-pyrrole and 1-methylpyrrole gave only a polymerized product and no fluorinated product was formed.
ð70Þ
Reaction of 3-substituted indoles with SelectfluorTM (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 310) as a key electrophilic fluorinating reagent <2004ACR31>, either in MeCN/H2O <2000OL639> or in an ionic liquid/alkanol <2002TL6573>, led to the formation of the 3-fluoro-1,3-dihydro-2H-indol-2-ones 311 in good to excellent yields (Scheme 71). Formation of the nonfluorinated 1,3-dihydro-2H-indol-2-ones 314 as a side products (Scheme 72) has also been observed in all cases <2000OL639>. High yield and better chemoselectivity were claimed when ionic liquids were employed as the reaction media <2002TL6573>. A proposed reaction mechanism for the formation of fluorinated 1,3-dihydro-2H-indol-2-ones is shown in Scheme 72 <2000OL639>. Reaction of 3-substituted indole with Selectfluor 310 gave 3-fluoro-3H-indole 312 as an unstable intermediate that underwent loss of HF due to addition of water. A subsequent [1,5]-prototropic shift gave the indol-2-ol 313. Fluorination of intermediate 313 with additional reagent resulted in indol-2-one 311 as the final product. Formation of nonfluorinated indol-2-one 314 as a minor side product was explained by the tautomerism
Pyrroles and their Benzo Derivatives: Reactivity
of indol-2-ol 313, catalyzed by water (solvent). An alternative pathway for the formation of indol-2-one 311 from indoles can be considered via the formation of 2-fluoroindole 315 and 2,3-difluoro-3H-indole 316 intermediates, especially in nonaqueous media.
Scheme 71
Scheme 72
Using an acetonitrile/2-propanol system led to high-yield transformation of N-alkylated indoles 317 into the fluorinated targets 318 (Equation 71) <2002TL6573>.
ð71Þ
Substantially different results were observed in the presence of thiols (Equation 72) <2002TL6573>. The reaction stopped at intermediate 319 in good yield. This intermediate is not obtained in the absence of Selectfluor. The excess of thiol is oxidized into disulfide 320, thus reducing Selectfluor and preventing the subsequent fluorination of intermediate 319. When using only 2 equiv of thiol, the fluorinated 2H-indol-2-one 311 (R ¼ Me) is obtained (63%).
95
96
Pyrroles and their Benzo Derivatives: Reactivity
ð72Þ
The synthesis of Fluorogypsetin 322 (Equation 73) and Fluorobrevianamide E 324 (Equation 74) by a novel fluorination cyclization of cyclo-L-Trp-L-Aas 321 and 323 with Selectfluor have been recently described <2001AGE4461>.
ð73Þ
ð74Þ
A kinetic and product study of the dichloroacetic acid (DCA) catalyzed chlorination of 1-methylpyrrole with a series of 3- and 4-substituted N-chlorobenzamides 325 under nitrogen, at 40 C was carried out (Scheme 73) <2003T2125>. Chlorination at C-2 of the pyrrole ring leads to the formation of 2-chloro-1-methylpyrrole 326 and subsequently 2,5-dichloro-1-methylpyrrole 327. The total yield of attack at C-2 is therefore the sum of the yields of pyrroles 326 and 327. The yields of 2-chlorination (ca. 84%) and 3-chlorination (ca. 2.6%) were essentially constant as
Scheme 73
Pyrroles and their Benzo Derivatives: Reactivity
the substituent on the reagent 325 was varied. No rearrangement into 3-chloro-1-methylpyrrole 328 and/or decomposition were/was observed when a mixture of 2-chloro-1-methylpyrrole 326 and DCA in CHCl3 was kept at 50 C for 2 h under a nitrogen atmosphere. Clearly the yields of chloropyrroles obtained are kinetically determined. Chlorination of 2-(pyrrol-1-yl)pyrrole 330 with sulfuryl dichloride gave the natural 2,3,4-trichloro-1-methyl-5(perchloropyrrol-1-yl)pyrrole (Q1) 331 in 16% yield (Scheme 74) <2002AGE1740>. Treatment of 1-(pyrrol-2-yl)dihydropyrrole-2,5-dione 329 with PCl5 at 55 C gave 1-(1-methyl-3,4,5-trichloropyrrol-2-yl)dihydropyrrole-2,5-dione 332. Treatment of compound 329 with a mixture of phosphorus pentachloride and phosphorus oxochloride at 100 C provided Q1 in a yield of 7%.
Scheme 74
Two of the four halogenated bipyrroles recently discovered in seabird eggs and eagle liver samples have been identified by synthesis as 1,19-dimethyl-3,39,4,49,5,59-hexabromo-2,29-bipyrrole 334 and 5,59-dichloro-1,19-dimethyl3,39,4,49-tetrabromo-2,29-bipyrrole 335 (Scheme 75) <1999CC2195>. 1,19-Dimethyl-2,29-bipyrrole 333, which is readily available from 1-methylpyrrole, was treated with excess N-bromosuccinimide (NBS) to give compound 334 in 79% yield. Regioselective halogen–lithium exchange to give the presumed more stable 5,59-dilithio intermediate followed by chlorination with 2 equiv of hexachloroethane gave compound 335 in 80% yield. Compound 335 was also prepared by treatment of bipyrrole 333 with N-chlorosuccinimide (NCS) to give dichloro derivative 336 (97% yield); reaction of this with excess of NBS afforded compound 335 in 76% yield.
Scheme 75
97
98
Pyrroles and their Benzo Derivatives: Reactivity
Hexachloro analog 337 has also been synthesized by treating compound 333 with excess NCS (Equation 75). The use of sulfuryl dichloride in chlorination of compound 333 to give chloro compounds 336 or 337 was less successful.
ð75Þ
4-Bromopyrrole 339, as a precursor of the compound 340, was easily prepared by bromination of pyrrole 338 with Br2 in chloroform (Scheme 76) <1997J(P1)1443>.
Scheme 76
Selective 3-bromination of indoles and 4-chloro-2-methyl-7-phenyl-7H-pyrrolo[2,3-d]pyrimidines with bromine in DMF <2003TL3927> or in dioxane <2004H(62)191> is the first step in the synthesis of a new family of isogranulatimide analogs and pharmaceutically important tricyclic pyrrolopyrimidines. 3-Brominated indoles 343 were conveniently prepared in a single operation by adding the halogen source (NBS can also be used in place of Br2) to the reaction mixture after the conversion of aniline 341 to indole 342 had been observed by GC analysis (Scheme 77) <2004S0610>.
Scheme 77
The tin amide, formed in situ by treating an N–H substrate with n-butyllithium, followed by addition of trimethyltin chloride, for one-pot bromination showed great selectivity for the reaction of indole and carbazole (Equations 76 and 77) <2002OL2321>. In both cases, the bromination gave a single product in good yield, 80% and 69% for indole and carbazole derivatives, respectively.
ð76Þ
Pyrroles and their Benzo Derivatives: Reactivity
ð77Þ
Regiospecific bromination of 3-methylindoles with NBS was applied to the concise synthesis of optically active unusual tryptophans present in marine cyclic peptides <1995TL3103, 1995TL7411, 1995TL9133, 1997JOC7447>. In the electrophilic bromination process, N-protected 3-methylindoles 344 were simply heated with NBS in refluxing CCl4 in the absence of the radical initiator AIBN to provide exclusively 2-brominated indoles 345 in high yield (Scheme 78) <1995TL3103>. In the radical bromination process, the indoles 344 were heated in refluxing CCl4 and then treated with NBS and AIBN to afford bromide 346. The bifunctional dibromide 347 provided by this process served as the key intermediate for the synthesis of 2-bromotryptophan, an amino acid which could be used in the preparation of Jaspamide, a marine cyclodepsipeptide, that has exhibited antifungal, antihelminthic, insecticidal, and ichthyotoxic activity.
Scheme 78
The 5-substituted indolylmalonates 348, carrying an electron-withdrawing group at the 1-position, prepared from the corresponding methyl 3-indolyl acetates by Claisen condensation with dimethylcarbonate in the presence of NaH in good yields (70–88%), react with 2 equiv of bromine in either carbon tetrachloride or acetic acid at room temperature. The malonates undergo oxidation in competition with the well-known aromatic bromination affording mixtures of variable composition of bromoindolylmalonates 349 (ring bromination product), indolylidenemalonates 350 (oxidation product), and bromoindolylidenemalonates 351 (ring bromination and oxidation product) (Scheme 79) <2003JOC305>. Depending on the 5-substituent, either aromatic bromination becomes prominent or the oxidation occurs to give 2-hydroxy-3-indolylidenemalonates predominantly. Thus, with parent indolylmalonate 348 (R ¼ H) (2 equiv of Br2, CCl4, rt, 2 h), chemospecific oxidation was observed (80% yield of compound 350 (R ¼ H, R2 ¼ H, OH)), whereas with 5-hydroxyindolylmalonate 348 (R ¼ OH), bromination at the 4- and 6-position is the dominating reaction (i, 1 equiv of Br2, CCl4, rt, 2 h, yield of products 349 (R1 ¼ 4-Br-5-OH, R2 ¼ H and R1 ¼ 4,6-Br2-5-OH, R2 ¼ H) 58% and 6%, respectively; ii, 2 equiv of Br2, CCl4, rt, 5 h, yield of products 349 (R1 ¼ 4-Br-5-OH, R2 ¼ H and R1 ¼ 4,6Br2-5-OH, R2 ¼ H) 13% and 49%, respectively). Treatment of indole 348 (R ¼ MeO) with 2 equiv of Br2 in AcOH for 5 h afforded compound 349 (R1 ¼ 4-Br-5-MeO, R2 ¼ H) and the regioisomer 351 (R1 ¼ 5-MeO-6-Br) in 70% and 25% yield, respectively. Investigation of the composition of products of several 5-substituted indolylmalonates 348 revealed the following trend: with a 5-substituted electron-withdrawing group, such as fluorine, malonate 348 undergoes oxidation rather than bromination. In contrast, with a 5-substituted electron-donating group, such as a hydroxyl group, the ring bromination occurs preferentially over the oxidation. When the 5-substituent is an alkoxy group, a significant amount of brominated-oxidized products is obtained.
99
100
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 79
2,5-Dibromopyrrole 352 and 3,4-dibromopyrrole 353, obtained by bromination of N-BOC pyrrole with NBS/THF and of N-BOC pyrrole-2,5-dicarboxylate with aqueous bromine, respectively, were used as a starting and intermediary products in a streamlined synthesis of the particularly promising storniamide core (Scheme 80) <2002T6373>.
Scheme 80
Treatment of the indoles 354 and 356 with potassium hydroxide and a solution of iodine in ethanol leads to 3-iododerivatives 355 and 357 (Equations 78 and 79) <2004S0610>. The alternative protocols require sophisticated iodonium source (Ipy2BF4?HBF4) at temperatures between 20 and 60 C or N-protecting groups and the use of excess of iodine (3 equiv), which could prove a disadvantage in relatively large-scale preparations in terms of work-up and by-product disposal <2003AGE2406, 2004TL539>.
ð78Þ
ð79Þ
Direct iodination of pyrrole 358 with NaI and I2 (H2O, reflux, 3 h) gave the 5-iodopyrrole 359 in excellent yield (Scheme 81) <2004T11283>. This compound was involved in the synthesis of a new terpyrrolic analog of DPQ (dipyrrolylquinoxaline) 360.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 81
4-Iodo-1H-pyrrole-2-carbaldehyde, used in the synthesis of nucleoside derivatives, was prepared via protection of the aldehyde group in 1H-pyrrole-2-carbaldehyde with an iminium salt for the efficient meta-directed electrophilic substitution of the starting pyrrole followed by a treatment of the iminium salt with N-iodosuccinimide in acetonitrile then with sodium bicarbonate (57%: two-step total yield) <2003BML4515>.
3.02.2.3.4
C-Acylation and C-sulfonylation
The synthesis of C-acylpyrroles and indoles has been the subject of considerable interest because they display a broad spectrum of biological and other useful properties <2003P699> and are used as synthetic intermediates in alkaloid synthesis <2003JNP885>. Pyrrole and its N-derivatives 363 react smoothly with acid chlorides in the presence of metallic zinc powder as promoter in toluene under very mild and neutral conditions (at room temperature for 1–3 h) to afford the corresponding 2-acetyl pyrrole derivatives 362 and 364 in high yields (75–90%) with high regioselectivity (Equations 80 and 81) <2002TL8133>. No N-acylated products were obtained under these reaction conditions. Thus, treatment of pyrrole with the acid chloride derivative of cyhalothrin 361 and zinc metal in toluene resulted in the formation of the corresponding 2-acyl pyrrole 362 in 87% yield (Equations 80).
ð80Þ
ð81Þ
Similarly, pyrroles 363 reacted smoothly with a range of alkyl- and aryl-substituted acid chlorides to afford the corresponding 2-acyl pyrrole derivatives 364 (Equation 81). Simple indolic modifications of the BOM-protected pyrrolo[3,2-e]indole 365, the cornerstone of natural product anticancer drugs such as CC-1035, proceeded as the literature would suggest. Namely, Vilsmeier–Haack conditions (POCl3 in DMF followed by basic hydrolysis of the resulting iminium intermediate) afforded the dicarboxaldehyde 366 in 68% yield (Scheme 82) <1997TL1673>. Treatment of the N-magnesium bromide salt of indole 365 with ethyl oxalyl chloride afforded only an 18% yield of the desired indole oxalate 367, with significant decomposition of starting material. N-Tosylpyrrole was acylated by 2-nitrobenzoyl chloride in 1,2-dichloroethane using either tetrachlorostannane or trichloroaluminium as catalyst <2000T9675>; 2- and 3-acylated products 368 and 369 were isolated by column chromatography in the yields shown (Equation 82).
101
102
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 82
ð82Þ
A Friedel–Crafts-type reaction of unsubstituted indole with different acylating agents such as acid chlorides, anhydrides, nitriles, and amino acid derivatives in the presence of Lewis acid (AlCl3, TiCl4, SnCl4) gives 3-acylindoles 370 regioselectively and in high yields without laborious work-up (Equation 83) <2001OL1005>. The order of addition is crucial for the synthesis of 3-acylindoles under acidic conditions. Lewis acid was added to a solution of indole in dichloromethane at 0 C giving a colored precipitate. The subsequent addition of the acylating agent to this suspension, followed by nitromethane as cosolvent, produced only 3-acylindoles, without the undesirable presence of indole oligomers or the other products previously observed, N-acyl and 1,3-diacylindoles. Without MeNO2 the acylation process was slow (24–48 h) and the starting material was always recovered.
ð83Þ
Indoles 371 are selectively acylated at the 3-position to give high yields of compounds 372 on treatment with a wide variety of acyl chlorides in dichloromethane in the presence of chloro(diethyl)aluminium or chloro(dimethyl)aluminium. The reaction proceeds under mild conditions (at 0 C or rt, mainly for 1.5–4 h) and is applicable to indoles bearing various functional groups (both acid and base sensitive indoles) without NH protection (Equation 84) <2000OL1485>.
Pyrroles and their Benzo Derivatives: Reactivity
ð84Þ
General conditions for attachment of acetyl chloride, benzoyl chloride, and chloromethyloxalate to the 3-position of 4-, 5-, 6-, or 7-azaindoles 373 leading to 3-acylated azaindoles 374, possessing a range of biological activities including the potential for the treatment of inflammation, asthma, anxiety, depression, sleeping disorders, Alzheimer’s disease, migraine, and pain <1991USP5023265, 1995WO199504472, 1996WO199611929>, were found. Best results were achieved with an excess of AlCl3 in CH2Cl2 followed by the addition of an acyl chloride at room temperature (Equation 85) <2002JOC6226>.
ð85Þ
The Vilsmeier formylation has been used for the solid-phase functionalization of five different 2-carboxyindoles 375 (Equation 86) <2001JCO542>. In all experiments the formylating agent was prepared in a separate vessel and resins 375 were added to the mixture after 20 min in 1,2-dichloroethane. The reaction time and the equivalents of formylating agent were kept constant in each attempt (16 h and 10 equiv, respectively). The aldehyde functionality has been utilized in the preparation of O-benzylhydroxyureas.
ð86Þ
The vapor-phase acylation of pyrrole was carried out over zeolite catalysts such as HZSM-5(19.7), HZSM-5(30), HZSM-5(280), HY, and cation-promoted modified zeolites like CeHZSM-5(30), LaHZSM-5(30), and CeHY, in a fixed-bed reactor at atmospheric pressure using acetic anhydride as an acylating agent <1998CAL95>. The catalytic activity of the zeolite catalysts was dependent on the reaction temperature and the type of cation polymer used in the modification of the zeolite surface. The acylation was found to be more active on Brønsted acidic sites available over zeolite systems. The yield of 1-(1H-pyrrol-2-yl)-1-ethanone 376 with respect to the conversion of pyrrole on HZSM-5(280) at 250 C was 75.5% (Equation 87).
ð87Þ
103
104
Pyrroles and their Benzo Derivatives: Reactivity
N-(Phenylsulfonyl)pyrrole was acylated under the usual conditions to give ketone 377 (Equation 88) <1995TL6185>.
ð88Þ
Heating of 1-vinyl-4,5,6,7-tetrahydro-5-methyl-4,6-ethanopyrrolo[3,2-c]pyridine 378 in anhydrous toluene in the presence of freshly distilled acetic or trifluoroacetic anhydride (TFAA) (70 C, 2 h) resulted in bicyclic saturated fragment cleavage (at the N–C(4) bond), affording cyclohepteno[b]pyrroles 379 in low yields (12–16%), which existed as mixtures of two isomers (52:48 and 60:40, respectively) due to the amide fragment steric hindrance (Scheme 83) <2000ARK147>. In the case of TFAA, the major product of the reaction, 2-trifluoroacetylsubstituted tetrahydropyrrolo[3,2-c]pyridine 380, was isolated in 34% yield. The reaction seems to proceed through the intermediacy of quaternary salt A, which then predictably is cleaved by the acyloxy anion.
Scheme 83
5-R-11,12-Dihydrobenzo[5,6]cyclohepta[1,2-b]indol-6(5H)-ones 382 were obtained by intramolecular cyclization of 2-[2-(1-R-1H-indol-3-yl)ethyl]benzenecarboxylic acids 381, using a large excess of polyphosphoric acid (PPA) and phosphorus pentoxide (80–96% yield) (Scheme 84) <1999T4341>. No cyclization on 4-position of the indole ring was observed. Hydrolysis of the phenylsulfonyl group of compound 381 (R ¼ PhSO2) occurred during the cyclization to give the unprotected ketone 382 (R ¼ H). 5-Phenylsulfonyl indol-6(5H)-one 382 was prepared in 61% yield through a lithiation in the 2-position of compound 381 (R ¼ PhSO2) with LDA in THF at 78 C followed by a nucleophilic addition of the intermediate anion to the carboxylic group. Oxidation of tetracycle 382 by DDQ in refluxing dioxane (12 h) leads to the unsaturated ketones 383. It was found that TFAA is an excellent reagent for achieving the direct acylation of N-sulfonylpyrroles 384 by carboxylic acids leading to 2-acylpyrroles 385 in good yield (Equation 89) <2004TL9573>. A few or none of the isomeric 3-acyl derivatives are formed. Only in the example involving acetylation of 2-(4-methoxyphenyl)-N-tosylpyrrole was an isolable amount (11%) of a 2-trifluoroacetyc derivative formed.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 84
ð89Þ
Substituted sulfonamide 386 (prepared from 2-methoxycarbonylbenzenesulfonyl chloride and the sodium salt of pyrrole followed by ester saponification) under relatively vigorous conditions was smoothly converted into the 56pyrrolo[1,2-b][1,2]benzothiazine-5,5,10-trione 387, in 78% isolated yield (Equation 90) <2004TL9573>.
ð90Þ
When 2-methyl-N-tosylpyrrole was exposed to glutaric acid (0.5 equiv) the 3,4-dihydro-2H-pyran-2-one 388 was obtained (Scheme 85) <2004TL9573>. Further oxidation then gave a moderate but unoptimized return of the 2H-pyran-2-one 389.
Scheme 85
In reactions between N-tosylpyrrole and crotonic or cinnamic acid in the presence of TFAA only 2-acylation products 390 were isolated, along with traces of the Michael adduct 391 in the case of later acid; no Nazarov cyclization with crotonic and cinnamic acid was observed (Equation 91) <2006OL163>. With 3,3-dimethylacrylic acid direct 2-acylation and annulation of N-tosylpyrrole occurs to give compounds 392 and 393, respectively (Equation 92).
105
106
Pyrroles and their Benzo Derivatives: Reactivity
ð91Þ
ð92Þ
Reactions between N-tosylpyrroles 394 and a-substituted unsaturated carboxylic acids in the presence of TFAA result in smooth 2-acylation of the pyrrole, followed by Nazarov cyclization to give 50–80% yields of 4,5-dihydrocyclopenta[b]pyrrol-6(1H)-ones 395 (Equation 93) <2006OL163>. The presence of an a-substituent in the unsaturated acid appears to be mandatory.
ð93Þ
Alkyl isocyanides undergo a smooth reaction with isopropylidene Meldrum’s acid 396 in the presence of pyrrole or indole to produce 1-alkyl-3,3-dimethyl-4-(1H-pyrrole-2-carbonyl)-pyrrolidine-2,5-diones 400 (Scheme 86) or 1-alkyl4-(1H-indole-3-carbonyl)-3,3-dimethyl-pyrrolidine-2,5-diones 401 (Equation 94) in good yields <2004S0989>.
Scheme 86
Pyrroles and their Benzo Derivatives: Reactivity
ð94Þ
The reaction starts from [4þ1] cycloaddition of the isocyanide to the electron-deficient heterodiene moiety of acid 396 to form intermediate iminolactone 397 that loses acetone to give acyl ketene 398 which then reacts with pyrrole at the ketene carbonyl to form the second acyl ketene 399 (Scheme 86). Ring closure of this ketene leads to the final product 400. Similar reaction conditions as described above, were employed for indole and 2-methylindole (Equation 94). Thermal decomposition of phenyliodonium ylide of 2-hydroxy-1,4-naphthoquinone (lawsone) 403 in the presence of indole derivatives 402 (CH2Cl2, reflux, 4–7 h) affords 3-acylated indoles existing in their enol forms 404, through a ring contraction and a,a9-dioxoketene formation reaction (Scheme 87) <2005JOC8780>.
Scheme 87
The same reactants afford 3-(3-indolyl)-2-hydroxy-1,4-naphthoquinones 405 in a copper-catalyzed reaction (CH2Cl2, Cu(CF3SO3)2, rt, overnight). In case the more electron-rich position 3 in the indole ring is substituted, as in 3-methylindole, the reaction takes place from position 2, but the yield of the corresponding derivative is very low (7%) (Equation 95). The thermal reaction of reagent 403 with 1-methylpyrrole afforded the expected acylation product 407 in high yield (Equation 96) <2005JOC8780>.
ð95Þ
107
108
Pyrroles and their Benzo Derivatives: Reactivity
ð96Þ
Mild thermal rearrangement of the carbonyl azides 408 in 1-methylpyrrole gave 1-methyl-N-(2-thiophene)-, 1-methyl-N-(2-selenophene)- and 1-methyl-N-(2-furano)-1H-pyrrole-2-carboxamides 409 in good yields, presumably involving the intermediacy of the corresponding isocyanate (Equation 97) <2000ARK58>. In this case, the successful outcome of such thermal reactions is ascribable to the pronounced acidic property of the pyrrole 2-proton.
ð97Þ
Reactions of pyrroles 410 with N-acylbenzotriazoles 411 in the presence of TiCl4 produced 2-acylpyrroles 412 in good to excellent yields (Equation 98) <2003JOC5720>. Similarly, indole and 1-methylindole gave the corresponding 3-acylated derivatives in 15–92% yields.
ð98Þ
1-Triisopropylsilylpyrrole under the same conditions gave the respective 3-acylpyrroles 413 (Scheme 88) <2003JOC5720>.
Scheme 88
PPA/phosphorus pentoxide (P2O5) cyclization of indole 414 provides azepino[3,4-b]indole-1,5-dione 415 in 86% yield as a precursor for azepino[3,4-b]indol-5-yl trifluoromethanesulfonate, the key intermediate in design of 5-substituted azepino[3,4-b]indol-1-ones (Equation 99) <2000T4491>.
ð99Þ
Pyrroles and their Benzo Derivatives: Reactivity
Activation of the amide with Tf2O in the presence of DMAP and intramolecular cyclization of the indole tethered amide 416 into cyclopenta[b]indol-1(2H)-one 417 requires heating at 40 C during several hours (Equation 100) <2006JOC704>. The activation of amide 416 with POCl3 was less efficient than the activation with Tf2O. Vilsmeier–Haack acylation with dimethylacetamide and POCl3 applied to 1,2,5,6,7,7a-hexahydropyrrolo[2,1,5-cd]indolizine gives two regioisomers as an inseparable mixture in 53–80% yield <2001JOC2522>.
ð100Þ
Pyrrol-1-yl and indol-3-yl aryl sulfones have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors acting at the nonnucleoside binding site of this enzyme <1996JME522 and references therein>. Compounds L-737,126 and PAS (Figure 3) exhibited the highest activity within the series <2000JME1886>. Preparation of the above sulfones was achieved by condensation of arylsulfonyl chlorides with the appropriate substituted pyrroles and indoles or by condensation of sulfonamides with 2,5-dimethoxytetrahydrofuran in glacial acetic acid according to the Clausson–Kaas method <1996JME522, 2000JME1886>.
Figure 3
A variety of indoles 418 react smoothly with sulfonyl chlorides in the presence of a catalytic amount of indium tribromide in 1,2-dichloroethane at reflux temperature to afford the corresponding 3-arylsulfonyl indole derivatives 419 in high yields (65–95%) with high regioselectivity (Equation 101) <2003TL6055>. No N-substituted products were observed under these reaction conditions.
ð101Þ
Sulfonation of pyrrole and its 1-methyl derivative with a sulfur trioxide–pyridine complex was found (by chemical and NMR experiments) to give 3-sulfonated pyrroles 420 (Scheme 89) <2000TL6605>, but not 2-sulfonates as described
Scheme 89
109
110
Pyrroles and their Benzo Derivatives: Reactivity
in textbooks and earlier publications <1995CB575>. The structures of pyrrolesulfonyl chloride (obtained from sodium pyrrolesulfonate and phosphorus pentachloride) and pyrrolesulfonamide (derived from pyrrolesulfonyl chloride and an amine) were also identified (by NOESY) as 3-substituted compounds 421 (R ¼ H) and 422 (R ¼ H), respectively. The reaction of 1-methyl-2-tri-n-butylstannylpyrrole 424 with trimethylsilyl chlorosulfonate, followed by quenching with aqueous NaHCO3 also generated sodium 1-methylpyrrole 3-sulfonate 423 (Scheme 90) <2000TL6605>, not the 2-sulfonate <1995CB575>.
Scheme 90
Compound 425, prepared from pyrrole according to a similar method described in the literature <1975MI43>, was hydrolyzed to give the corresponding acid 426, which was cyclized by treatment with PPA at 80 C (Equation 102) <2000TL6605>. These sequential reactions produced two products. X-ray crystal analysis has shown that the major one is 2-methyl-3,4-dihydro-2H-pyrrolo[2,3-f ][1,2]thiazepin-5(6H)-one 1,1-dioxide 427, and the minor one is 2-methyl-3,4-dihydro-2H-pyrrolo[3,4-f ][1,2]thiazepin-5(7H)-one 1,1-dioxide 428. No amount of the 2-sulfonyl derivative 429 was detected.
ð102Þ
These results suggest that the starting material did not give sodium pyrrole-2-sulfonate, but 3-sulfonate 420 (Scheme 89), or that rearrangement occurred in the formation of sulfonyl chloride from pyrrole-2-sulfonate to afford pyrrole-3-sulfonyl chloride 421 or in a cyclization step of 2-substituted acid 426.
3.02.2.3.5
C-Alkylation
C-Alkylated derivatives of pyrroles and indoles have high chemical utility also as important intermediates for the synthesis of alkaloids and pharmaceutically useful compounds <1998HCA317, 1999EJO1395, 2000T8579, 2004T1505>. In the literature, there are many reports concerning the alkylation of pyrrole derivatives, such as: Wolff–Kishner reduction of formyl or acetyl pyrroles <2000OL1749>, direct alkylation of pyrroles in the presence of Lewis acids <2001AGE160, 2001TL8063, 2002TL1565, 2005OL5215>, and organocatalytic alkylation <2001JA4370, 2002JA1172, 2005JA4154, 2005JA8942>. An exceptional result in the formation of ring-contracted product was observed in the reaction of azepinium ion with pyrrole <2005OL5215>. When an excess of pyrrole was added to the chloroform solution of compound 430 and iron trichloride at room temperature (24 h), 5-t-butyl-2-methoxy-3-(1H-pyrrol-2-yl)-3H-azepine 432 (12%), 5-t-butyl2-methoxy-7-(1H-pyrrol-2-yl)-3H-azepine 433 (11%), and 2-vinylpyrrole 434 (37%) were obtained (Scheme 91). It is assumed that compounds 433 and 434 were obtained by the isomerizations of compound 431 that, unfortunately, could not be isolated even by reaction at 0 C.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 91
Michael reactions promoted by Lewis acids have attracted much attention as one of the important carbon–carbon bondforming reactions in organic synthesis. Several addition reactions of indoles to enones using Lewis and Brønsted acids have been published <1996SL1047, 1998CJC1256>. Acid-catalyzed reactions of pyrroles and indoles are limited and require careful (precise) control of the acidity to prevent side reactions, including dimerization and polymerization . In recent years, indium halides have emerged as mild and water-tolerant Lewis acids imparting high regio- and chemoselectivity in various organic transformations. It has been demonstrated that InBr3 mediates the conjugate addition of indoles to enones <2001S2165, 2002JOC3700>. However, with less electron-rich indoles, the yield of the products was not satisfactory. In this case, indium trichloride was proved to be very effective. Pyrroles undergo conjugated addition with electron-deficient olefins in the presence of a catalytic amount of InCl3 in dichloromethane at ambient temperature to afford the corresponding Michael adducts 435 and 436 in excellent yields with high selectivity (without the formation of any side products that are normally observed under the influence of strong acids <2001S2165>) (Scheme 92) <2001TL8063>. The procedure does not require any acidic promoters or activators or anhydrous conditions. In general, a,b-unsaturated ketones, b-nitrostyrenes and benzylidene malononitrile worked well under the influence of InCl3 at ambient temperature. Among various Lewis acids, such as YbCl3, YCl3, CeCl3?7H2O, and TaCl5 used for this transformation, InCl3 was found to be the most effective in terms of yield and reaction time. The catalyst was recovered from the aqueous layer during work-up and recycled in subsequent reactions without loss of activity.
Scheme 92
A new versatile multistep synthetic strategy to 4-functionalyzed 1,3,4,9-tetrahydro-b-carbolines 437 and 438 (Scheme 93) and 1,3,4,9-tetrahydropyrano[3,4-b]indoles 439 which are important for pharmacology (Equation 103)
111
112
Pyrroles and their Benzo Derivatives: Reactivity
starting from indole-2-carboxylic acid involves a final intramolecular Michael addition promoted by a catalytic amount of InBr3 (5–10 mol%) in either anhydrous organic or aqueous media <2003JOC7126>. The expected polycyclic compounds were obtained in excellent yields (up to 97%).
Scheme 93
ð103Þ
Starting from 1-methyl-1H-pyrrole-2-carboxylic acid, the tricyclic fused quinolin-4-one and naphthyridin-4-one derivatives 441 were prepared, in only three steps, by an intramolecular Heck cyclization of derivative 440 (Scheme 94) <2005EJO2091>. This reaction was performed in DMA as solvent, with potassium acetate as base and Pd(PPh3)4 as catalyst. The use of microwave irradiation, in some cases, gives better yields of cyclized products.
Scheme 94
The highly efficient Michael addition of acid sensitive substrates such as pyrrole and indoles to structurally diverse electron-deficient olefins in aqueous media at room temperature using aluminium dodecyl sulfate trihydrate, [Al(DS)3]?3H2O, as a new Lewis acid surfactant catalyst affords 2-substituted pyrroles 442–445 (Scheme 95) and
Pyrroles and their Benzo Derivatives: Reactivity
3-substituted indoles 446 in high isolated yields (Equation 104) <2005CC789>. The catalytic activity of [Al(DS)3]?3H2O for Michael addition reaction of indole with methyl vinyl ketone has been given in comparison with InCl3 <2001S2165>, Sc(DS)3 <2001ASC174> and CeCl3?7H2O/NaI <2003JOC4594> catalysts used for the similar reaction in aqueous media.
Scheme 95
ð104Þ
In a continuation of the work on developing greener and cleaner technologies, the cerium(III) chloride heptahydrate and sodium iodide combination supported on silica gel catalyzes the alkylation of various indoles 447 with a,b-unsaturated ketones giving 3-(3-oxoalkyl)indole derivatives 448 in good yields (Equation 105) <2003JOC4594>. The substitution on the indole nucleus occurred exclusively at the 3-position, and N-alkylation products have not been observed. In accordance with this finding, 3-methylindole gave only 9% of 1,4-adduct after the mixture was mechanically stirred at an external temperature of 50 C for 4 d, together with other uncharacterized products.
ð105Þ
Very simple and efficient Michael reaction of indoles 449 with cyclic and acyclic unsaturated ketones has been accomplished in the presence of only 1 mol% of iodine as catalyst at room temperature under solvent-free conditions (Equation 106) <2005TL2479>.
ð106Þ
113
114
Pyrroles and their Benzo Derivatives: Reactivity
The crude material in most of the cases is sufficiently pure (80–90%) for further use. Unlike the processes described in earlier reports, this method is totally independent of solvent choice <2002OL1319> or external proton source <2002JOC3700>. Even reagents that are undistilled or unpurified can be used with equal success. In general, the reactions took place at the 3-position of the indole ring when this position was unoccupied. When the 3-position was occupied by a methyl group, the reaction took place at the C(2)-positions. There are few studies on the metal triflate-catalyzed addition of pyrroles to a,b-unsaturated compounds <2001AGE160, 2001TL8063>. The Friedel–Crafts reaction of homochiral pyrrole derivatives 450 with a,b-unsaturated esters catalyzed by metal triflates furnished conjugated addition products 451 in good yields without racemization (Equation 107) <2004S2574>. The addition worked regioselectively at C-5 of pyrrole. The best yields were obtained by using yttrium triflate and methyl 4-phenyl-2-oxobut-3-enoate. The diastereoisomers were separated by column chromatography.
ð107Þ
Ytterbium triflate-catalyzed Michael addition of N-methylindole to mesityl oxide 452 was carried out using a modification of the Kerr procedure (4% of Yb(OTf)3, 4 equiv of compound 452) <1996SL1047, 1998CJC1256> to give the desired 4-(indol-3-yl)-4-methyl-2-pentanone 453 in 81% yield (Scheme 96) <2001TL6835>. Product 453 was converted into the a-diazo-b-keto ester 454 having an N-methylindole unit.
Scheme 96
An enantioselective organocatalytic (with tetrahydro-4H-imidazol-4-one-based catalysts of type 456?HX) Friedel– Crafts alkylation of pyrroles 455 by a,b-unsaturated aldehydes generates b-pyrrolyl carbonyls 457, useful synthons for the construction of a variety of biomedical agents (Equation 108) <2001JA4370, 2002JA1172, 2004ASC1175, 2005JA15051 and references therein>.
ð108Þ
Pyrroles and their Benzo Derivatives: Reactivity
Although electron-rich aromatics typically undergo 1,2-carbonyl addition, the iminium ions derived from 4H-imidazol-4-one 456a are inert to the 1,2-pathway due to steric constraints imposed by the catalyst framework. The heteroaromatic nucleophiles react via the less sterically demanding 1,4-addition pathway (Equation 109). With TFA as the cocatalyst, ee values of 89–97% were obtained with a range of substituted pyrroles (R2 ¼ Me, Bn, allyl). In addition, ee values of 87–93% were obtained with alkyl, aromatic, or electron-withdrawing substituents on the a,b-unsaturated aldehydes (R3 ¼ Me, Pri, Bn, Ph, MeCO2).
ð109Þ
Initial screening reactions carried out with enone 460 and N-methyl pyrrole in the presence of 10 mol% of a series of chiral bis(oxazoline)/metal complexes in CH2Cl2 as solvent, revealed complexes 458 and 459 as the most effective (Equation 110) <2005JA4154>. Using these catalysts Friedel–Crafts adduct 461 (R ¼ BnCH2) was formed in yields of 86% and 80% and most notably, with ee 92% and 91%, respectively. Indole derivatives 462 worked as efficiently as pyrroles and provided adducts 463 in good to excellent yields and enantiomeric excess (Equation 111).
ð110Þ
ð111Þ
It was found that C(2)-symmetric chiral bis(oxazoline)/Cu(OTf)2 complex 458 could promote asymmetric Michael addition of indoles to alkilidene malonates in moderate to good ee value (up to ee 69%) <2001CC347>. The newly designed pseudo-C(3)-symmetric tris(oxazoline) 464/Cu(ClO4)2?6H2O complex as a chiral Lewis acid has the encouraging ability to achieve high face selectivity in asymmetric Michael reaction of indoles to alkylidene malonates (Equation 112) <2002JA9030>. The alkylation of indole with benzylidenemalonate 465 proceeded quite slowly at
115
116
Pyrroles and their Benzo Derivatives: Reactivity
0 C, and the yield was only 50%, even when the reaction time was prolonged to 72 h. The addition of 1,1,1,3,3,3hexafluoro-2-propanol (2 equiv) can greatly improve the reactivity without loss of ee. The generality of this reaction was successfully illustrated by investigation of a variety of structurally different indole derivatives and alkylidene malonates. Reactions were run in acetone/Et2O (1:3, v/v) with 10 mol% chiral catalyst at –20 C. Isolated yields of malonate 466 were 73–99% (ee 60–93%). The cheap and easy synthesis of tris(oxazoline)/Cu(II) complexes, the high selectivity, and the mild reaction conditions including water and air tolerance make this method potentially useful.
ð112Þ
The Friedel–Crafts alkylation of the parent pyrrole and of substituted indoles with a,b-unsaturated acyl phosphonates 468 <2003JA10780> and 2-acyl N-methylimidazoles 469 catalyzed by the chiral bis(oxazolinyl)pyridine (pybox)/scandium(III) triflate complex 467 exhibits good enantioselectivities over a broad range of substrates (Scheme 97, Equation 113) <2005JA8942>. The desired alkylation products 470–472 were formed in good yields and enantioselectivities.
Scheme 97
Pyrroles and their Benzo Derivatives: Reactivity
ð113Þ
A class of mixed zinc reagents, for example, (trimethylsilylmethyl)(2-pyrrolyl or 2-indolyl)zincs, bearing one transferable functional group (2-pyrrolyl or 2-indolyl) and one nontransferable group (the trimethylsilylmethyl group), add efficiently to a Michael acceptors, 2-cyclohexenone (in the presence of trimethylsilyl bromide in THF/ NMP mixture (ca. 6:1)) in high yield (57% and 78%, respectively) and with exclusive 1,4-regioselectivity, without the need for transition metal catalysts (Scheme 98) <1998T1471>.
Scheme 98
The aminoalkylation of indole 473 via treatment with Eschenmoser’s salt (N,N-dimethylmethyleneiminium iodide) gives Gramine derivative 474 (Equation 114) <1996JOC1916, 1997JOC3597>. When the 2-acyl analog of indole 473 was treated with Eschenmoser’s salt no reaction was observed.
ð114Þ
The reaction of 1-(2-isocyanophenyl)pyrroles 475 with Eschenmoser’s salt 476 proceeded smoothly at 0 C in dichloromethane to give the dimethyl(pyrrolo[1,2-a]quinoxalin-4-ylmethyl)ammonium iodides 479, which could be isolated by filtration after addition of diethyl ether in good yield (74–75%) and readily converted into the corresponding free amine derivatives 480 quantitatively by treating with aqueous NaHCO3 (Scheme 99) <2001H(55)973>. Pyrrole 475 (R1 ¼ H) was also found to react slowly with a range of iminium salts 481 and 483, derived from secondary amines and aldehydes in the presence of Me3SiCl/NaI/Et3N, at room temperature to give, after work-up with aqueous NaHCO3, 4-(1-dialkylaminoalkyl)pyrrolo[1,2-a]quinoxaline derivatives 482, 484, and 485 in isolated
117
118
Pyrroles and their Benzo Derivatives: Reactivity
yields ranging from 47% to 99% (Scheme 99, Equation 115). The reaction sequence involves the addition of isocyano carbon to iminium salts, followed by cyclization by the attack of pyrrole ring at the 2-position to the resulting imino iodide 477. The products 480 and 482 are formed through intermediates of type 478.
Scheme 99
ð115Þ
The cyclization reaction of 4-chloro-6-(1H-indol-1-yl)-5-pyrimidinamine with various aldehydes and ketones in refluxing acetonitrile in the presence of TFA occurred at the electron-rich pyrrole moiety of the indole ring to give 4-chloro-5,6-dihydroindolo[2,1-h]pteridines in moderate to excellent yields <2005JCO813>, while a 4-chloro-6-(2,3dihydro-1H-indol-1-yl)-5-pyrimidinamine under similar conditions leads to pyrimidine-fused benzodiazepines via an electrophilic cyclization with an aldehydes or ketones at the phenyl ring <2006JCO381>. This strategy provides an efficient way to access a library of compounds with structures that are of interest in drug discovery. The NaI/TMSCl/Et3N-mediated condensation between 2-(pyrrol-1-yl)benzaldehydes 486 and secondary amine hydrochlorides followed by intramolecular trapping of the resulting iminium carbon by the 2-position of the pyrrole ring 487 afforded corresponding 9H-pyrrolo[1,2-a]indoles 488 generally in good yields (Scheme 100) <2006T3158>.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 100
Addition of certain pyrrolyl and indolyl Grignard reagents to 1-acyl salts of 4-methoxy-3-(triisopropylsilyl)pyridine 489 affords the corresponding 1-acyl-2-heteroaryl-2,3-dihydro-4(1H)-pyridones 490–492, 494, and 496 in good to high yield (Equations 116–119) <2004JOC2863>.
ð116Þ
ð117Þ
ð118Þ
ð119Þ
119
120
Pyrroles and their Benzo Derivatives: Reactivity
In contrast to indolyl Grignards 493 and 495 the corresponding isomeric Grignard reagents 497 and 499 failed to add to pyridinium salt 489 (Equations 120 and 121) <2004JOC2863>. The only observed products were the dehalogenated indoles 498 and 500, respectively, and other unidentified decomposition products. When the 1-acyl group contained a chiral auxiliary, ()-(E)-2-(a-cumyl)cyclohexyloxy, addition of the indolyl Grignards resulted in a separable mixture of diastereomeric 2,3-dihydro-4-pyridones. Indoles bearing a highly functionalized piperidine ring in either the 2- or 3-position encompass several structural classes of natural products including Aspidosperma, Strychnos, Eburnan, Corynanthean, and Rauwolfia families of alkaloids.
ð120Þ
ð121Þ
The 3-indolyl methanamine structural motif 503 is embedded in numerous indole alkaloids and synthetic indole derivatives . An efficient catalytic asymmetric Friedel–Crafts reaction of indoles 501 with imines 502 provides a direct, convergent, and versatile method for the highly enantioselective construction of 3-indolyl methanamines 503 from readily accessible achiral precursors (Scheme 101) <2006JA8156 and references therein>.
Scheme 101
After optimization, it was established that quinidine- or quinine-derived 9-thiourea cinchona alkaloids (10 mol%) as bifunctional chiral organic catalysts promote asymmetric C–C bond forming reaction in ethyl acetate at 50 C. Unprecedentedly, the high enantioselectivity of this catalytic reaction is sustainable not only for indoles of various electronic properties but also for both aryl and alkyl imines. A simple approach to optically active 3-indolylmethanamine derivatives (in 47–94% yield) via the enantioselective copper(II) Friedel–Crafts addition of indoles to N-sulfonyl aldimines, RNTCHAr (R ¼ Ts or Ns), using chiral bisoxazoline as ligands (10 mol% of Cu(OTf)2, 15 mol% of L, CH2Cl2, rt, 3–5 d] was developed, and high enantioselectivities (up to ee 96%) were achieved <2006OL1621>. Enantioselective Friedel–Crafts alkylation of N-benzylpyrrole and 5-nitroindole with benzoylhydrazones 504 promoted by a simple strained silacycle reagent 505 gives 2- and 3-derivatives 506 and 507, respectively (Scheme 102) <2005JA2858>. Indole itself provides the corresponding product with significantly reduced enantioselectivity (ee 24%). A novel protocol for three-component aza-Friedel–Crafts (AFC) reactions of aldehydes, primary amines, and indoles in water catalyzed by carboxylic acid has been developed (Scheme 103) <2006OL4939 and references therein>. The AFC product 508 contains a reactive C–N bond, which could be easily transformed to various functional groups.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 102
Scheme 103
The initial product 508 of AFC reactions of aromatic aldehydes, primary amines, and indoles is highly reactive and further addition of indoles gives undesired adduct 509 (Scheme 104) <2006OL4939>. In addition, aromatic aldehydes are themselves known to react with indoles directly to afford the undesired bisindolyl product 509. After screening catalysts (AcOH, TFA, Sc(DS)3, dodecylbenzenesulfonic acid, carboxylic acids from n-C7H15 to n-C13H27), it was revealed that decanoic acid (n-C9H19CO2H) efficiently promoted the reaction without formation of product 509.
Scheme 104
121
122
Pyrroles and their Benzo Derivatives: Reactivity
The condensation of an aldehyde with a chiral amine leads to the formation of an iminium intermediate 510. The product 511 can be hydrolyzed to yield the enantioenriched product 512 and regenerates the chiral amine catalyst (Scheme 105) <2004ASC1175>.
Scheme 105
A synthetic strategy towards indolocarbazole alkaloids based on acid-induced intra- or intermolecular transformations of 2-(1H-indol-3-yl)acetic acid, or derivatives thereof, 513 is depicted in Scheme 106 <1995TL3945>. When acid 513 (R ¼ H) was dissolved in trifluoroacetic acid for 3 h at room temperature, the expected dimer 514 was obtained in 75% yield. The corresponding diester 514 formed from ester 513 (R ¼ Me) could be isolated in 95% yield using careful work-up procedures, but showed a strong propensity to give lactam 515. Heating pure dimer 514 (R ¼ Me) above its melting point (120–125 C), or gentle heating of a slightly acidic 2-propanol solution thereof, completely converted dimer 514 to tetracycle 515. This is obviously the consequence of a nucleophilic attack of the indoline nitrogen on the ester carbonyl. The less electrophilic character of the acid carbonyl in diacid 514 (R ¼ H), as compared to the one in diester 514 (R ¼ Me), prevents the diacid 514 from undergoing a similar reaction. Dehydrogenation of the diester 514 with DDQ in dioxane gave the 2,29-biindole 516.
Scheme 106
Pyrrole-substituted a,o-diamines 517 varying in length and number of heteroatoms between the amine functionalities were obtained from the corresponding acid and appropriate diamine under standard amide-forming conditions in yields of 18–70%. The amines 517 were reacted with 1,19-ferrocenedimethanol 518 under pseudo high-dilution conditions to form ansa-ferrocenes 519, the macrocyclic anion receptors, in 20–35% yields (Equation 122) <2001JOM(637)343>.
Pyrroles and their Benzo Derivatives: Reactivity
ð122Þ
3-Allylation of indoles has been achieved by different ways <1999JOC2751, 2002JOC2705, 2002OL127, 2002TL5185, 2004OL3199, 2005JA4592, 2006JA6314, 2006TL3535>. Indoles are allylated and benzylated in moderate to quantitative yield when stirred with allyl and benzyl halides in 80% aqueous acetone in the presence of bicarbonate at room temperature (Equation 123) <2006OL4791 and references therein>.
ð123Þ
Under palladium catalysis, triethylborane promotes the C(3)-selective allylation of indoles and tryptophans using a wide structural variety of allyl alcohols (Equation 124) <2005JA4592>. The yields of allylation are excellent and in most cases exceed 80%.
ð124Þ
A new palladium-catalyzed enantioselective C(3)-allylation of 3-substituted 1H-indoles 520 using trialkylboranes leads to the corresponding 3,3-disubstituted indolenines 522 (Equation 125) and indolines <2006JA6314>. The anthracene derived ligand 521 gave the best enantioselectivities.
ð125Þ
New versatile Pd-catalyzed alkylation of indoles 523 via nucleophilic allylic substitution provides 3-allylindoles 524 in good to excellent yields (Scheme 107) <2004OL3199 and references therein>. The regioselectivity of the reaction
123
124
Pyrroles and their Benzo Derivatives: Reactivity
can be controlled by a proper choice of the base and the reaction media. From several commercially available Pd complexes that were tested in the model reaction (between indole and rac-1,3-diphenylprop-2-enyl methyl carbonate), the use of [PdCl(p-allyl)]2 provided the highest yields and selectivity. The data obtained clearly proved that, in the presence of 5 mol% of [PdCl(p-allyl)]2/dppe as the catalytic system, indoles 523 (1 equiv) coupled smoothly with rac1,3-diphenylprop-2-enyl methyl carbonate (2 equiv), and the combined use of a low-coordinating solvent and lithium carbonate as the base drove the reaction course toward the exclusive formation of the thermodynamic C-attack (62–92%) with the double-alkylated adduct 525 being the only side product (0–19%). No kinetic N-allylic indole 526 was observed under these conditions. Under similar conditions a mixture of C-alkylated and N-alkylated products (C-3/ N-1 3.7:1) was isolated in moderate yield (62%), when less reactive pent-2-enyl methyl carbonate (2 equiv) was used in the reaction with indole. The combined use of low-coordinating solvent with triphenylphosphine and N,O-bis(trimethylsilyl)acetamide (BSA)/lithium carbonate as the base system provided the desired C-alkylated product in 80% yield after flash chromatography (C-3/N-1 16:1), while on running the allylic substitution in tetrahydrofuran with a catalytic amount of dppe (11 mol%) and potassium carbonate (2 equiv), the regiochemistry was completely switched toward the formation of the N-alkylated compound 526 (90% yield, C-3/N-1 > 1:50).
Scheme 107
The method proved to be effective also for intramolecular asymmetric allylic alkylation (AAA) of variously functionalized indoles 527 and 530 as an alternative procedure to the conventional Friedel–Crafts strategies leading to highly enantioselective synthesis of polycyclic fused indolyl alkaloids such as 4-vinyl-1,2,3,4-tetrahydro-b-carbolines 528 and 531, pyrazino[1,2-a]indoles 529 (Equations 126 and 127) and 1-vinyl-1,2,3,4-tetrahydro-g-carbolines 533 (Equation 128) <2004OL3199, 2006JA1424>. Among all the chiral promoters employed, the DPPBA-based ligands (L), commonly known as Trost’s ligands, furnished the highest level of regio- and stereoselectivity (Equations 127 and 128). The scope of the process was further extended to the synthesis of pyrrolyl-based polycyclic systems, obtaining the 6-benzyl-4vinyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine 531 (R2 ¼ R3 ¼ H) in 85% yield and ee 95%.
ð126Þ
Pyrroles and their Benzo Derivatives: Reactivity
ð127Þ
ð128Þ
Intramolecular catalytic AAA was also effectively applied to indolyl carbonates 532. Notably, also in this case, the combined use of [Pd2(dba)3]?CHCl3 and L in anhydrous CH2Cl2 provided the corresponding 1-vinyl-1,2,3,4-tetrahydro--carbolines 533 in good yield, high regiochemistry (C-3/N-1 > 50:1), and excellent enantiomeric excess (92–93%) (Equation 128) <2006JA1424>. Platinum(II)-catalyzed cyclization of 2-alkenyl indoles forms tetrahydrocarbazole 535 and related derivatives (Scheme 108), but all efforts to realize the platinum-catalyzed cyclization–carboalkoxylation of 2-alkenyl indoles have been unsuccessful <2004JA3700>. In an optimized procedure 1-methyl-2-(4-pentenyl)indole 534 gave tetrahydrocarbazole 536 in 83% yield as a single regioisomer (Scheme 108) <2004JA10250>. Unprotected, electron-rich, and electron-poor 2-(4-alkenyl)indoles underwent efficient palladium-catalyzed cyclization–carboalkoxylation.
Scheme 108
125
126
Pyrroles and their Benzo Derivatives: Reactivity
Palladium-catalyzed cyclization–carboalkoxylation of alkenyl indoles tolerated substitution along the alkenyl chain and at the internal and cis-terminal olefinic position. In addition to 2-(4-alkenyl)indoles, 2-(3-alkenyl)-, 2-(5-hexenyl)-, 3-(3-butenyl)-, and 3-(4-pentenyl)indoles also underwent efficient palladium-catalyzed cyclization–carboalkoxylation to form the corresponding tricyclic indole derivatives in moderate to good yield with excellent regioselectivity. By employing this procedure, efficient palladium-catalyzed cyclization–carboalkoxylation of 2-(4-pentenyl)indole with ethanol, 1-octanol, 2-propanol, and cyclohexanol was achieved. Heating of 3-acetylindole derivatives 537 with an alkene in toluene in the presence of 10 mol% of RuH2CO(PPh3)3 afforded only the product of the alkylation of the pyrrole ring 538 in good yield (Equation 129) <1997TL5737>. The free NH indole 537 (R ¼ H) deactivated the catalyst.
ð129Þ
The thermal-catalyzed (115 C, 2 min or Rh2(OAc)4, 80–115 C, 1–5 min or CHCl3, Cu(acac)2, reflux, 10–90 min) or photochemical (MeCN, irradiation by 400 W Hg street lamp, medium pressure, rt, 1.5 h) reaction of iodonium ylides with pyrroles yields exclusively 2-substitited pyrroles in moderate to good yields (Equation 130, Scheme 109) <2003OL1511>. Malonate derivative 539 constitutes the core moiety of Amtolmetin guacil 540 and Tolmetin 541, important nonsteroidal antiinflammatory agents. Amtolmetin guacil is a novel drug for the treatment of osteoarthritis, rheumatoid arthritis, and postoperative pain. Tolmetin is used for the treatment of arthritis, and its sodium salt is sold under the registered trademark Tolectin.
ð130Þ
Scheme 109
Novel electrophilic trifluoromethylating agents, S-(trifluoromethyl)diphenylsulphonium triflates 542, react with pyrrole under mild conditions to give 2-trifluoromethylpyrrole 543 in high yield (Equation 131) <1998JOC2656>. Treatment of indolines and N-acylindoles with HF/SbF5/CCl4 yields 6-trifluoromethyl derivatives (indole numbering), whereas indoles and oxindoles give the 5-trifluoromethyl derivatives in good yields <2004TL21>.
Pyrroles and their Benzo Derivatives: Reactivity
ð131Þ
The asymmetric synthesis of b-phenyl-substituted tryptophan 545 was successfully achieved via regiospecific ring opening of optically pure benzyl 3-phenylaziridine-2-carboxylate 544 with indole in dichloromethane in the presence of BF3?Et2O (Scheme 110) <2002JOC1399>. Treatment of cycloalkyl N-tosylaziridines 546 with indole in the presence of 10% of InCl3 resulted in the formation of 3-indolyl cycloalkyl amine derivatives 547 in high yields <2002TL1565>. Similarly, styrene N-tosylaziridine underwent cleavage to give products resulting from both benzylic 548 and terminal 549 attack of indole in 85% yield (in the ratio of 3:2, respectively). Under these conditions, pyrrole reacted smoothly with cyclopentene and cyclohexene N-tosylaziridines to give the corresponding 2-alkylated pyrrole derivatives 550 in high regioselectivity (Scheme 111) <2002TL1565>. Aryl N-tosylaziridines underwent cleavage by pyrrole with preferential attack at the benzylic position resulting in the formation of 2-alkylated pyrrole derivatives 551 with a minor amount of 3-alkylated pyrroles 552 (13–25% in mixture). The ring opening of alkyl substituted N-tosylaziridines gave the products resulting from terminal attack of pyrrole, the corresponding 2- and 3-alkylated pyrrole derivatives, 553 and 554 (25–30% in mixture), respectively.
Scheme 110
Aromatic optically active epoxides 556 can be opened in a regioselective and clean way with indoles 555 in the presence of 1 mol% of InBr3. The reaction takes place with a SN2 pathway affording the 2-aryl-2-(indol-3-yl)-1-ethanols 557 in good yield (up to 84%) with excellent enantioselectivity (ee up to 99%) (Equation 132) <2002JOC5386>.
127
128
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 111
ð132Þ
With (1R,2S)-1,2-dihydronaphthalene oxide 558 remarkable enantioselectivity was also recorded (ee 83%) showing the effectiveness of InBr3 in the synthesis of indolyl derivatives 559 in enantiomerically pure form (Equation 133) <2002JOC5386>.
ð133Þ
Indole and several indoles functionalized at C-2 were condensed with aziridines, vinylaziridines, oxiranes, and vinyloxiranes in the solid state on the surface of silica (Equations 134 and 135) <2005JOC3490>.
Pyrroles and their Benzo Derivatives: Reactivity
ð134Þ
ð135Þ
Methyl 2-indolecarboxylate 560 was found to react on the silica gel surface with N-tosylvinylaziridine in 68% yield. The solid-phase aziridine opening constituted a key step in the synthesis of the b-carbolin-1-one mimic of Pancratistatin (Equation 135) <2005JOC3490>. The additional key transformation in a nine-step synthesis of the Pancratistatin mimic involved silica gel-catalyzed opening of an epoxide and hydrolysis of an acetonide (Scheme 112) <2005JOC3490>. The yields of condensation products depend on reaction conditions that were used: (1) silica gel surface at 70 C; (2) 0.1 equiv of InCl3 in CH2Cl2; (3) InCl3-doped silica at 70 C; (4) 10% aq InCl3-treated silica at 70 C; (5) rt, TLC plate silica.
Scheme 112
The high-pressure-promoted (MeCN or CH2Cl2, 10 kbar, 42 or 65 C, 1–3 d) and silica gel-catalyzed (rt, 2–10 d) reactions of epoxides with pyrroles and indoles have been demonstrated to be effective for the alkylation of these heterocycles (Scheme 113) <1996JOC984>. Nucleophilic epoxide-opening reaction with indoles 561 by adsorption on silica gel gave 2-(3-indolyl)-2-phenylethanols 562 in yield up to 88%. Indoles 562 were obtained also under highpressure conditions in 13–61% yields. Reaction of lithiated 1-methylindole 563 with ethylene oxide followed by transformation to tosylate 564 and treatment with MeSNa allowed the simple preparation of 1-methyl-2-[2-(methylsulfanyl)ethyl]-1H-indole 565 (Scheme 114) that was used in the synthesis of 4-methyl-3,4-dihydro-2H-thieno[3,2-b]indole (see Section 3.02.4.8) <2003S1191>. The reaction of a mesylate with indolylmagnesium iodide 566 gave indole 567, which was finally desilylated by careful treatment with aqueous HF to afford alcohol 568 with ee 70% (27% overall yield starting from 2-[t-butyl(dimethyl)silyl]oxy-1-phenyl-1-ethanol) (Scheme 115) <1996JOC984>.
129
130
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 113
Scheme 114
Scheme 115
Pyrroles and their Benzo Derivatives: Reactivity
A novel ionic liquid methodology for pyrrole C-alkylation is described (Equation 136) <2005OL1231>. The pyrrole alkylation is achieved with various simple alkyl halides (1-bromopentadecane, 1-(bromomethyl)-, 1-(3chloropropyl)- and 1-(3-iodopropyl)benzenes, 2-(2-bromoethyl)- and 2-(3-bromopropyl)naphthalenes) and mesylates (3-phenylpropyl-, 1-methyl-3-phenylpropyl-, 2-(2-naphthyl)ethyl- and 3-(2-naphthyl)propyl methanesulfonates) selectively at C(2)- and C(5)-positions in good yields with minimal by-products under relatively mild conditions in various ionic liquids. 2-(3-Phenylpropyl)pyrrole 569 was synthesized from pyrrole and 1-bromo-3-phenylpropane in a mixed solvent system, [Bmim][SbF6] and MeCN, in 81% yield at 115 C for 44 h with 5% yield of dialkylated compound.
ð136Þ
In the synthesis of 2-[3-(methylsulfanyl)propyl]-1H-indole 572, the key step was the alkylation of indolyllithium 570 with excess of 1-bromo-3-chloropropane (Scheme 116) <2003S1191>. Treatment of the indole 571 with sodium methanethiolate gave the target sulfide 572 in high yield. This compound was used in the synthesis of 5-methyl2,3,4,5-tetrahydrothiopyrano[3,2-b]indole (see Section 3.02.4.8).
Scheme 116
Only 2-fluoroalkyl derivatives 573 were obtained when pyrrole and indole were treated with per(poly)fluoroalkyl chlorides (RFCl) in the presence of sodium dithionite in DMSO (Equation 137) <2001JFC(111)107>.
ð137Þ
The Friedel–Crafts reaction of 2,2,2-trifluoro-1-(alkylamino)-1-ethanols 574 with indole is a convenient way to prepare 2,2,2-trifluoro-1-(indol-3-yl)-N-alkyl-1-ethanamines 575 in moderate to excellent yield (46–82%) (Equation 138) <2001JFC(108)83>. Formation of 575 is preferred in the presence of BF3 (63–99% in mixture),
131
132
Pyrroles and their Benzo Derivatives: Reactivity
but the yield of 2,2,2-trifluoro-1-(indol-3-yl)-1-ethanol 576 markedly increases (38–75% in mixture) when ZnI2 was used. 1,19-Bis(indol-3-yl)-2,2,2-trifluoroethane 577 was also generated in low to modest yields.
ð138Þ
N-Trimethylsilyl hemiaminals 578, derived from 1,1,1,3,3,3-hexamethyldisilazane and gaseous trifluoroacetaldehyde, also smoothly underwent electrophilic substitution with pyrrole and indoles in the presence of a Lewis acid <2002JFC(116)103>. Aminofluoroalkylation of pyrrole activated with an equivalent amount of BF3?OEt2 (10 C, 2 h) afforded a good yield of [2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethyl]amine 579 (61%) and a small amount (10%) of bis-1Hpyrrole 581, as well as about 9% of bis[2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethyl]amine 580 (Scheme 117). Formation of the amine 579 was also preferred in the presence of 10 mol% of ZnI2 (10 C, 16 h), albeit in low conversion (10% of amine 579 and 1% of dimer 581). In contrast, more of bispyrrole compound 581 was generated with 50 mol% of ZnI2 (10 C, 16 h): amines 579 (29%) and 580 (6%), dimer 581 (31%).
Scheme 117
N-Trimethylsilyl hemiaminals 578 did not react with indole at room temperature without a promoter. In the presence of BF3?OEt2, the reaction proceeded smoothly at about 10 C, giving mainly [2,2,2-trifluoro-1-(1H-indol-3yl)ethyl]amine 582 (R ¼ H) (84% with 100 mol% of BF3 for 2 h) and a small amount of 3,39-(2,2,2-trifluoro-1,1-ethanediyl)bis-1H-indole 583 (R ¼ H) (2–8%) (Equation 139) <2002JFC(116)103>. With AlCl3, a similar result was observed (76% of amine 582 and 15% of bis-1H-indole 583). Moreover, catalysis with 50% of ZnI2 gave amine 582 (R ¼ H) in good yield (82%), although substitution occurred very slowly (36 h) under similar experimental conditions. Titanium tetraisopropoxide showed no catalytic activity in the reaction. In the presence of 100 mol% of BF3?OEt2, the reaction with 2-methylindole provided the amine 582 (R ¼ Me, 48%) and bis-1Hindole 583, the yield of compound 583 (R ¼ Me, 27%) being higher than that of compound 583 (R ¼ H, 8%) <2002JFC(116)103>.
Pyrroles and their Benzo Derivatives: Reactivity
ð139Þ
Activation of a side-chain primary alcohol function with trifluoromethanesulfonic acid anhydride led to exclusive C-alkylation resulting in a cationic ring closure to afford the tetrahydroindoles (S)-584 (Equation 140) <2004T1197>. When R ¼ H the N-Tf-substituted compound (S)-584 was formed as a side product in 18% yield. It was important to conduct the reaction in the presence of 4-methyl-2,6-di-t-butylpyridine as a sterically demanding and effective proton scavenger.
ð140Þ
Vapor-phase alkylation of indole with methanol (using a feed of indole:methanol, 1:6) was carried out over HZSM5 (30), HY (Si/Al ¼ 2.6), CeHY, LaHY, CrHY, and CuHY zeolites in a continuous fixed-bed glass reactor at atmospheric pressure in the temperature range 200–350 C <2002AC121>. Rare earth metal cation-modified HY zeolites are found to be more active for the alkylation of indole than HY zeolites and transition metal-modified HY zeolites. A maximum of 33.6% yield of 3-methylindole 585 at 72.6% conversion was obtained over 3 wt.% CeHY catalyst at 300 C and time-on-stream of 4 h. A possible reaction mechanism for alkylation of indole based on the product distribution is given in Scheme 118. The p-excessive character of the pyrrole ring makes the indole ring susceptible to electrophilic attack at the 3-position to give indole 585 as the major alkylation product. Further alkylation results in the formation of 3,3-dimethylindoline 586, 2,3-dimethylindole 587, 2,3,3-trimethylindoline 588 and 1,2,3,3-tetramethylindoline 589 as shown in Scheme 118. 1-Methylindole and 2-methylindole are also formed in small amounts either by direct attack of methyl cation at the 1- or 2-positions or by rearrangement of indole 585.
Scheme 118
133
134
Pyrroles and their Benzo Derivatives: Reactivity
3.02.2.3.6
C-Arylation
Because C-arylpyrroles are of interest in the synthesis of fluorescent dyes <2000CC2203>, pharmaceuticals <2001CPB1406>, and insecticides <1996MI201>, general methods for the arylation of pyrroles could be widely useful. The direct C-arylation of free NH-azoles holds significant synthetic potential as it eliminates the need for introducing protecting groups and reactive functionalities prior to C–C formation, thereby enabling direct access to valuable heteroaromatic compounds. Such methods require selective targeting of C–H bonds in the presence of a reactive N–H functionality. Virtually exclusive photo-SN1 aminoarylation in position 2 via phenyl cation 591 (derived via photodecomposition of chloroaniline 590) is obtained with pyrrole <2005ACR713>, though 2,5-dimethylderivatives 592 were smoothly arylated in position 3 (Scheme 119) <2000T9383>.
Scheme 119
Pyrrole derivatives were used as aromatic partners in photochemical heteroarylation reactions with a number of halogencontaining compounds, for example, the quinone 593 reacts with N-methylpyrrole to give the corresponding pyrrolyl derivative 594 (Equation 141) <1997J(P1)2369>. This reaction occurs via a charge transfer complex in the ground state.
ð141Þ
With 6-iodo-2,4(1H,3H)-pyrimidinedione 595, use of N-phenylpyrrole as the reagent, gave a double arylation leading to condensed product 596 (Equation 142) <1997J(P1)2369>.
ð142Þ
Pyrroles and their Benzo Derivatives: Reactivity
Photochemical substitution of some iodo-substituted pyrroles 597 in the presence of aromatic compounds depends on the structure of the pyrrole and on reaction conditions and gives the corresponding aryl derivatives 598 and/or dehalogenated product 599 (Scheme 120) <1997J(P1)2369>. Use of 4,5-diiodopyrrole-2-carbaldehyde 597 (R1 ¼ I, R2 ¼ H, R3 ¼ CHO) as substrate and irradiation in benzene, m-xylene, thiophene and 2-chlorothiophene as solvents gives solely the corresponding 5-aryl derivatives 598 in good yields (57–100%). There is no competition between 4and 5-substitution.
Scheme 120
Photoreactions (at > 300 nm, 7 h) of 5-bromocytosine and its 1-substituted analogs 601 with Na-acetyl-Ltryptophan N-ethylamide 600 in aqueous buffered (pH 7) solutions yield Na-acetyl-2-(cytosin-5-yl)tryptophan N-ethylamides 602 as the main photoproducts (35–46%) (Equation 143) <1995JPH129>.
ð143Þ
The palladium-catalyzed arylation of protected azoles (pyrrole and indole) has been reported with aryl halides in the presence of a base <1998BCJ467>. However, these reactions often suffered from low yields and poor selectivity <2000OL3111>. Furthermore, it was found that the free pyrrole and indole were unreactive under standard arylation conditions, yielding little or no C-arylation products (Equation 144) <2003JA5274>. The use of magnesium oxide afforded 2-phenylindole 603 as a single product in 53% yield (unoptimized). Indole Grignard salt 604a, prepared from indole and EtMgBr prior to the arylation reaction, furnished product 603 exclusively in 65% yield. As judged by 1 H and 13C NMR, a species similar to indolylmagnesium bromide 604a, presumably magnesium hydroxide salt 604b, was formed from indole and MgO. After some optimization (solvent, temperature), 2-phenylindole was prepared as the exclusive product in 84% yield (Scheme 121). In contrast, 2-iodotoluene underwent slower reaction, affording two products, 2-arylation product 605 (39%) and 3-arylation product 606 (12%). The yields were improved by addition of an excess of 2-iodotoluene (2.5 equiv), yielding compounds 605 and 606 in 55% and 17% yield, respectively. Pyrrole afforded 2-phenylpyrrole in 86% yield.
135
136
Pyrroles and their Benzo Derivatives: Reactivity
ð144Þ
Scheme 121
Selective targeting of C–H bonds in the presence of a reactive N–H functionality was realized by using azolylmagnesium or zinc salts as ‘protected’ and ‘activated’ substrates in a palladium (or cobalt)-catalyzed coupling with haloarenes (Scheme 122, route A) <2003JA5274, 2003OL3607, 2004OL3981>. An entirely different approach to direct C(2)-arylation of free (NH)-indoles and pyrroles catalyzed by Ar–Rh(III) complexes, assembled in situ, in the presence of a mild base (Scheme 122, route B) was found very recently <2005JA4996>.
Scheme 122
Pyrroles and their Benzo Derivatives: Reactivity
A general method for the conversion of pyrrole anions 607 to 2-arylpyrroles 609–611 has been developed (Scheme 123) <2004OL3981>.
Scheme 123
Using a palladium precatalyst and sterically demanding 2-(dialkylphosphino)biphenyl ligands, (pyrrolyl)zinc chloride 608 may be cross-coupled with a wide range of aryl halides, including aryl chlorides and aryl bromides, at low catalyst loading and under mild conditions (THF, 0.5 mol% of Pd(OAc)2 or 0.25–2 mol% of Pd2(dba)3, 16–44 h). A high degree of steric hindrance is tolerated. The N-(chlorozinc) derivatives of certain ring-substituted pyrroles, bearing methyl 612 or aryl 613 groups, may also be arylated by this method (Equations 145 and 146) <2004OL3981>.
ð145Þ
ð146Þ
The metallated pyrroles protected with the vinyl, pyridyl, PhSO2, TMS, MOM, BOC, and SEM groups either did not couple with bromobenzenes, or the protecting group was cleaved from the pyrrole during reaction. Successful coupling of protected pyrroles was accomplished by the use of the dimethylamino protecting group as outlined in Scheme 124.
137
138
Pyrroles and their Benzo Derivatives: Reactivity
The protected metallated pyrrole was obtained by reacting N,N-dimethyl-1H-pyrrol-1-amine 614 with BunLi followed by treatment with ZnCl2 to give zinc derivative 615 <1999SM(99)181>. Successful coupling of compound 615 was accomplished with bromobenzene or 1,4-dibromobenzene using Pd(0) catalyst to form N,N-dimethyl-2-phenyl-1Hpyrrol-1-amine 616 and 1,4-di[1-(dimethylamino)-1H-pyrrol-2-yl]benzene 617, respectively. Deprotection of product 616 to form 2-phenylpyrrole was carried out by hydrogenation over Raney nickel. Identical deprotecting conditions were attempted in the preparation of 1,4-di(1H-pyrrol-2-yl)benzene and found to be unsuccessful.
Scheme 124
A cross-coupling reaction (Negishi coupling) between N-SEM-pyrrol-2-yl-zinc chloride 618 and the appropriate dibromo derivative catalyzed by a Ni catalyst leads to 2-[4-(1H-pyrrol-2-yl)phenyl]-1H-pyrroles 619 (Scheme 125) <1997CM2876>. The SEM-protecting group can be easily removed by reaction with Bu4NF.
Scheme 125
2-[4-Methoxy-5-(1H-pyrrol-2-yl)-2-thienyl]-1H-pyrrole 621 was also prepared by a cross-coupling reaction, Stille reaction in this case, between N-SEM-2-(trimethylstannyl)-1H-pyrrole 620 and 2,5-dibromo-3-methoxythiophene in the presence of a Pd catalyst, followed by nitrogen deprotection (Scheme 126) <1997CM2876>. If Negishi coupling is applied, the main reaction product is, in this case, N-SEM-2,29-dipyrrole, and the desired compound can be isolated only in trace amount. A mild and general cross-coupling reaction of 2-indolylsilanols has been developed <2004OL3649>. The experimental variables that lead to successful coupling are (1) the use of ButONa as the activator, (2) the use of copper(I) iodide in stoichiometric quantities, and (3) the use of Pd2(dba)3?CHCl3 as the catalyst. Under these conditions (1-BOC-indol-2-yl)(dimethyl)silanol 622 reacts with a variety of aromatic iodides to afford the coupling products 623 in good yield (70–84%) (Equation 147).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 126
ð147Þ
To probe the use of other nitrogen substituents, the dimethyl(1-methyl-indol-2-yl)silanol 624 was submitted subjected to these reaction conditions with several aryl iodides and bromides (Equation 148). Although the reactions proceeded to completion at room temperature, for cases with electron-withdrawing substituents (4-CN or 4-NO2) the isolated yields of the desired cross-coupling products 625 were lower (62%) because the 2,3-disubstituted indole 626 was formed as a minor by-product (16–30%). Switching from an aryl iodide to an aryl bromide, employing 1,4-bis(diphenylphosphino)butane (dppb) and heating these reactions to 55 C furnished the desired products in good yields (80–84%) <2004OL3649>.
ð148Þ
Stille reaction between a tin derivative of 7-azaindole 627 and the aryl or heteroaryl halide proved to be more useful than Suzuki, Negishi, or other Pd-catalyzed cross-coupling reactions for the formation of aryl or heteroaryl-7azaindoles 628 (Scheme 127) <2004M615>. The synthesis of pyrrolo[1,2-c]pyrimidin-1(2H)-one 630 was achieved by a four-step procedure from pyrrole as shown in Scheme 128 <2004M615>. N-Acylation of pyrrole with bromoacetyl bromide and lutidine as base in chloroform followed by reaction with potassium cyanate in refluxing acetonitrile gave the bicyclic system of 2,3dihydropyrrolo[1,2-c]pyrimidine-1,4-dione 629. Reduction of the carbonyl group followed by formation of the mesylate and in situ elimination afforded pyrimidinone 630. The tin derivative of compound 630 was prepared by a route similar to that described for 7-azaindoles. N-Protection, bromination, interchange of halogen by lithium, and quenching the lithio derivative with Me3SnCl afforded in a good overall yield the new 5-stannyl-derivatives 631. The coupling reactions between compound 631 and several aryl or heteroaryl halides were tested using the best conditions found for the 7-azaindole.
139
140
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 127
Scheme 128
3.02.2.3.7
C-Vinylation
C-Vinylpyrrole and C-vinylindole are not only common structural features in natural products, but also viable key building blocks that are frequently employed in the synthesis of alkaloids and other biologically important heterocycles <2004CRV2481, 2004JOC2084, 2004OL329, 2004T5315, 2005JOC2206, 2006JME1271>. As a result, considerable efforts have been devoted to the development of new methodologies for efficient synthesis of C-vinylpyrroles and C-vinylindoles. The latest advances in the synthesis of C-vinylpyrroles and their reactivity were reviewed <2002RCR563, 2004CRV2481>. The most important of the methods of synthesis of C-vinylpyrroles is direct introduction of the vinyl group into pyrrole and indole rings by addition of pyrrole or indole to alkynes or substitution reactions at the double bond. Such processes preclude the need for a prior functionalization step, making the overall chemical transformations highly effective. In recent years, the addition of pyrroles as C-nucleophiles to the electron-deficient triple bond has been extensively studied because this reaction provides the most direct approach to functionally substituted C-vinylpyrroles. Thus, the noncatalytic reactions of pyrroles 632 with terminal aroyl ethynes 633 proceeded under mild conditions either without a
Pyrroles and their Benzo Derivatives: Reactivity
solvent or in protic (methanol or ethanol) or aprotic (diethyl ether, benzene, hexane or acetonitrile) solvents to give 2-(2acylvinyl)pyrroles (predominantly, the (Z)-isomers) 634 (Equation 149). In the course of isolation and purification and even upon storage, the (Z)-isomers are readily transformed into the (E)-isomers <1998MC119, 1999RCB1542>.
ð149Þ
Unlike the ethynes 633, disubstituted ethynes 635 are less reactive and do not react with pyrroles at room temperature. The latter reaction was performed upon heating of equimolar amounts of the reagents in the presence of a five- to tenfold excess of silica gel (Equation 150). The (Z)-isomers of 2-(2-acyl-1-phenylvinyl)pyrroles 636 were obtained in 13–89% yields <1999CHE1107, 2000RCB1914, 2002RCB111, 2003RJO1636>.
ð150Þ
The reactions of the pyrroles 632 with 1-aroyl-2-phenyl ethynes 635 (R3 ¼ Ph, 2-furyl) in the superbase KOH/DMSO system afforded a mixture of N- 637 ((E)- and (Z)-isomers) and C- 638 ((Z)-isomers) adducts, in a total yield of 60–80%, the ratio of the products being dependent on the structure of the starting pyrrole (Equation 151) <2003RJO1195, 2003S1272>.
ð151Þ
Regio- and stereospecific C-vinylation of 1-vinylpyrroles 639 with benzoyl ethyne proceeded at room temperature on the surface of silica gel under the conditions of mechanochemical activation to form (E)-isomers of 1,2-divinylpyrroles 640 with small amounts of ketones of type 634 (Equation 152) <2001S1878, 2002RJO1775>.
ð152Þ
The formation of the compounds 634 is associated with the hydrolysis of the vinyl group both in the starting pyrroles 639 and in the reaction products 640 that occurs on SiO2 <2001S1878>. A mixture of 2-vinyl- 642 and (E,Z)-2,5-divinyl- 643 pyrrolo[3,2-b]pyrroles was obtained in the reaction of pyrrolo[3,2-b]pyrrole 641 with an excess of dimethyl acetylenedicarboxylate (DMAD). A mixture of the (E)- and (Z)-isomers of the divinylpyrrole 643 (in 24% and 47% yields, respectively) can also be prepared by the addition of the monoadduct 642 to dimethyl acetylenedicarboxylate under the same conditions (Equation 153) <1998H(48)433>.
141
142
Pyrroles and their Benzo Derivatives: Reactivity
ð153Þ
Reaction of 4,7-dihydroindoles with DMAD led to Michael product 644 (ratio of (E):(Z) ¼ 1:2.5). Aromatization of the cyclohexadiene ring by DDQ gave the not easily accessible 2-vinylindole 645 (Scheme 129) <2006JOC7793>. 4,5,6,7Tetrahydroindole with DMAD (CH2Cl2, 20 C, 36 h) gives addition product in a yield of 50% (ratio of (E):(Z) ¼ 1:3.3).
Scheme 129
The reaction of 2,3,4-trimethylpyrrole with but-2-ynedinitrile produced (E)-2-(1,2-dicyanovinyl)pyrrole 646 as the major product (in 63% yield), whereas the yield of the (Z)-isomer was only 9% (Equation 154) <1998CEJ107>.
ð154Þ
Heating of pyrrolesulfone 647 with alkyne 648 produced a mixture of (E)-isomers of 2-vinyl- 649 and 2,5-divinyl650 pyrroles (Equation 155) <1995T129>.
ð155Þ
The photochemical reactions of pyrrole with phenyl- and diphenylethynes afforded 2-(1-phenylvinyl)- 651a and 2-(1,2-diphenylvinyl)- 651b pyrroles, respectively, as a mixture of (E)- and (Z)-isomers in approximately equal amounts in yields of only 7% and 9%, respectively (Equation 156) <1997LA943>. The low yields of the adducts were accounted <1997LA943> for by photoinduced dimerization of phenylethynes and the instability of the adducts 651a in air.
Pyrroles and their Benzo Derivatives: Reactivity
ð156Þ
The catalytic activation of aromatic C–H bonds leading to the formation of a C–C bond also provides convenient, clean, and economic methodologies to C-vinylpyrroles and C-vinylindoles. Thus, heteroarenes 652 (pyrroles and indoles) undergo addition reactions to alkynoates 653 in the presence of catalytic amount (5%) of Pd(OAc)2 under mild conditions, affording either monoaddition products, (Z)-3-arylpropenoates 654, in most cases or diaddition products, 3-diarylpropanoates 655, depending on the substituents in alkynoates and the solvent (Scheme 130) <2000OL2927, 2002CL20>.
Scheme 130
With R1 ¼ Me or n-C5H11 in the alkynoates, the reaction in acetic acid mainly gave diaddition products 655, while with R ¼ Ph monoaddition products exclusively formed. Even with small R1 substituents such as H and Me in alkynoates, the reaction can be controlled to stop at the monoaddition step to give 3-heteroarylpropenoates 654 when CH2Cl2 was used as the solvent, although the reactions in CH2Cl2 were slow. For pyrrole 652a and 1-methylpyrrole 652b, the substitution of aromatic C–H bonds occurred exclusively at the 2-position of the ring, characteristic of electrophilic substitution. When the a-positions of pyrrole were occupied as in 652c, the reaction with alkyne 653 took place to give the corresponding b-alkenylpyrroles <2002CL20>. For indole 652d and 1-methylindole 652e the reaction occurred at the 3-position predominantly while a very small amount of 2-substituted adducts could be detected. However, when the 3-position of indole was substituted by a methyl group 652f, the reaction proceeded smoothly at the 2-position. Dinuclear palladium complexes, 656, in the presence of tri(n-butyl)borane, catalyzed addition of pyrroles to inactivated alkynes, to afford (E)-alkenylpyrroles with high stereoselectivity. However, the regioselectivity of the reaction depended on substituents on the nitrogen atom and alkynes. Thus, the 1-methylpyrrole reacted with 3-hexyne to form the mixtures of 2- 657 and 3- 658 alkenylpyrroles (R ¼ Me) in ratio 2–4:1, while the reaction of N-(t-butoxycarbonyl)pyrrole proceeded with high regioselectivity to give 3-alkenylpyrrole 658 (R ¼ BOC), although the yield was low (29%) (Equation 157) <2005TL7515>. The products were obtained in higher yields (34–45%) in hydrocarbon solvents than in dioxane and p-xylene. When N-methylpyrrole was used as solvent, the products 657 and 658 were obtained in 55–69% yield. 1
ð157Þ
143
144
Pyrroles and their Benzo Derivatives: Reactivity
N-Methylpyrrole and diphenylethyne gave exclusively 2-alkenylpyrrole 659 as a mixture of (E)- and (Z)-isomers (Equation 158) <2005TL7515>.
ð158Þ
A highly regio- and stereoselective Brønsted acid-catalyzed coupling of ynamides and indoles leads to the efficient synthesis of vinylindoles <2005TL6483, 2006T3917>. Based on the nucleophilic property of indoles, possibility of intermolecular trapping of the in situ generated ketene iminium intermediates 660 with indoles was thought possible, and is outlined in Scheme 131.
Scheme 131
This process furnishes exclusively the C(3)-vinylindoles 661. The generality of this protocol was tested using various indoles and ynamides. The hydroarylation process proved to be very efficient for indoles with electronically neutral alkyl and aryl substitution, giving the desired vinylindoles in good to excellent yields. Pyrroles also participated well in this vinylation process <2006T3917>. Unfortunately, the hydroarylation involving pyrroles was only slightly regioselective affording C(3)- and C(2)-vinylation products in roughly 1:2 ratio. Variation of the reaction temperature does not have significant affect on the ratio of C(2)- and C(3)-isomers. When the C(2)-carbon was blocked, as in 2,3-dimethylpyrrole, C(3)-vinylpyrrole was the only product in 79% yield. Following the observation that both C(2)- and C(3)-positions of pyrroles can undergo the vinylation process, 2,3-divinylpyrroles were prepared in good yields by simply employing an excess of ynamides. This vinylation protocol is not efficient for pyrroles with electron-withdrawing substituents. The substitution of functional groups at the electrophilic double bond or catalytic replacement of the hydrogen atom of alkene fragment by pyrroles or indoles has found wide use in the synthesis of C-vinylpyrroles or -indoles. Thus, indole was reacted with ethyl 2-nitro-3-ethoxyacrylate 662 to give ethyl 2-nitro-3-(3-indolyl)acrylate 663 as a 1:1 mixture of the (E)- and (Z)-isomers (Equation 159) <1996TL3309>.
ð159Þ
The reaction of pyrrole and 1-methylpyrrole with the trifluorovinyl compounds 664a and 664b, which are products of mono- and bistrifluoroacetylation of ethyl vinyl ether, respectively, led to the substitution of the ethoxy group and the formation of 2-(2-trifluoroacetyl)vinylpyrroles 665. The reaction proceeded under mild conditions in the presence of 25 mol% of ZnCl2. In the presence of other Lewis acids, the reactions are accompanied by substantial resinification. The reaction of the ketone 664a proceeded stereospecifically to produce the (E)-isomer (Equation 160) <1999RCR437, 1999RJO711>.
Pyrroles and their Benzo Derivatives: Reactivity
ð160Þ
The pyrrole 665a was also synthesized from 1H-pyrrole and compound 666, which was prepared as shown (Scheme 132). The reaction proceeded under mild conditions as an addition–elimination <1997SL1349, 1999RCR437>.
Scheme 132
The reactions of iminium complex 668, generated in the reaction of 4-(dimethylamino)-1,1,1-trifluorobut-3-en-2one 667 with phosphoryl chloride or trifluoromethanesulfonic anhydride, with pyrroles proceeded stereospecifically to give finally (after hydrolysis of intermediates 669) the (E)-isomers of 2-vinylpyrroles 670 (Scheme 133) <1998T119, 1999RCR437>. The reactions with trifluoroacetyl alkenes depicted in Equation (160) and Schemes 132 and 133 are also applied to indole systems <1999RCR437>.
Scheme 133
A vinylogous Vilsmeier reaction of 3,4-dimethylpyrrole 671a and dipyrrinone 671b with 3-(dimethylamino)acrolein afforded 2-vinylpyrroles 672 (Equation 161) <1996M77>.
ð161Þ
145
146
Pyrroles and their Benzo Derivatives: Reactivity
The reactions of 2-methyl- and 2-phenylpyrroles with the methoxymethylene derivative of Meldrum’s acid 673 proceeded regioselectively under mild conditions to give 2-vinylpyrroles 674 in 60% and 70% yields, respectively (Scheme 134) <1997J(P1)2195>. Under analogous conditions, the reaction of 3-phenylpyrrole with the compound 673 produced a mixture (1:1) of 3- and 4-phenyl-2-vinylpyrroles 675.
Scheme 134
Some new six-membered Aplysinopsin analogues, 5-(1H-indol-3-ylmethylene)-2,4,6(1H,3H,5H)-pyrimidinetriones 678, were prepared in 11–73% yield from indole derivatives 676 and 5-[(dimethylamino)methylene]2,4,6(1H,3H,5H)-pyrimidinetriones 677 by heating in glacial acetic acid (Equation 162) <2001T3159>. 2-Methylindole reacts with pyrimidinetrione 677b (when R3 ¼ Me) in a different manner from 677a (when R3 ¼ H). Instead of the expected 3-vinylindole 678, 3-[bis(2-methyl-1H-indol-3-yl)methyl]-2-methyl-1H-indole 679 was isolated in 71% yield (Scheme 135).
ð162Þ
Scheme 135
Pyrroles and their Benzo Derivatives: Reactivity
In the reactions of the pyrroles 680a (R3 ¼ H) with tetracyanoethylene, one of the nitrile groups in the latter compound was replaced to form 2-(tricyanovinyl)pyrroles 681a in quantitative yields (Equation 163) <2000RJO1504>. The pyrroles 680b containing substituents at both -positions (R3 ¼ Me) reacted with tetracyanoethylene under the same conditions to give 3-(tricyanovinyl)pyrroles 681b (Equation 163) <2001ARK37>.
ð163Þ
Tricyanovinylation of 2-thienylpyrroles 682 proceeded regioselectively in the pyrrole ring to form the corresponding tricyanovinyl-substituted thienylpyrroles 683 in 31–73% yields. The thienypyrrole 682 behaves quite differently in this reaction: the main reaction product was 3-(tricyanovinyl)pyrrole 684 (29%); in addition, the 5- 683 (12%) and 4- 685 (8%) tricyanovinyl-substituted pyrroles were also isolated (Equation 164) <2005T11991>. In interpreting these results it seems appropriate to take into account the possible steric influence of the n-propyl group impeding the substitution at the a-position of the pyrrole ring.
ð164Þ
5-Methyl-2-(2-thienyl)pyrrole 686 (X ¼ S) reacted with tetracyanoethylene to yield the 3-tricyanovinyl isomer 687 along with 4-tricyanovinyl derivative 688 (Equation 165) <2001ARK37>. Under these conditions, 2-(2-furyl)-5methylpyrrole 686 (X ¼ O) behaved differently, namely, the major direction of the reaction with tetracyanoethylene involves the attack on the a-position of the furan ring giving rise to product 689 (Equation 165) <2001ARK37>.
ð165Þ
147
148
Pyrroles and their Benzo Derivatives: Reactivity
The reactions of 1-vinyl- (R ¼ H) and 1-prop-2-enyl- (R ¼ Me) substituted tetrahydroindoles 690 with tetracyanoethylene in equimolar amounts in DMSO afforded 3-tricyanovinyl-substituted derivatives 691 as the only products (Equation 166) <2001ARK37>. Hence, the N-alkenyl substituent in the pyrroles does not react with tetracyanoethylene according to the [2þ2] cycloaddition mechanism typical of other 1-vinyl-substituted heterocyclic compounds.
ð166Þ
The substitution of a hydrogen atom in the alkene fragment has been performed efficiently only in the presence of catalyst. In particular, C–H activating Pd-catalyzed alkenylation of indoles or pyrroles has found use in the synthesis of their C-vinyl derivatives. The new palladium(II) catalyst system (10 mol% of Pd(OAc)2, ButOOBz, dioxane/AcOH/ DMSO) was used for direct pyrrole C – H bond alkenylation by acrylates. The regioselectivity of this reaction depended on substituents on the nitrogen atom. Thus, the N-Bn and N-SEM pyrroles 692 formed the C(2)- 693 and C(3)- 694 vinylpyrroles in 2:1 ratio. Introduction of an electron-withdrawing N-protecting group (N-Ac, N-Ts, N-BOC) afforded only C(2)-products 693 in good yields. In contrast, reactions with N-TIPS-pyrrole gave only C(3)-products 694 (Equation 167) <2006JA2528>. The use of oxygen or air without any further additives as oxidants, instead of ButOOBz, significantly increases the efficiency of this process.
ð167Þ
The natural reactivity of indole suggested that palladation and Heck coupling would take place preferentially at the 3-position. Indeed, the oxidative coupling of 1H-indole with methyl acrylate has been performed efficiently in the presence of catalytic amounts of palladium acetate and benzoquinone (BQ) with t-butyl hydroperoxide as the oxidant. The reaction is highly regio- and stereoselective, giving trans-methyl 3-(1H-indol-3-yl)-2-propenoate in 52% yield predominantly <1999OL2097>. However, the reaction between indole and n-butyl acrylate in the presence of Pd(OAc)2 and Cu(OAc)2 as the oxidant in polar solvents (DMF, DMSO) gave exclusively C(3)-functionalized indole, while the use of dioxane and t-butyl benzoyl peroxide as the soluble reoxidation agent led to a 2:1 mixture of C(2)695 and C(3)- 696 substituted indoles (Equation 168) <2005AGE3125>.
ð168Þ
Benzoic acid is probably produced as a result of the reoxidation of Pd(0) by ButOOBz, and it was believed that the increasing concentration of acid may be responsible for the switch in selectivity as the reaction progresses. Reaction in DMF/AcOH led to a 1:1 mixture of isomers and use of AcOH as a cosolvent with dioxane gave a 7:1 ratio of compounds 695:696.
Pyrroles and their Benzo Derivatives: Reactivity
A C–H activating Pd-catalyzed alkenylation of indole is regiospecific for 2-substitution when the nitrogen carries a 2-pyridylmethyl substituent (Equation 169) <2005CC1854>. Under the same conditions N-Bn-indole reacted with methyl acrylate regioselectively to afford 3-isomers in 95% yield.
ð169Þ
These experiments demonstrated that the regioselectivity of palladium-catalyzed indole alkenylation could be controlled.
3.02.2.3.8
C-Ethynylation
Development of efficient methodologies for regioselective functionalization of pyrroles and indoles are of great importance, since these ring systems can be found as a structural motif in numerous biologically active natural products and pharmaceuticals <1996CHEC-II(2)207, B-1996MI2>. Among these heterocycles, their ethynyl derivatives have attracted major attention due to the rich chemistry of the acetylene function. As a result, a considerable amount of effort has been devoted to the development of new methodologies for efficient synthesis of ethynylpyrroles and ethynylindoles. However, almost all the known methods for C-ethynylation of pyrroles and indoles require prefunctionalized pyrroles or indoles – either halo (mostly iodo) <2002JOC7048, 2002S1810, 2005JA12214, 2005JCO809, 2006JOC62> or metal (Sn) <1999J(P1)2669> substituted ones as reactants (see also Section 3.02.2.4). A facile direct regio- and chemoselective ethynylation of pyrroles 697 with bromoethynyl ketones 698 has been developed (Scheme 136) <2004TL6513, 2005MC229, 2006RJO1348>. The reaction proceeds at room temperature for 0.5–1 h and is slightly exothermic (5–8 C on a 0.5–1.0 mmol scale). Experimentally, the reactants are pulverized with a 10-fold mass excess of Al2O3 under solvent-free conditions, though some amounts of solvents (n-hexane, Et2O) for extraction of the products from the reaction mixture are required. In the absence of Al2O3, the ethynylation did not take place. The reaction is 100% regioselective: no isomeric 1- or 3-(acylethynyl)pyrroles were detected in the reaction mixture.
Scheme 136
The mechanism of this new ethynylation involves an addition–elimination sequence, probably promoted by the coordinatively unsaturated center (electrophilic assistance) and by mechanoactivation (grinding up the reactants with Al2O3) <2004TL6513, 2006RJO1348>. The intermediates of this reaction, 2-(1-bromo-2-acylethenyl)pyrroles 700, are isolated and converted upon Al2O3 to 2-ethynylpyrroles 699 (Scheme 136) <2006RJO1348>.
149
150
Pyrroles and their Benzo Derivatives: Reactivity
Side products of the coupling are 1,1-di(2-pyrrolyl)-2-acylethenes 701, which are probably formed as a result of the exchange of a bromine atom in 2-(2-acyl-1-bromoethenyl)pyrroles 700 for a second molecule of the pyrrole 697 (through an addition–elimination two-step process). An alternative route to compounds 701 is the addition of the pyrrole 697 to ethynylpyrroles 699. It is also possible that both of these routes take place (Scheme 137) <2004TL6513, 2006RJO1348>. The yields of adducts 701 are normally up to 19%, expectedly, increasing (up to 39%), when excess of pyrrole, higher temperatures or longer reaction times are employed. If silica, instead of alumina, was employed as the reaction medium, the adducts 701 became the major products (the yield reaches 60%) and the ethynylpyrroles 699 were detectable as traces only <2004S2736>.
Scheme 137
An attempt to effect the coupling of (bromoethynyl)benzene with pyrroles 697 under the same conditions led to recovery of starting materials. This may imply that the reaction is limited to alkynes bearing a carbonyl functionality and other electron-withdrawing substituents <2004TL6513>. In similar conditions indoles 702 reacted smoothly with 3-bromo-1-phenylprop-2-yn-1-one to give 3-(2-benzoylethynyl)indoles 703 chemo- and regioselectively in 72–76% yields (Scheme 138) <2006TL7139>.
Scheme 138
The only side products of the reaction were 1,1-di(indol-3-yl)-2-benzoylethenes 704, detectable in all cases (1H NMR) in small amounts (5–8%). The adducts 704 were most probably formed by substitution of bromine in the intermediates of this reaction, namely 3-(2-benzoyl-1-bromoethenyl)indoles 705, since ethynylindoles 703 can not add indoles 702 under the reaction conditions (Scheme 138) <2006TL7139>.
Pyrroles and their Benzo Derivatives: Reactivity
The condensed indole, 1H-benzo[g]indole 706, under the same conditions, was coupled with 3-bromo-1-phenylprop2-yn-1-one to furnish a mixture of 3- 707 and 2- 708 ethynylindoles in 45% overall yield (Equation 170) <2006TL7139>.
ð170Þ
4,5-Dihydro-1H-benzo[g]indole 709 reacted with bromoethynyl ketone 698 (R3 ¼ Ph) on alumina was readily converted to the corresponding 2-ethynylated derivative 710 in 68% yield <2006TL7139>. A side product of coupling, ketone 711, was isolated in 9% yield (Equation 171).
ð171Þ
3.02.2.3.9
C-Reactions with carbonyl compounds
Direct coupling of indoles with carbonyl compounds have developed as key step in short, enantioselective, protecting group-free, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families <2004JA7450, 2006ARK310 and references therein>. The optimum protocol was addition of LHMDS (3 equiv) to a solution of indole (2 equiv) and carvone 712 (1 equiv) in THF at 78 C followed by addition of copper(II) 2-ethylhexanoate (1.5 equiv) as oxidant to furnish adduct 713 in 53% isolated yield as a single diastereomer (Scheme 139) <2004JA7450>. The synthetic pathway to (þ)-hapalindole Q 714 and (–)-12-epi-fischerindole U isothiocyanate 715 proceeds in 22% and 15% overall yield from (R)-carvone, respectively. This protocol can be used for preparation of other a-indole carbonyl compounds 716 (Scheme 140) <2004JA7450, 2006ARK310>. Pyrroles have been found to be amenable to coupling with ketones, esters, amides, lactones, and lactams under slightly modified of indole coupling conditions to give 2-substituted derivatives 717 (Scheme 140). The proposed mechanism of direct coupling reaction is depicted in the Scheme 141 <2006ARK310>. Although conceptually similar, the direct coupling of carbonyl compounds with pyrroles (Scheme 141) using a Cu(II) oxidant probably differs mechanistically from the intramolecular cyclization of pyrrole 718 to 2,3-dihydro-1Hpyrrolizine 719 (in 65% yield as a 4.5:1 mixture of diastereomers) using Fe(III)-based oxidant (ferrocenium hexafluorophosphate) (Scheme 142) <2006ARK310>. Treatment of the crude reaction mixture containing compounds 718, 719 and ferrocene without purification with benzoyl chloride (70 C) followed by hydrolysis of the resulting benzoylated pyrrole 720 using tetrabutylammonium hydroperoxide (TBAH) furnished pharmaceutical agent (S)-Ketorolac (ToradolTM and AcularTM, 721, ee 90% determined by chiral HPLC, 25% isolated yield over three steps) along with recovered chiral auxiliary. The coupling of indoles 722 with isonicotinaldehyde 723 gives 3-indolyl 4-pyridinyl methanols 724, which upon treatment with triethylsilane in the presence of CF3CO2H afford 3-(4-pyridinyl)methylindoles 725 in 64–76% overall yield (Scheme 143) <2001TL7333>. Thus, treatment of 5-fluoroindole 722 (R1 ¼ F, R2 ¼ H) with aldehyde 723
151
152
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 139
Scheme 140
Scheme 141
Pyrroles and their Benzo Derivatives: Reactivity
using sodium hydroxide in methanol at room temperature for 4 h afforded cleanly 3-(5-fluoroindolyl) 4-pyridinyl methanol 724 in 97% yield. Other 3-indolyl 4-pyridinyl methanols 724 were prepared similarly <2001TL7333>. Triethylsilane was selected for reduction of 3-indolyl 4-pyridinyl methanols 724 to 3-(4-pyridinyl)methylindoles 725 as a mild and readily available reducing agent. Thus, treatment of product 724 (R1 ¼ F, R2 ¼ H) with Et3SiH in CH2Cl2 in the presence of CF3CO2H at room temperature overnight gave the compound 725 (R1 ¼ F, R2 ¼ H) as a single product, which was isolated in 80% yield. Under similar conditions, other 3-(4-pyridinyl)methylindoles 725 were prepared in 66–78% overall yield <2001TL7333>.
Scheme 142
Scheme 143
153
154
Pyrroles and their Benzo Derivatives: Reactivity
As an extension to the new method, 3-(3-pyridinyl)methylindole 727 was prepared in 50% overall yield using nicotinaldehyde 726 (Equation 172) <2001TL7333>. The new method is an improvement on other approaches and can be used to prepare other pyridinylmethylindole isomers.
ð172Þ
New bridged b-carbolines were synthesized via a short synthetic route, the key step of which is a Pictet–Spengler condensation under neutral conditions, employing a cyclic amine and several aldehydes <1998TL1441>. Reaction of indole with 1-benzylpiperidin-3-one in the presence of MeONa was followed by in situ dehydration of the intermediate indolyl-3-piperidinol, which occurs unconjugated to the nitrogen lone pair, resulting in tetrahydropyridine 728 (Scheme 144). Reduction of the double bond and debenzylation were achieved in one step by hydrogenation affording indolylpiperidine 729. The Pictet–Spengler condensation of piperidine 729 was performed using various aldehydes under nonacidic, aprotic conditions. Usually the new bridged tetrahydro-b-carbolines were formed in good yield and as a mixture of diastereomers 730 and 731 (in a ratio of 730:731 ¼ 1–19:1).
Scheme 144
Treatment of different substituted indoles 732 with commercially available 1-acetylimidazolidin-2-one 733 in the presence of phosphorus oxychloride afforded after hydrolysis in ethanol the corresponding C-connected 3-(4,5dihydro-1H-imidazole-2-yl)-1H-indoles 734 in moderate to good yields (Equation 173) <2001TL5187>.
ð173Þ
Pyrroles and their Benzo Derivatives: Reactivity
After treatment of cyclobut-3-ene-1,2-dione 735 at 78 C with 2-lithiated N-methylindole followed by quenching the reaction mixture at 78 C with methyl triflate and warming to room temperature, adduct 736 was isolated in good yield (Scheme 145) <1997TL3663>. After prolonged thermolysis in refluxing mesitylene (64 h) adduct 736 was transformed into the angularly-fused xanthone 738 in 97% yield. The formation of xanthone 738 most likely proceeds through the benzannulation product 737 which is produced by a cascade of electrocyclization reactions initiated by ring-opening of the cyclobutenedione. Intermediate 737 underwent in situ cyclization and elimination of methanol to produce xanthone 738.
Scheme 145
A novel Mannich reaction between N-alkoxycarbonylpyrroles 739, formaldehyde, and primary amine hydrochlorides catalyzed by Y(OTf)3 gave a monoaminoalkylation product 741 some times in good yield (14–81%) in aqueous media (Scheme 146) <2001TL461>. When formaldehyde was replaced by acetaldehyde or benzaldehyde, no reaction occurred. There was no formation of the 2,7-diazabicyclo[2.2.1]hept-5-ene 740 (through the aza-Diels– Alder reaction of an N-protected pyrrole with an aldehyde and amine salts by catalysis with triflate).
Scheme 146
Reaction of lithiated N-phenylsulfonylindole with 3-decanone and a variety of aromatic ethyl ketones produced the aldol adducts of type 742 in 60–90% yield (Scheme 147) <2000SL1757>. Subsequent treatment of the carbinol 742
155
156
Pyrroles and their Benzo Derivatives: Reactivity
(R ¼ n-C7H15) first with TFA/TEA mixture in chloroform and then via addition of NaOH in EtOH provided the isomeric 2-vinylindoles 743 and 744 (NMR ratio of 2:1) in which the indole was desulfonylated. In the case of the corresponding transformation of the indole carbinols 742 when R ¼ Ar or HetAr other conditions were necessary. Direct elimination of water, and hydrolysis of carbinols 742 with ethanolic aqueous NaOH resulted in the formation of the aromatic 2-vinylindoles 745.
Scheme 147
An efficient method was developed for the synthesis of new 6,11-dihydroindolo[1,2-b]isoquinoline derivatives 747 by reaction of easily available N-(2-lithiobenzyl)-2-lithioindole 746 with a wide range of aliphatic or aromatic carboxylic esters as electrophiles (Scheme 148) <2007ARK84>.
Scheme 148
The treatment of dilithiated compound 748, formed from 2-bromo-N-(2-bromoallyl)aniline with ButLi (5 equiv), with 1,2diketones afforded tetrahydrocyclopenta[b]indole derivatives 749 as single diastereomers (Equation 174) <1998JA4865>.
ð174Þ
Pyrroles and their Benzo Derivatives: Reactivity
With the application of pseudoenantiomeric cinchona alkaloids 750 (C(8)-(R),C(9)-(S)-cinchonidine, quinine, N-benzylcinchonidine, 9-O-acetylcinchonidine and (C(8)-(S),C(9)-(R)-cinchonine, quinidine, dihydroquinidine, N-benzylcinchonine, 9-O-acetylcinchonine) as catalysts in the Friedel–Crafts-type reaction of substituted indoles and ethyl 3,3,3-trifluoropyruvate, the synthesis of both enantiomeric hydroxyalkylated products becomes possible (Equation 175) <2005AGE3086>. It was found that cinchonidine was the best catalyst for the formation of enantiomer 751 (R5, R6, R7 ¼ H), while cinchonine gave the highest yield and ee value for enantiomer 752. Both catalysts provided excellent yields and enantioselectivities (up to 99% yield, ee 95%) of the opposite enantiomers.
ð175Þ
3.02.2.3.10
C-Reactions with heterocumulenes
Pyrrole-2-carboxylate decarboxylase from Bacillus megaterium PYR2910 catalyzes the decarboxylation of pyrrole-2carboxylate to stoichiometric amounts of pyrrole and CO2 <1998MI480, 2001JMO179>. Due to an equilibrium constant of 0.3–0.4 M, the enzyme also catalyzes the reverse carboxylation of pyrrole after the addition of bicarbonate, but the concentration of solubilized bicarbonate was the carboxylation limiting factor (Equation 176) <1998TL4309>. By addition of high amounts of bicarbonate, the reaction equilibrium was shifted towards pyrrole-2-carboxylate. Addition of bicarbonate was accompanied by CO2 gas evolution resulting in an increased pressure in the tightly closed reaction vessel. Bioconversion was carried out at 20 C in a mixture of ammonium acetate (as enzyme cofactor), potassium phosphate buffer (KPB), sodium L-ascorbate (as antioxidizing, enzyme protecting agent), pyrrole, KHCO3, and concentrated cells (optical density at 610 nm of 40) as biocatalyst. The yield was 80%, limited by the equilibrium. Pyrrole-2-carboxylate is employed in the synthesis of various pharmaceuticals, antiviral for AIDS, HIV-1, IL-1 inhibitor, angiotensin II blocker <1990AJC355, 1991JME3350> and a potential herbicide <1996BML2853>.
ð176Þ
The CO2 fixation on pyrrole catalyzed by cells of Bacillus megaterium PYR2910 is also reported <1998MI495, 2000MI111, 2001CC2194, 2001JMO179, 2004GC440>. Pyrrole was converted to pyrrole-2-carboxylate in supercritical carbon dioxide (scCO2) using these cells at 10 MPa and 40 C and the yield of the carboxylation reaction in this medium was 12 times higher than that under atmospheric pressure (Equation 177).
ð177Þ
Starting from the 1-[(trifluoromethyl)phenyl]pyrroles 753, 756, and 760, the mono- 754, 758, 759, 762, and 763 and the dicarboxylated 755, 757, and 761 derivatives were selectively prepared as shown (Equation 178, Schemes 149 and 150) <1999T7881>. The regioselective formation of the monocarboxylic acids could be rationalized in light of the data
157
158
Pyrroles and their Benzo Derivatives: Reactivity
collected from the literature. Explanation of the other phenomena, such as regioselective dilithiation and the strong effect of the trifluoromethyl group on the structure and aromaticity of the pyrrole ring in the ortho-position, has been elucidated by the aid of molecular modeling and single-crystal X-ray measurements.
ð178Þ
Scheme 149
Scheme 150
Novel methods for site-selective lithiation of 1-(chlorophenyl)-1H-pyrroles and 1-(methoxyphenyl)-1H-pyrroles are described (Equations 179–181) <2001J(P1)1039>.
Pyrroles and their Benzo Derivatives: Reactivity
ð179Þ
ð180Þ
ð181Þ
Mono- or dilithiations are governed by change of both the temperature and the solvent from THF to Et2O. Regioselectivities could be influenced by the quality of the metallating agent. Thus, 1-(4-chlorophenyl)-1H-pyrrole was dilithiated with activated (TMEDA, PMDTA) BunLi at 0 C to afford a valuable intermediate in a pyrrolobenzoxazepine synthesis. Consecutive treatment of the o-, m- and p-substituted 1-phenylpyrroles 764–766 with organometallic base and solid CO2 provided mono- and dicarboxylic acids as a mixtures or sole products depending on the reaction conditions used. Multicomponent mixtures formed instead of the desired products when the o- and m-brominecontaining substrates were consecutively treated with LITMP and solid CO2. Metallation and consecutive carboxylation of the p-isomer 766 afforded acid 767 as the main product, but the formation of acid 768 (due to elimination of LiBr) could not be avoided even when 20% excess of 2,2,6,6-tetramethylpiperidide (TMP) was used relative to the amount of BunLi <2001J(P1)1039>. Previously it is believed that addition of pyrrole anion to carbon disulfide gives mainly pyrrole-N-carbodithioates . However, the pyrrole anions generated in the KOH/DMSO system attack carbon disulfide either exclusively or preferably at their position 2 to afford pyrrole-2-carbodithioate anions, which, after alkylation, give the corresponding esters of pyrrole-2-carbodithioic acids 769 in 44–71% yield (Equation 182). The only exception is unsubstituted pyrrole giving exclusively pyrrole-1-carbodithioate. Under the same conditions in diethyl ether, THF or isopropyl alcohol pyrroles are returned unreacted, that is, the KOH/DMSO system is a specific reagent for this synthesis .
159
160
Pyrroles and their Benzo Derivatives: Reactivity
ð182Þ
Substituents in the pyrrole ring affect drastically the ratio of pyrrole-1- and pyrrole-2-carbodithioate isomers. In the case of unsubstituted pyrrole only the N-isomer is formed in 63% yield and practically no the 2-isomer is detected. As soon as just one methyl is introduced into the pyrrole a-position, the pyrrole-2-carbodithioate becomes the only product of the reaction in 46% yield and none of the N-isomers is discernible in the reaction mixture at all. Any combinations of alkyl substituents in the pyrrole ring give selectively pyrrole-2-carbodithioates, in a yield of up to 71%. The regioselectivity of this reaction changes again when the aryl substituent appears at the pyrrole a-position: along with the major pyrrole-2-carbodithioates (44–59%), the N-isomers 770 are also formed in 24–33% yields . When both the pyrrole a-positions are substituted only pyrrole-3-carbodithioates 771 have been isolated, the yield being 36–61% (Equation 183). No pyrrole-1-carbodithioates have been detected among the products <2000T7325, B-2003MI127, 2005MI97>.
ð183Þ
The regiochemistry of the addition of multident pyrrole anions to carbon disulfide has been theoretically analyzed. Results have been explained by the basic regularities of the pyrrole derivatives reactions in superbasic systems <2001SUL181, 2001ZSK645, 2002IJQ542, 2004IJQ360, 2004ZSK990>. As highly nucleophilic species, pyrrole-2-carbodithioate-anions 772, generated in situ from pyrrole and carbon disulfide in the KOH/DMSO system, add smoothly to electrophilic alkenes like acrylonitrile, acrylamide or methyl acrylate to afford the corresponding derivatives of propionic acid 773 in a yield of up to 62% (Scheme 151) <1999ZOR1534, 2001S0293>.
Scheme 151
Electrophilic alkynes are also very active acceptors of pyrrole-2-carbodithioate-anions. Thus, the addition of 4,5,6,7-tetrahydroindole-2-carbodithioate 772b to acylalkynes occurs to furnish stereoselectively the (Z)-adducts 774 (Scheme 152). The sterically overcrowded double bond of adducts 774 still remains active enough to participate
Pyrroles and their Benzo Derivatives: Reactivity
in the further intramolecular ring closure to give (in a one-pot procedure) functionally substituted pyrrolothiazolidines 775. The reaction proceeds readily in a two-phase system (aq DMSO/Et2O) in the presence of KOH (Scheme 152) <2001RJO547, 2001S0293>.
Scheme 152
An acyl isocyanate 777 was used as the electrophile in a Friedel–Crafts-type substitution of suitable pyrrole derivatives 776 and 778 (Scheme 153) <1999MOL151>.
Scheme 153
Pyrroles 779 and 781 were regioselectively acylated with ethoxycarbonyl isothiocyanate, affording acylated thioamides 780 and 782, respectively, as intermediates in the synthesis of pyrroloamidines, guanidine bioisostere analogs (Equations 184 and 185) <2001JME1217>.
ð184Þ
ð185Þ
161
162
Pyrroles and their Benzo Derivatives: Reactivity
3.02.2.3.11
C-Reactions with miscellaneous electrophiles
2-Indolyl borates are prepared via addition of LDA to a mixture of N-BOC-indole and triisopropyl borate at 0–5 C (Equation 186) <2002JOC7551>. Following acidic hydrolysis, the boronic acids 783 are isolated by crystallization in good to excellent yield (73–99%). The method is quite general, tolerating a wide range of functional groups. A similar procedure provides access to 2-silyl derivatives 784 (80–91%) (Equation 187).
ð186Þ
ð187Þ
An iridium(I) complex, generated from 1=2[Ir(OMe)(COD)]2 and 4,49-di-t-butyl-2,29-bipyridine (dtbpy), catalyzed the direct borylation of 2-substituted pyrroles in stoichiometric amounts relative to 2,29-bi-1,3,2-dioxaborolane 785 in hexane at room temperature (Equation 188) <2003ASC1103>. The pyrrolylborates 786 from regioselective C–H activation at the 5-position were formed in high yields. Similar borylation of unsubstituted pyrrole with an equimolar amount of borolane 785 regioselectively provided 2,5-bis(boryl)pyrrole 787 (Equation 189).
ð188Þ
ð189Þ
Iridium complexes generated from [IrCl(COD)]2 and 2,29-bipyridine (bpy) catalyze the borylation of pyrrole and indole derivatives to yield the borylated products 788 in moderate to good yields (Equation 190) <2004JMO21>.
ð190Þ
Treatment of dianion 746 with the metallodichlorides of silicon or germanium gave rise to the new fused indolo silicium derivative 789 (M ¼ SiMe2) or indolo germanium derivative 789 (M ¼ GeMe2), respectively (Equation 191), in good yields referred to the starting N-(2-bromobenzyl)-1H-indole (see Section 3.02.2.3.9) <2007ARK84>.
Pyrroles and their Benzo Derivatives: Reactivity
ð191Þ
A simple, convenient and efficient protocol for the electrophilic thiocyanation of indoles with ammonium thiocyanate using anhydrous FeCl3 as an inexpensive and readily available catalyst was developed <2005S0961>. The reaction went to completion within 3 h at room temperature in dichloromethane and the product, for example, 1H-indol-3-yl thiocyanate 790 (R1, R2, R3 ¼ H), was obtained in 92% yield (Equation 192).
ð192Þ
5-Chloro-2-(phenylsulfanyl)-1H-indole 792, the starting compound for various syntheses, was prepared in 67% yield in two earlier described steps (Scheme 154) <2001TL5187>. 5-Chloro-1H-indole was treated with diphenyl disulfide as described in the general procedure <1988S0480> and the resulting 5-chloro-3-(phenylsulfanyl)-1Hindole 791 was isomerized in PPA into the indole 792 <1992JOC2694>.
Scheme 154
A facile and efficient sulfenylation method using quinone mono-O,S-acetals (793 or PhS-analog) under mild conditions was successfully applied to various pyrroles and indoles (Equations 193 and 194) <2001JOC2434>. The phenylsulfenyl analog of compound 793 reacted similarly to give regioselectively the corresponding sulfide in 43–99% yields.
ð193Þ
ð194Þ
163
164
Pyrroles and their Benzo Derivatives: Reactivity
Sulfenylation of indole using sulfenyl chlorides leads to the initial formation of a 1H-indol-3-yl sulfide, while excess reagent introduces a second sulfide at the 2-position of the ring. Sulfenylation of 1H-indol-2-yl sulfides 794 occurs as expected at the 3-position, selectively affording 2,3-bis(methyl- or arylsulfanyl)-1H-indoles 795 in good yields (Equation 195) <1996JOC1573>. These results have allowed the study of the sulfenylation of 1H-indol-3-yl sulfides 796 using a different sulfenyl chloride (Scheme 155). The results obtained (formation of the derivatives 797–800) afford evidence that the reaction proceeds via an intermediate 3,3-disulfenylated indolenine species 801, with subsequent migration of one of the sulfide groups to the 2-position, as has been suggested earlier (Equation 196) <1986T4503>.
ð195Þ
Scheme 155
ð196Þ
3,39-Dipyrrolyl sulfides 803, useful building blocks for linear or cyclic polypyrrolic ligands, were prepared, in high yield, by the reaction of sulfur dichloride with 3-unsubstituted pyrroles 802 at low temperature (Equation 197) <2001S0040>.
ð197Þ
Pyrroles and their Benzo Derivatives: Reactivity
Di- and trisulfide linked oligopyrrolic macrocycles 805, 807, and 809 are obtained when appropriate 2,5-free pyrrolic precursors 804, 806, and 808 are reacted with disulfur dichloride (Equations 198–200). The isolated yields were 21%, 34% (R ¼ Me), and 27%, respectively <2005CC2122>. These systems represent the first examples of what might be a general new class of porphyrin analogs.
ð198Þ
ð199Þ
ð200Þ
Treatment of pyrroles with disulfur dichloride (S2Cl2) in the presence of a base in chloroform at ambient temperature provides a simple and direct one-pot synthesis of fused mono- and bis(1,2,3,4,5-pentathiepins), that are of particular interest because of their unusual stability, stereochemistry, occurrence in nature, and significant biological activity <2002CRV3905, 2002CC1204, 2003ARA101, 2003ARB161, 2004CRV2617, 2004MC91, 2005OBC3496, 2005OL5725, 2006OL4529>. Thus, N-methylpyrrole is converted by S2Cl2/DABCO (1,4-diazabicyclo[2.2.2]octane) into the 2,5-dichloropentathiepine 810 in CHCl3 at room temperature (Equation 201) <2002CC1204, 2003ARA101, 2003ARB161>. Without added base, the yields were very low even though the starting pyrrole was consumed, but with pyridine, triethylamine, or DABCO the yields were 30–50%, the best being obtained with 5 equiv each of S2Cl2 and DABCO.
165
166
Pyrroles and their Benzo Derivatives: Reactivity
ð201Þ
The decisive role of DABCO was also seen in the analogous reactions of N-methylindole (Equation 202). Treatment of the latter with S2Cl2 (5 equiv) and DABCO (5 equiv) gave the 2,3-dichloroindole 811 in high yield (78%), but with a deficiency of S2Cl2 (0.8 equiv) in the absence of a base the only product was the unchlorinated pentathiepin 812 in 72% yield.
ð202Þ
A mixture of equimolar amounts of S2Cl2 and DABCO in CHCl3, stored for 48 h at 0 C before use, gave different products to those formed when azole, S2Cl2 and DABCO were all mixed together at the beginning. It was assumed that the 1:1 mixture contains complex 813 predominantly, and the 1:2 mixture, complex 814 predominantly (Scheme 156). These complexes could well display different reactivities since complex 813 is a potential source of Clþ and þS–SCl and could be an electrophilic chlorinating and sulfurating agent whilst complex 814 should react only as the latter. Complex 814 in the 1:2 mixture is also fully formed in about 1 h at 20 C and then decomposes slowly with the formation of S8 and, in the presence of a reacting substrate, DABCO hydrochloride.
Scheme 156
Treatment of N-alkylpyrroles with a fivefold excess of a complex 814 gave products 815 in low yields (23% and 14%) together with dichlorinated 7H-[1,2,3,4,5]pentathiepino[6,7-c]pyrroles 816 (Equation 203) <2004MC91>. Sulfur dichloride chlorinated thiepin 815 (R ¼ Me) with concomitant rearrangement of the pentasulfur ring to give product 816 (R ¼ Me). If this migration of the intact pentasulfur ring in compounds 815 ! 816 is prevented by substitution as in N-alkylindoles, initially formed b-fused products 817 are isolated in relatively high yields (Equation 204).
ð203Þ
Pyrroles and their Benzo Derivatives: Reactivity
ð204Þ
Treatment of N-substituted 2,5-dimethylpyrroles 818 with complex 813 in chloroform at 0 C gives 7H-[1,2,3,4,5]pentathiepino[6,7-c]pyrroles 819 in moderate yields (36–40%) (Scheme 157) <2005OL5725>. Further reaction of pyrroles 819 with the same mixture at room temperature leads, in an extensive reaction cascade, to 4-alkyl-3H-di[1,2]dithiolo[4,3-b:3,4-d]pyrrole-3,5(4H)-dithiones 820 in high yield (74–85%). Compounds 818 can be converted into the tricycles 820 in a one-pot operation under unusually mild conditions (with excess of S2Cl2 and DABCO). Pentathiepino[6,7-c]pyrroles 819 were obtained directly with a nonequilibrated mixture of S2Cl2 and DABCO, but in low yields (8–17%).
Scheme 157
When N-methyl-2,5-diphenylpyrrole was treated with complex 813 under the same conditions pentathiepinopyrrole 821 was obtained in good yield (62%), but treatment of this with complex 813 gave no further reaction even on heating for 3 h, the pentathiepane ring remaining intact (Scheme 158).
Scheme 158
If the pyrrole C(1)-positions are chlorinated, the pentathiepane ring is fused across the 3,4-pyrrole bond to give pentathiepinopyrroles of type 819 (Cl for Me) in high yield <2005OBC3496>. Thionation of 3,39-biindolyl derivatives 822 with elemental sulfur in refluxing DMF produced the tetrasulfides 823 in a moderate yield (Equation 205) <2002J(P1)330>. Treatment of the diketone 824 with P4S10 in pyridine gave a complicated mixture from which a small yield of thienoindole derivative 825 could be isolated (Equation 206).
ð205Þ
167
168
Pyrroles and their Benzo Derivatives: Reactivity
ð206Þ
3.02.2.4 Reactions with Nucleophiles Although pyrrole is an electron-rich heterocycle which does not react with nucleophiles, the Z5-coordination of pyrrole or of the pyrrolyl anion to certain transition metal fragments activates the heterocycle toward nucleophilic attack <1998CCR191 and references therein>. In the pyrrolyl complexes (C4H4N)Re(PPh3)2(H) and (C4H4N)Ru(PEt3)2Cl, nucleophilic substitution reactions at the 2-position of the ring follow a pathway that involves hydrogen transfer from the ring to the metal ion with displacement of a labile halide ligand from the metal center. Nucleophilic addition of hydride and methoxide anions to the neutral pentamethylpyrrole ligands in [(MeNC4Me4)M(cymene)](OTf)2, M ¼ Ru and Os, has been found to occur at the a-carbon atom of the heterocycle <1998CCR191>. Several examples have been reported and discussed in recent reviews <2001T1639, 2002CHE371, 2004CRV2631> of nucleophilic substitution of hydrogen in N-substituted nitropyrroles and nitroindoles, including vicarious nucleophilic substitution (VNS), cine- and tele-substitution. Unprotected 5-(4-nitrophenyl)-10,15,20-triphenylporphyrin and 5,10-bis(4-nitrophenyl)-15,20-diphenylporphyrin react with carbanions (which bear a leaving group X such as Cl, Br, PhO, PhS at the carbanionic center) in the presence of a base at low temperature affording VNS products in good yields (50–89%) <2003TL4373>. The products of VNS of 2-nitro- and 3-nitropyrroles with chloromethyl sulfones are depicted in Equations 207 and 208, respectively <1995T8339>. When R1 ¼ Ts, pyrrole 827 (83% yield) was the only reaction product, but in the case of 1-(methoxymethyl)-2-nitro-1H-pyrrole a mixture of pyrroles 826 and 827 (14%), with predominance of 5-substituted isomer 826 (74%), was obtained. Electron-donating alkyl substituents direct the reaction exclusively to position 5 with formation of pyrroles 826 in 68–93% yields. From the reaction of 1-methyl-3-nitropyrrole with chloromethyl sulfones 2-substituted products 828 were isolated.
ð207Þ
ð208Þ
2-Nitro-1-(phenylsulfonyl)-1H-indole 829 undergoes nucleophilic addition reactions with enolates of diethyl malonate and cyclohexanone, lithium dimethylcuprate (Scheme 159), and indole anion (Equation 209) to afford the corresponding 3-substituted 2-nitroindoles in low to high yields <1997TL5603, 1999TL7615>. Replacement of hydrogen in position 3 is accompanied by elimination of the benzenesulfonyl group in a process resembling tele-substitution. The reaction of indole 829 with anion of indole yielded a mixture of the bis-indoles 830 and 831, separable by column (Equation 209).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 159
ð209Þ
1,2-Bis(phenylsulfonyl)-1H-indole 832 with lithium dimethylcuprate gave 3-methyl-2-(phenylsulfonyl)-1H-indole 833 in 68% yield (Equation 210) <1997TL5603, 1999TL7615>, but preliminary attempts to effect similar C(3)nucleophilic addition with lithium dimethylcuprate to 2-acetyl-, 2-cyano-, and 2-carbomethoxy-1-(phenylsulfonyl)1H-indoles were unsuccessful, although small amounts of product seem to form.
ð210Þ
The indole 836, the product of cine-substitution in the Stille reaction of the 3-iodoindole 834 with the trimethylstannyl derivative of imidazole 835, was obtained as shown in Equation 211 <1998H(48)11>.
ð211Þ
Reactions of pyrroles 837 with ethanethiol and various bases at room temperature gave the products 838 of nucleophilic substitution at the pyrrole 5-position (Equation 212) <2005T5831>.
169
170
Pyrroles and their Benzo Derivatives: Reactivity
ð212Þ
In the reaction of the N-methyl-2,5-dichloropyrrole-3,4-dicarbaldehyde 839 with 4-methoxyaniline, substitution of one of the chloro groups can be accompanied by imine formation with both aldehyde groups (Equation 213) <2005T5831> while the reaction of 2-chloropyrrole-3-carbaldehydes 840 with N-allyl-N-methylamine and allyl hydrosulfide led to the substitution of the chloro group, resulting in the formation of pyrroles 841 in high yield (70–83% and 60–74%, respectively) (Equation 214) <2000T3013>.
ð213Þ
ð214Þ
Two new alkylsulfanyl derivatives of pyrrole, 3,4-bis(methylsulfanyl)- and 3,4-bis(butylsulfanyl)-2,5-dimethyl-1phenylpyrroles 843 have been prepared by different methods as good models to study the influence of the substituents into the generation and stability of their radical cations, by cyclic voltammetry and EPR spectroscopy. 2,5-Dimethyl-1-phenylpyrrole was reacted with N-bromosuccinimide to yield 3,4-dibromo derivative 842 in quantitative yield (Scheme 160) <2000J(P2)905>.
Scheme 160
Pyrrole 843 (R ¼ Me) was formed in moderate yield (30%) by treatment of 3,4-dibromo pyrrole 842 with BunLi and then with dimethyl disulfide. Pyrrole 843 (R ¼ Bun) was prepared according to Klingsberg’s method, by treatment of dibromide 842 with copper(I) n-butanethiolate in a mixture of quinoline and pyridine to give the desired product in 33% yield. In both cases, the monosubstituted derivatives 844 were obtained as intermediates in 45% and 10.5% yields, respectively.
Pyrroles and their Benzo Derivatives: Reactivity
Solid-phase synthesized polymer-bound 3-iodoindole 845 subjected to the Sonogashira and Suzuki coupling reactions afforded the corresponding coupling products 846 and 847 in 91% and 80% yields, respectively, as determined by transesterification and isolation of the corresponding methyl esters (Scheme 161) <2005JCO809>.
Scheme 161
Similarly, palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the 3-iodoindoles proceed smoothly in good yields to give 2,3-disubstituted indoles 848, 849, and 850, respectively (Scheme 162) <2006JOC62>.
Scheme 162
A variety of 3-substituted b- and g-carbolines have been synthesized from N-substituted 3-iodo-1H-indole-2-carbaldehydes and 2-bromo(iodo)-1H-indole-3-carbaldehydes, respectively (Schemes 163 and 164) <2002JOC7048>. The coupling of these aldehydes with various terminal acetylenes with PdCl2(PPh3)2/CuI as the catalyst readily affords the corresponding alkynylindole carbaldehydes, which have subsequently been converted to the corresponding t-butylimines and cyclized to b- and g-carbolines either a copper-catalyzed or a thermal process.
171
172
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 163
Scheme 164
Oligoindoles 855–857 (Figure 4), which can serve as foldamers with a helical conformation induced by chloride, were prepared by repeating Sonogashira coupling reactions: tetramer 855 from indoles 851 and 852 (2 equiv), hexamer 856 from two trimers 853 and 854, and octamer 857 from dimer 851 and trimer 854 (2 equiv) (Scheme 165) <2005JA12214>.
3.02.2.5 Oxidation of the Heterocyclic Ring Oxidation of pyrroles and indoles continues to be extensively studied because these heterocyclic nuclei are involved in photobiochemical processes covering various physiological functions of mammals and photodynamic therapy and diagnosis in clinics <1995CSR19, 2001BP351, 2001MI39, 2001T2279>. Oxidation or oxidant-mediated reactions of pyrrole ring and its substituents are the key steps in construction or modification of porphyrins, porphyrin-like systems <2000TL8121, 2001TL2447, 2001TL4527, 2004CC1902, 2004S2205, 2005ACR10>, alkaloids <2003AGE3582, 2004AGE2674, 2004M615> and other naturally occurring important bioactive compounds <2004JA10252, 2004TL2809>, as well as polymeric materials <1996JEC197, 1997PCB5698, 1998CC2409, 1998JEC(453)139, 2001MI3279, 2002SM(129)309>.
Pyrroles and their Benzo Derivatives: Reactivity
Figure 4
Scheme 165
Autooxidation of the pyrrole 858 (30 C) leads to the 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one 859 (Equation 215) <2003T8499>. In similar reactions, pyrroles were transformed to hydroxypyrrolones by oxidation with O2 (UV irradiation, a photosensitizer or an radical initiator) .
ð215Þ
The N-(pyrrol-2-yl)carbamates 860 are oxidized smoothly by air to a mixture of the N-(5-hydroxy- 862 and 5-hydroperoxy- 863 -1,5-dihydro-2H-pyrrol-2-yliden)carbamates (in 63% and 8% yield, respectively, when R1 ¼ H, R4 ¼ Bn) (Scheme 166) <1997TL1293>. Oxidation with pure oxygen gives the same products in a yield of 47% and
173
174
Pyrroles and their Benzo Derivatives: Reactivity
of 41%. Similar results were obtained with the N-methyl derivative 860 (R1 ¼ Me, R4 ¼ Bn). In the reaction, 1,3-dihydro-2H-pyrrol-2-one 864 (R1 ¼ Me, R4 ¼ Bn) is also formed in yield of 65% (with air) or 21% (with oxygen). The intermediate endo-peroxide 861 was identified by 1H NMR at low temperature (78 C).
Scheme 166
The dioxygenolysis (THF or CH2Cl2, air, 25 C, 24 h) of tryptophan analogs 865 (3-methylindole and methyl N-acetyl-L (or D)-tryptophanate) with achiral metalloporphyrins (MIITPP (M ¼ Mn, Fe, or Co)) or chiral manganese(II) porphyrins (MnIITPP) gives ring-opening products 866 in a yield of 9–32% together with minor products 867–871 (Equation 216) <1996JMO269>. 3H-Indol-3-yl hydroperoxides 872 were observed (NMR) as a stable precursor of the formamide 866 (Scheme 167). From isotopic experiments it follows that the rate-determining step is the deprotonation of the 1-NH-position by the activated dioxygen (O2 – ).
ð216Þ
Photooxidation of pyrroles often gives a mixture of both 1,2- and 1,4-adducts. When both electron-releasing and electron-withdrawing substituents are present in the pyrrole ring, the reactions can be better controlled. Singlet oxygen oxidation of t-butyl 3-methoxy-1H-pyrrole-2-carboxylate 873 activates the pyrrole ring for nucleophilic substitution <1996TL6657, 1999TL6145, 1999TL7587>. The oxidation of pyrrole 873 by 1O2 (CH2Cl2, oxygen, methylene blue, UV irradiation, 78 C) yields an intermediate t-butyl 2-hydroperoxy-3-methoxy-2H-pyrrole-2carboxylate 874, which may be trapped by a variety of nucleophiles to form 5-substituted pyrroles 875 in 25–78%
Pyrroles and their Benzo Derivatives: Reactivity
yield (Scheme 168). The coupling of intermediate 874 with pyrroles as nucleophiles yields precursors of prodigiosin 876, readily convertible to the corresponding tripyrromethanes <1999TL7587>. With strong electron-releasing substituents at the 5-position, pyrroles 875 may add to unreacted hydroperoxide 874 to form the dipyrrole 877 <1999TL6145>. In alcohols 5-alkoxypyrroles are formed <1996TL6657>.
Scheme 167
Scheme 168
The photooxygenation of 2-methylpyrroles 878 (CH2Cl2, oxygen, TPP, irradiation, rt, 1–2 h) furnishes the corresponding 5-methylene-1,5-dihydro-2H-pyrrol-2-ones 880 in 58–76% yield along with minor products – 5-hydroxy- 881 and 3-hydroxy- 882 dihydropyrrolones (Scheme 169) <2002TA601>. The base-catalyzed (10% pyridine) opening of the intermediate endo-peroxide 879 decreases the yield of products and selectivity of the reaction. Dihydropyrrolones 880 or 881 are building blocks for a variety of biologically active compounds <2000TL9859>. Under similar conditions, the 2-(2-methyl-1H-pyrrol-1-yl)ethanol derivatives 883 afford in high diastereoselectivities the bicyclic pyrrol-2-ones 885 in 47–61% yield, which are utilized in total synthesis of some natural products (Scheme 170) <2000TL9859, 2004TA259>. The formation of bicycles 885 from the endo-peroxide 884 involves either the intramolecular nucleophilic attack of OH or an open zwitterion.
Scheme 169
175
176
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 170
Oxidation of the pyrrole 886 mainly gives the pyrrol-2-one 887 (Equation 217) <2004TA259>.
ð217Þ
The substituted pyrrole-2-carbaldehydes 888 and the 5-(1H-pyrrol-2-ylmethyl)-1H-pyrrole-2-carbaldehydes 891 are oxidized by hydrogen peroxide under mild conditions to give pyrrol-2-ones 889, 890 and 892 (Equations 218 and 219) <2000TL2825>. In the study of the metabolism of ergot alkaloids, an oxidation (H2O2) catalyzed by a chloroperoxidase was observed (Equation 220) <1997LA2379>. The oxidation of indoles with H2O2 in the presence of the fungal chloroperoxidase from Caldariomyces fumago affords the 1,3-dihydro-2H-indol-2-ones 893 and 3-hydroxy1,3-dihydro-2H-indol-2-ones 894 (Equation 221) <2001T8581>. After a short reaction time, the indol-2-ones 893 were the main products; longer reaction time gave mainly the 3-hydroxyindol-2-ones 894. The 2-(1H-indol-3yl)ethanol and the 2-(1H-indol-3-yl)acetic acid were also tested as substrates, but no compounds could be isolated from their biotransformation, unchanged starting material being recovered.
ð218Þ
ð219Þ
Pyrroles and their Benzo Derivatives: Reactivity
ð220Þ
ð221Þ
Electrooxidation of indole in phosphate buffers gives the trimer 899 (presumably via intermediates 895–898) (Scheme 171) <1998MI47>. The results may provide a deeper insight into the redox chemistry of naturally occurring indoles. At pH > 6.0 the proton abstraction occurs from the intermediate 895 and the reaction proceeds through free radicals and neutral species.
Scheme 171
Both electrochemical and persulfate oxidations of indol-3-ylmethanol in phosphate buffers include a stepwise electron transfer <2001J(P2)618>. The final products of the two reactions are different: electrochemical reaction leads to the dialdehyde 901 (Scheme 172), whereas chemical reaction produces the dimer 902 via the common intermediate 900 (Scheme 173). In contrast to pentamethylpyrrole, octamethyl-1,19-dipyrrole 903 is stable to air for some days. The reaction of the dipyrrole with common chemical oxidants such as ferricenium (fcþ) or silver salts leads to complex mixtures of unidentified products. Oxidation with I2 in acetonitrile results in a dipyrrolium iodide [903Hþ]I3?1=2I2. Treatment of the dipyrrole 903 with NO[BF4] (CH2Cl2, rt, 12 h) gives the radical cation salt 904 (Scheme 174) <2000J(P2)353>. The primarily formed radical-cation 904 slowly abstracts a hydrogen atom, possibly from the solvent or the supporting electrolyte, to yield protonated dipyrrole 905.
177
178
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 172
Scheme 173
Scheme 174
3.02.2.6 Reduction of the Heterocyclic Ring The Birch reduction (with group I or II metals in ammonia) is one of the most convenient methods for the synthesis of partially hydrogenated aromatic and heteroaromatic compounds <1996TA317>. By analogy with both furan and thiophene, Birch reduction of the pyrrole nucleus should give the 3-pyrroline skeleton (2,5-dihydro-1H-pyrrole), which is a useful and versatile synthetic intermediate <1998J(P1)667, 1999T12309, 2000TL1327, 2004CC1422>. But
Pyrroles and their Benzo Derivatives: Reactivity
insofar as the pyrrole nucleus is too electron-rich to accept electrons and be reduced, and the presence of an acidic hydrogen atom on the pyrrole nitrogen which presents the possibility of deprotonation under Birch-type conditions, when the resulting anion would be extremely resistant to reduction, the first successful studies were carried out on the electron-deficient pyrroles such as N-alkylated and N-acylated 2-substituted (with an electron-withdrawing group) pyrroles 906 and 909, respectively (Equation 222 and Scheme 175) <1996JOC7664>. Birch reduction– alkylation of N-methylated pyrrole 906 with sodium in liquid ammonia (using 1 equiv of ButOH and quenching with MeI) gave the pyrroline 907 (albeit in modest yield) (Equation 222). In this reaction, pyrrole 906 was completely consumed, and the major product was the volatile aldehyde 908, which had resulted from amide reduction rather than pyrrole reduction.
ð222Þ
Scheme 175
A versatile and high-yielding protocol for reductive alkylation was found for N-BOC amide 909 by employing sodium metal (3 equiv) and omitting ButOH (Scheme 175). Both the amide and N-BOC protecting groups should be removable if this chemistry is to become synthetically useful. The Birch reduction–methylation of 1-(t-butyl) 2-isopropyl-1H-pyrrole-1,2-dicarboxylate also proceeded well and gave the corresponding pyrroline ester in excellent yield (87%). Saponification of this ester (aq KOH, MeOH) yields 1-(t-butoxycarbonyl)-2-methyl-2,5-dihydro-1Hpyrrole-2-carboxylic acid in 71% yield <1996JOC7664>. It was demonstrated that a series of electron-deficient pyrroles are capable of undergoing Birch reduction and reductive alkylation procedures to give C(2)-substituted 3-pyrrolines in good to excellent yields. The role of various activating groups (amide, ester, carbamate, and urea) has been examined with regard to both stability under the Birch conditions and ease of deprotection after reduction <1998J(P1)667>. Both the BOC and urea groups provide suitable protection for the pyrrole nitrogen and also activate the heterocycle towards reduction. Introduction of an ester or amide at C-2 allowed a reductive alkylation protocol to be performed and ensured the regiochemical outcome of the reaction. The identity of the Birch reduced products has been confirmed by X-ray crystallography on one derivative. The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either ()-8-phenylmenthol or (þ)-trans-2-(a-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the 1H-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THF at 78 C. The addition of N,N-bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities.
179
180
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 176
Nonalkylated 3,4-dehydroprolines 914 were obtained in 76–81% yields by diastereoselective protonation of an enolate resulting from Birch reduction of the N-BOC-pyrrole-2-carboxamide 913 (Equation 223) <1999T12309>. The reaction was quenched by addition of solid ammonium chloride after a reaction time of 1 h. The results using lithium and sodium are similar but the reaction with potassium failed. Remarkably, asymmetric protonation is more selective (de 88–90%) than methylation (de 50%). The selectivity decreases with increasing temperature (de 82% at 30 C). The diastereoselectivity of the reaction was detected by HPLC.
ð223Þ
The use of 1,1-diiodomethane as an electrophile in the Birch reduction (with lithium in liquid ammonia) of electron-deficient pyrroles 915 furnished pyrrolines 916 (in high to excellent yields), which provided access to the synthetically important functionalized 5,6-dihydro-2(1H)-pyridinones 917 (via radical ring expansion), substructures commonly found in biologically active natural products (Scheme 177) <2004CC1422>. 2-(Chloroalkyl)-substituted pyrrolines 919 were duly prepared by the reductive alkylation (with 1-chloro-3-iodopropane or 1-chloro-4-iodobutane) of electron-deficient pyrrole 918. Allylic oxidation then furnished lactams 920 (Scheme 178).
Scheme 177
Scheme 178
Pyrroles and their Benzo Derivatives: Reactivity
The synthesis of (S)-()-N-BOC-2-hydroxymethyl-2,5-dihydropyrrole (S)-()-923 with ee up to 98% was achieved by its irreversible acetylation catalyzed by Pseudomonas fluorescens lipase (Scheme 179) <1998TA403>. Precursor ()-922 for compound 923 can be easily prepared from commercially available pyrrole-2-carboxylic acid 921 by Birch reduction, followed by esterification and reduction according to literature procedure <1996JOC7664>.
Scheme 179
Changing the position of the electron-withdrawing group (either an amide or ester) to the C-3 of pyrrole allowed access via regioselective reductive alkylations to the corresponding 4-alkyl-2-pyrrolines 924 (Equation 224) and 925 (Equation 225) in good yields <1998TL3075>. Reduction of 3-substituted pyrroles was more difficult to achieve than that of the 2-substituted isomers.
ð224Þ
ð225Þ
Reduction of the mixture of 1-[(2-aziranyl)methyl]-1H-indole-3-carbaldehydes 926 was readily achieved with NaBH4 in MeOH to produce {1-[(2-aziranyl)methyl]-1H-indol-3-yl}methanols 927, reductive cyclization of which is a route to (1,1a,2,8,8a,8b-hexahydroazireno[29,39:3,4]pyrrolo[1,2-a]indol-8-yl)methanol 928 (Scheme 180) <1997JOC1083>.
Scheme 180
Some earlier methods for reduction of pyrrole and indole nucleus (including metal-promoted reduction, hydrogenation and reduction with use hydride sources) have been examined in a recent review <1996TA317>.
181
182
Pyrroles and their Benzo Derivatives: Reactivity
3.02.2.7 Reactions with Radicals, Carbenes, Nitrenes, and Silylenes Earlier reported intramolecular radical cyclizations of 1-(o-iodoalkyl)pyrroles and indoles under oxidative conditions <1992CJC1838, 1994CJC15, 1994JOC2456> have received further development. The utility of the oxidative protocol using tributylstannane in the syntheses of novel heterocyclic systems is well exemplified. Further studies are being carried out also to elucidate the mechanism of these reactions. Cyclization of aryl radicals on to either 2- or 3-carbonyl substituted pyrroles occurs preferentially at the 2-position. In the case of the former cyclizations, the yields are poor but this could represent a rapid approach to a range of indole alkaloids. Thus, cyclization of 2-substituted pyrroles 929 by treatment with Bu3SnH (0.02 M) and AIBN (catalytic amounts) as initiator in refluxing toluene for 12 h gave the 5-exo cyclization products 931 and 932 as the major products judging by 1H NMR of the crude product (Scheme 181) <1995TL6743>.
Scheme 181
Presumably, isomer 931 arises via reaction of the allylic radical 930 with Bu3SnH. No product of cyclization to C-3 of the pyrrole (6-endo) was detected indicating a preference for radical addition to C-2. Cyclization of pyrroles 933, in which the linking chain is attached to C-3 of the pyrrole ring, gave exclusively the rearomatized 6-endo cyclization product 935 via the intermediate radical 934 (Scheme 182). This cyclization proceeds in moderate yield to give a novel pyrroloquinolone ring system.
Scheme 182
Later it was shown that the intramolecular cyclization of aryl radicals onto a pyrrole in which the linking chain is attached to the C(3)-position allows the synthesis of either the pyrrolo[3,2-c]quinoline 940 or the spiropyrrolidinyloxindole 942 skeleton depending on the nature of the protecting group on the N-pyrrole atom <2000TL8951, 2002T1453>. The regiochemistry of the cyclization is not affected by the substituent on the benzene ring. When R1 ¼ H, the radical cyclization precursors 936 subjected to standard reductive radical cyclization conditions gave a mixture (ca. 2:1) of regioisomeric pyrroloquinolines 940 (6-endo-products, via radical 937) and 941 (6-exo-products, via radical 938), respectively (Scheme 183). In a similar manner, cyclization of precursor 936, when R1 ¼ BOC, under the standard conditions furnished a mixture of three products with 942 (5-exo cyclization via radical 939) as the major product (26–31%). Pyrroles substituted on nitrogen with an electron-withdrawing group (carbamate), give rise to the spiropyrrolidinyloxindole 942 as the major product. Pyrroles substituted with an electron-donating group (Me) on nitrogen give exclusively the pyrrolo[3,2-c]quinoline 940 (43%). Reaction of the N-methylindole 943 with Bu3SnH yielded compound 948 derives from the spiro radical intermediate 944 as a minor component (8%) and the main products derived by rearrangement of the spiro radical 944 to the radical 945, which accept a hydrogen radical to give cis-isomer 946 (16%) and trans-isomer 947 (20%). In addition the radical 945 undergoes oxidation to yield compound 949 (47.2%) (Scheme 184) <2004TL883>.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 183
Scheme 184
Oxidative radical cyclization using Bu3SnH has been applied to the synthesis of [1,2-a]-fused pyrroles 951 from 1-[1(o-bromoalkyl)-1H-pyrrol-3-yl]-1-ethanones 950 (Equation 226) <1997TL7937>. The intermediate nucleophilic N-alkyl radicals cyclize to the pyrrole ring followed by oxidative rearomatization. Cyclization at C-2 was completely selective for six-membered ring cyclization and largely selective for five- and seven-membered ring cyclization. In the last case (when n ¼ 1 or 3) some amounts (11–18%) of reduction products 952 were formed. The 1-(o-bromoalkyl)1H-pyrrole-2-carbaldehydes 953 gave selective five-, six-, and seven-membered ring cyclization to C-5 to yield the 2,3-dihydro-1H-pyrrolizine-5-carbaldehydes 954 without any traces of the corresponding N-alkylpyrrole-2carbaldehydes (Equation 227).
183
184
Pyrroles and their Benzo Derivatives: Reactivity
ð226Þ
ð227Þ
Treatment of the 1-(o-iodoalkyl)indole-3-carbaldehydes 955 with excess of Bu3SnH (by slow addition) and AIBN in boiling toluene gives 1,2-fused indoles 956 containing five-, six-, and seven-membered rings, in variable yield (Equation 228) <1995TL9051, 1997J(P1)2639>. A possible mechanism is illustrated in Scheme 185 for the sixmembered ring, involving as a key step the reaction of the radical 959, formed by the addition of the initial radical 958 to the indole ring, with tributylstannane to give the indole radical anion 960, the tributyltin cation and hydrogen. The highly delocalized radical anion 960 presumably subsequently undergoes single electron transfer with the indole 957 to give the product 961 and to regenerate, after loss of iodide, the initial radical 958 to continue the chain process.
ð228Þ
Scheme 185
Pyrroles and their Benzo Derivatives: Reactivity
Benzindolizidine systems 963 are generated in moderate yields by a hexabutylditin-mediated consecutive radical addition, cyclization, and oxidation process from easily accessible 1-(2-iodoethyl)indoles 962 and methyl acrylate, in one step (Scheme 186) <2000TL10181>. 1-(2-Iodoethyl)-1H-pyrrole-2-carbaldehyde was also subjected to the tandem radical addition–cyclization process, and the indolizidine derivative 964 was isolated in modest yield as the major product together with a small amount of starting material (Equation 229).
Scheme 186
ð229Þ
Alkyl radicals 968, generated on the 1-N-alkyl group of 2-(phenylsulfanyl)indole from the corresponding N-alkyl bromides 965 by the action of Ph3SnH/AIBN (reflux 6 h in benzene under Ar), triphenyltincobaloxime (Ar, DMF, 130 C, 24 h) or by the photolysis (350 nm, benzene, 24 h, Ar) of the corresponding N-alkylcobaloxime, transform into a reduction product 966 and a cyclization product 969 (Scheme 187) <1997J(P1)3591>. Reaction modes differ little
Scheme 187
185
186
Pyrroles and their Benzo Derivatives: Reactivity
with the method of radical generation except for the substantial formation of alkyl phenyl sulfide 967, a radical substitution product of the alkylcobaloximes, in the photolysis of the cobaloximes. The cobaloxime(II) species, which exists in the reaction system N-alkyl bromide/triphenyltincobaloxime, activates the phenylsulfanyl group for the radical substitution, and the lack of the tin hydride makes it possible for the reaction to occur at a higher concentration than the reaction with the hydride reagent. A tandem carbonylation–cyclization radical process in heteroaromatic systems bearing electron-attracting substituents such as 1-(2-iodoethyl)indoles and pyrroles 970 result in the formation of 2,3-dihydro-1H-pyrrolo[1,2-a]indol1-ones and 2,3-dihydro-1H-pyrrolizin-1-ones 974 (Scheme 188). The AIBN-induced radical reaction of compounds 970 with Bu3SnH under pressure of CO suggests that the acyl radical 972, derived from radical 971 and CO, would undergo intramolecular addition to C-2 of heteroaromatic system, and the benzylic radical 973 so obtained, upon in situ oxidation would produce final product 974 <1999TL7153>.
Scheme 188
When a benzene solution of 1-(2-iodoethyl)indole 975 was heated at 80 C with 1.2 equiv of Bu3SnH and 0.2 equiv of AIBN under 80 atm of carbon monoxide for 3 h, most of the starting material was recovered and low yields of cyclization and reduction products 976, 977, and 978 were isolated (Equation 230) <1996AGE1050>. Addition of tin hydride in three small portions (0.4 equiv each time) at 1 h intervals allowed minimization of the reduction product 977 and almost completely transformed starting material into 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ones 976 <1999TL7153>. When 1-(2-iodoethyl)-1H-pyrrole-2-carbaldehyde was subjected to the optimum conditions, 1-oxo-2,3-dihydro-1H-pyrrolizine5-carbaldehyde 979 was isolated in a 30% yield (Equation 231).
ð230Þ
ð231Þ
Intramolecular radical acylation of 1-(o-halogenoalkyl)-2-methylsulfonylpyrroles led to bicyclic ketones with retention or loss of the sulfonyl moiety (Scheme 189, Equations 232–234) <2000TL3035>. Under standard conditions, 1-(2bromoethyl)-2-(methylsulfonyl)-1H-pyrroles 980 gave the expected 2,3-dihydro-1H-pyrrolizin-1-ones 981 in moderate to good yields, and a small amount of the reductive dehalogenation products 982 (Equation 232).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 189
ð232Þ
ð233Þ
ð234Þ
The homologous compound 983 gave the expected 6,7-dihydro-8(5H)-indolizinone 985 in moderate yield and 2,3dihydro-1H-pyrrolizine 984, resulting from competitive 5-exo-cyclization of the alkyl radical, in low yield (Equation 233) <2000TL3035>. The formation of 6,7-dihydro-8(5H)-indolizinone 986, the product derived from radical attack at C-5, is interesting, and has precedence in oxidative intramolecular radical alkylation of pyrrole 983 and related compounds. When pyrrole 987 was subjected to the usual reaction conditions, 1-(2,3-dihydro-1H-pyrrolizin-5-yl)-1-ethanone 988 was obtained as the major product. The desired diketone 989 was isolated in very low yield together with a small amount of the unexpected sulfone 984 (Equation 234). This compound is formed by alkyl radical addition at C-5, and subsequent aromatization by the loss of an acetyl radical. When pyrrole 987 was reacted with Bu3SnH/AIBN in the absence of CO, dihydropyrrolizines 988 and 984 were isolated in 74% and 23% yields, respectively <2000TL3035>. It is noteworthy that 1-(2-iodoethyl)-1H-pyrrole, under the usual radical carbonylation conditions, gave 3-(1H-pyrrol1-yl)propanal 990 in 60% yield (Equation 235), and no 2,3-dihydro-1H-pyrrolizin-1-one 981 (R ¼ H) (Equation 232) <2000TL3035>.
ð235Þ
Cyclization of acyl radicals can be carried out in high yields from acyl selenide precursors 991 without using high pressures of CO (Scheme 190) <2001TL7887>.
187
188
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 190
The cyclizations under ‘normal’ conditions for Bu3SnH-mediated oxidative radical reactions (Bu3SnH (2.2 equiv, addition by syringe pump over 5–6 h), AIBN or AMBN (azobismethylisobutyronitrile) (2 equiv, added portionwise every 0.5 h), cyclohexane, reflux under N2) lead to expected cyclized ketones 997 in each case in moderate yield along with a mixture of other products (Scheme 191) <2001TL7887>. Significant decarbonylation took place from the acyl radical intermediates 993 to yield the alkyl radical intermediates 994. The precursor 992 (n ¼ 2) gave cyclization to the known pyrrolizidine 995 and pyrrole 992 (n ¼ 1) gave reduction to compound 996.
Scheme 191
The cyclizations of analogous Se–phenyl 3-(3-formyl-1H-pyrrol-1-yl)alkaneselenoates 998 were carried out using a carbon monoxide atmosphere and two-phase solution protocol (Bu3SnH (1.8 equiv) in a solution of cyclohexane was added by syringe pump over 7 h and AIBN (for selenoate 998, n ¼ 1) or AIBMe (azobisisobutyrate methyl ester) (for selenoates 998, n ¼ 2, 3) (1.8 equiv) added portionwise over 5 h under an atmosphere of carbon monoxide to a solution of selenoates 998 in acetonitrile under reflux) to give the cyclized compounds 999 in moderate yields (Equation 236) <2001TL7887>. No reduced uncyclized aldehydes [1-(3-oxoalkyl)-1H-pyrrole-3-carbaldehydes] were formed in any of the reactions but 1-ethyl-1H-pyrrole-3-carbaldehyde (17%) was formed in the reaction of selenoate 998 (n ¼ 1). A cyclized product 1000 (n ¼ 3) (54%), resulting from decarbonylation, was isolated for the reaction of selenoate 998 (n ¼ 3).
ð236Þ
Pyrroles and their Benzo Derivatives: Reactivity
Novel and efficient radical alkylation of several heterocyclic systems including pyrroles and indoles is described using xanthate based radical chemistry <2003CC2316>. The proposed mechanism for the reaction is depicted in Scheme 192. a-Acetyl or a-acetonyl radical 1002, generated by the action of dilauroyl peroxide (DLP) on xanthate 1001, adds to the pyrrole 1003 producing the conjugated radical 1004. Aromatized derivative 1005 could then be produced either by a DLP-mediated oxidative pathway in a chain reaction (Scheme 192, path i) or by a direct abstraction of the hydrogen by the alkyl radical derived from fragmentation of the peroxide in a nonchain process (path ii). Following reaction conditions were used: portionwise addition of a stoichiometric amount of DLP (over 12 h) to a boiling solution of pyrrole (1 equiv) and xanthate 1001 (1.2 equiv) in 1,2-dichloroethane (2 mL mmol1) led to alkylation at C-5 and furnished 1005 in good yield (65–86%).
Scheme 192
The reaction of indole 1006 and xanthate 1001 (R3 ¼ EtO) gave the ethyl 1H-indol-2-ylacetate 1007 with high regioselectivity (Equation 237). It is worth noting that electrophilic substitution reactions of indole, including alkylation, occur at C-3 <2003CC2316>.
ð237Þ
The reaction of the secondary xanthate 1009 and pyrrole 1008 afforded methyl 2-(5-benzoyl-1H-pyrrol-2-yl)propanoate 1010 in high yield, a new representative of 2-arylpropionic acids constituting a large class of nonsteroidal antiinflammatory drugs, which are used worldwide (Equation 238) <2003CC2316>.
ð238Þ
Reaction of ethyl iodoacetate with an excess (5 equiv) of pyrrole in the presence of 2-methyloxirane and Bu3SnSnBu3 led to the desired substitution product 1011 in 43% yield, in addition to an undetermined quantity of ethyl phenylacetate 1012 (Equation 239), indicating reactivity with the benzene solvent under the reaction conditions <1999TL2677>. The less toxic solvent, methyl t-butyl ether (MTBE), provided product 1011 in improved (64%) yield.
189
190
Pyrroles and their Benzo Derivatives: Reactivity
ð239Þ
Atom-transfer radical addition methodology leads to formation of ester 1015 (R1 ¼ H, R2 ¼ Et) in 90% yield (Scheme 193) <1999TL2677>. The putative addition product 1014 spontaneously undergoes elimination of HI to generate substitution product 1015. The addition of Na2S2O3 as an iodine reductant in the presence of the phasetransfer catalyst Bu4NþBr or Bu4NþI to aid in thiosulfate solubility provided an efficient alternative to the use of distannanes. It was also found that 2-methyloxirane served as an effective HI trap. Following this procedure, a number of pyrrol-2-acetic acids 1015 (R2 ¼ H) were generated directly in yields of 72–90% by photolysis of iodoacetic acids 1013 in the presence of 15 equiv of pyrrole in MTBE (Scheme 193) <2003TL6853>. The significant excess of pyrrole was necessary in order to minimize the formation of dialkylated products. The successful generation of acid 1015 (R1 ¼ R2 ¼ H) was dependent on careful control of the reaction temperature in the course of the photolysis. If the reaction temperature was allowed to warm above ca. 30 C, the major product obtained was acid 1016, presumably arising from nucleophilic attack of one of several possible carboxylic acid intermediates on iodoacetic acid.
Scheme 193
The addition of other alkyl iodides and bromides to pyrrole or indole under these conditions is shown in Schemes 194 and 195 <1999TL2677>.
Scheme 194
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 195
Attempted addition of malonate monoester 1017 to pyrrole led to the formation of ester 1018 in 65% yield, presumably through a sequence of events involving radical substitution followed by decarboxylation, as shown in Scheme 196 <2003TL6853>.
Scheme 196
Photolysis of phenylselenomalonates in the presence of an excess of indole or N-methylindole led to the desired substituted products 1019 in poor yield (25–28%) (Scheme 197) <1999TL2677>.
Scheme 197
The reaction of atomic carbon with N-methylpyrrole 1020 at 77 K generates the N-methyl-3-dehydropyridinium ylide 1021, novel reactive intermediate (Scheme 198), which can be trapped with added hydrogen halides or carbon dioxide <1997JA5091>. The intermediacy of ylide 1021 in the 77 K cocondensation of arc generated carbon with pyrrole 1020 is implied by the fact that addition of methanolic HCl to the cold condensate generates the N-methylpyridinium ion 1023. Addition of methyl iodide to the 77 K matrix of atomic carbon þ pyrrole 1020 followed by treatment with HCl gave only salt 1023 and none of the anticipated N-methyl-3-methylpyridinium ion. When an attempt was made to alkylate ylide 1021 as it is formed by condensing of atomic carbon þ pyrrole 1020 þ MeI at 77 K, the products were salt 1023 and the 3-iodo-N-methylpyridinium ion 1024 (X ¼ I) in a 4:1 ratio (Scheme 199) <1997JA5091>. The condensation of other alkyl halides invariably results in the formation of 3-halo-N-methylpyridinium ions 1024. It was supposed that pyridinium salt 1024 results from halomethylidynes formed directly in the reaction of atomic carbon with alkyl halide as shown in Scheme 199. The exothermicity of the addition reaction to form a-halocyclopropyl radical 1025 drives the ring opening to radical 1026 which subsequently generates the pyridium salt 1024 in an electron transfer.
191
192
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 198
Scheme 199
Co-condensation of pyrrole 1020 þ atomic carbon þ CO2 at 77 K followed by addition of methanolic HCl generates ion 1023 and N-methylpyridinium 3-carboxylic acid 1027 in a 1.2:1 ratio (Scheme 200) <1997JA5091>. The observation of acid 1027 provides strong chemical evidence for the ylide 1021 rather than cumulene 1022 (Scheme 198) which would not be expected to react with CO2. However, acid 1027 is not generated when CO2 is added to 77 K matrix formed upon reaction of atomic carbon with pyrrole 1020.
Scheme 200
Deuterium and 13C labeling studies demonstrate that ylide 1021 rapidly rearranges to the N-methyl-2-dehydropyridinium ylide 1028, by an intermolecular mechanism (Scheme 201) <1997JA5091>. Ylide 1028 can be trapped with added acids or with O2 to form 1-methyl-2(1H)-pyridinone 1030 via stabilized carbonyl oxide 1029.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 201
The cyclopropanation of pyrrole 1031 (R ¼ MeCO2) with methyl diazoacetate using copper(I) bromide as catalyst at 80 C yielded bicycle 1032 in 17% yield <1972JA6495>. This reaction was improved by using catalytic amounts of copper(II) triflate, activated by phenylhydrazine (Scheme 202) <2000JOC8960, 2006JOC2173>. In this way, the cyclopropanation of pyrrole 1031 (R ¼ BOC) proceeds smoothly at room temperature, yielding adduct (rac)-1033 in 39% yield along with the twofold cyclopropanated adduct (rac)-1034 (3%) and recovered starting material (36%). Adduct (rac)-1033 is obtained as a single diastereomer, having the ester group oriented at the convex face of the bicyclic structure.
Scheme 202
a-Diazoketones derived from pyrrolyl- and indolyl-carboxylic acids were prepared and their Rh2(OAc)4 catalyzed decomposition chemistry was studied <2000T8063>. These reactions generally resulted in the alkylation of the heteroaromatic system by the ketocarbenoid and in some instances the systems underwent CH or NH insertions. Evidence that some of these reactions proceed via a cyclopropane intermediate was presented. The methodology described provides facile access to fused pyrrolyl- or indolyl-cycloalkanone systems wherein the carbonyl is b to the heteroaromatic system (Equations 240 and 241).
ð240Þ
ð241Þ
Indoles, when treated with methyl diazomalonate 1035 under catalysis by rhodium(II) acetate, undergo C–H and N–H carbenoid insertion reactions regioselectively depending on the substitution pattern on the indole moiety (Equations 242–244) <2002JOC6247>. Indoles in which the nitrogen is unprotected yield varying degrees of N–H insertion (Equation 242).
193
194
Pyrroles and their Benzo Derivatives: Reactivity
ð242Þ
ð243Þ
ð244Þ
In indoles where the 3-position is unsubstituted, high yields of the C(3)–H insertion product were observed (Equation 243). In 3-alkylindoles, 2-substitution predominated (Equation 244), while N-methyltetrahydrocarbazole 1036 (R ¼ Me) yielded the product 1037 resulting from insertion into the C(7)–H bond (Scheme 203). This type of reaction could proceed via a intermediary cyclopropaindoline 1039 which could conceivably collapse to two regioisomeric products giving either the 2-alkyl 1041 or 3-alkyl 1040 product (Scheme 204). Loss of a proton from the benzylic position and dissociation of the cyclopropane bond leads to 3-alkylation (compound 1040 via path a). Loss of a proton a to the nitrogen atom and dissociation of a cyclopropane bond leads to 2-substitution (compound 1041 via path b). In N-methyltetrahydrocarbazole 1036 with the nitrogen atom unprotected (R ¼ H), insertion took place at the N–H bond to form compound 1038 in 33% yield (Scheme 203). A variety of Lewis acids (ZnCl2, BF3?OEt2, Bu2OTf, and YbOTf3?2H2O) failed to yield identifiable products.
Scheme 203
Scheme 204
Pyrroles and their Benzo Derivatives: Reactivity
The reaction of vinyldiazomethanes with suitable protected pyrroles has proved to be a valuable and efficient route into the tropane ring system that is found in numerous naturally occurring alkaloids, many of which possess potent biological activity <1991JOC5696, 1995TL7205, 1996JME2554, 1996JOC2305, 1997JOC1095>. Rhodium(II) octanoate-catalyzed decomposition of the vinyldiazomethane 1042 in refluxing hexane in the presence of N-BOC-pyrrole (5 equiv) resulted in the formation of tropanes 1043, the products of a tandem cyclopropanation/Cope rearrangement, in 37–83% isolated yield (Equation 245) <1991JOC5696, 1995TL7205>. No other obvious products were observed in the NMR of the crude reaction mixture. The results obtained indicate that neighboring group (R) participation result in the stabilization of the vinylcarbenoid intermediate and, consequently, on the efficiency of its trapping by the pyrrole. The highest isolated yield (83%) was obtained when R ¼ EtCO2CH2, the lowest (37%) – when R was Bun. In the case of methyl ester 1042 (R ¼ Me) tropane 1043 (R ¼ Me) was isolated in 63% yield.
ð245Þ
In contrast to the previous results with achiral catalysts <1991JOC5696>, rhodium(II) (N-SO2C6H4But)prolinate 1044-catalyzed decomposition of the vinyldiazomethanes 1042 in the presence of N-BOC-pyrrole failed to form the tropane products cleanly (Equation 246) <1995TL7205>. In addition to the desired tropanes 1043 (42–62% yields), the isomeric 1,3a,6,6a-tetrahydrocyclopenta[b]pyrroles 1045 (12–13% yields) were formed.
ð246Þ
Side reactions became even more prevalent when 2-methyl-N-BOC-pyrrole 1046 was used as substrate (the addition of the methyl group increased the electronic density on the pyrrole and this led to enhanced formation of products derived from zwitterionic intermediates) (Equation 247). Thus, rhodium(II) octanoate-catalyzed decomposition of diazoalkane 1042 in the presence of pyrrole 1046 resulted in the formation of three types of products: two isomeric tropanes, 1047 (38% and 56% for R ¼ Me and R ¼ EtCO2CH2, respectively) and 1048 (16% and 8% for R ¼ Me and R ¼ EtCO2CH2, respectively), as well as two other products, the 1,3a,6,6a-tetrahydrocyclopenta[b]pyrrole 1049 (10% and 8% for R ¼ Me and R ¼ EtCO2CH2, respectively) and the 7-azabicyclo[4.2.0]octa-2,4-diene 1050 (27% and 12% for R ¼ Me and R ¼ EtCO2CH2, respectively) <1995TL7205>. It was postulated that both 1,3a,6,6a-tetrahydrocyclopenta[b]pyrroles 1045 and 1049 and the 7-azabicyclo[4.2.0]octa-2,4-dienes 1050 form via zwitterionic intermediates <1994TL5209, 1995TL7205, 1996JOC2305, 1997JOC1095>. The regiochemistry observed in the formation of compounds 1045 and 1049 would require electrophilic attack of the carbenoid at the b-position of the pyrrole ring to form intermediate 1051 followed by ring closure at C-5 (Scheme 205). Intermediate 1052, arising from initial electrophilic attack of the carbenoid at the a-position of the pyrrole ring, first undergoes a ring opening to generate a trienimine species, which undergoes successive 8p and 6p electrocyclic reactions to eventually form the 7-azabicyclo[4.2.0]octa-2,4-diene nucleus.
195
196
Pyrroles and their Benzo Derivatives: Reactivity
ð247Þ
Scheme 205
Although some changes in the enantioselectivity were observed on modifying the protecting group on the pyrrole 1053 from N-BOC (ee 51%) to N-CO2Me (ee 42%), N-Ac (ee 17–51%) or N-Ms (ee 29%), no overall improvement in enantioselectivity or yield of tropane 1054 was observed (Equation 248).
ð248Þ
A series of enantiomerically enriched tropanes 1057 was synthesized by the rhodium(II) octanoate-catalyzed reaction of various N-BOC-protected pyrroles 1055 with vinyldiazomethanes 1056 (Equation 249) <1997JOC1095>.
Pyrroles and their Benzo Derivatives: Reactivity
ð249Þ
Slow addition of the vinyldiazomethanes 1059 to a stirred solution of rhodium(II) octanoate and 2-substituted N-BOC-pyrroles 1058 in refluxing hexane resulted in the formation of the tropanes 1060 in 53–70% de (30–82% yield) (Equation 250) <1997JOC1095>. Unlike the results seen with the prolinate catalysts (Equations 246 and 247), no [3.3.0]- or [4.2.0]-bicyclic products are formed in these reactions in most cases. Furthermore, the tropane regioselectivity is greater than 10:1 favoring the products derived from initial cyclopropanation at the unsubstituted double bond of the pyrrole.
ð250Þ
The diastereoselectivity of the tropanes 1062 obtained from vinyldiazomethanes 1061 containing (R)-pantolactone as the chiral auxiliary and various pyrroles (Equation 251) was roughly parallel to the results observed with the (S)-lactate auxiliary and ranged from 37% to 78% de <1997JOC1095>.
ð251Þ
The rhodium(II)-catalyzed intramolecular reaction between linked vinyldiazomethanes and pyrroles leads to a novel synthesis of fused tropanes <1996JOC2305>. The reaction occurs by a stepwise [3þ4]-annulation mechanism between a rhodium-stabilized vinylcarbenoid intermediate and the pyrrole rather than by the typical tandem cyclopropanation/Cope rearrangement sequence. The outcome of the reaction is very sensitive to the vinylcarbenoid structure. In particular, the presence of a siloxy substituent on the vinylcarbenoid strongly favors the formation of fused tropanes 1063 or 1064 (Scheme 206) <1996JOC2305>. In the absence of such functionality, the formation of the fused 7-azabicyclo[4.2.0]octa-2,4-dienes, for example, 1065, becomes the dominant reaction pathway. A reasonable mechanism to explain its formation is shown in Scheme 207 <1996JOC2305>.
197
198
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 206
Scheme 207
The dramatic influence of the 1-siloxy group to enhance tropane formation was observed in the reaction of the compound having the vinyldiazomethane tethered to the 3-position of pyrrole. Rhodium(II) octanoate-catalyzed decomposition of pyrrole 1066 resulted in the formation of the tropane 1067 that was isolated in 53% yield (Equation 252) <1996JOC2305>.
ð252Þ
Similar reaction of the unsubstituted vinyldiazomethane 1068 resulted in the formation of the trienamine 1069 in 77% yield (Equation 253) <1996JOC2305>. This would be the expected product from the zwitterionic intermediate 1070, as ring opening of ion 1070 would form compound 1069, which is incapable of undergoing an 8p-electrocyclization.
ð253Þ
Pyrroles and their Benzo Derivatives: Reactivity
The observation that carbenoids are capable of electrophilic attack at the 3-position of N-BOC-pyrrole may shed light on other carbenoid reactions that have stood out as rather unusual transformations. For example, a very useful [3þ2]-annulation between diazodimedone 1071 and ethyl 1H-pyrrole-1-carboxylate leading to the tricyclic product 1072 was discovered (Scheme 208) <1995JOC2112>. It was proposed that the reactions occurred through initial cyclopropanation followed by ring opening of the pyrrolocyclopropane 1073 to a zwitterionic intermediate 1074.
Scheme 208
Pyrrole 1075 (n ¼ 1), obtained via the coupling of an enyne-hydrazone with Fischer carbene complexes, undergoes an intramolecular Diels–Alder reaction followed by aminonitrene extrusion to afford the phenanthrene derivative 1076 (Scheme 209) <2003OL2043>. The reaction is quite efficient and affords dehydrosteroid product 1077 in 68% yield. The reaction employing the six-membered ring analog 1075 (n ¼ 2) proceeded similarly; however, the nitrogen bridge remained intact under the reaction conditions, leading to corresponding compound 1076 in 72% yield.
Scheme 209
Di-t-butylsilylene 1079, generated by photolysis of hexa-t-butylcyclotrisilane 1078, reacts with N-methylpyrrole possibly via an intermediate [2þ1] cycloadduct to furnish 3,3-di(t-butyl)-2-methyl-2-aza-3-silabicyclo[2.2.0]hex-5-ene 1080 (Scheme 210) <1997OM3080>. On heating, compound 1080 rearranges by an electrocyclic reaction to provide the correspondingly substituted 1-methyl-1,2-dihydro-1,2-azasiline 1081. Further treatment of compound 1080 with silylene 1079 gives, presumably through a tricyclic compound 1082, the final product, 2,2,5,5-tetra(t-butyl)-1-methyl2,5-dihydro-1H-1,2,5-azadisilepine 1083, which was characterized by an X-ray structure analysis.
3.02.2.8 Cycloaddition Reactions Cycloaddition between N-tosyl-protected 3,4-disubstituted pyrroles 1084 and electron-deficient dienophiles (e.g., DMAD, which was also used as solvent) leads to aza-bicyclic systems 1085 (Equation 254), which were used in the synthesis of new highly functionalized cyclotrimers for future derivatization and application in supramolecular chemistry <2005OL1003>.
199
200
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 210
ð254Þ
3,4-Dibromopyrrole 1084 (R ¼ Br) and benzyne generated from anthranilic acid and isoamyl nitrile gave dibromoderivative 1086, the metallation of which led to product 1087 (Scheme 211) <2005OL1003>, which was later successfully used in a cyclotrimerization reaction.
Scheme 211
N-Protected 7-azabicyclo[2.2.1]heptan-2-one 1090 was conveniently synthesized from the cycloaddition adduct 1089 obtained in 60% yield by heating of methyl 3-bromo-2-propynoate 1088 with N-BOC pyrrole (Scheme 212) <1996JOC7189>.
Scheme 212
A new [4þ2] cycloaddition between N-acyl pyrroles and electron-deficient allenes 1091 is an excellent method to prepare 5-alkylidene-7-azabicyclo[2.2.1]hept-2-enes 1092 (Equation 255) <1997TL7993>. When R2 ¼ R3 ¼ MeCO2 or EtCO2, only two of the possible four isomers were obtained (in 65–75% yields) where the exo-isomer was present in
Pyrroles and their Benzo Derivatives: Reactivity
slight excess (endo:exo, 2:3). With allenic sulfone 1091 (R2 ¼ PhSO2, R3 ¼ H) N-BOC-pyrrole reacts to give the endocycloadduct 1092 as the sole product in 45% yield.
ð255Þ
These compounds can then be readily converted into 7-azabicyclo[2.2.1]heptan-2-ones of type 1090 (Scheme 212), which have been shown to be useful precursors for the synthesis of the novel alkaloid epibatidine <1996JOC7189>. Epibatidine has been found to be 200–400 times more potent than morphine as an analgesic, and more importantly should prove to be useful for the preparation of its analogs with reduced toxicity. The approach with phenyl 1,2-propadienyl sulfone 1091 (R2 ¼ SO2Ph, R3 ¼ H) proved to be more efficient and high yielding than the ester sequence and provided azabicycle 1090 in 19% overall yield (four steps). Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2þ2þ2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <2000OL2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2þ2þ2] cycloaddition reaction between the N-(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R1 ¼ (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213).
Scheme 213
Thus, in tetrahydrofuran solution, indole 1093 (R1¼(CH2)2NHAc) was converted to tetracyclic lactam 1094 (in 46% yield as a single diastereomer) in the presence of CpCo(C2H4)2 and acetylene gas (the experiment was performed on a submillimolar scale). The primary by-products of this reaction, isolated in 20–30% yield, are the cis- and trans- (3:1) cinnamic amides 1095. Presumably, these arise from the cyclization of the terminal acetylene moiety of indole 1093 with two acetylene molecules and subsequent equilibration. Attempts to scale-up the procedure to 0.5 mmol or more of indole 1093 led to a significant decrease in yield (17–24%) of tetracycle 1094. The main product of the reaction was amide 1095, isolated in 50–60% yield as a mixture of cis- and trans-isomers. Utilizing the reactivity of CpCo(C2H4)2 at low temperatures to minimize cyclobutadiene formation, reaction of unsubstituted enynoylindole 1093 (R1 ¼ H) with bis(trimethylsilyl)acetylene (R2 ¼ TMS), which is resistant to
201
202
Pyrroles and their Benzo Derivatives: Reactivity
autocyclization, gave a favorable yield of tetracycle 1094 (70%) over compound 1096 (27%). However, the reaction of indole 1093 with bis(trimethylsilyl)acetylene gave significantly more (41%) of the undesired cyclobutadiene complex 1096 (R2 ¼ TMS) at the expense of tetracycle 1094 (47%) (Scheme 213). b-Carbolines, an important class of alkaloids expressing a variety of pharmacologically relevant biological responses, have been prepared by intramolecular cycloaddition using indoles 1100 which have 1,2,4-triazines tethered to the indolyl nitrogen using a thiourea linkage (Scheme 214). Indoles 1100 were easily prepared in near quantitative yields from the triazines 1099 and the stable indolylimidazolylthiourea 1098. Cycloaddition proceeded smoothly in triisopropylbenzene (TIPB) in the presence of 2,6-di-t-butyl-4-methylphenol (BHT) in excellent yields (minimum 85%) to provide cycloadduct 1101. Subsequent to the cycloaddition, reductive cleavage of the thiourea subunit provides the b-carboline 1102 in 65% yield <1995TL6591>.
Scheme 214
Deprotection of triazines 1099 followed by reaction of triazines 1103 with the unstable indolylimidazolylurea 1104, generated in situ from CDI and indole Grignard salt, gave the desired urea-tethered triazine 1105 albeit in poor yield (38%, Scheme 215) <1995TL6591>. Heating the urea 1105 in TIPB produced cycloadduct 1106 in 65% yield. The
Scheme 215
Pyrroles and their Benzo Derivatives: Reactivity
reverse urea formation, initial acylation of the glycine derived triazines 1099 with CDI, also met with only limited success (Scheme 216). The stable imidazoylureas 1107 were produced in near quantitative yield. Subsequent indolyl urea formation (1107 ! 1108) by reaction with the indole potassium salt worked only with N-methylated urea 1107 (R ¼ Me, 50%). In a single trial, heating of compound 1108 in TIPB (170–180 C) produced the cycloadduct 1109 in poor yield (<10%). The addition of BHT (1 equiv) did not significantly improve the yield of cycloadduct.
Scheme 216
The inverse electron demand Diels–Alder (IDA) reactions of 3-substituted indoles as 2p-components with 1,2,4-triazines and 1,2,4,5-tetrazines proceeded in excellent yields both inter- and intramolecularly <1996TL5061>. The reaction of N!-BOC-tryptamine (1110, R1 ¼ BOCNH(CH2)2) and indole 1110 (R1 ¼ Me) with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate 1111 in refluxing dioxane (3 h) provided cycloadducts 1112 (R2 ¼ BOC) and 1113, respectively, in excellent yields (80% and 82%, Scheme 217). Deprotection of compound 1112 produced derivative 1112 (R2 ¼ H, >99%).
Scheme 217
203
204
Pyrroles and their Benzo Derivatives: Reactivity
3-(Methylsulfanyl)-1,2,4-triazine 1115 and 3-(methylsulfanyl)-1,2,4,5-tetrazines 1118, underwent displacements with tryptamine 1114 in refluxing methanol to produce tethered triazines 1116 (Scheme 218) and tetrazines 1119 (Scheme 219).
Scheme 218
Scheme 219
Neither 1116 (R ¼ H) nor 1119 produced cycloadducts upon refluxing in neat solvent, even at 232 C (TIPB). However, refluxing indole 1116 (R ¼ H) in acetic anhydride containing sodium acetate produced cycloadduct 1117 with the tethering nitrogen acetylated. In contrast, refluxing compound 1116 (R ¼ Me) in acetic anhydride (or any other solvent) with the tethering amino group methylated did not produce a cycloadduct. Even more remarkable, simply stirring compound 1119 with trifluoroacetc anhydride produced cycloadducts 1120 in quantitative crude yields. The inverse electron demand Diels–Alder reactions of 5-amino-1H-pyrrole-3-carbonitriles 1121 with various 1,3,5triazines 1122 are suitable for one-pot syntheses of highly substituted and highly functionalized 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitriles 1123 (Scheme 220) <2002JOC8703>. These are the central heterocyclic nuclei of various nucleoside natural products such as Toyocamycin, Sangivamycin, and Tubercidin (Figure 5).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 220
Figure 5
Pyrroles 1121 (R ¼ alkyl, cycloalkyl, arylalkyl, and sulfide containing group) were proved to be effective dienophiles for this facile reaction with triazines 1122 (X ¼ EtCO2) and generated various pyrrolo[2,3-d]pyrimidines 1123 in very good yields (84–96%). The 1,3,5-triazine 1122 (X ¼ H) was found to be less reactive and required moderate heating (95 C, 2 h), but pyrrolo[2,3-d]pyrimidines 1123 were also generated in good to excellent yields (57–92%). It was suggested that the initial [4þ2]-cycloaddition reactions may proceed in two different pathways. In one path, a retro-Diels–Alder (RDA) reaction (step A) of the [4þ2]-cycloadduct (with the loss of XCN) followed by elimination of ammonia or ammonium chloride (step B) produces compounds 1123 in a regioselective manner. In another path, elimination of ammonia or ammonium chloride (step C) from the [4þ2]-cycloadduct followed by a RDA reaction (step D) also gives compounds 1123. Treatment of the 2,3-unsubstituted pyrrole 1124 and indoles 1127 with 1 equiv of 1,3,5-trichloro-14,34,54,2,4,6trithiatriazine 1125 in refluxing carbon tetrachloride under nitrogen gives the 2,3-fused 1,2,5-thiadiazolo derivatives 1126 and 1128 (Equations 256 and 257) <1997J(P1)2695>.
ð256Þ
205
206
Pyrroles and their Benzo Derivatives: Reactivity
ð257Þ
2,3,4,5-Unsubstituted pyrroles 1130 (R ¼ Me, Ph) are similarly converted directly into the pyrrolobis(thiadiazoles) 1132, without detection of the presumed, highly reactive, bicyclic intermediate 1131 (Equation 258) <1997J(P1)2695>. Pyrrole itself with the trimer 1125 gave complex reaction mixtures from which no pure products could be isolated. The reaction of N-benzylpyrrole with trithiatriazine 1125 under the above conditions was also complex; N-phenylsulfonylpyrrole was inert to the reagent even when refluxed in toluene, as might be expected if the initial attack on the ring is electrophilic in nature. The indoles were more reactive than the corresponding pyrroles and gave higher yields of the fused thiadiazoles 1128 (23–60%). Some 3-chlorinated indoles 1129 were also isolated (10–21%) (Equation 257).
ð258Þ
The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels–Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example N-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>.
Scheme 221
2,3,6,7-Tetrasubstituted-1,2,3,4,5,6,7,8-octahydrocarbazoles 1137 were synthesized in 46–90% yields by a novel tandem Diels–Alder reaction in one step from N-benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole 1136 and dienophiles such as maleic anhydride, maleimide, ethyl maleate, fumaronitrile, and ethyl acrylate (Scheme 222) <2000OL73>. The 2,3,6,7tetrasubstituted carbazoles 1138 were then synthesized in 29–87% yields from compound 1137 by oxidation with DDQ.
Scheme 222
Pyrroles and their Benzo Derivatives: Reactivity
The mechanism of the formation of compound 1137 appears to be two sequential [4þ2] cycloadditions between the exocyclic diene of compounds 1139 and 1141 and a dienophile (Scheme 223). The 2,3-dimethylenepyrrole required for the Diels–Alder reaction can be generated by the thermal elimination of acetic acid to form compound 1139, which is observed by mass spectroscopy. There are two possible pathway by which diene 1139 can proceed to tricycle 1137. The first is the elimination of a second molecule of acetic acid from diene 1139 to form 5-benzylaza[5]radialene 1140, which is also observed by mass spectroscopy. Attempts to improve the yield of compound 1137 by accelerating the elimination of acetic acid by acid or base catalysis failed, resulting in the decomposition of compound 1136 <2000OL73>.
Scheme 223
Indoles bearing alkenyl and alkynyl moieties in different positions of the nucleus are used as substrates for the intramolecular Pauson–Khand reaction (PKR), which was carried out in toluene in the presence of Co2(CO)8 (1.1 equiv or catalytic amount (0.1 equiv)) in various experimental conditions (A: Me3NO, 4 A˚ mol sieves, rt; B: 4 A˚ mol sieves, reflux; C: reflux; D: Me3NO, rt; E: CO (1 atm), 0.1 equiv of Co2(CO)8, 4 A˚ mol sieves, 65 C), leading to tetracyclic cyclopentenones with formation of additional five- to seven-membered rings. Products are related to natural alkaloids such as Mitosenes, Clausines, Ergotamines, or Apogeissochizines <2004JOC5413>. Most of these reactions give only one diastereomer. Some representatives (e.g., 1142, 1144, 1146, 1147) of 1,2-fused systems obtained are shown in Equations 259–262. It can be seen from comparing the stereochemical result of the reaction of compound 1143 with that of compound 1145 that the hydroxy group present in these two substrates may act as directing group as in the directed PKR (Equations 260 and 261).
ð259Þ
ð260Þ
207
208
Pyrroles and their Benzo Derivatives: Reactivity
ð261Þ
ð262Þ
2,3-Fused tetracyclic indole derivatives 1149 were obtained from indoles 1148 in the above conditions (Equation 263) <2004JOC5413>. When indoles bearing a methyl on the nitrogen are used, total diastereoselectivity is observed, which almost disappears with nonmethylated substrates 1148 (R ¼ H).
ð263Þ
Fused polycyclic compound 1151, that may serve as an intermediate in the synthesis of Ergot alkaloids, was obtained by submitting indole 1150 to the PKR under the usual conditions (Equation 264) <2004JOC5413>. The results showed the formation of compound 1151 in good yield (60%) using method B and in moderate yield (37%) using catalytic conditions E.
ð264Þ
3-Nitroindoles 1155 are prepared in good yields (69–85%) via a thermal 6p-electrocyclization of 2,3-dialkenyl-4nitropyrroles 1152 in refluxing nitrobenzene (1–5 h), a solvent which causes in situ aromatization of dihydroindoles 1154 resulted from the initially formed dihydroindoles 1153 by [1,5]-H shift (Scheme 224) <1998T1913>. The corresponding reaction of 2-alkenyl-3-alkadienyl-4-nitropyrrole 1156 also leads to 3-nitroindoles 1158 (21–90%) via intermediate 1157, however, now together with 3-nitrotetrahydroindole derivatives 1159 (Scheme 225) <1998T1913>. The latter compounds are formed by a tandem 6p-electrocyclization–intramolecular Diels–Alder reaction, and are the predominant (or only) products when nitrobenzene is replaced by triglyme (70–78% yield).
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 224
Scheme 225
The electrocyclization (and dehydrogenation) of 3-nitropyrrole 1160, which bears an aromatic side chain at C-3, was achieved photochemically in ethanol to give 3-nitrobenzindole 1161 in 18% yield (Equation 265) <1998T1913>.
ð265Þ
Modifying the aldehyde function in the pyrroles 1162 into 1,3-dipoles 1163 (nitrone) and 1167 (nitrile oxide) furnished tricyclic heterocycles 1164 and 1168 via intramolecular 1,3-dipolar cycloaddition reactions (Scheme 226) <2000T3013>. None of the isomeric bridged product 1165 is produced despite the preference for that regiochemistry in the intermolecular reaction. Generated in situ (from the oximes 1166) nitrile oxides 1167 cyclized spontaneously to the dihydroisooxazole 1168 in quantitative yield at room temperature.
209
210
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 226
Tandem cationic Au(I)-catalyzed activations both of propargylic esters 1169 and the in situ generated allenylic esters provides an expeditious access to highly functionalized 2,3-indoline-fused cyclobutanes 1170 via sequential [3,3]-rearrangement and [2þ2] cycloaddition (Equation 266) <2005JA16804>. The treatment of ester 1171 which has a 2-propenyl group at the propargylic position with 1 mol% of AuCl(PPh3)/AgSbF6 resulted in a 1:4 mixture of the desired cyclobutane 1172 and cyclopentenone derivative 1173, respectively (Equation 267).
ð266Þ
ð267Þ
Pyrroles and their Benzo Derivatives: Reactivity
3.02.3 Reactivity of Nonconjugated Rings 3.02.3.1 Pyrrolenines and Indolenines Pyrrole and pyrrolenine rings linked by methyne and methylene groups constitute the framework of many biologically important cyclic and linear tetrapyrrolic compounds (e.g., heme, chlorophylls, biliverdin, bilirubins, pheophytins, chromophores of phytochrome and of phycobiliproteins). The chemistry of the pyrrolenines is therefore mainly connected with construction and further transformations of such or related systems <1996JA5690, 1998J(P1)1493, 1998J(P1)1509, 1998J(P1)1519, 1999CRV2379, 2000T1025, 2001J(P1)1030, 2003ARK107 and references therein, 2003JOM(680)232, 2003NPR327, 2003TL4373, 2004JOC4159, 2006JA3396, 2006JOC8352> and their precursors <1996JMT(338)121, 2000JME2557, 2004M223, 2004M519, 2006OL4951>. There are not many reports on reactions of individual pyrrolenines (2H-pyrroles) and indolenines (3H-indoles). New fused 6,8a-dihydro-4H-pyrrolo[1,2-e][1,2,5]oxadiazines 1176 and 5,7a-dihydro-3H-pyrrolo[1,2-a]imidazole 1-oxides 1177 were obtained via hetero-Diels–Alder reactions ([4þ2] and 1,3-dipolar) adding 2H-pyrrole 1174 to substituted nitrosoalkenes [CH2TC(R)NTO], generated in situ thorough base-mediated dehydrohalogenations of a-bromooximes 1175 (Equation 268) <2002T1507>.
ð268Þ
The synthesis of 29-methylspiro[cyclohexane-1,39-indole] chromium tricarbonyl 1179 was carried out by treatment of 3H-indole 1178 with chromium hexacarbonyl in THF/dioxane (1:5), under rigorous dryness, argon atmosphere and sunlight coverture, in a Strohmeier-type system, in good yield (Scheme 227) <1996JOM(522)231>. Solvent mixture was very important for the complex formation, and when Bun2 O=THF (9:1) was used, a brown oil was obtained which contained the free 3H-indole 1178 and the CTN reduction product, while complex 1179 was not detected.
Scheme 227
The reaction of the complex 1179 with lithium aluminium hydride in THF gave the reduction products 1180 and 1181, in high yield (90%). The two stable isomers were isolated by silica gel column chromatography, in the ratio 62:38, corresponding to the attack of the hydride from the opposite face to the chromium carbonyl ligand 1181 (endo) or from the same one 1180 (exo), respectively (Scheme 227) <1996JOM(522)231>. Heterocyclic ketenes with a-nitrogen atoms such as 2H-indol-2-ylidenemethanone 1182 dimerize to a pyrazinedione type molecule 1183 (Equation 269) <1995TL3913>.
211
212
Pyrroles and their Benzo Derivatives: Reactivity
ð269Þ
However, the b-nitrogen analogue, namely 3H-indol-3-ylidenemethanone 1186 oligomerizes to tetramer 1187 (Scheme 228) <1995TL3913>. Ketene 1186 can be generated by photolysis of 3-diazo-3H-indole 1184 in an argon matrix in the presence of carbon monoxide at 12 K. Generation of ketene 1186 by FVP of compound 1185 in a preparative pyrolysis experiment without trapping reagent resulted in the formation of the 1,39-tetrakis(indolylmethanone) 1187 in 75% yield. FVP of tetramer 1187 at 700 C regenerated the ketene 1186 as observed by Ar matrix IR spectroscopy. Stirring of compound 1186 with methanol at room temperature slowly gave methyl indole-3-carboxylate 1188 (30% conversion in 9 d).
Scheme 228
3.02.3.2 Dihydro Derivatives Asymmetric hydroformylation of N-protected 2,5-dihydro-1H-pyrroles 1190 catalyzed by rhodium(I) complexes of chiral phosphine–phosphite ligands 1189 afforded the corresponding optically active aldehydes 1191 as single products with ee 47–92% (R ¼ BOC, 98%, 47% ee (R) and R ¼ Ac, 92%, 66% ee (–)) (Equation 270) <1997MI175>.
ð270Þ
Pyrroles and their Benzo Derivatives: Reactivity
The unsymmetrical alkene, t-butyl 2,3-dihydro-1H-pyrrole-1-carboxylate 1192, gave a mixture of the regioisomers 1191 (33%, 71% ee (S)) and 1193 (67%, 88% ee (S)) (Equation 271). With the same catalyst, Rh(acac)[(R,S)-1189], the product 1191 from pyrrolenine 1190 has the configuration opposite to that from pyrrolenine 1192 <1997MI175>.
ð271Þ
Facile synthesis of simple 3-arylpyrroles from pyrroline by tandem Suzuki dehydrogenation reaction is depicted in Scheme 229. Thus, treatment of 1-benzyl-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate 1195 (prepared in 55% yield from 1-benzyl-3-pyrrolidinone 1194 by trapping the enolate with a triflating reagent), with boronic acid derivatives leads to the formation of 3-arylpyrroles 1196 in good yields (65–74%) <2000TL3423>.
Scheme 229
The treatment of 4,6-dichloro-5-aminopyrimidine 1198 with indoline 1197 gave 4-chloro-6-(2,3-dihydro-1H-indol1-yl)-5-pyrimidinamine 1199 in 79% yield (Scheme 230) <2005JCO813>. Subsequent oxidation of the indoline moiety to the corresponding indole was achieved with DDQ in refluxing benzene to yield the indole-substituted pyrimidine 1200, the key compound in the cyclization reactions with various aldehydes and ketones leading to a novel heterocyclic scaffold consisting of indole-fused pteridines.
Scheme 230
2,3-Dihydroindol-1-yl-pyrimidine 1199 underwent productive cyclization reactions with a wide range of aldehydes to give the corresponding tetracyclic pyrimidobenzodiazepines 1201 in excellent yields (81–97%) (Scheme 231) <2006JCO381>. In a very similar fashion, aliphatic ketones yielded the expected cyclized products 1201 in high yields (84–95%), whereas aromatic ketones tended to react at a slower rate and gave moderate to good yields (57–87%). It is noteworthy that various functional groups in the carbonyl compounds, such as nitro, methoxy, and carboxylic acid groups, are tolerated under these reaction conditions. This cyclization reaction is believed to follow a pathway similar to the Pictet–Spengler isoquinoline synthesis <1995CRV1797> as shown in Scheme 231. It was proposed that pyrimidine 1199 reacted with an aldehyde or ketone to form an iminium intermediate 1202 under the prevailing acidic conditions. The reactive iminium ion 1202 underwent an intramolecular electrophilic reaction at the adjacent electron-rich phenyl ring to produce the expected benzodiazepine skeleton 1203. Elimination of a proton from cation 1203 to regenerate the aromatic phenyl ring led to the final products 1201.
213
214
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 231
3.02.4 Reactivity of Substituents Attached to Ring Carbon Atoms 3.02.4.1 Fused Benzene Rings and Aryl Groups A high-pressure hydrogenolysis of 5-chloro-7-methyl-1H-pyrrolo[3,2-b]pyridine 1204 afforded 7-methyl-1H-pyrrolo[3,2-b]pyridine 1205 in 88% yield (Equation 272) <2002JOC2345>. In a similar manner, starting from 7-chloro-1Hpyrrolo[2,3-c]pyridine, 1H-pyrrolo[2,3-c]pyridine was obtained in 86% yield.
ð272Þ
The use of radical cyclizations (see Section 3.02.2.7) in the synthesis of intermediates to biologically active indolequinones was illustrated by the conversion of compound 956 (n ¼ 2, R1 ¼ BnO, R2 ¼ MeO) into the indolequinone 1206 by hydrogenolytic removal of the benzyl group followed by oxidation with Fremy’s salt (Equation 273) <1997J(P1)2639>.
ð273Þ
Reductive cyclization of the indolylacetonitrile 1207 required precise conditions in order to dictate the exact course of the reaction because some debenzylation accompanied the reductive cyclization <1997TL1673>. If the reduction was carried out using 10% palladium on carbon (50% w/w) at a temperature slightly above ambient temperature (35–45 C) for 12 h, a moderate yield (62%) of the BOM-protected pyrrolo[3,2-e]indole 1208 could be isolated (Scheme 232). In this reaction, 1-hydroxymethylpyrrolo[3,2-e]indole 1209 could always be seen as a byproduct (ca. 10%). If the hydrogenation was carried out at 50–60 C for 48 h, the only product isolated from this reaction was pyrroloindole 1209 (69%). Hydrogenation of compound 1208 at elevated temperature (50–60 C) over 3 d using 50% w/w Pd on carbon afforded only 51% of pyrroloindole 1209. Alternatively, use of ammonium formate as the hydrogen source in refluxing PriOH with 50% w/w 10% Pd/C effected the conversion of compound 1208 to compound 1209 more rapidly (7 h), but only a 40% yield of tricycle 1209 could be obtained. Elimination of formaldehyde from compound 1209 (with solid sodium hydroxide in a solution of THF/water) leads to the symmetrical pyrrolo[3,2-e]indole 1210 as a potential bioisostere of the 5-hydroxyindole component of serotonin.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 232
The indole 1211 was converted to quinone 1212 by a convenient procedure involving reduction to the indoline followed by Fremy oxidation (Scheme 233) <1998B15199>. The indoline is an aminobenzene derivative, a class of compounds known to undergo Fremy oxidations readily. The Fremy’s salt also converts the indoline back to the indole resulting in quinone 1212 as the final product. Aziridination of quinone 1212 to afford compound 1213 was carried out with aziridine under aerobic conditions (reductive addition of aziridine followed by air oxidation to the quinone).
Scheme 233
The Lewis acid-catalyzed amidation of 9-ethyl-9H-carbazole gave 9H-carbazole-3,6-dicarboxamide 1214 that was saponified to carbazole-3,6-dicarboxylic acid 1215, followed by conversion into carbazole-3,6-dicarbonyl dichloride 1216, utilizing SOCl2 (Scheme 234) <1997CM1578, 1999SM(99)181>. Compound 1216 was then reacted with allylamine in the presence of Et3N to give N 3,N 6-diallyl-9H-carbazole-3,6dicarboxamide 1217, subsequent treatment of compound 1217 with phosgene gave 3,6-dicarboximidoyl dichloride derivative 1218. Ring closure of dichloride 1218 was carried out under basic conditions to give 9-ethyl-3,6-di(1Hpyrrol-2-yl)-9H-carbazole 1219, a relatively low oxidation potential monomer with electron-rich pyrrole rings as terminal electropolymerizable moieties, in an overall synthetic yield of 5.8%. A few other new highly conjugated carbazole containing monomers such as 1222 that undergo polymerization at low oxidation potential were synthesized via NiCl2(dppp)-catalyzed cross-coupling of the dibromo-N-substituted carbazole 1221 with the Grignard reagent from 2,3-dihydrothieno[3,4-b][1,4]dioxine 1220 in 62–73% yields (Equation 274) <1997CM1578>.
215
216
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 234
ð274Þ
The pyrrolyl-pyridine and -quinoline precursors 1225 have been prepared via an electroinduced SRN1 reaction in liquid ammonia by reacting pyrrolyl anions 1223 and the corresponding aryl halides 1224 (pyridyl and quinolyl chlorides) (Scheme 235) <2004S0517>. Alkylation of compounds 1225 was achieved by a Menschutkin reaction, using CF3SO3Me as quaternization reagent. In all cases, methylation occurred selectively at the pyridine and quinoline nitrogen atoms with no methylation on the nitrogen of pyrrole. New pyrrolyl-pyridinium and -quinolinium salts 1226 have been prepared in high yields. Preliminary investigations revealed that these salts show a good response as nonlinear optics.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 235
Tetrahydropyrrolo[3,2-c]pyridines (THPP) 1227 upon reaction with DMAD underwent ring expansion, affording tetrahydropyrrolo[2,3-d]azocines 1229 in 20–35% yields (Scheme 236) <2002TL6767>. Compounds 1229 have not previously been reported in the literature. Their crystal structure and conformation was established by X-ray crystallography. In both cases the corresponding 3-vinylpyrroles 1228 were formed in 15–25% yields. The reaction probably proceeds via the intermediate zwitterion A, resulting from the Michael addition of the tertiary nitrogen to DMAD (Scheme 236). Intramolecular attack of the resulting anion on the 4-Me group (pathway a) leads to the corresponding vinylpyrroles, while the alternative nucleophilic attack on the C(4)-position (pathway b) results in pyrrolo[2,3-d]azocine formation. When this synthetic protocol was applied to the THPP 1230, having a piperidine ring without C-alkyl substituents, the corresponding pyrrolo[2,3-d]azocine 1231 was isolated in 42% yield (Equation 275).
Scheme 236
ð275Þ
217
218
Pyrroles and their Benzo Derivatives: Reactivity
3.02.4.2 Alkyl and Substituted Alkyl Groups The 2-(benzotriazol-1-yl)methyl side chains of pyrrole 1232 or its 2-methyl analogs were elaborated by nucleophilic substitution and also by initial alkylation followed by replacement or elimination of the benzotriazolyl moiety to afford a variety of 1,2,4-trisubstituted (Scheme 237) and 1,2,4,5-tetrasubstituted pyrroles <1989CL1107, 1996JOC1624>.
Scheme 237
The benzotriazole-functionalized pyrrole derivative 1233 was deprotonated and allowed to react with chalcone to afford a mixture of compounds 1235 and 1236, which without separation was refluxed in 2-propanol/10% H2SO4 to give the corresponding indole 1237 (Scheme 238) <2003JOC5728>. The reaction proceeded through the selective 1,4-addition of lithium derivative 1234 to the enones. Attempts to generalize this methodology with use of a,b-unsaturated esters failed.
Scheme 238
Pyrroles and their Benzo Derivatives: Reactivity
A new, highly efficient method to prepare symmetrical and unsymmetrical bisindolylmaleimides 1240 in 84–100% yield by reaction of the readily available indole-3-acetamides 1238 with methyl indolyl-3-glyoxylates 1239 using a 1.0 M solution of ButOK in THF has been described (Equation 276) <1998JOC1961, 1998JOC6053, 2003JOC8008>. The reaction is successful in the presence of a variety of functional groups (H, Alk, OH, OTr, NMe2).
ð276Þ
The oxidative formation of a new pyrrole ring in the indol-3-yl-indoloquinone system afforded a simple synthesis of the Wakayin model compound 1243. Tryptamine 1241 (R ¼ H) was reacted with 2-methoxynaphthoquinone 1242 in refluxing ethanol to afford aminonaphthoquinone derivative 1243 in high yield (68%), but various attempts to oxidatively cyclize compound 1243 (R ¼ H) to compound 1244 failed (Scheme 239) <1998TL7677>.
Scheme 239
Similarly, N-methyltryptamine 1241 (R ¼ Me) yielded compound 1243 (R ¼ Me) in excellent yield (91%). Reaction of compound 1243 (R ¼ Me) with the oxidant DDQ in AcOH gave the desired model compound 1244 in good yield (78%), the structure being confirmed by X-ray crystallography <1998TL7677>.
3.02.4.3 Alkenyl and Alkynyl Groups The synthetic utility of C-vinylpyrroles has been described in a recent review <2004CRV2481>. Hydrogenation of 3-vinylindoles 1245 affords compounds 1246 in 92–96% yield (Equation 277) <1999T4341>. 2-Formyl-3-iodopyrrole 1248 has been obtained in 48% yield via the oxidative cleavage of the double bond of 2-vinyl indole 1247 with potassium permanganate (Scheme 240) <1999TL4555>. Pyrrole 1248 was coupled with a wide variety of arylboronic acids to give the corresponding biaryl compounds 1249 in high yields.
219
220
Pyrroles and their Benzo Derivatives: Reactivity
ð277Þ
Scheme 240
The hydroboration of 2-allylpyrrole 1250 with various hydroborating agents (Et2BH2BEt2, (9-BBN)2, (CH2)4BH2B(CH2)4, thex(H)BH2B(H)thex, Az-BH2?THF (pyrrole, 2,5-dimethylpyrrole), Et2O?BH2Cl, Me3Si(H)NB2H5) (mainly THF, –78 C to rt) leads to B-substituted bicyclic N-pyrrolylboranes 1254–1259 (Scheme 241) <1997JOM(534)181>. In the reaction with tetraalkyldiboranes, stable intramolecular 2H-pyrrole-borane adducts 1251–1253 are formed first, which, in the case of adducts 1251 and 1253, can be converted into the bicyclic N-pyrrolylboranes 1258 and 1259, respectively.
Scheme 241
Pyrroles and their Benzo Derivatives: Reactivity
The N,C-dilithiated derivative 1260 of allylpyrrole 1250 (Scheme 242) reacts selectively in THF with electrophiles (H2O, MeI, Me3SiCl) to give the (Z)-isomers 1261a–1263a (Scheme 243) <1997JOM(527)163>. In diethyl ether, the analogous reactions lead selectively to the (E)-isomers 1261b–1263b. Reactions of the N,C-dilithio-2allylpyrrole 1260 with various halides in tetrahydrofuran give selectively (Z)-isomers, and in the case of dihalides (Me2SiCl2, Me2SnCl2, Cp2ZrCl2) or SiCl4 give new heterobicycles 1265 (E ¼ Si), 1266 (E ¼ Sn), and 1268 (E ¼ Zr) or the spirosilane 1267 (Scheme 244) <1997JOM(532)71>. In the reaction of compound 1260 with Me2SiCl2 the product 1264 was formed together with bicycle 1265 in comparable yield.
Scheme 242
Scheme 243
Scheme 244
221
222
Pyrroles and their Benzo Derivatives: Reactivity
The methyl 2-(1H-pyrrol-2-yl)ethenyl ethers 1269, derived from enyne-imines and Fischer carbene complexes, were unstable with respect to air oxidation and were hydrolyzed to the corresponding ketones 1270 for characterization purposes (Equation 278) <2003OL2043>.
ð278Þ
The alkaloid carbazoquinocin C 1272, R1 ¼ n-C7H15, R2 ¼ Me, and related carbazole-3,4-quinones 1272 as biological antioxidants were synthesized in a few steps in good to excellent yields <2000SL1757, 2004OL329>. The key step comprises a cyclization reaction of appropriate 2-vinylindoles 1271 with oxalyl chloride (Equation 279) <2000SL1757>. An alternative synthesis of carbazoquinocin C utilizing 2-vinylindoles has been reported <2004OL329>.
ð279Þ
Applications of C-alkenyl-, C-allenyl-, and C-alkynylpyrroles and indoles to the synthesis of some other useful molecules are also described <1995MC226, 1996JOC4136, 1996T4555, 1997T4447, 2000T1587, 2000T3189, 2001JOC8599, 2001OL3189, 2001TL3641, 2002CRV4303, 2002COR507, 2002JOC7048, 2002PPS1017, 2002OL2791, 2002OL3107, 2003JOC5728, 2003JOC7342, 2003MI658, 2004H(63)1455, 2004HCA1060, 2004M519, 2004TL6513, 2006JOC7793, 2006RJO1348>.
3.02.4.4 Carboxylic Acids and Their Derivatives From indole-2-carboxylic acid 1273, a quantitative esterification was achieved with boiling methanol saturated with HCl (Equation 280) <2002S1810>. The reduction of the ester was carried out with DIBAL-H and also gave quantitatively the alcohol. None of the tested reaction conditions (slow addition at 78 C of the hydride or keeping the reaction at low temperature) gave directly the aldehyde. Other reduction conditions with LiAlH4 gave poor yields (<20%). The subsequent oxidation was done with MnO2 which gave the aldehyde 1274 in 80% overall yield (three steps) and after purification.
ð280Þ
Efficient preparation of dicarboxylic acid 1275 <2001J(P1)1039> was the starting point of the novel, convenient synthesis of a known, central nervous system active 8-chloro-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine 1276 (Equation 281). In the two-step synthesis the dicarboxylic acid 1275 was reduced to the diol, then this was treated with silica gel. Silica is acidic enough to promote elimination of water under mild conditions. In this way, compound 1276 could be prepared conveniently while the known methods (use of P2O5 or other strong acid) initiate serious side reactions of the pyrrole moiety.
Pyrroles and their Benzo Derivatives: Reactivity
ð281Þ
Deprotonation of the moderately stable 1H-pyrrole-2-carboxylate 1278, Lamellarin O dimethyl ether, obtained in 91% isolated yield through smooth N-alkylation of 1H-pyrrole-2-carboxylate 1277 with 2-bromo-1-(4-methoxyphenyl)-1-ethanone (Scheme 245), with LDA led directly to 1H-pyrrolo[2,1-c][1,4]oxazin-1-one 1279 (Ar2 ¼ 4MeOC6H4), but this transformation turned out to be capricious and rather low-yielding <1995JOC6637>. A much more reliable method for the formation of the 1H-pyrrolo[2,1-c][1,4]oxazin-1-one core of lukianol consisted in the saponification of the methyl ester of acid 1278 followed by enol-lactonization of the crude oxo-acid formed with Ac2O/AcONa, according to the known procedures. Cleavage of the MeO groups of oxazinone 1279 with BBr3 in CH2Cl2 gave (in quantitative yield) 3,7,8-tris(4-hydroxyphenyl)-1H-pyrrolo[2,1-c][1,4]oxazin-1-one 1279 (Ar2 ¼ 4HOC6H4), lukianol A, a pyrrole alkaloid which was isolated from marine sources and exhibits some activity against a cell line derived from human epidermatoid carcinoma.
Scheme 245
Basic hydrolysis of the 1H-pyrrole-2-carboxylate 1280, obtained in 71% yield by a procedure similar to described <2000JOC2479> (by alkylation of the corresponding NH-pyrrole with 3,4-dimethoxyphenethyl methanesulfonate (N2, NaH, DMF, 70 C, 12 h)), with NaOH in aqueous EtOH produces the respective pyrrole carboxylic acid 1281 in 90% yield and in an analytically pure form (Scheme 246) <2003T207>. When the acid 1281 was heated with lead tetraacetate in refluxing ethyl acetate, a 52% yield of ningalin B hexamethyl ether 1282, the multidrug-resistant reversal agent, a marine natural product derivative, was obtained. The acid-catalyzed condensation of ethyl 4,7-dihydro-2H-4,7-ethanoisoindole-1-carboxylate 1283 with 2,5bis(hydroxymethyl)thiophene 1284 was used for the preparation of the tripyrrane analog with a central thiophene ring 1285 (Equation 282), precursors of bicyclo[2.2.3]octadiene-fused porphyrins, which were converted to the corresponding highly conjugated core-modified tetrabenzoporphyrins, including thia-, dithia-, and oxathiatetrabenzoporphyrins <2004CC374>. Hydrolysis of the ester groups with LiOH afforded dicarboxylic acid 1285 (R ¼ H) in 98% yield.
223
224
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 246
ð282Þ
3.02.4.5 Aldehydes and Ketones Chlorinated 2-(hydroxymethyl)- and 2-(alkoxymethyl)pyrroles are a class of compounds with currently renewed interest as physiologically active heterocycles. A new methodology to access these was developed via the reduction of chlorinated 2-formylpyrroles 1286 (Equation 283) <2005T4631>. Pyrroles 1286 were reduced with sodium borohydride to produce new 2-(hydroxymethyl)pyrrole derivatives 1287 (R2 ¼ OH) bearing a chloro atom at the 5-position. 2-(Methoxymethyl)pyrroles 1287 (R2 ¼ MeO) were obtained directly by reducing pyrroles 1286 with NaBH4 in methanol instead of tetrahydrofuran, resulting in a substitution of the hydroxy function by methanol.
ð283Þ
Employing a mixture of borane/t-butylamine complex and AlCl3 as an effective reducing system, the carbonyl function in compound 1288 could be degraded to a methylene group resulting in formation of the cyclization precursor (S)-1289 (Equation 284) <2004T1197>.
ð284Þ
Pyrroles and their Benzo Derivatives: Reactivity
A Wittig reaction was used to obtain 2-vinyl indoles 1291 (Equation 285) <2002S1810>. The ylide was generated from methyltriphenylphosphonium bromide in anhydrous THF under argon using KHMDS in toluene at room temperature for 0.5 h and then was cannulated to a solution of aldehyde 1290. These conditions were essential to obtain high yields.
ð285Þ
A Wittig reaction of aldehyde 1292 with the ylide prepared from triphenylphosphonium bromide 1293 and lithium diisopropylamide gave an (E)/(Z) mixture (1:1, when R ¼ Me, and 5:3, when R ¼ PhSO2) of 3-(2-arylethenyl)-1Hindoles 1294 in 70–86% yield (Equation 286) <1999T4341>.
ð286Þ
Compound 1295 undergoes a smooth reaction in boiling THF to produce triphenylphosphine oxide and 1-(trifluoromethyl)-3H-pyrrolizines 1296 that may be considered as a product of an intramolecular Wittig reaction (Scheme 247) <2006ARK55>. The tautomeric 1H-pyrrolizine 1297 was not formed. When phosphorus ylides containing the trichloromethyl group 1298 were heated in THF the expected pyrrolizine 1299 was not formed, and the 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone 1300, dialkyl 2-butynedioate and triphenylphosphine were obtained instead (Scheme 248).
Scheme 247
Scheme 248
225
226
Pyrroles and their Benzo Derivatives: Reactivity
A series of substituted 3-pyrrolylalkenes 1302–1306 (Scheme 249), the prospective synthons for new heterocycles (e.g., derivative 1304 for the distrontium salt of 3-(1-carboxymethyl-2-carboxypyrrol-4-yl)pentanedioic acid (immobilization of osteoporosis) <1990EUP1990349432>), were obtained under the conditions of the Knoevenagel reaction of 4-formyl-1H-pyrrole 1301 and various C-acids, such as ethyl hydrogen malonate, diethyl malonate, (1,3-benzoxazol-2-yl)acetonitrile, (1,3-benzothiazol-2-yl)acetonitrile, (1H-benzimidazol-2-yl)acetonitrile, N-(1,3-benzothiazol-2yl)cyanoacetamide, as well as its 6-methoxyderivative, and malonodinitrile <2005ARK127>. Catalyzed by piperidine, glycine, 10% ethanolic sodium ethoxide, or potassium acetate, the reactions gave yields ranging from 50% to 97%.
Scheme 249
4-Formyl-1H-pyrroles have also been used as synthons for the preparation of polysubstituted 4-(1H-pyrrol-3-yl)1,4-dihydropyridines 1307–1310 under the conditions of the standard and modified Hantzsch’s dihydropyridine synthesis or by regioselective alkylation of the 1,4-dihydropyridine skeleton (Scheme 250) <2005ARK127>. The Michael-addition of 1H-pyrrole-2-carbaldehyde 1311 to Cr(CO)3-complexed aryl allenylphosphonates 1312 followed by an intramolecular Horner–Emmons–Wadsworth olefination in boiling THF gives rise to arene Cr(CO)3substituted 3-(1-methylethylidene)-3H-pyrrolizines 1313 and 1314 in moderate to good yields (Scheme 251) <1998T1457>.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 250
Scheme 251
227
228
Pyrroles and their Benzo Derivatives: Reactivity
The synthesis of the pyrazino[1,2-a]indole nucleus was achieved by intramolecular cyclization in the presence of ammonia of several 2-carbonyl-1-propargylindoles 1316, derived from 1-propargylindoles 1315 (Scheme 252) <2005JOC4088>. Cyclization of 1-alkynylindole-2-carbaldehydes was easily accomplished under standard heating conditions (indole 1316/2 M NH3 in MeOH ¼ 1:20, sealed tube, 90–110 C, 3–387 h, isolated yields: 0–58% of tricycle 1317 and 0–80% of tricycle 1318), whereas microwave heating contributed to reduce reaction times and improved overall yields (indole 1316/2 M NH3 in MeOH ¼ 1:20, sealed tube, 150 C, 25–300 min, isolated yields: 0–100% of tricycle 1317 and 0–95% of tricycle 1318). Moreover, a fine-tuning of the microwave irradiation time made possible the selective synthesis of both pyrazino[1,2-a]indole isomers <2005JOC4088>. TiCl4 proved the catalytic system of choice to achieve pyrazinoindoles in satisfactory yields (100 C, 120–1020 min, 0–90% of compound 1317 and 0–89% of compound 1318) starting from 1-alkynyl-2-acetylindole and 1-alkynyl-2-benzoylindole derivatives. Also in these cases, microwave heating contributed to faster reactions (130 C, 43–313 min) and improved yields.
Scheme 252
An intramolecular reaction with primary amine as the nucleophile that was prepared in situ by the reduction of the nitro group in pyrrole 1319 resulted in the pyrrolo[2,1-c]benzo[f ]diazepine 1320, which indicates that the amino group reacts via condensation with the aldehyde group rather than via substitution of the chloro group (Equation 287) <2005T5831>.
ð287Þ
The reaction of pyrrole 1321 with piperidine or morpholine, in ethanol at room temperature, afforded crystalline products after purification, which were shown to be 3,5-dichloro-2-(19-piperidinylmethylene)-2H-pyrrole-4-carbaldehyde 1322 (X ¼ CH2) and 3,5-dichloro-2-(49-morpholinylmethylene)-2H-pyrrole-4-carbaldehyde 1322 (X ¼ O) (Equation 288) <2005T5831>.
ð288Þ
Pyrroles and their Benzo Derivatives: Reactivity
The aza-Diels–Alder reaction of substituted 1H-indole-2-carbaldehydes 1323 with Danishevsky’s diene 1324 proceeds with a high degree of diastereoselectivity providing highly functionalized 1-R3-2-(1-methyl-1H-indol-2-yl)2,3-dihydro-4(1H)-pyridinones 1325 which were further elaborated into novel polycyclic heterocycles (Equation 289) <2002TL29>. Attempts to form the imine of 1H-indole-2-carbaldehyde 1326 in situ in the presence of diene 1324 and zinc chloride or zinc triflate at 0 C or at room temperature did not afford the expected cycloadduct 1327. Instead, 2-(1H-indol-2-yl)-2,3-dihydro-4H-pyran-4-one 1328 and the 5-hydroxy-1-methoxy-5-(1H-indol-2-yl)-1-penten-3-one 1329 were isolated in 45% and 25% yields, respectively (Equation 290).
ð289Þ
ð290Þ
2-[3-(6-Nitro-1,3-benzoxazol-2-yl)-1H-indol-1-yl]-1-ethanol 1334, a photoconducting nonlinear optical chromophore with thermal and photochemical stabilities and broad transparency at the visible region, was synthesized through the three-step reactions of 2-(3-formyl-1H-indol-1-yl)ethyl acetate 1331 (derived from 2-(1H-indol-1-yl)ethanol 1330) and 2-amino-5-nitrophenol, that is, formation of Schiff base 1333, oxidative ring closing and deprotection (Scheme 253) <2001PLM3023>. Because the hydroxy group normally reduces the solubility of Schiff base and leads to various side reactions, deprotection was carried out after ring closing. Compound 1332 has been employed in the synthesis of a photoconducting indole-hydrazone chromophore (by reaction with 1,1-diphenyl hydrazine hydrochloride). In this case, deprotection was carried out before the formation of hydrazone, since the azomethine bond in hydrazone is unstable in alkaline conditions. The 1-acryloyl-1H-pyrrole-2-carbaldehyde 1335 was synthesized and submitted to reaction with benzylhydroxylamine (Scheme 254) <2001H(55)1987>. The first-formed nitrone 1336 escaped isolation; nevertheless, the workup of the reaction mixture after 5 days at room temperature furnished, apart from some uncharacterizable material, one intramolecular bridged-ring cycloadduct 1337 in 28% yield. Its structure was established unequivocally by X-ray diffractometric crystal analysis. Further elaboration of the adduct 1337 led to 8-amino-6-hydroxyhexahydro-5(1H)indolizinone 1338 and 6-hydroxyhexahydro-5(1H)-indolizinone 1339, which can be seen as useful intermediates in alkaloid synthesis. The cleavage of the isoxazolidine ring of compound 1337 upon catalytic hydrogenation with the concomitant aim of saturating the pyrrole nucleus was achieved only in a strongly protic medium which, however, also promoted the detachment of the benzylic amino group. As a consequence, although the hydrogenation was fully stereoselective, a mixture of amino alcohol 1338 and alcohol 1339 was formed.
229
230
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 253
Scheme 254
Thermal intramolecular cycloaddition reactions of unsaturated nitrones 1341 derived from a series of N-(2alkenyl)-2-pyrrolecarbaldehydes 1340 and benzylhydroxylamine lead to competitive formation of two kinds of intramolecular cycloadducts, namely the fused- and the bridged-ring regioisomers 1342 and 1343, respectively (Scheme 255) <2001T8323>. Further elaboration of compounds 1342 and 1343 has given pyrrolizidine and indolizidine derivatives, respectively. A similar regiochemical trend was observed when aldehydes 1340 were reacted with (R)-a-methylbenzylhydroxylamine in order to synthesize optically active compounds.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 255
The synthesis of crystalline pyrrolecarbaldiminate/Cu(II) complexes can be carried out by reacting the ligand, either premade or (more conveniently) generated in situ, with a Cu(II) salt in methanol or water <2003JCR975>. The Yeh–Barker procedure (1H-pyrrole-2-carbaldehyde þ Cu(OAc)2 þ RNH2 neat or in EtOH) <1967IC830> afforded some of the Cu complexes in satisfactory yield but did not work for R ¼ Pri. Once water was used instead of EtOH, the desired Cu/bis-chelate was produced in 92% yield. When the reaction with other amines was carried out in water, a variety of pyrrolecarbaldiminate/Cu(II) complexes 1344 were obtained in considerably better (up to 94%) isolated yields (Equation 291) <2003JCR975, 2004WO2004015164>.
ð291Þ
A new bicyclic betaine, a pyrrolo[1,2-d][1,2,4]triazin-2-ium-4-olate 1347, was prepared by the thermolysis of a ringexpansion reaction product 1346, 2,3-di(t-butyl)-1-hydroxy-2,3-dihydropyrrolo[1,2-d][1,2,4]triazin-4(1H)-one, of 1,2di(t-butyl)-1,2-diaziran-3-one 1345 with 1H-pyrrole-2-carbaldehyde (Scheme 256) <1995MI1>. Its cyclization reaction with a dipolarophile such as dimethyl 2-butynedioate leads to a fused ring-enlarged compound, a triazocinone derivative 1348 in rather low yield. Heating a solution of triazocine 1348 in benzene-d6 in an NMR tube at 140 C for 0.5 h leads to its thermal transformation into compound 1349 in 21% yield via skeletal isomerization <1999T13703>.
Scheme 256
231
232
Pyrroles and their Benzo Derivatives: Reactivity
Dehydrative condensation of 1H-pyrrole-2-carbaldehyde and ethyl 1-hydrazinecarboxylate gives ethyl 2-(1Hpyrrol-2-ylmethylidene)-1-hydrazinecarboxylate 1350 in quantitative yield (Scheme 257) <1999T13703>. A cyclization of the hydrazinecarboxylate 1350 by a stoichiometric amount of NaH was then examined, but a complicated mixture was obtained. It was found that pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one 1351 can be prepared by treatment of compound 1350 with a catalytic amount (0.1 equiv) of the base, in 75% yield. It is noteworthy that the liberated ethoxide ion which functioned as a base instead of NaH provided a catalytic system.
Scheme 257
The pyrrole derivative (E)-1352 was readily prepared from 1H-pyrrole-2-carbaldehyde by N-allylation with 3-bromo2-iodopropene under basic conditions (50% NaOH/CH2Cl2, benzyltriethylammonium chloride (BTEAC), rt) and subsequent olefination with ethyl p-tolylsulfinylmethanephosphonate to give a 67:33 mixture of (E)/(Z)-isomers (82% yield), which were separated by flash chromatography (Scheme 258) <2000TL1983>. However, the pyrrole (E)-1352 failed to react under the usual Heck reaction conditions (Pd(OAc)2, PPh3, Ag2CO3, MeCN, rt), its lack of reactivity being probably due to the strain associated with the formation of the bicyclic 1,3-diene (Z)-1353. The Heck reaction of pyrrole (E)-1352 occurred under somewhat harsher conditions as shown, furnishing after chromatographic purification the diene (Z)-1353 in 44% yield along with 40% of starting pyrrole (E)-1352.
Scheme 258
Synthesis of 2-[5-(1H-pyrrol-2-yl)-2-thienyl]-1H-pyrrole 1355, monomer for polyconjugated polymers, is based on the reaction of 1,4-di(1H-pyrrol-2-yl)-1,4-butanedione 1354 with Lawesson’s reagent (Equation 292) <1997CM2876>. Compound 1356 was prepared by Triton B-catalyzed condensation of 1H-pyrrole-2-carbaldehyde and the appropriate nitrile derivative (Equation 293).
ð292Þ
ð293Þ
Pyrroles and their Benzo Derivatives: Reactivity
The acylation of cyclohexane-1,3-dione 1358 with pyrrole-2-carbonyl chloride 1357 (X ¼ Cl) proceeded normally and gave the O-acylated product 1359 (Scheme 259) <1996TL1007>.
Scheme 259
Subsequent rearrangement with Et3N and KCN failed to give the C-acylated product 1362. Instead, the carboxylic acid 1361 (R ¼ CO2H) and its decarboxylation product 1361 (R ¼ H) were obtained. This result can be interpreted in terms of the intermediate spirocyclic lactone 1360 which opens to compound 1361. When acyl cyanide 1357 (X ¼ CN) was allowed to react with diketone 1358 in the presence of Et3N, the desired C-acylated product 1362 was obtained directly in 78% yield. Surprisingly, the seemingly trivial aromatization of compound 1362 into the resorcinol 1364, a known precursor to pyoluteorin 1365, could not be achieved. The use of mercuric acetate, following a standard protocol for synthesizing resorcinols, gave 8-hydroxy-9H-pyrrolo[1,2-a]indol-9-one 1363 in 85% yield. Successive treatment of compound 1362 with isopropenyl acetate and DDQ in a one-pot procedure was not efficient, affording the resorcinol 1364 in only 18% yield <1996TL1007>.
3.02.4.6 N-Linked Substituents The exchange of the benzyl protecting groups with the pharmacophoric propyl substituents was done by catalytic debenzylation of tetrahydroindole (S)-1366 followed by a reductive alkylation of the resulting primary amine with propionaldehyde and sodium triacetoxyborohydride to give the test compounds (S)-1367 (Scheme 260) <2004T1197>. Subjecting compound (S)-1367 to Vilsmeier conditions gave the 2-formyl derivative (S)-1368 in 85% yield. Hydrogenolysis of tetrahydroindole (S)-1366 (R ¼ Me) and coupling of the resulting primary amine with the chiral isocyanates (S)-1369 and (R)-1369 gave the diastereomeric ureas (S,S)-1370 and (S,R)-1370, respectively (Scheme 261).
Scheme 260
233
234
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 261
An efficient procedure for the nucleophilic displacement of the N,N-dimethylamino group of 1-triisopropylsilylgramines via the fluoride ion-induced elimination–addition reaction has been devised. 1-Triisopropylsilylgramine methiodide 1371 reacted smoothly with a variety of nucleophiles in the presence of tetrabutylammonium fluoride (TBAF) to give 3-substituted indoles 1372 (Scheme 262) <1995TL5929>.
Scheme 262
The 3,4-disubstituted indoles of synthetic value were efficiently synthesized by sequential use of 4-selective lithiation of 1-triisopropylsilylgramine 1371 followed by this new substitution reaction. Thus, the compound 1373, which could be prepared from amine 1371 in two steps, was quaternized with iodomethane (2 equiv) in benzene at room temperature overnight in 99% yield. The resulting methiodide was treated with TBAF in the presence of nitromethane (10 equiv) to give compound 1374 (Nu ¼ CH2NO2) in 85% yield. This compound has been employed as the key intermediate in the synthesis of the ergot alkaloids, such as secoagroclavine and aurantioclavine. In similar manner, the 3,4-disubstituted indole 1374 (Nu ¼ C(TrocNH)(CO2Et)2) was synthesized from compound 1373 using 1.1 equiv of diethyl (2,2,2-trichloroethoxycarbonyl)aminomalonate as nucleophile in 92% yield. This compound has been converted to clavicipitic acid <1995TL5929>. The three-component reaction of 1,5-dimethyl-1H-pyrrole-2-carbonitrile 1375, 2H-azaphosphirene tungsten complex 1376 and ethyl acetylenecarboxylate 1377 led to the formation of the regioisomeric 2H-1,2-azaphospholone complexes 1378 and 1379 (ratio 8:1) (Scheme 263) <2002POL119>. Complex 1378 was formed predominantly
Pyrroles and their Benzo Derivatives: Reactivity
(yield 23%), as established unambiguously by its X-ray structure analysis. Formation of a 1H-phosphirine complex was not observed in this reaction, but the same reaction with phenylacetylene, instead of ester 1377, furnished exclusively the 1H-phosphirine complex 1380 as the only phosphorus-containing product, which was readily identified by 31P NMR spectroscopy (Scheme 264). Using pyrrole 1375, complex 1376 and ethoxyacetylene, having an electron-donating group, the reaction afforded selectively the 1H-phosphirine complex 1381.
Scheme 263
Scheme 264
A pyrrole oxime anion 1382, among similar (Z)-heteroaryl oxime anions, was utilized to effect nucleophilic azirane ring opening involving attack of the nitrogen atom of the oxime anion generating the corresponding nitrone (Scheme 265) <2001T7951>. The yield of nitrone obtained from the standard reaction of the oxime anion with 1-[(4-chlorophenyl)sulfonyl]azirane 1383 increased from 56% in the case of furan, oxygen being the least
Scheme 265
235
236
Pyrroles and their Benzo Derivatives: Reactivity
electron-donating heteroatom, to 70% in the case of thiophene. However, the yield dropped to 53%, in the case of pyrrole, which is the most strongly electron-donating heterocycle. This is may be due to deprotonation of the weakly acidic proton on the pyrrole nitrogen (pKa ca. 16), by NaH, generating a second ambident nucleophile. Pyrrole nitrone 1384, unlike the furan and thiophene nitrones, did not undergo 1,3-dipolar cycloaddition with N-methylmaleimide (NMM) to yield the corresponding isoxazolidine 1386 even after prolonged reaction times. This is probably due to the formation of a stable 6,6-hydrogen bonded system 1385 as can be seen in the crystal structure determined by X-ray diffraction studies. The 1H-pyrrol-2-amine 1387 reacted in dry CH2Cl2 with 0.5 equiv of 1H-pyrrole-2,5-dicarbonyl dichloride 1388 in the presence of Et3N, to give compound 1389, a new heterocyclic anion receptor, which was isolated in 47% yield (Equation 294) <2006OL1593>. The moderate yields for this reaction are ascribed to the inherent instability of compound 1388 and to the formation of the three-ring dimer species 1390. Structural proof for receptor 1389 came from a single-crystal X-ray diffraction analysis.
ð294Þ
Rh(I)-catalyzed [2þ2þ2] cyclotrimerization of 1,6-diynes (e.g., 1391 and 1394) with monoynes (e.g., 1392) in combination with stereospecific Ag(I)-catalyzed aldimine ! (metallo)azomethine ylide ! cycloaddition cascades affords rapid access to complex heterocyclic benzene derivatives 1393 and 1395 in one-pot processes with the generation of five new bonds, four stereocenters and three rings (Schemes 266 and 267) <2000T8967>.
Scheme 266
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 267
3.02.4.7 Hydroxy and Alkoxy Groups The demethylation of 4-methoxy- and 4,11-dimethoxy-derivatives 1396 was carried out by the action of dimethyl sulfide/BCl3 complex in dichloromethane under reflux to give 4-hydroxy- and 4,11-dihydroxy-1H-naphtho[2,3-f ]indole-5,10-diones 1397 (Equation 295) <2001CHE944>.
ð295Þ
Within the framework of a fundamentally new strategy for the synchronous construction and functionalization of pyrrole rings, which utilizes readily available isothiocyanates and metal (Li or K) derivatives of 1,2-dienes or alkynes as key building blocks <1996CHE781, 1996RJC1986, 1997RJO76, 1997RJO80, 1997TL2409, 1997TL7241, 1999EJO2663, 1999MI1, 1999RJO928, 2000CHE876, 2000CHE1241, 2001EJO4569, 2002CHE54, 2002CHE745, 2002RJO907, 2002RJO1070, 2003RJO609, 2004RJO775, 2004S0735, 2006RJO607>, a novel general approach to the 3-hydroxy- (Scheme 268) <1999MI1, 2000RCB1634, 2004S0735> and 2-hydroxypyrroles (Scheme 269) <2001CHE364, 2002RJO907> was proposed. A few representatives of unexpectedly and unprecedently stable (in hydroxy-form) 3-hydroxypyrroles 1400 (R ¼ Alk, Ar) were prepared in good yields by treatment of the 3-(1-ethoxyethoxy)-2-(methylsulfanyl)-1H-pyrroles 1399, obtained by copper-catalyzed cyclization of 1-aza-1,3,4-triene 1398, with a catalytic amount of hydrochloric acid in methanol (Scheme 268). The content of keto-tautomer 1401, a 1,2dihydro-3H-pyrrol-3-one, was found to be about 5–10% (IR and NMR data). Acidic hydrolysis or methanolysis of 5-(1-ethoxyethoxy)-1H-pyrroles 1403, assembled from lithiated 1-(1-ethoxyethoxy)-2-heptyne 1402 and isothiocyanates in one-pot (Scheme 269), leads to 2-hydroxypyrroles 1404 that, unlike the 3-hydroxy-2-(alkylsulfanyl)-1H-pyrroles 1400, exist exclusively in the form of the tautomeric 1,5-dihydro-2Hpyrrol-2-ones 1405 (IR and NMR data). An unprecedented inertness of N-(2-vinyloxy)ethyl group under conditions of acidic hydrolysis (dioxane/H2O, HCl, 0 C, 5 min) was revealed <2002RJO907>. 2-(Methylsulfanyl)-1H-pyrrole-3-carbaldehydes 1407 were obtained in high yields using the same approach, starting from lithiated 1,1,4-trialkoxy-2-butynes and isothiocyanates, followed by hydrolysis of the resulting 3-(dialkoxymethyl)5-alkoxy-2-(methylsulfanyl)-1H-pyrroles 1406 in acidic medium (Scheme 270) <2001CHE366, 2002RJO1070>.
237
238
Pyrroles and their Benzo Derivatives: Reactivity
Regioselective protolytic cleavage of the acetal moiety in compound 1406 which contains a hydrolytically unstable vinyloxy group was carried out in the presence of an acid (aq dioxane, HCl, 5 C, 1 min), and it led to formation of compound 1407 in 91% yield. Treatment of pyrrole 1406 (R3 ¼ CH2TCHOCH2CH2) with hydrochloric acid in aqueous dioxane at 30–35 C for 0.5 h resulted in removal of the acetal protection and hydrolytic cleavage of the vinyloxy group to afford pyrrole 1408 in 92% yield.
Scheme 268
Scheme 269
Scheme 270
Pyrroles and their Benzo Derivatives: Reactivity
3.02.4.8 S-Linked Substituents A new approach to the synthesis of annulated sulfur heterocycles based on triflic anhydride-promoted electrophilic cyclization of the hetaryl-containing alkyl sulfides, including 1409, was elaborated <2003S1191>. The proposed method includes intermediate formation of sulfonylsulfonium salts 1410 followed by electrophilic attack on the aromatic ring (Scheme 271). Smooth demethylation of initially formed cyclic sulfonium salts 1411 by treatment with Et3N afforded a number of five- 1412 and six- 1413 membered fused sulfur heterocycles. Unexpected ring opening with formation of compound 1414 took place in the reaction of diethylamine with five-membered sulfonium salt 1411.
Scheme 271
The previously unknown 2-mercapto-1-methylpyrrole 1417 (Y ¼ S) and the analogous selenol 1417 (Y ¼ Se) have been generated by hydrolysis of 1-methyl-2-[(trimethylsilyl)sulfanyl]-1H-pyrrole 1416 (Y ¼ S) and the corresponding seleno derivative 1416 (Y ¼ Se) obtained as depicted in Scheme 272 <1997T13079>. The thiol–thione (or selenol– selenone) tautomerism (1417 ! 1418 ! 1419) appeared from the formation of dimeric products 1420 – adducts of the thiol or selenol 1417 with their tautomers 1419 (THF, H2O, HCl, concentration in vacuo, then standing at rt, 48 h under N2), from the addition of benzenethiol to the thione 1419 leading to product 1421 (Y ¼ S) and from NMRspectroscopic data. The metallation of N-methylpyrrole 1415 was carried out with BunLi in THF/hexane mixtures at ca. 30 C; a large (100 mol%) excess of pyrrole 1415 was used in order to repress the competitive reaction of BunLi with THF. After addition of sulfur or selenium to 2-lithio-1-methylpyrrole, the corresponding lithium thiolate or selenolate was converted into the trimethylsilyl derivative 1416. The latter could be isolated in good yield (57–77%) by a dry work-up. Application of the BunLi/TMEDA reagent for the lithiation of pyrrole 1415 was considered to involve the risk of decomposition of the trimethylsilyl derivative 1416 by TMEDA under the conditions of the workup. Hydrolysis of a solution of compound 1416 (Y ¼ S) in CDCl3 by (distilled) water gave ratios 1417:1419:1418 of 75:15:10, 25:75:5 and 14:85:1 after 1, 24 and 80 h, respectively. Using MeCN as solvent, a final ratio of 5:90:5 for products 1417, 1419, and 1418 was obtained after only 2 min. Similar experiments with the selenide 1416 (Y ¼ Se) in a CCl4/MeCN mixture showed ratios for compounds 1417 and 1419 of 9:1, 1:1, and 1:9 after 1, 3, and 220 min, respectively, from introduction of water. Pyrrolecarbodithioates are good electrophiles. Carbanions 1422 generated in situ from diverse CH-acids such as malononitrile and cyanoacetamide add to the thiocarbonyl group of pyrrole-2- and pyrrole-3-carbodithioates to afford the vinyl thiolates 1423, which, after alkylation by alkyl halides, give the functionalized 2- and 3-vinylpyrroles 1424 (Scheme 273) <1995T4223, 2002RCR563, 2003SUL95, 2003TL3501>, intermediates in the synthesis of diverse functionalized heterocyclic assemblies with pyrrolyl substituents (e.g., pyrrolyl-pyrazoles and pyrrolyl-pyrazolopyrimidines, pyrrolyl-isoxazoles, iminopyrrolizines, pyrrolizine-3-ones) <1996CHE783, 1996SUL9, 1997SUL205, 1999RJO1214, 2000SUL1, 2001RJO1736, 2003RJO1471, 2004CRV2481, 2005T4841>.
239
240
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 272
Scheme 273
The reaction of enethiolates 1425 with halogenoacetylenes, such as bromobenzoylacetylenes and ethylthio(chloro)acetylene, lead to functionally substituted pyrrolothiazolidines 1426 in 37–85% yields (Scheme 274) <2002CHE86, 2002SUL87>.
Scheme 274
Pyrroles and their Benzo Derivatives: Reactivity
All stages of assembly of the compounds, namely: CH-acid ionization, carbanion addition to the dithioate group of pyrrolecarbodithioates, ethanethiol elimination, and nucleophilic substitution of the halogen at the Csp in the halogenoacetylenes by enethiolate 1425, occur as a one-pot process without isolation of the intermediates.
3.02.4.9 Halogeno Groups Halogenated pyrroles and indoles are versatile synthetic intermediates <1996TL3247, 2004OL7> and very useful starting compounds in the preparation of functionalized heteroaromatic organolithium reagents by nondeprotonating methods (via a halogen–lithium exchange) <1996PLM1493, 2000TL5211, 2002T6373, 2003T9255 and references therein>. An easy and convergent method for the preparation of new series of 6-substituted and 6,8-disubstituted 1-aryl-3,4-dihydropyrrolo[1,2-a]pyrazines based on the use of palladium-catalyzed reactions to introduced aryl and heteroaryl substituents in 1-aryl-3,4-dihydropyrrolo[1,2-a]pyrazines was reported <2004JOC8668>. Compound 1427 was treated with BunLi, and the metallated intermediate 1428 was converted into the heteroarylboronic acid 1429, the heteroaryltin 1430, and the heteroarylzincate 1431 to test the well-known Suzuki, Stille, and Negishi reactions with a variety of commercially available aryl and heteroaryl halides (Scheme 275). The palladium-catalyzed Suzuki cross-coupling reaction of arylboronic acids (phenyl-, 4-methoxyphenyl-, 3-nitrophenyl-, 3,5-dichlorophenyl-, 3-thienylboronic acid) and 6-bromo- 1427 and 6,8dibromo- 1433 3,4-dihydropyrrolo[1,2-a]pyrazines (toluene/EtOH (20:1), K2CO3 or DME/H2O (6:1), Ba(OH)2?8H2O) afforded 6-substituted 1432, 1435, and 6,8-disubstituted 1434, 1436 1-aryl-3,4-dihydropyrrolo[1,2-a]pyrazines in good yields (70–90%) (Schemes 275 and 276). The reactivities of the C(6)- and C(8)-positions in the dibromo compound 1433 are different toward the palladium-catalyzed coupling reaction that allowed the preparation of the disubstituted compound 1436 bearing a 3-thienyl and a phenyl substituents at C-6 and C-8, respectively, by employing consecutive coupling reactions with two different boronic acids. Stille and Negishi coupling reactions have been used to prepare 6-heteroarylsubstituted derivatives in moderate yields (30–67%) by employing heteroaryl halides (1-(5-bromo-2-thienyl)-1-ethanone, 2- and 3-bromopyridines, 2-bromo-5-nitropyridine, 3-bromoquinoline, 4-bromo-2,8-bis(trifluoromethyl)quinoline, 5-bromopyrimidine, 2-bromo-1,3-thiazole, 2-bromo-5-nitro-1,3-thiazole, methyl 3-bromo-2-methyl-1H-indole-1-carboxylate) with 6-metallated 3,4-dihydropyrrolo[1,2-a]pyrazines 1430 and 1431 as reaction partners using (Pd(PPh3)4 (0.01 mmol), LiCl, THF or Pd(PPh3)4 (0.05 mmol), THF or Pd(dba)2 (0.01 mmol), dpf (0.01 mmol)) <2004JOC8668>.
Scheme 275
The attempted Stille coupling of ethyl 4-bromo-1H-pyrrole-2-carboxylate 1437 with tributylphenyltin under standard conditions led to the generation of the desired coupling product 1438 as the minor product (<35%), with debrominated compound 1439 being the major isolated product (>50%) (Scheme 277) <2003TL427>. The Suzuki coupling of compound 1437 with phenylboronic acid did lead to some improvement in terms of the preparation of the desired coupling adduct 1438 (Scheme 277), but the best result that was obtained was 55% of pyrrole 1438 along with 28% of debrominated compound 1439. This unusual dehalogenation of pyrrole 1437 under Suzuki coupling
241
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Pyrroles and their Benzo Derivatives: Reactivity
conditions can be suppressed by protection of the pyrrole nitrogen (with Me, Bn, TIPS, BOC). Using a BOC-protecting group, not only is dehalogenation suppressed, but the protecting group is also removed under the reaction conditions (Equation 296). 4,5-Dibromopyrrole 1440 exhibits dehalogenation, but only at C-4, affording a mixture of bis-coupling product 1441 and mono-coupling product 1442 (Equation 297).
Scheme 276
Scheme 277
ð296Þ
ð297Þ
The Suzuki cross-coupling reaction between 1,2,5-trisubstituted pyrrole halides 1443 and 2-N-(t-butoxycarbonyl)aminophenyl boronic acid 1444 performed with benzyl[bis(triphenylphosphine)]palladium(II) chloride (PdBnCl(PPh3)2)
Pyrroles and their Benzo Derivatives: Reactivity
in a DME/water solution under reflux for 3 h in the presence of base (Na2CO3, K3PO4) gave the corresponding 3-phenyl pyrroles 1445, key intermediates in the synthesis of di-norsecorhazinilam analogue, in modest to high yields (30–80%) (Equation 298) <1995CRV2457, 2000TL5853>.
ð298Þ
The photochemical substitution of some iodo substituted pyrroles 1446 in the presence of an aromatic compound (benzene, m-xylene, thiophene, 2-chlorothiophene, 2-methylthiophene) varies with the structure of the pyrrole and reaction conditions and gives the corresponding aryl derivatives 1447 and/or dehalogenated product 1448 (Equation 299) <1997J(P1)2369>.
ð299Þ
3,4-Diiodo-1-methyl-1H-pyrrole-2-carbaldehyde and 5-iodo-1H-pyrrole-2-carbaldehyde are unreactive when they are irradiated in benzene solution. In contrast, ethyl 5-iodo-3,4-dimethyl-1H-pyrrole-2-carboxylate 1446 (R1 ¼ R2 ¼ Me, R3 ¼ EtCO2) gives a 1:1 mixture of the corresponding 5-phenyl-1H-pyrrole-2-carboxylate 1447 and compound 1448 in quantitative yields. The same reaction when attempted with acetonitrile as solvent gives compound 1448 as the sole product in quantitative yield. Use of 4,5-diiodo-1H-pyrrole-2-carbaldehyde 1446 (R1 ¼ I, R2 ¼ H, R3 ¼ HC(O)) as substrate and irradiation in benzene gives the corresponding 5-phenyl derivative 1447. The same behavior is observed with m-xylene, thiophene and 2-chlorothiophene as solvent. With MeCN as solvent, the reaction with benzene does not work. Irradiation in 2-methylthiophene as solvent gave mainly the decarbonylated arylation product, 3-iodo-2-(5methyl-2-thienyl)-1H-pyrrole 1449 (Equation 300), a compound not previously reported.
ð300Þ
The first intermolecular C–N bond-forming reactions between substituted 2-bromopyrroles 1450 and 1453 with primary (1-propanamine, 2-methoxy-1-ethanamine, (4-methoxyphenyl)methanamine, cyclopropanamine, cyclobutanamine), and cyclic secondary amines (pyrrolidine, morpholine, 1-methylpiperazine, ethyl tetrahydro-1(2H)-pyrazinecarboxylate, 1-phenylpiperazine, 1-(3-phenyl-2-propenyl)piperazine) 1451 were performed using Pd2(dba)3 as catalyst with BINAP as the ligand. The aminations proceeded in the presence of ButONa at 80–100 C in 31–93% yields (Equations 301 and 302) <2004TL769>. However, when the above optimized conditions were applied to the coupling reaction of pyrrole 1450 and acyclic secondary amines such as di-n-butylamine, diphenylamine and dipropenylamine, no reaction was observed.
ð301Þ
243
244
Pyrroles and their Benzo Derivatives: Reactivity
ð302Þ
6-Bromo-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine 1453 reacted only with cyclic secondary amines, affording compounds 1454 (Equation 302) <2004JOC8668, 2004TL769>. Heating at 100 C (instead of 80 C used for substrate 1450) affords the best isolated yields. No acyclic secondary or primary amines reacted under the conditions employed for the successful coupling of cyclic secondary amines or under any of other conditions tested (Pd(dba)2 or Pd(OAc)2 and PBut3 , ferrocenyl di-t-butylphosphine, biphenyl PBut2 or dppf), with substrate 1453 being recovered unaltered or as the debrominated compound. Iodopyrrole 1455 and 1-(2-phenylethynyl)benzene 1456 react to furnish compound 1457 in 50% yield when treated with a palladium catalyst (Scheme 278) <1996TL3399>.
Scheme 278
Homoallylic alcohol 1459 was obtained in 64% yield from 5-iodo-1-methylindole 1458 (1.5 mmol), allene (1.0 bar) and 4-methoxybenzaldehyde (1.0 mmol) (DMF, 80 C, 18 h, Schlenk tube) in the presence of indium (100 mesh powder, 1.5 mmol), Pd(OAc)2 (0.1 mmol) and tris(2-furyl)phosphine (0.2 mmol) (Equation 303) <2000CC645>. The use of triphenylphosphine resulted in an incomplete conversion of the starting materials.
ð303Þ
3.02.5 Reactivity of Substituents Attached to Ring Nitrogen Atom 3.02.5.1 N-Alkyl and Substituted N-Alkyl Groups The palladium-catalyzed Sonogashira reaction between 1-(2-propynyl)-1H-indole 1460 and 1-iodo-2-(2-phenylethynyl)benzene 1461 was successful in producing 1H-indole 1462 in excellent yield (Scheme 279) <2005JOC6647>. Treatment of indole 1462 with a strong base produced 12-phenyl-7H-indeno[19,29:4,5]pyrido[1,2-a]indole 1463 in
Pyrroles and their Benzo Derivatives: Reactivity
98% yield. The 1H NMR spectrum of compound 1463 in CDCl3, taken immediately after the solution was prepared, was found to be relatively clean, but gradually turned dark.
Scheme 279
Indole N-substituted diyne tetracobalt complexes 1467 undergo a Lewis acid-mediated dimerization–cyclization reaction through the indole 3-position to afford indolophanetetrayne cobalt complexes 1468 (Scheme 280) <2003OL1003>.
Scheme 280
245
246
Pyrroles and their Benzo Derivatives: Reactivity
Substitution of the indole fragment of compound 1467 with a 3-methyl function allows analogous formation of indolophanetetrayne complexes 1469, linked through the indole 2-position. Preparation of the N-functionalized indole cyclization precursor 1467 was initiated by Sonogashira coupling of N-propargyl indole 1464 with iodoarylpropargyl acetate 1465 to give diyne 1466 in 81–88% yield (Scheme 280). Both alkyne units of diyne 1466 could be converted to their Co2(CO)6 complexes in the presence of excess Co2(CO)8, giving complex 1467 in 84–92% yields. No evidence of single alkyne complexation products could be detected under these conditions. Treatment of a solution of compound 1467 (R1 ¼ R2 ¼ H: CH2Cl2, 10–2 M, 0 C, 5.5 h) with excess of BF3?OEt2 (6.5 equiv) gave two chromatographically separable main products: cyclophane 1468 (55% yield) and the trimerized indolophanehexayne complex linked through the indole 3-position (28% yield) (by X-ray crystallographic analysis). Similarly, from compound 1467 (R1 ¼ Me, R2 ¼ H: CH2Cl2, 10–4 M, –10 C, 12 h) C(3)-linked indolophanetetrayne 1468 was obtained in 40% yield. Conversely, subjecting compound 1467 (R1 ¼ H, R2 ¼ Me) to BF3?OEt2 resulted in a noticeably more sluggish reaction, but at room temperature (CH2Cl2, 10–4 M, 4 h), C(2)-linked indolophanetetrayne 1469 could be obtained in 25% yield <2003OL1003>. Very simple and straightforward alkylation of NH-heterocycles (NaH, Cl(CH2)nSMe, n ¼ 2 or 3, 68–86%) permits one-pot preparation of pyrrole and carbazole sulfide models for the reaction with triflic anhydride <2003S1191>. Cyclization of the (1H-pyrrol-1-yl)alkyl sulfides 1470 obtained leads to 2,3-dihydropyrrolo[2,1-b][1,3]thiazole 1472 and 3,4-dihydro-2H-pyrrolo[2,1-b][1,3]thiazine 1473 via intermediate 1-methyl-2,3-dihydropyrrolo[2,1-b][1,3]thiazol1-ium or 1-methyl-3,4-dihydro-2H-pyrrolo[2,1-b][1,3]thiazin-1-ium salts 1471 (n ¼ 2 or 3), respectively, that were isolated in high yields in most cases (Scheme 281) <2003S1191>.
Scheme 281
Triflic anhydride-promoted cyclization of 3-(9H-carbazol-9-yl)alkyl methyl sulfides 1474 gives a new approach to thiazine 1475 and thiazepine 1476 derivatives (Scheme 282) <2003S1191>.
Scheme 282
1-(2-Iodo-3-phenylprop-2-enyl)-1H-pyrrol-2-yl cyanide 1477 gave 10H-pyrrolizino[1,2-b]quinoline 1478 in a 3% yield using the hexamethylditin and di-t-butyl peroxide conditions (Scheme 283) <2002J(P1)58>. The radical precursor 1477 was recovered in a 28% yield and decomposition was the dominant event in the reaction. A short and efficient synthesis of a 12H-pyrido[1,2-a:3,4-b9]diindole system and a total synthesis of homofascaplysin C 1482 (four steps) starting from 3-methylindole is described (Scheme 284) <1996TL5207>. 4-(3-Methyl-1H-indol1-yl)butanoic acid 1479 and 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-one 1480 were prepared by known methods <1987JME388>. Treatment of the pyrido[1,2-a]indolone 1480 with phenylhydrazine hydrochloride in refluxing acetic acid gave 6,7-dihydro-13-methyl-12H-pyrido[1,2-a:3,4-b9]diindole 1481 in 91% yield. The latter underwent oxidative dehydrogenation and oxidation of methyl group to formyl group by DDQ to give a homofascaplysin C 1482 in one step.
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 283
Scheme 284
Aryllithiums, generated by a halogen–lithium exchange from N-(o-iodobenzyl)pyrroles 1484 (prepared by N-alkylation of N,N-diethylpyrrole-2-carboxamide 1483 with benzyl bromides under standard conditions), undergo the intramolecular Parham-type cyclization to give pyrrolo[1,2-b]isoquinolinones 1485 in moderate to good yields, if the N,N-diethylcarbamoyl group is used as internal electrophile and the aromatic ring is activated (Scheme 285) <2000TL5211>. It was found that lithium–halogen exchange took place very efficiently under the conditions shown in Scheme 285.
Scheme 285
Bromoindole 1486 was synthesized using published chemistry from 3-methylindole (Scheme 286) <1995TL3103>. Suzuki coupling of indole 1486 with the boronic acid 1487 gave ethanone 1488 <2004TL1117>. Exposure of ethanone 1488 to irradiation in a basic medium afforded the ring-closed alcohols 1489 and 1490 as diastereoisomers (ca. 1:3 ratio). The major diastereoisomer was shown to have structure 1490 by NOE spectroscopy. Exposure of compound 1490 to 15 mol% of TsOH afforded the dibenzoindolizine 1491 in very good yield (Scheme 286).
247
248
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 286
N-Benzyl protected indole 1496 was obtained from N-BOC protected indole 1492 (Scheme 287). Reaction of indole 1492 with BunLi and trimethylborate followed by work-up with aqueous acid afforded boronic acid 1493, which was only stable if kept in a Et2O solution after work-up. Boronic acid 1493 was then reacted with dihydronaphthalene 1494 in the presence of a catalytic amount of Pd(PPh3)4 under Suzuki coupling reaction conditions to afford the desired coupled product 1495. Exposure of compound 1495 to the Lewis acid AlCl3 yielded the intermediate deprotected indole, treatment of which with benzyl bromide gave the required N-benzyl protected indole 1496. Treatment of indole 1496 with ButOK in DMF provided benzo[h]indolo[2,1-a]isoquinoline 1497 in good yield instead of the expected naphtho[a]carbazole 1498 (Scheme 287) <2004TL1117>. Analogous N-benzylpyrrole 1499 precursors could similarly be cyclized to give pyrrolo[2,1-a]isoquinolines 1500 (Scheme 288). Exposure of pyrrole 1499 (R ¼ Me) to ButOK in DMF afforded a diastereomeric mixture of tricyclic alcohols (ratio ca. 2.5:1). The major product was dehydrated under acidic conditions to give compound 1500 (R ¼ Me) in 74% yield.
Scheme 287
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 288
N-(1-Cycloalkenyl)pyrroles 1503 were prepared in three steps starting from N-(benzotriazol-1-ylmethyl)pyrrole 1501 (Scheme 289) <2002JOC8230>. Two methods have been used for the removal of benzotriazole from product 1502 to form pyrroles 1503: (i) Lewis acid-promoted removal of Bt (method A: 20–23% yield) <1998CRV409> and (ii) base/DMSO effected removal of Bt (method B: 77–94% yield).
Scheme 289
Treatment of 1-(2-propynyl)-1H-pyrrole- and 1-(2-propynyl)-1H-indole-2-carboxylates 1505 with a low-valent titanium reagent, diisopropoxy(Z2-propene)-titanium 1504, generated in situ in an essentially quantitative yield by the reaction of Ti(OPri)4 and PriMgCl or PriMgBr (Equation 304), resulted in an intramolecular nucleophilic acyl substitution (INAS) reaction to afford 2-exo-methylene-2,3-dihydro-1H-pyrrolizin-1-ones 1506 (65–76%) and 2-methylene-2,3dihydro-1H-pyrrolo[1,2-a]indol-1-ones 1506 (53–62%), respectively (Equation 305) <1997JA6984>. Deuterolysis of the reaction mixture gave the product 1506 (R1 ¼ SiMe3) containing >98% D. In the reaction of N-(2- or 3-alkenyl)amino esters, including N-alkenyl-1H-pyrrole- and N-alkenyl-1H-indole-2-carboxylates 1507, with reagent 1504, the resulting INAS product underwent intramolecular carbonyl addition reaction to afford the N-heterocyclic compounds, annulated pyrroles and indoles 1508, having a cyclopropanol moiety in good to excellent yields (74–94%) (Equation 306). Fused [1,2-a]indoles represent the basic skeleton of many naturally occurring indole alkaloids and pharmaceutically important compounds.
ð304Þ
249
250
Pyrroles and their Benzo Derivatives: Reactivity
ð305Þ
ð306Þ
An original TiCl4/ButNH2-mediated hydroamination–annulation domino reaction of d-keto-acetylenes is described (Equation 307) <2006OL4839>. The synthesis of pyrrolo[1,2-a]indole-2-carbaldehydes 1510, starting from 2-carbonyl-1-propargyl-1H-indoles 1509 runs under mild reaction conditions. When reacting thiophen-2-yl and furan-2-yl derivatives 1509, only the isomeric 9H-pyrrolo[1,2-a]indole-2-carbaldehydes 1511 (fluorazene form) were isolated in 75% and 77% yield, respectively. All 3H-pyrrolo[1,2-a]indole-2-carbaldehydes 1510 isomerize into the more stable tautomeric fluorazene form 1511 after standing in a CDCl3 solution at room temperature for 24 h. The same result was obtained by stirring a solution of aldehyde 1510 (R ¼ Ph) in toluene at room temperature for 40 min in the presence of a catalytic amount of p–toluenesulphonic acid.
ð307Þ
The reaction of 2-acetyl-1-propargylpyrrole under optimized conditions gave the corresponding 1-methyl-3Hpyrrolizine-2-carbaldehyde 1512 in moderate yield as a single product (Scheme 290) <2006OL4839>. The treatment of product 1512 with p-TSA did not give either of the possible tautomers.
Scheme 290
3.02.5.2 Carboxylic Acids and Their Derivatives Treatment of N-acylpyrrole 1513 (R1 ¼ Et) with 2.2–3.0 equiv of ethylmagnesiun bromide in the presence of Ti(OPri)4 (1.1–1.5 equiv) in ether at room temperature, followed by addition of D2O and subsequent aqueous work-up (or direct silica gel column chromatography), gave pyrrolyl carbinol 1514a (R2 ¼ H) in 92% yield (Equation 308) <2005OL2105 and
Pyrroles and their Benzo Derivatives: Reactivity
references therein>. When isopropylmagnesiun bromide was employed in place of the ethyl Grignard reagent, the corresponding carbinol 1514a (R2 ¼ Me) was obtained in 62% yield, along with 10% yield of reduced product 1515. Except for the ethyl Grignard reagent, other reagents produced varying amounts of the reduction products 1515. Their unexpected formation might be related in part to the ketone-like reactivity of N-acylpyrrole, as pyrroles are p-excessive heterocycles due to the nitrogen lone pair delocalization. Use of cyclopentyl and cyclohexyl Grignard reagents gave larger amounts of products 1515 (41% and 35%), along with poor yields of carbinol 1514b (29% for n ¼ 1 and 8% for n ¼ 2).
ð308Þ
Inter- and intramolecular titanium-mediated coupling reactions of N-acylpyrroles are reported for convenient functionalization of terminal alkenes <2005OL2105>. Both products 1517 and 1518 were obtained from o-vinyl N-acylpyrrole 1516 (Equation 309); the product ratios were dependent on the nature of the Grignard reagent, and the combined yields were moderate to good (64–79%). The unexpected formation of significant amounts of the intermolecular products 1518 is in sharp contrast to efficient cyclization of vinyl tethered esters, amides, carbonates, and imides that proceeds with little intermolecular reaction <1996JA291, 1996JA4198, 1997JA8127, 1999JOC6771>.
ð309Þ
Reaction of 1-propionyl-1H-pyrrole and homoallylic alcohols with a 3:1 mixture of Grignard reagents and Ti(OPri)4 (1 equiv) afforded the desired products 1519, accompanied by rather significant amounts of products 1514a or 1514b (Equation 310) <2005OL2105>. No reduction product was found in the crude reaction mixture.
ð310Þ N-Acylated indoles 1520 furnished tricyclic compounds 1521 in the presence of samarium diiodide (2.5 equiv) in tetrahydrofuran along with an excess of hexamethylphosphoramide (10 equiv) and phenol (2 equiv) as proton source (Equation 311) <2003OL4305>. Whereas methyl ketone 1520 (R ¼ Me) smoothly cyclized to compound 1521 (in 73% yield), the corresponding aldehyde 1520 (R ¼ H) provided compound 1521 only in low yield (28%).
251
252
Pyrroles and their Benzo Derivatives: Reactivity
ð311Þ
Polycyclic products 1523, 1524, 1526, and 1528 were formed with essentially perfect diastereoselectivity and good to excellent yields when the reactions of N-acylated indoles 1522, 1525, and 1527 were performed in the absence of HMPA (Scheme 291, Equations 312 and 313) <2003OL4305>.
Scheme 291
ð312Þ
ð313Þ
Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids.
Pyrroles and their Benzo Derivatives: Reactivity
3.02.5.3 Hydroxy and Alkoxy Groups 1-Hydroxy-2-phenylindole exists in solution in both hydroxylamine 1529a and nitrone 1529b tautomeric forms (Equation 314) <1998T5305>. The latter is able to add organometallic compounds (Grignard and alkyl lithium reagents) with subsequent oxidation using activated lead dioxide for 1 h, forming stable indolinic aminoxyls 1531 (Scheme 292), which were also prepared for comparison by an independent way.
ð314Þ
Scheme 292
Treatment of 1-hydroxy-2-phenylindole with Grignard and alkyl lithium reagents did not afford complete transformation into aminoxyls 1531; on the contrary, most of 1-hydroxyindole 1529a transformed into the salt 1532 (Scheme 293), which regenerates indole 1529 during hydrolysis in the working-up of the reaction. Thus, hydrolysis of the reaction mixture gave a solution containing starting material and the hydroxylamino derivatives corresponding to anions 1530. By oxidation with lead dioxide, the latter were converted into aminoxyls 1531, while indole 1529a gave rise to the bis-nitrone 1534, through the ‘semiquinone’ 1533, as shown in Scheme 293 <1998T5305>.
Scheme 293
Irradiation of benzene solution of the isomeric mixture 1529 within the ESP cavity leads to detection of signals to which the structure of the spin adduct 1536 was tentatively assigned (Scheme 294) <1998T5305>. The formation of the spin adduct 1536 may be explained on the basis of the Forrester–Hepburn nucleophilic addition of 1-hydroxyindole 1529a to its nitronic form 1529b, which gives product 1535, and of the subsequent oxidation of the latter.
253
254
Pyrroles and their Benzo Derivatives: Reactivity
Scheme 294
When irradiation was repeated in dioxane for 6 h, the products shown in Figure 6 were isolated. Compounds 1538 and 1539 are the products of the disproportionation of indolyl radical 1537, which could likely be formed from homolytic scission of compound 1536 during irradiation (Scheme 294). Bis-indoles 1540–1542 may be explained as arising from dimerization of the indolyl radical 1537a followed by partial or total deoxygenation <1998T5305>. The bis-nitrone 1534 may probably arise from dimerization of radical 1537a followed by oxidation during the reaction work-up.
Figure 6
3.02.6 Further Developments The chemistry of pyrrole and its annulated derivatives continues to be an area of intense interest among chemists, biologists, and material scientists. Researches addressing new catalytic chemo-, regio-, and stereocontrolled reactions of pyrrole or indole nuclei have been the subject of a number of reports. A conceptually new approach to direct C-alkynylation of pyrroles with haloalkynes (see Section 3.02.2.3.8) got further development. A palladium-, copper-, and solvent-free cross-coupling of ethyl 3-halo-2-propynoates with 4,5,6,7-tetrahydroindoles <2007TL4661> and acylbromoalkynes with 1-vinylpyrroles <2007S0447> on Al2O3 afford regioselectively corresponding 2-ethynyl derivatives in high yields. Further efforts in palladium-catalyzed cross-coupling reactions has led to the synthesis of acetylenic derivatives of indolizines from bromoalkynes and corresponding N-fused heterocycles <2007JA7742>.
Pyrroles and their Benzo Derivatives: Reactivity
Hypervalent iodine(III) was shown to catalyze the direct cyanation of N-tosylpyrroles and -indoles under mild conditions, without the need for any prefunctionalization <2007JOC109>. Phenyliodine(III) bis(trifluoroacetate)induced oxidative regioselective coupling of pyrroles in the presence of bromotrimethylsilane gave a series of electron-rich bipyrroles <2007S2913>. Organic catalysts (e.g., amine salts <2007OL1403>, C(2)-symmetric bis(oxazoline) copper(II) complex <2007OL2281>, zirconium(IV)–BINOL complexes <2007OL2601>, chiral BINOL-derived phosphoric acids <2007JA292, 2007JA1484, 2007OL2609, 2007OL4065>, imidazolidinone derivatives <2007OL1847>) were successfully employed for enantioselective Friedel–Crafts alkylation of pyrroles and indoles with diverse enones, N-acyl imines and the like. A new organocatalytic procedure for the synthesis of bis(indolyl)methanes from indoles and a variety of aryl and aliphatic aldehydes with acidic ionic liquid immobilized on silica gel has been developed <2007SL1320>. Palladium-catalyzed reduction of N-(t-butoxycarbonyl)indoles by polymethylhydrosiloxane gives readily N-(tbutoxycarbonyl)indolines in good yields <2007S1509>. Indoles and azaindoles undergo smooth oxidation with 2-iodoxybenzoic acid in the presence of indium(III) chloride (aqueous media, 80 C) to afford the corresponding isatins in excellent yields <2007S0693>. A peculiar rearrangement to 3H-benzo[e]indole during the NiS-catalyzed dehydrogenation of 4,5-dihydro-1H-benzo[g]indole (350 C) was reported <2007MC296>. The reaction of indoles and pyrrole with pyrylium catalyzed by ceric ammonium nitrate in methanol furnishes the indole- and pyrrole-substituted xanthene derivatives in high yields <2007SL2222>. Naphthalene-photocatalyzed [4þ2]-cycloaddition between indole and cyclohexadiene based on selective irradiation of naphthalene-indole ground-state charge-transfer complex in the presence of 1,3-cyclohexadiene, has been published <2007OL453>. 1-Vinylpyrrole-2-carbaldehydes are selectively thiylated with ethanethiol either at the aldehyde (acid catalyst) or at the N-vinyl group (free-radical initiation) to give 1-vinylpyrrole-2-carbaldehyde thioacetals (88–99% yield) or 1(2-ethylthioethyl)pyrrole-2-carbaldehydes (68–89% yield) <2007S0452>. Functionalized pyrrolic enols, 2-(2,2-dicyano-1-hydroxyethenyl)-1-methylpyrroles, synthesized from 2-ethenylpyrroles by a nucleophilic SEt–OH exchange, upon heating (75–142 C) are readily rearranged to their 3-isomers in near to quantitative yield <2006TL3645>.
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Biographical Sketch
Boris A. Trofimov was born in Tchita, Russia in 1938. He received his Diploma in 1961, his PhD in 1964, and his Doctor of Chemistry in 1970. He became a Professor in 1974 and in 1990 a Corresponding Member of the Academy of Sciences (USSR). He became a Full Member (Academician) of the Russian Academy of Sciences in 2000. He is currently Director of A. E. Favorsky Irkutsk Institute of Chemistry, Head of the Laboratory of Unsaturated Heteroatomic Compounds. Boris Trofimov is a member of the editorial board of the Russian Journal of Organic Chemistry, Journal of Sulfur Chemistry and Arkivoc. He was awarded the Butlerov Prize of Russian Academy of Sciences in 1997 and the Medal and Diploma of a Mendeleev Reader (St. Petersburg) in 2003. He is the author of over 850 articles, 49 reviews and 15 monographs. His current scientific interests are focused on: organic synthesis based on acetylene and its derivatives; heterocyclic chemistry, particularly, the chemistry of pyrrole and its derivatives; organic chemistry of sulfur, selenium, tellurium, and phosphorus; organo-sulfur polymers; functional polyethylene glycol derivatives; chemistry and physical chemistry of vinyl and allenyl ethers and vinyl azoles, -sulfides, -selenides, -tellurides, -phosphines, -phosphine oxides; addition reactions to multiple bonds; super bases as catalysts and reagents.
Nina A. Nedolya was born in Irkutsk (Russia) and educated in organic chemistry at the Irkutsk State University (Diploma 1972, PhD 1982, DSc 1998). From 1995 to 1999 she was associated with Prof. L. Brandsma at the Utrecht University (The Netherlands). In 1999 she obtained her second PhD from the Utrecht University. She is presently Head of the Research Group of Chemistry of Heterocyclic Compounds at A. E. Favorsky Irkutsk Institute of Chemistry. She is the author of over 210 review articles and research papers. She is also one of the inventors for 112 patents. She is interested in the chemistry of polyfunctional unsaturated heteroatomic systems (vinyl, allenyl, and alkynyl ethers and their derivatives, linear and cyclic heteropolyenes, heterocumulenes), including synthesis of important heterocycles, particularly pyrroles, thiophenes, thiazoles, imidazoles, dihydrofurans, dihydropyridines, pyridines, quinolines, dihydroazepines, and azepines, based on metallated allenes or alkynes and/or heterocumulenes.
3.03 Pyrroles and their Benzo Derivatives: Synthesis J. Bergman and T. Janosik Karolinska Institute, Huddinge, Sweden ª 2008 Elsevier Ltd. All rights reserved. 3.03.1
Introduction
269
3.03.2
Category Ia Cyclizations
270
3.03.3
Category Ib Cyclizations
286
3.03.4
Category Ic Cyclizations
290
3.03.5
Category IIab Cyclizations
299
3.03.6
Category IIac Cyclizations
302
3.03.7
Category IIad Cyclizations
319
3.03.8
Category IIae Cyclizations
322
3.03.9
Category IIbd Cyclizations
327
3.03.10
Syntheses by Contraction or Fragmentation of Existing Rings
331
3.03.11
Miscellaneous Methods for Pyrrole and Indole Synthesis
333
3.03.12
Further Developments
334
References
336
3.03.1 Introduction This chapter provides coverage of the advances in heterocyclic ring synthesis leading to derivatives of pyrrole 1, as well as the related systems indole 2, isoindole 3, and carbazole 4 (Figure 1), reported during the period 1995–2005, including some references from the early part of 2006. Particular attention will be devoted to reactions displaying generality, versatility, and practical applicability, emphasizing new promising developments, valuable improvements and applications of the existing routes, and procedures allowing preparation of structures with unusual substitution patterns. Some new routes to acyclic starting materials, which is often one of the most critical aspects affecting the choice of a suitable synthetic method, will be outlined in connection with certain cyclizations. Papers published prior to 1995 are not included, as readers will find all the important developments summarized in the previous chapter on this subject appearing in CHEC-II(1996) <1996CHEC-II(2)119>. Excellent reviews on pyrroles <2002SOS(9)441> and indoles <2001SOS(10)361> are also available in Science of Synthesis. Moreover, updates on the advances in pyrrole and indole chemistry appear anually in Progress in Heterocyclic Chemistry <2005PHC(17)109>. The ring systems depicted in Figure 1, with the exception of derivatives of the rather rare molecule isoindole 3, are well-represented structural units not only in the rapidly growing field of biologically active compounds of natural or synthetic origin, but also in molecules specially designed for various novel applications, for instance electrical devices. The progress in a research area which exhibits such diversity has consequently triggered considerable advances in the ring synthesis of pyrrole-based systems, in order to meet the increasing demand for suitable building blocks. Several specialized accounts dealing with this subject have appeared during the reporting period of this chapter. General reviews detailing the progress in pyrrole ring synthesis between 1995 and 2000 <2001OPP411>, synthesis of indoles covering the period 1994–1999 <2000J(P1)1045>, and practical methodologies for indole ring synthesis <2006CRV2875> are available. The achievements in the area of palladium-catalyzed cyclizations leading to indoles have also been reviewed <2005CRV2873>. Compilations of synthetic approaches to 2,5-disubstituted pyrrolidines <1996TA927>, and stereoselective approaches to pyrrolidine derivatives from azomethine ylides <2005TA2047>, have also been provided. A number of rather specialized accounts focusing on the ring synthesis and reactions of certain classes of pyrroles, for instance, C-vinylpyrroles <2002RCR563, 2004CRV2481> (which may, for example, give indoles via Diels–Alder reactions), and arylpyrroles <1998RJO911, 1998RJO1691>, have also become available. The progress in synthesis of pyrroles by contraction of existing rings has also been discussed <2005COR261>.
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Pyrroles and their Benzo Derivatives: Synthesis
Figure 1
For the sake of convenience, the material in this chapter is arranged according to the systematic organization introduced by Richard J. Sundberg in his contribution on the same theme in CHEC-II(1996) <1996CHECII(2)119>. Thus, each reaction falls into a category designating the location and number of bonds formed in the cyclization (Figure 2). This organization is however not completely unambiguous depending upon the definition of which acyclic precursors are regarded as the starting compounds for each synthesis, and may in some cases differ from the previous account appearing in CHEC-II(1996) <1996CHEC-II(2)119>. The final sections are devoted to miscellaneous approaches, such as multicomponent reactions, elaboration of existing rings, as well as some unusual routes.
Figure 2
3.03.2 Category Ia Cyclizations Numerous routes to pyrroles rely on cyclization of suitable nitrogen-containing precursors incorporating all the necessary carbon atoms. For example, a set of -amino-,-enals 5 can be annulated to the products 6 upon exposure to acidic reaction conditions without touching the t-butoxycarbonyl (BOC) protecting group (Equation 1) <2002EJO2565>. Likewise, BOC-protected -amino-,-enones have been converted to pyrroles with concomitant removal of the BOC functionality by cyclization employing the phenol/TMSCl reagent combination (TMSCl ¼ trimethylsilyl chloride) <2000OL2283>. An organoaluminium-mediated approach starting from structurally related ,-disubstituted -amino-,-enones lacking the BOC group has also been realized <2004TL9315>. Thermal or acid-induced cyclization of dimers derived by electrochemical dimerization of phenacyl bromide N-acylhydrazones has been shown to give 1-amino-2,5-diarylpyrrole derivatives <2004T10787>. Ring closure of some 3-aryl-4-oxopentanamides occurs spontaneously in dimethyl sulfoxide (DMSO), or in the presence of catalytic amounts of sulfuric acid, providing a series of 3-pyrrolin-2-ones, which may be subsequently converted to pyrroles by treatment with 9-borabicyclo[3.3.1]nonane (9-BBN) <2003SL2013>. Heating of N-substituted 3-aroylpropionamides in acetic anhydride provides convenient access to the corresponding N-substituted 2-acetoxy-5-arylpyrroles <2004TL9353>.
ð1Þ
A synthesis of 2H-pyrroles has been reported, relying on reductive annulation of -nitroketones (Scheme 1), as exemplified by the transformation of the substrate 7 into the pyrrolidine 8, which was eventually dehydrogenated to the 2H-pyrrole 9 by treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) <2003TL3701>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 1
Reductive cyclization of the precursor 10 enabled practical gram-scale preparation of the dipyrrin 11, a building block for partially saturated porphyrin derivatives (Equation 2) <2005OPD651>.
ð2Þ
The -nitroketone 12, which was prepared by Michael addition of ethyl nitroacetate to the appropriate enone, was treated with formamidinesulfinic acid and triethylamine, yielding the pyrrole-2-carboxylate 13, presumably via the oxime or imine 14, thus demonstrating a route to this handy class of pyrrole derivatives (Equation 3) <1995TL9469>.
ð3Þ
The azaallylic anion generated from the substrate 15 underwent alkylation to provide the intermediate 16, which could be cyclized to the 1-pyrrolines 17. Treatment of the latter with methoxide eventually gave the pyrrole 18 (Scheme 2) <2001JOC53>.
Scheme 2
Treatment of the aldehyde 19 with amines in the presence of TiCl4 furnished the precursor 20, which was converted to the 2-pyrrolines 21. The products 21 could thereafter be exposed to methoxide, leading to the corresponding -chloropyrroles after elimination of cyanide (Scheme 3) <2005T2879>. A series of pyrroles has also been prepared by a procedure featuring acid-induced cyclization of precursors constructed by sequential lithiation and alkylation of 1-benzylbenzotriazoles with 2-bromoacetaldehyde diethyl acetal and N-benzylideneaniline <1997JHC1379>. Cyclization of intermediates derived by addition of lithium enolates to BOC-protected aminoaldehydes or ketones has been used as a route to a set of pyrroles with interesting substitution patterns (Equation 4). For example, treatment of the in situ-generated precursor 22 with hydrochloric acid gave the fused system 23. However, a drawback
271
272
Pyrroles and their Benzo Derivatives: Synthesis
of this route is the generally low or modest overall yields <1996JOC4999>. Similar acyclic precursors bearing two benzyl groups on the nitrogen atom may undergo reductive cyclization to pyrroles with concomitant loss of one of the N-benzyl moieties <2001TL6027>.
Scheme 3
ð4Þ
Several strategies belonging to this class rely on cyclization of various enamine precursors. This has for instance been demonstrated by the conversion of the substrate 24 to the fused 2-pyrroline 25 (Equation 5) <1995JOC7357>. Related annulations have been reported to occur in the presence of iodine and Al2O3 under basic conditions <1999T10915>. Likewise, a set of -enaminoketones featuring a 2-bromoallyl unit have been converted to pyrroles by exposure to base <2002T9793>. Annulation of -dienaminoester derivatives using N-bromosuccinimide (NBS) offers access to various polysubstituted pyrroles <2001SL1440, 2003S859>.
ð5Þ
It has been established that the azadienes 26 may be converted to the precursors 27, which will cyclize to the pyrroles 28 under thermal conditions. Subsequent hydrolysis in the presence of hydrochloric acid gives access to the substituted -acylpyrroles 29 (Scheme 4) <1996JOC2185>. Studies of a related CuCl-mediated cyclization have also been reported <2006HC66>.
Scheme 4
Pyrroles and their Benzo Derivatives: Synthesis
Exposure of the imine 30 to the Fischer carbene complex 31 led to formation of the pyrrole 32. This material underwent subsequent hydrolysis providing the final product 33 (Scheme 5) <2003OL2043>. An approach to pyrroles taking advantage of rhodium-catalyzed reactions between similar imine precursors, incorporating all the required carbon atoms, and terminal alkenes has also been reported <2003OL2615>. A related route featuring ruthenium-catalyzed annulations has also been studied <2004TL9245>.
Scheme 5
Copper catalyzed cyclization of the thiopropargyl imines 34, featuring a 1,2-migration of the alkylthio- or arylthio substituents, has been demonstrated to provide good yields of the pyrroles 35 (Equation 6) <2003AGE98>. Similar cyclization reactions of related precursors bearing a hydrogen atom instead of the sulfur-containing moiety leading to pyrroles have also been reported <2001JA2074>. A one-pot procedure involving a CuBr-mediated intramolecular cyclization of an allenylimine precursor rendering a substituted -(methylthio)pyrrole derivative has been performed <2002CHC745>. Pyrroles have also been prepared by HBr-induced cyclization of N-substituted 4-oxobut-2-ynyl benzenesulfonamides <1995S276>, as well as a structurally related acetal <1999TL4555>. Palladium-catalyzed reactions of ethyl 2-acetyl-4-pentynoate tosylhydrazone with aryl iodides constitute a route to 1-aminopyrrole derivatives <1997SL1315>. In addition, a bromopropargylsulfonamide has been used as the starting material for generation of a tungsten-1-2,5-dihydropyrrole complex <1997OM4232>.
ð6Þ
Likewise, the homopropargylic sulfonamides 36 served as starting compounds for pyrroles, as annulation thereof with iodine gave the 2-pyrrolines 37, which could be subsequently dehydrogenated to the corresponding pyrroles 38 by treatment with base (Scheme 6) <1998CC2207, 2002J(P1)622>. Similar homopropargylic sulfonamides possessing a hydroxyl functionality adjacent to the acetylene unit may be directly converted to pyrroles by acid-catalyzed 5-endo-dig-cyclizations <2003SL2258>, and annulation of related precursors bearing an alkene unit instead of an alkyne using iodine in the presence of potassium carbonate gave a set of -iodopyrrolidine derivatives <1998SL731, 1998TL8909>. Moreover, homopropargylic carbamates have been converted to 1-pyrrolines in the presence of a silver catalyst <2005JOC1791>, whereas a set of homopropargylic sulfonamides have undergone palladium-catalyzed annulation to 2-pyrrolines <2002ASC70>.
Scheme 6
273
274
Pyrroles and their Benzo Derivatives: Synthesis
Heating of the epoxyalkynes 39 (Bt ¼ benzotriazol-1-yl) with primary amines leads to formation of the intermediate homopropargylamines 40, which undergo cyclization to the 2-(benzotriazol-1-yl)methylpyrroles 41, useful substrates for elaboration to further multiply substituted pyrrole derivatives (Equation 7) <1996JOC1624, 1997JOC4148>. In addition, routes to pyrroles based on silver(I), mediated oxidative annulation of homopropargylamines have been reported <2004OBC3060, 2004SL1767>. An approach featuring silver-catalyzed annulation of propargyl-substituted enaminones has also appeared <2004TL6787>. Finally, homopropargylamine precursors have been annulated to 2-pyrrolines employing (Et3N)Mo(CO)5 via carbene intermediates <1997TL7687>.
ð7Þ
Lithiation of N-allylbenzotriazole 42, and subsequent treatment of the resulting anion with an imine gave the precursor 43, which could finally be annulated to 1,2-diphenylpyrroles 44 in the presence of a palladium catalyst, illustrating a general route to 1,2-diarylpyrroles (Scheme 7) <2000JOC8074>.
Scheme 7
It has been demonstrated that Pd(II)-catalyzed <2001TL1339> annulation of the 2-en-4-ynylamine 45 gives the pyrrole 46 in a good yield (Equation 8). Related copper-catalyzed reactions leading to pyrroles required higher temperatures <2003JOC7853>. Interestingly, certain substrates, for instance those containing a terminal acetylene unit, underwent spontaneous cycloisomerization to the target heterocycles <2001TL1339, 2003JOC7853>.
ð8Þ
Palladium-catalyzed cyclization of the oxime derivative 47 provided a good yield of the pyrrole 48 (Equation 9) <1999CL45>. Similar reactions have been observed in connection with cyclization studies of related ketone trimethylhydrazonium salts <2005H(65)273>. Photochemical radical cyclization of ,-unsaturated ketone oximes has been reported to produce 1-pyrrolines <2005TL2373>. Similar O-acetyloximes may also be annulated to 1-pyrrolines by treatment with acetic acid in the presence of 1,4-cyclohexadiene and naphthalene-1,5-diol, possibly proceeding via a radical mechanism <2002CL144>.
ð9Þ
Pyrroles and their Benzo Derivatives: Synthesis
Palladium-catalyzed cyclization of allene precursors may also be a viable route to pyrroles, as illustrated by the conversion of 49 to the tetrasubstituted pyrrole 50 (Equation 10). Application of similar conditions at lower temperature in the presence of a phase-transfer catalyst afforded the corresponding 3-pyrroline in modest yield. Alternatively, 3-pyrroline products were observed upon cyclizations mediated by AgNO3 <2001OL3855>. The latter reagent has also been used for annulation of an allene precursor generated by addition of -lithiomethoxyallene to benzaldehyde N-tosylimine, which gives a 3-methoxy-3-pyrroline derivative. In contrast, base-induced cyclization of the same substrate leads to direct formation of a 3-methoxypyrrole <1999SL1871>. Likewise, cyclizations involving (4-methylpenta-2,3-dienyl)benzylamine resulted in formation of 2,2-dimethyl-3-pyrroline derivatives <2002H(57)2261>. A study of gold-catalyzed intramolecular hydroamination of allene substrates gave access to high yields of pyrrolidine derivatives <2006TL4749>. In addition, allenic hydrazides derived from addition of -lithiomethoxyallene to hydrazones have been shown to give 1-amino-3-pyrroline derivatives upon cyclizations induced by BuLi <2001T1939>.
ð10Þ
Rhodium acetate-catalyzed diazo decomposition has been used in a synthesis of the pyrrole 51, illustrating a route to several similar 3-oxypyrrole systems (Equation 11) <2002SL1913>. Similar annulations of some related fluorine containing substrates resulted in various unusual fluoropyrrole derivatives <2003OL745>.
ð11Þ
Sharpless oxidation of the oxazole 52 provides an intermediate epoxide, which is attacked by the neighboring amino group, eventually leading to the pyrrolo[2,3-d]isoxazole 53 (Equation 12). Variation of the aryl substituent provided access to a set of related derivatives in excellent yields <2006TL4957>.
ð12Þ
The Hemetsberger–Knittel indole synthesis has enjoyed considerable popularity, as it requires simple and readily available starting materials, tolerates a number of useful functional groups, and often proceeds in good overall yields. The standard procedure involves condensation of a benzaldehyde with an alkyl azidoacetate in the presence of a base, and subsequent cyclization of the resulting azidocinnamates 54 to the corresponding alkyl indole-2-carboxylate 55 by a thermally induced nitrene insertion (Scheme 8). A selection of indoles prepared using this approach is presented in Table 1. The indole-2-carboxylates may thereafter be subjected to saponification, followed by decarboxylation, providing the parent indoles. A mechanistically related formation of indoles featuring nitrene insertion has been reported to occur upon thermolysis of phenyl azirines <2006JA1058>.
Scheme 8
275
276
Pyrroles and their Benzo Derivatives: Synthesis
Table 1 Selected indoles prepared by the Hemetsberger–Knittel route
Entry
R2
R4
R5
R6
R7
Yield a (%)
Reference
1 2 3 4 5 6
CO2Me CO2Et CO2Me CO2Me CO2Et CO2Me
H OMe H H OBn CH2OTHP
OMe H OBn H H H
OMe H H O(CH2)5OTBS H H
H OMe OBn H Br H
86 99 N/A 67 92 55
2004JME6270 2002EJO4005 2003BML3859 2002BMC3849 2001T2355 2004OBC701
a
From the corresponding azidocinnamate precursors.
An interesting variant of this route has been employed for construction of the tricyclic system 56 from the precursor 57, involving both a nitrene insertion and a Claisen cyclization (Equation 13) <2005TL9013>. In addition, derivatives of the fused systems 5,6-methylenedioxyindole <2004JME5298>, cyclopenta[g]indole <2005JME893>, phenanthro[9,10-b]pyrrole <1997T14599>, pyreno[2,1-b]pyrrole <2004JOC6674>, pyrrolo[2,3-c]carbazole, pyrrolo[2,3-b]carbazole <2000T4511>, furo[3,2-b]pyrrole <2003TL4257>, oxazino[2,3-f]indole, oxazino[2,3-g]indole <2002EJO1646>, thieno[2,3-b]pyrrole <2005JME8289>, and pyrrolo[3,2-c]--carboline <2004JHC531> have been prepared according to the Hemetsberger–Knittel reaction.
ð13Þ
An alternative approach, the Sundberg indole synthesis, involves thermolysis of 2-azidostyrene precursors, as illustrated by preparation of 2-nitroindole 58 (Equation 14) <1997TL5603>. Such methodology has also been utilized in syntheses of, for instance, 2-aryl-4-arylsulfonyl-6-nitroindoles <2002SC1465>, 2-aryl- and 2-heteroaryl4,6-dinitroindoles <1999S2065>, 1,19-bis(indol-2-ylcarbonyl)ferrocene <2000TL2479, 2002OM2055>, and an intermediate en route to the alkaloid caulersin <1999SL1651>. Thermolysis of o-azidophenyl-containing molecules has also been employed in preparation of pyridazino[4,5-b]indoles <2001H(55)1105, 2002T10137, 2006T121>, indolo[2,3:4,5]pyrido[3,2,1-jk]carbazol-9-one <2005JHC85>, the alkaloids cryptotackieine and cryptosanguinolentine <1999TL7275, 2001T6197>, indolo[2,3-c]isoquinoline <2002TL6035>, and a 2,7-disubstituted carbazole <2003JOC5091>.
ð14Þ
Intramolecular amination of aryl bromides <1996T7525, 1997JA8451, 1999OL35> has emerged as a powerful tool for the construction of indolines. Typical conditions involve annulation of secondary amide or carbamate precursors 59 with Pd(OAc)2 and DPEphos 60 as the ligand, giving the N-protected indolines 61 (Equation 15) <1999OL35>. This methodology has also proven to be suitable for stereoselective preparation of 2-substituted indolines <1997JA8451, 2002J(P1)733>, as well as a tetrahydropyrroloquinoline system <1996JA1028>. It has also been shown that nickel catalysts may be useful in intramolecular annulations of aryl chlorides leading to indolines
Pyrroles and their Benzo Derivatives: Synthesis
<2003OL2311>. In addition, there is also a solid-phase variant available <2003TL2569>. A related approach based on intramolecular palladium-catalyzed cyclization of (o-chloroaryl)acetaldehyde N,N-dimethylhydrazones provides direct access to 1-aminoindole derivatives <2000AGE2501>. Intramolecular palladium-catalyzed amination of N-Cbz-dehydrophenylalanines bearing a bromo or triflate substituent in the ortho-position has been shown to produce indole-2-carboxylates <2003JOC6011>, whereas cyclization of similar substrates possessing an aryl group at the nitrogen atom has been previously used for preparation of 1-arylindole-2-carboxylates <2000TL1623>. A direct approach to 4-aryloxindoles based on intramolecular palladium-catalyzed amidation of N-methyl-2,6-dibromophenylacetamide and ensuing Suzuki cross-coupling with arylboronic acids is also available <2006TL4361>. Intramolecular copper-catalyzed amidation onto a phenyl ring has been employed in preparation of oxindoles bearing a 1,4benzoxazine moiety <2006T6774>.
ð15Þ
Indolines can also be prepared by radical cyclization. For example, the precursor 62 was annulated to the indoline 63 with incorporation of a N-substituent originating from the ketone component (Equation 16). This reaction seems to proceed via aryl radical addition onto an initially formed imine <2001OL1009>.
ð16Þ
The substrate 64 has been converted to the acetate 65 using phenyliodine(III) diacetate (PIDA), followed by annulation to the indoline 66 (Scheme 9). A similar methodology can also be applied for preparation of oxindoles <2002JOC3425>.
Scheme 9
A popular route involving C–N bond formation is based on intramolecular annulation of 2-alkynylanilines, which are in turn readily available by, for instance, palladium-catalyzed coupling of the corresponding 2-iodoanilines, or triflates derived from 2-aminophenols, with suitable acetylenes. In a representative example, base-induced
277
278
Pyrroles and their Benzo Derivatives: Synthesis
cyclization of the precursors 67 and 68 with concomitant elimination of the TMS moiety gave the indoles 69 and 70 (Scheme 10) <1997JOC6507>. Such base-induced annulations have been used successfully for preparation of 7-substituted indoles <1996H(43)2741>. Cyclizations involving substrates bearing other alkynyl units have been performed under mild conditions at ambient temperature using KH or t-BuOK as the bases in N-methyl-2-pyrrolidone (NMP), leading to 2-substituted indoles <2000AGE2488, 2003T1571>, whereas annulation of related amide precursors under similar conditions seems to require some heating <2001TL5275, 2002TL7699, 2004T10983>. Solid-phase variants based on t-BuOK-induced or palladium-catalyzed annulations have also been developed <2003OL2919>. Application of tetrabutylammonium fluoride (TBAF) as the reagent for cyclization of 2-ethynylaniline derivatives allows preparation of indoles with sensitive functional groups <1999J(P1)529>. The use of a polymer-supported fluoride source has also been evaluated <2002TL6579>. Base-mediated cyclization reactions of 2-[3(Z)-hexen-1,5-diynyl]anilines have been demonstrated to yield carbazoles as the major products <2004JOC2106>. Excellent results may also be achieved upon cyclization of BOC-protected 2-alkynylanilines with tetrabutylammonium hydroxide, which does also proceed with concomitant removal of the BOC moiety <2003TL8697>, or annulation of related alkyl carbamates with sodium ethoxide, which has been employed in routes to 5,6-difluoroindole <2005TL907>, 2,29-biindolyl <1995SL859>, and an intermediate en route to the Strychnos alkaloid ()-19(S)-acetoxy-N1-acetyl-20-epitubifolidine <1998TL3765>.
Scheme 10
As indicated above, such annulation reactions may also be mediated or catalyzed by transition metal reagents, as demonstrated by the conversion of the precursor 71 to the indole 72 (Equation 17) <1996JOC5804>. A related CuImediated reaction produced an unusual 2-arylindole derivative <2003TA3503>. Useful catalysts for similar applications are for instance Pd(CH3CN)2Cl2 (10 mol%) <1998TL9347>, PdCl2 (10 mol%) <2002T4487>, or Cu(OAc)2 (10 mol%) <2002TL1277, 2004JOC1126>. Palladium-catalyzed variants of this approach have been employed in synthesis of optically active tryptophan analogues having the side chain at C-2 <2003OL1717, 2004ASC823>, an indolo[7,6-g]indole system <1999TL2429>, and -mannosylindoles <1999SL123>. Finally, gold(III)-catalyzed annulations of 2-alkynylanilines followed by treatment with bromine, NBS, or iodine in the presence of potassium hydroxide provide routes to 3-haloindoles <2004S610>.
ð17Þ
A versatile route to indoles based on palladium-catalyzed cyclization of 2-(alkynyl)trifluoroacetanilides was developed by Cacchi in the early 1990s, and the progress of this particular approach has been detailed in a review <2002EJO2671>. The general sequence is considered to involve a palladium-catalyzed reaction of the starting materials 73 with, for instance, aryl or vinyl triflates or halides, rendering the (2-alkyne)organopalladium complexes 74, which undergo cyclization to the indolylpalladium intermediates 75. A final reductive elimination provides the target heterocycles 76 (Scheme 11) <2002EJO2671>. The use of allyl esters in this sequence gives access to 3-allylindoles <1998JOC1001>. Solid-phase variants employing 2-(alkynyl)anilines immobilized via an ester linkage to the benzene ring have also appeared <1997TL2307, 1997TL7963>. It has been shown that substituted 1-bromoalkynes may also participate in this reaction, providing 2-substituted 3-alkynylindoles, which can subsequently be converted to the corresponding 3-acylindole derivatives <2005JOC6213>. Application of heterocyclic
Pyrroles and their Benzo Derivatives: Synthesis
substrates has enabled syntheses of fused pyrrole derivatives, such as 7-aza- and 4-azaindoles <2005JCO510>, or pyrrolo[2,3-b]quinoxalines <2004TL2431>. In addition, PtCl2-catalyzed cyclization of N-methyl-N-acetyl-o-(alkynyl)amides has been demonstrated to give 3-acetyl-1-methylindole derivatives <2004JA10546>. Further extensions of this methodology have yielded indolo[2,3-a]carbazole systems <1995TL7841> as well as 3,39-disubstituted 2,29-biindolyls <2006T3033>.
Scheme 11
An additional interesting development in this field offers access to 2-(aminomethyl)indoles. For example, reaction of the 2-(alkynyl)trifluoroacetanilide 77 with the piperazine derivative 78 gave the indole 79 (Equation 18). Good results were obtained for a set of similar piperazines, whereas the use of primary amines gave rise to complex mixtures <2006OL2083>. Palladium-catalyzed annulations of N-(2-ethynylphenyl)methanesulfonamides and ensuing Heck reactions with acrylic acid derivatives give 2-substituted 3-alkenylindoles <1998H(48)1793>.
ð18Þ
Copper-catalyzed annulation of the imine precursor 80 to the indole 81 (Equation 19) serves as an example representing an approach providing a series of similar products <2004TL35>. Treatment of related substrates with W(CO)6 under irradiation generates tungsten-containing azomethine ylides, which may participate in [3þ2] cycloadditions with alkenes producing cyclopenta[a]indole derivatives <2002JA11592, 2004CL16>.
ð19Þ
Annulation of 2-ethynylanilines with bis(pyridine)iodonium(I) tetrafluoroborate (IPy2BF4) has been shown to provide a direct route to 3-iodoindole derivatives <2003AGE2406>. It was later found that the use of iodine gives similar results, as illustrated by the synthesis of the indole 82 from the precursor 83 (Equation 20) <2004TL539>. Interestingly, iodine-induced cyclization of N,N-dimethyl-2-alkynylanilines gives 1-methylindoles, presumably by an elimination of one of the methyl groups by an SN2 displacement involving iodide as the nucleophile <2004OL1037>.
279
280
Pyrroles and their Benzo Derivatives: Synthesis
ð20Þ
The transition metal-catalyzed reaction of the isocyanate 84 with the allyl carbonate 85 furnished the indole 86 (Equation 21). A set of similar indole derivatives could be obtained in good yields by varying the two reactants <2002AGE3230, 2003JOC4764>. Palladium-catalyzed annulation reactions involving aryl isocyanides, allyl carbonates, and TMSN3 gave a series of 1-cyanoindoles <2002JA11940>.
ð21Þ
Metalation of the amidine 87, followed by introduction of 2-methoxyallyl bromide, furnished the intermediate 88, which underwent acid-induced cyclization to the product 89 (Scheme 12), illustrating an interesting approach to polyfunctionalized indoles suitable for further elaboration <2002OL1819>.
Scheme 12
The pharmacologically relevant system 90 has been constructed by treatment of the precursor 91 with lithium hexamethyldisilazide (LHMDS), followed by introduction of the appropriate electrophile (Equation 22). A number of 2,3-disubstituted 1-methylindoles could be prepared in a similar manner, but the drawback of this route appears to be the multistep preparation of the required precursors <2005OL4641>.
ð22Þ
The phosphorylated indole derivative 92 was obtained upon palladium-assisted annulation of the 2-alkenylaniline 93 in the presence of HP(O)(OEt2) (Equation 23). Similarly, a cyclization involving 4-methoxyphenylboronic acid with the N-acetyl derivative of 93 gave a 2-(4-methoxyphenyl)indole <2004TL907>. Palladium-catalyzed annulation of o-methallyl-N-tosylaniline with vinylic halides provided access to a set of 2,2-disubstituted N-tosylindolines <1998TL2515>. Previously, it has been reported that palladium-catalyzed annulation of 2-aminostyrenes may be employed as a route to indoles or 2-vinylindolines <1996JOC3584>. In addition, o-allylanilines may undergo direct conversion to resin-bound indolines attached via a –CH2Se– linkage at C-2 upon exposure to a selenyl bromide resin in the presence of SnCl4 <2000JA2966>.
Pyrroles and their Benzo Derivatives: Synthesis
ð23Þ
Yet another transition metal-catalyzed route to indoles involves the use of aminoalcohol precursors, for instance 94, which could be efficiently converted to 6-chloroindole 95 (Equation 24). A plausible mechanism seems to feature an oxidation of the alcohol to an aldehyde functionality, which undergoes intramolecular condensation with the amino group <2002OL2691>.
ð24Þ
An interesting reaction featuring loss of a two-carbon unit was observed upon treatment of the triphenylphosphonium bromide 96 with acetic anhydride in the presence of base, which afforded the indole 97 (Equation 25). The authors provided a plausible mechanistic rationale accounting for this result <2002TL8893>.
ð25Þ
In an example illustrating an approach to tryptamines, the aniline derivative 98, which is available by a Heck reaction involving the corresponding o-iodoaniline, was subjected to rhodium-catalyzed hydroformylation leading to the target indole 99 via the intermediate 100 (Equation 26) <1997JOC6464>.
ð26Þ The conversion of the (E)-2-aminocinnamate 101 to the indole derivative 102, which proceeds via the intermediate indoline 103, illustrates a new approach to functionalized indole-3-acetic acids (Scheme 13) <2003TL7269>.
Scheme 13
281
282
Pyrroles and their Benzo Derivatives: Synthesis
Base-induced annulation has also been utilized in a synthesis of, for instance, the fluoroindole 104, which results from a 5-endo-trig-cyclization of the precursor 105 (Equation 27). Some related cyclizations could also be used in preparation of fluorinated 2-pyrrolines <2002S1917>.
ð27Þ
In a practical and efficient route to a 5-HT2C receptor agonist precursor, the aniline 106 was subjected to double metalation, followed by treatment with the morpholide 107, affording the intermediate 108, which via annulation eventually gave the indole 109 (Scheme 14) <2005OPD508>.
Scheme 14
It has been shown that suitable precursors for annulation to indoles may also be efficiently prepared by Diels–Alder reactions between quinone imine acetals and dienes, followed by oxidative cleavage and recyclization of the resulting adducts. For example, the substrate 110 with 1,3-pentadiene, followed by treatment with acid, gave the intermediate 111, which was subsequently ring-opened and cyclized to the interesting indole 112 (Scheme 15) <2001OL3325>. Similar chemistry has been developed for N-arylsulfonyl quinone monoamine derivatives <2003SL971, 2005JOC6519>. Related strategy involving a quinone-1,4-diimine has been reported in connection with a total synthesis of the alkaloid (þ)-yatakemycin <2004JA8396>. Quinone monoimines may also react with alkenes in the presence of a Lewis acid giving indoline derivatives <1996JOC9297>.
Scheme 15
Elaboration of the bicyclic intermediate 113, which was prepared over several steps from methyl 3-amino-4chlorobenzoate, gave the target indole 114 (Equation 28) <2003JOC2051>.
Pyrroles and their Benzo Derivatives: Synthesis
ð28Þ
The development of a fairly general palladium-catalyzed synthesis of indoles involving a reductive cyclization of 2-nitrostyrenes <1997JOC5838> has enabled straightforward access to several natural products, for instance, 4-(methoxymethyl)-2-methylindole 115, a constituent of a Tricholoma sp. (Equation 29) <1999JOC9731>. The methodology has also been extended to the construction of fused indole systems <1999TL3657>, such as 1,2dihydro-4(3H)-carbazolones <2002TL1621>, leading eventually to a formal total synthesis of the carbazole alkaloid murrayaquinone A <2003T6323>. An additional variant has been employed for the construction of some related -carboline derivatives <2003T5507>.
ð29Þ
A further extension of this strategy has been employed as a route to carbazoles, as illustrated by the synthesis of the system 116 from the 2-nitrobiphenyl derivative 117 (Equation 30) <2004OL533>. A substituted 2-nitrobiphenyl derivative has been cyclized to a carbazole using P(OEt)3 en route to the pyridocarbazole alkaloid ellipticine <2006HCA111>. It should also be mentioned that annulation of o-(alkynyl)nitrobenzene precursors with TBAF or pyridine gave access to indol-3-one-1-oxides (isatogens) <2003T2497>.
ð30Þ
An efficient approach to substituted biindoles has been elaborated, as illustrated by the one-pot conversion of the nitrobenzene 118 into the precursor 119, followed by palladium-catalyzed annulation to the target system 120 (Scheme 16) <2003OL3721>. Alternatively, cyclization of such substrates may be performed using P(OEt)3 as
Scheme 16
283
284
Pyrroles and their Benzo Derivatives: Synthesis
the reagent <2001T5199, 2003OL3721>. Similar ring-formation methodology has found application in syntheses of 3-(indol-2-yl)-quinolines <2003OL3975>. Other efficient conditions for annulation of o-nitrostyrenes to indoles encompass the use of 0.1 mol% palladium(II) trifluoroacetate and 0.7 mol% 3,4,7,8-tetramethylphenanthroline in dimethylformamide (DMF) at 80 C under CO (15 psig) <2005T6425>. A related approach to indoles involving reductive cyclization based on treatment of o-nitrostilbenes with phenylmagnesium chloride has been discovered, wherein one specific example afforded the system 122 (Equation 31). It was also noted that exposure of 2-nitrobiphenyl to such conditions gave the parent ring system carbazole 4 in 24% yield <2003CEJ5323>. A series of o-nitrostyrenes have also been annulated to indoles by selenium-catalyzed reductive cyclization in the presence of carbon monoxide <1999TL5717>. In addition, reductive annulation of ethyl 3-hydroxy-2-(2-nitrophenyl)propenoate and related compounds provided access to a set of ethyl indole-3carboxylates <2006JOC4675>, whereas nitrostyrene precursors formed by condensation of nitroalkanes and suitable o-nitrobenzaldehydes underwent ring closure to 7-methoxy-2-alkylindoles <2001H(55)951>.
ð31Þ
Reductive cyclization of nitrostyrene precursors has also proven to be a useful route to 5,6-dihydroxyindole and its derivatives, as illustrated by the efficient preparation of the system 123 (Equation 32) <1999S793>.
ð32Þ
Initial esterification of the carboxylic acid 124, followed by reductive cyclization of the resulting methyl ester with an excess of TiCl3 provided a procedure to the oxindole 125 (Equation 33) <2002T3605>. Similar reductive annulations induced by H2 in the presence of Pd/C have been employed for the construction of the spirooxindole alkaloids ()-coerulescine and ()-horsfiline <2002TL9175>, whereas iron powder in aqueous HCl has been employed for cyclization of nitroarene precursors to 3-aminooxindoles <2003SL2135>. A related example of a cyclization onto an amide providing a fused indoline precursor to the natural product physostigmine has been reported <2003JOC6133>, whereas catalytic reductive annulation of (2-nitrophenyl)acetonitrile derivatives furnished indoles <2003SC2229>. Moreover, there are examples of reductive cyclizations involving cyclic enones bearing 2-nitrophenyl substituents prepared via palladium-catalyzed coupling of 2-halonitrobenzenes with -haloenones, leading for instance to tetrahydrocarbazole or cyclohepta[b]indole derivatives <2003OL2497>.
ð33Þ
Access to a variety of 1-hydroxyindoles has been gained by lead-induced reductive ring closure of o-nitrobenzyl ketones or aldehydes in the presence of triethylammonium formate (TEAF). In a representative example, the substrate 126 could be efficiently converted to the 1-hydroxyindole 127 (Equation 34) <2003JOC9865>. Reductive cyclization of o-nitrobenzylcarbonyl compounds has also served as an entry to the 3-(indol-2-yl)-quinoline system <2004JOC7761>, whereas precursors generated by palladium-catalyzed arylation of ketone enolates by o-bromo- or o-chloronitrobenzes in the presence of phenol as the additive have been cyclized to a variety of indoles by the system TiCl3/NH4OAc <2002JA15168>. Substrates suitable for this type of cyclization may also be accessed by arylation of silyl enol ethers with o-nitrophenylphenyliodonium fluoride <1999OL673>.
Pyrroles and their Benzo Derivatives: Synthesis
ð34Þ
Basic conditions are employed in conversion of the precursors 128, which are available from the corresponding nitrobenzene derivatives via vicarious nucleophilic substitution followed by alkylation, to the 3-cyano-1-hydroxyindoles 129 (Equation 35) <1997T5501>.
ð35Þ
The precursor 130, which was prepared using a combined VNSAr–SNAr three-component reaction, has been employed in a route toward the 3-aryloxindole derivative 131 (Equation 36) <2004OL4957>. Similar reductive annulations of intermediates derived by nucleophilic displacement of an immobilized aryl fluoride with dimethyl malonate anions, eventually providing 1,2-dialkoxyindole derivatives, have been described previously <2003OL2935>.
ð36Þ
Conversion of the readily available precursor 132 into the 1-hydroxyindole 133 proceeds via nucleophilic trapping of the intermediate 134, illustrating an elegant approach to a series of 1-hydroxyindoles with unusual substitution patterns (Scheme 17) <2005AGE3736>.
Scheme 17
An interesting rearrangement occurred upon treatment of the diester 135 with NaCl in hot DMSO providing the product 136 (Equation 37). Similar results were observed for a series of related substrates, giving access to a set of 1-methoxyindoles in moderate yields <2003TL7065>.
285
286
Pyrroles and their Benzo Derivatives: Synthesis
ð37Þ
Catalytic hydrogenation of the molecule 137, which is available by exposure of 1-methoxy-4-nitro-2-(trifluoromethyl)benzene to 4-chlorophenoxyacetonitrile in the presence of potassium t-butoxide, provided a practical approach to the indole 138 (Equation 38) <1998JME1598>. A related strategy has also been used in preparation of pyrroloquinolines <2002H(57)129> and ethyl (7-methoxyindol-3-yl)acetate <1995JHC947>.
ð38Þ
3.03.3 Category Ib Cyclizations The substrate 139, which is readily available by reaction of glycine with the corresponding dimethylaminomethylene compound, underwent cyclization to the unusual pyrrole 140 in a useful yield (Equation 39). A similar strategy could also be employed for instance in syntheses of isoindoles <2002J(P1)2799>.
ð39Þ
Annulation of the precursor 141 under basic conditions gave the fluorinated pyrrole derivative 142 (Equation 40) <1997BSF725>. Likewise, base-induced cyclization of N-(cyanomethyl)propargylamines has been shown to produce pyrroles in moderate yields <1995TL2823>.
ð40Þ
A route involving annulation of ketene-N,S-acetals has been developed, as illustrated by the transformation of the substrate 143 into the tetrasubstituted pyrrole 144 (Equation 41). This methodology was used for the synthesis of some key pyrrole intermediates toward the alkaloids lukianol A and lamellarin Q <2005TL475>.
Pyrroles and their Benzo Derivatives: Synthesis
ð41Þ
Titanium-induced cyclization of somewhat related substrates, for instance 145, has also been used previously for pyrrole ring formation, for example, the pyrrole 146 (Equation 42), as well as a number of similar systems bearing two phenyl substituents <1995JOC6637>.
ð42Þ
Yet another route to pyrroles starting from precursors which contain all the necessary atoms relies on conversion of allylamides into the corresponding imidoyl chlorides using the reagent (PhO)3P–Cl2 (formed from chlorine gas and (PhO)3P), followed by base-induced annulation, for instance, as shown in the preparation of the biheterocycle 147 (Equation 43) <2006S995>. In addition, it has been demonstrated that intramolecular cyclization of 2-benzamidobenzophenones mediated by SmI2 gives 2,3-diarylindoles <2003T1917>.
ð43Þ
Electrocyclization of the precursor 148, which was prepared by condensation of a chromium aminocarbene complex with a suitable amide, provided the pyrrole 149 (Equation 44) <2002OM1819>.
ð44Þ
Treatment of allyl isothiocyanate with the system lithium diisopropylamide (LDA)/t-BuOK will result in annulation generating the intermediate dianion 150, which may subsequently be reacted with water, followed by iodomethane, to provide the 2-(alkylthio)pyrrole 151 in a respectable yield (Scheme 18) <1997TL7247>.
Scheme 18
287
288
Pyrroles and their Benzo Derivatives: Synthesis
The Madelung cyclization is sometimes a useful approach to indoles lacking sensitive functional groups. For example, heating of the diamide 152 with potassium tert-butoxide provides the method of choice for the preparation of 2,29-biindolyl 153 (Equation 45). Careful control of the reaction conditions is crucial for optimal results <1995T5631>. The Madelung approach has also been used for synthesis of fused 2-methylindole derivatives <2002TL4707>, whereas a modified form involving cyclization of amides derived from (2-aminophenyl)acetonitrile has been adapted to solid phase <2002TL5189>. Related cyclizations of suitable N-aryl succinimide or phthalimide substrates have been used as a route to [1,2-a]-fused indoles <1997H(45)1979>.
ð45Þ
An interesting route leading to various unusual indole derivatives is illustrated by the conversion of the precursor 154 into 2-trifluoromethylindole 155 (Equation 46). Application of a variant based on annulation of related 2-(Nacylamino)benzyl methyl ethers with PPh3 in the presence of p-TsOH has also been elaborated, presumably proceeding via similar phosphonium intermedates <1996H(42)513, 1996J(P1)1261>. A solid-phase route based on an intramolecular Wittig reaction of polymer bound [2-(4-methoxybenzoylamino)benzyl]triphenylphosphonium bromide gave 2-(4-methoxyphenyl)indole in good yield <1996TL7595>.
ð46Þ
Palladium-catalyzed intramolecular cyclization of the imine 156, which is available from the corresponding o-alkynylaniline and thiophene-2-carboxaldehyde, gave the indole 157 (Equation 47). Several other related indoles were prepared in this manner by varying the aldehyde or o-alkynylaniline components <2000JA5662>.
ð47Þ
An interesting [4þ2] cycloaddition approach to various indoline systems has been devised, as illustrated by the preparation of the tricyclic molecule 158 (Equation 48). The inclusion of 2,6-di-t-butyl-4-methylphenol (BHT) in the reaction mixture gave somewhat improved yields <2005JA5776>.
ð48Þ
Treatment of the imine 159 with base provided access to the 3-(arylsulfonyl)indole 160 (Equation 49). Reactions involving other substrates gave a set of related indoles in 48–83% yields <1998S986>. An approach featuring a related base-mediated ring closure onto an isocyanide has also been reported <1997T193>.
Pyrroles and their Benzo Derivatives: Synthesis
ð49Þ
Thiol-mediated radical cyclization of the isocyanide 161, followed by desulfurization using Raney nickel, provided the indole 162 (Equation 50) <2001SL1403>. Similar cyclizations employing Bu3SnH without the presence of a thiol have been used as the key ring-forming step in syntheses of 6-hydroxytryptamine <1996TL7099>, as well as a number of other 3-substituted indoles <1998JHC1043>, whereas related annulations led after introduction of N-iodosuccinimide (NIS) <1999TL1519> or iodine <2000SL883, 2000S429> to 2-iodoindole derivatives. It has also been established that radical cyclization of 2-alkenylthioanilides gives rise to 2,3-disubstituted indoles <1999JA3791, 1999OL973>. Palladium-catalyzed three-component reactions involving an o-alkenylphenyl isocyanide, aryl halides, and diethylamine provided a set of 3-aminomethyl-2-arylindole derivatives in modest yields <2002TL6197>. Exposure of o-alkenylphenyl isocyanides to methylpalladium complexes resulted in formation of (3-indolylmethyl)palladium complexes <2002OM581>, or some other palladium-containing indole systems <1998OM4335>.
ð50Þ
Similar radical cyclizations involving the substrate 163 have been demonstrated to give the indoles 164 (Equation 51), which are useful for further elaboration <1999TL6325, 2000JOC6213>.
ð51Þ
Annulation of the carbamoyl chloride 165 into the oxindole derivative 166 (Equation 52) illustrates an approach that has also been used for the construction of several related molecules <2000CC2239>.
ð52Þ
Intramolecular addition of benzylic radicals to ketenimines offers a route to 2-(diphenylmethyl)indoles, for instance, the system 167 (Equation 53) <2003OBC4282>.
289
290
Pyrroles and their Benzo Derivatives: Synthesis
ð53Þ
In an example illustrating an approach featuring the intermediacy of a ruthenium hydride reagent, initial isomerization of the starting compound 168 generated the intermediate 169, which was thereafter annulated to the target indole 170 (Scheme 19) <2006JOC4255>.
Scheme 19
3.03.4 Category Ic Cyclizations The discovery of the ring-closing metathesis (RCM) reaction has enabled new approaches to pyrrole derivatives based on formation of the C(3)–C(4) bond as the key step. Exposure of a set of diallylamine precursors to secondgeneration Grubbs catalyst 171 in combination with RuCl3?H2O to induce dehydrogenation, produced a series of pyrroles, for instance 172 (Equation 54) <2004TL8995>. Application of the catalyst 171 or variants thereof on diallylamine substrates <1998T14869, 2004JOC8372> or related eneynes <1998TL6815, 1998JOC6082> is known to usually give 3-pyrrolines, whereas pyrroles have in some cases been isolated as the final products when the reaction was performed under microwave irradiation <2003TL1783>. Several 2-pyrrolines have also been prepared using RCM methodology <2001OL2045>. An extension based on alkyne cyclotrimerization reactions catalyzed by the Grubbs’ catalyst leading for instance to isoindole derivatives has also been described <2000CC1965>.
ð54Þ
An example of realization of a related route toward pyrroles involving assembly of the precursor 173 from the sulfonamide 174, methoxyallene, and iodobenzene, was completed by a RCM reaction, and subsequent acid-induced elimination of methanol, giving the target heterocycle 175 (Scheme 20) <2005EJO1969>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 20
An application of the RCM strategy features polycyclization reactions, wherein for instance the substrate 176 could be converted in good yield into the 3-pyrroline trimer 177 using the catalyst 178 (Equation 55) <1998JOC4291>.
ð55Þ
Iridium-catalyzed annulation of the precursor 179, which is available by a three-component reaction of 1-hexyne, allylbenzylamine, and ethyl glyoxalate, provided the conceivable intermediate 180, which was trapped with N-phenylmaleimide to provide the tricyclic system 181 in respectable yield (Scheme 21). Variation of the alkyne components gave a set of similar products <2005JA10804>.
Scheme 21
A metathesis approach has also been used in efficient routes to macrocyclic compounds featuring a pyrrole unit, as illustrated by the Lewis acid-mediated conversion of the precursor 182 into the heterocycle 183 (Equation 56) <1998JA8305>.
ð56Þ
291
292
Pyrroles and their Benzo Derivatives: Synthesis
Metalation of the amine substrate 184, followed by annulation promoted by tetramethylethylenediamine (TMEDA), gave the intermediate 185, which could thereafter be converted to the fused 3-pyrroline system 186 (Scheme 22). Subsequent dehydrogenation with DDQ gave the corresponding fused pyrrole. This methodology was used for preparation of an extended set of related pyrroles, as well as a series of indole derivatives, which were accessed by lithiation of N-bromoallyl-2-bromoanilines <2001CEJ2896>.
Scheme 22
Treatment of the Weinreb amide 187 with 2-thienyllithium gave the intermediate 188, which was thereafter annulated to the fused pyrrole 189 upon heating in xylene (Scheme 23) <2005S3152>. Variations of this approach were applied in preparation of a series of pyrroles feturing fused carbocyclic or heterocyclic rings <1999T13211, 2005S3152>. Enaminones derived by aza-Wittig reactions between 1,3-diketones and 2-azido-1,1-diethoxyethane have served as substrates for acid-induced cyclizations to pyrroles <2006TL2151>.
Scheme 23
The base-induced cyclization of the precursor 190 to the densely substituted 3-pyrrolin-2-one 191 illustrates an approach to a series of similar products (Equation 57). Other bases, for instance, t-BuOK or K2CO3, also proved to be efficient reagents for such transformations <2006S2019>.
ð57Þ
A base-mediated ring closure of the phenacylamide 192 afforded the 3-pyrroline-2-one 193 (Equation 58), whereas the application of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the reagent at room temperature in acetonitrile provided a route to the corresponding maleimide, demonstrating practical approaches to these types of pyrrole derivatives <2004T3987>.
Pyrroles and their Benzo Derivatives: Synthesis
ð58Þ
Intramolecular Heck cyclization is a useful route to certain indole derivatives, for instance, the 3-cyanoindole 194 (Equation 59), which was obtained as the major product along with minor amounts of the corresponding deacetylated product <2004BMC2867>. Similar Heck cyclizations have also been previously employed in syntheses of tryptophan derivatives <1996T14975> and some tryptamine-like systems <1996TL4289>, whereas a variant leading to 3-alkylideneoxindoles has also been performed on solid phase <1997TL6473>. Solid-phase protocols based on Heck reactions providing access to indole-3-carboxylates <2002JCO191> or indole-2-carboxylates <2002CC210> are also available.
ð59Þ
Likewise, it has been demonstrated that Heck cyclization of the substrate 195 gives indole-3-acetic acid methyl ester 196 in good yield (Equation 60). This methodology has been further used in preparation of (indol-3-yl)acetamides on solid phase <1997JOC1804>. Related intramolecular Heck reactions proved to be useful for asymmetric synthesis of various 3,3-substituted oxindoles <1998JA6488>, 3-alkyl-3-aryloxindoles <2003JA6261>, in construction of the skeleton of the antitumor antibiotic CC-1065 <1998CEJ1554>, as well as other 1,2-dihydro-3Hbenzo[e]indoles <2002JOC8958>. A strategy based on this type of annulation involving generation of the precursors by a four-component reaction between acrylic aldehydes, 2-bromoanilines, carboxylic acids, and isocyanides has also appeared <2006TL4683>. It should also be noted that palladium-catalyzed annulation of electron-rich N-(2-bromoallyl)anilines may in some cases lead to useful yields of hydroxyindoles <1997TL6379>.
ð60Þ
A sequence occurred upon cyclization of the substrate 197 under Heck conditions, which produced the tetracyclic system 198 (Equation 61), a precursor for a prostaglandin D2 receptor antagonist <2005JOC268>.
ð61Þ
Grigg has reported extensive studies of cascade cyclizations leading to various indole derivatives. For example, the propargylaniline 199 reacted with allene and piperidine in the presence of a palladium catalyst to afford the
293
294
Pyrroles and their Benzo Derivatives: Synthesis
heterocyclic system 200 in a respectable yield (Equation 62) <1996TL6565>. Extensions providing access to fused indolines <1996TL3399, 1996T11479> have also been elaborated.
ð62Þ
A cascade reaction of the amide 201 with a protected hydroxylamine provided the hydroxamic acid 202 in good yield (Equation 63) <1999TL7709>. Related reactions may also be performed with amines <1999TL3021>, as well as various combinations of allene and amines <1996TL4221>. Many additional papers have appeared exploiting further useful aspects of this chemistry, leading to a diversity of indoline and oxindole derivatives <1996TL4413, 1997T11803, 1999TL8277, 2001T1347, 2001T1361, 2001T10335, 2000CC2241, 2001CC964>. In addition, it has been demonstrated that palladium-catalyzed cyclization of enamines bearing a bromoallyl substituent gives moderate to good yields of pyrroles <2000CC873>.
ð63Þ
Studies on asymmetric annulation of the precursor 203 resulted in development of reaction conditions for the construction of the fused indoline system 204 (Equation 64). Similar cyclization of a substrate containing a longer chain gave a corresponding indoline fused to a six-membered ring <2002TA1351>.
ð64Þ
An interesting ring closure featuring palladium catalysis has been employed in the conversion of the precursor 205 to the fused indoline system 206 (Equation 65), a starting material for further elaboration to the natural product ()-tubifoline <2001OL1913>. Heck cyclization of an N-arylenaminone precursor prepared in situ from 1,2-dibromobenzene and a cyclic enaminone gave rise to a carbazolone structure <2000OL1109>. It has also been shown that intramolecular palladium-catalyzed annulation of 2-haloaniline precursors bearing a N-substituent incorporating a ketone functionality may proceed either by enolate arylation, or via addition to the ketone carbonyl group, leading for instance to carbazole structures <2001CC1888>.
ð65Þ
Pyrroles and their Benzo Derivatives: Synthesis
Approaches involving final formation of the C(3)–C(4) bond in the pyrrolic part have also been used for the synthesis of other carbazole derivatives. For example, palladium-catalyzed annulation of the arylamino-1,4-benzoquinone 207 gave the system 208 (Equation 66), an intermediate en route to the alkaloid carbazomycin H <1998J(P1)173>. The same catalyst system has been used in conversion of a diarylamine precursor into 7-methoxy3-methylcarbazole <2006OBC3215>. A related route to similar systems relies on the use of tert-butyl hydroperoxide as the oxidant <1995TL1325>. Conversion of an arylamino-1,2-benzoquinone system to a carbazole-3,4-quinone required stoichiometric amounts of Pd(OAc)2 <1999SL596>, in similarity with annulations leading, for instance, to the carbazole alkaloid murrayanine <2004S2499>. Additional palladium-catalyzed cyclizations have also been employed in syntheses of indolobenzo[b]thiophenes <2003T3737>, cyclopenta[b]indol-1-ones <2004HCA82>, and -carbolines <2003OL4195>.
ð66Þ
An example illustrating an approach to a set of substituted aminoindoles employed the starting material 209, which could be annulated to the protected indole 210 in a palladium-catalyzed reaction involving allylamine (Equation 67). The application of cyclic secondary amines as well as aniline derivatives also gave excellent results <2003AGE4257>. An indium-mediated synthesis of (E)-3-alkylideneoxindoles by annulation of related N-(2-iodophenyl)-ynamides has also been described <2004OL2825>.
ð67Þ
Acid-induced annulation of the propargylaniline 211 resulted in formation of the indole 212 (Equation 68). Similar conditions were used for preparation of several related systems in useful yields <1998TL4595>.
ð68Þ
Cyclization of the anilide 213 using TiCl4 produced the 3-chloro-substituted oxindole 214 (Equation 69), whereas a similar reaction induced by BF3?OEt2 gave the corresponding methoxy-substituted derivative <1998T4889>. Lewis acids have also been used in an approach to indole-2-carboxylates based on cyclization of (Z)-N,N-dimethylaminopropenoates derived by exposure of N-arylglycinates to DMFDMA <2006SL749>.
ð69Þ
295
296
Pyrroles and their Benzo Derivatives: Synthesis
Metalation of the aniline derivative 215 in a hydrocarbon/ether medium produced the corresponding lithio intermediate, which could thereafter undergo asymmetric cyclization induced by ()-sparteine rendering the indoline 216 (Equation 70) <2000JA6787>. Similar reactions leading to optically active indolines may be performed at low temperatures in toluene <2000JA6789>. Approaches based on annulation of similar substrates with Bu3MnLi <1997JOC1910>, the system t-BuLi/t-BuOMe <1996JOC2594>, or t-BuLi followed by treatment with TMEDA <1996JOC2596> leading to racemic indolines have also been reported. A particular application of this methodology has been applied in a synthesis of benzo[ f ]tryptophan <1997TL5111>. In addition, studies on annulations of related fluorine containing anilines proceed via benzyne intermediates, leading to 3,4-disubstituted indolines after final introduction of an electrophile <1997TL1329>.
ð70Þ
Exposure of the substrate 217 to excess t-butyllithium induces bromine–lithium exchange and metalation ortho to the fluorine substituent, thus generating the benzyne intermediate 218, and subsequent treatment of the second intermediate species 219 with an electrophile eventually leads to the 4-substituted indole 220, illustrating an interesting entry into the indole nucleus (Scheme 24) <1999TL1049, 2002CEJ2034>. This chemistry has also been extended to preparation of carbazole derivatives <2002CEJ2034>.
Scheme 24
Benzynes are also involved in a route to indoles illustrated by conversion of the imine 221 into the indole 222, which proceeds via the intermediate 223 (Scheme 25). This methodology is also useful for synthesis of fused indole derivatives <2003S1661>.
Scheme 25
An interesting approach to carbazoles has been devised, wherein for instance the diarylamine 224 underwent lithiation initially generating the benzyne 225, which provided the final product 226 after ring closure to 227 followed by introduction of a suitable electrophile (Scheme 26) <2006JOC6291>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 26
Oxindoles substituted in unusual positions have been obtained by base-induced intramolecular nucleophilic substitution of hydrogen in m-nitroacylanilides. For example, treatment of the substrate 228 with potassium t-butoxide in DMSO gave the product 229 (Equation 71). However, the yields in such annulations are generally low, and some substrates give mixtures of isomeric oxindoles <2002S2203>.
ð71Þ
It has also been demonstrated that palladium-catalyzed annulation of -chloroacetanilides provides an entry to a series of oxindoles, as exemplified by the conversion of the substrate 230 into the product 231 (Equation 72) <2003JA12084>.
ð72Þ
Based on a previously published procedure, it was shown that cyclohexane-1,3-dione reacts with sodium sarcosinate to provide the precursor 233, which could thereafter be efficently annulated to the tetrahydroindole derivative 234 (Equation 73), which should be a useful substrate for further synthetic manipulations <1995SL49>.
297
298
Pyrroles and their Benzo Derivatives: Synthesis
ð73Þ
Rhodium(II)-catalyzed decomposition of the diazoamide 235 has been shown to provide the indole 236 (Equation 74). In contrast, attempts involving Rh2(OAc)4 failed to give indolic products <1996T2489>. Decomposition of related substrates induced by zeolite K leads to formation of oxindoles <1996J(P1)2793>.
ð74Þ
Radical chemistry has also found application in preparation of indoles by intramolecular reactions of aryl radicals with vinyl halides. This has for instance been demonstrated by conversion of a diazonium salt which is readily available from the aniline 237, into the target system 238 (Equation 75) <1997TL7295, 2000J(P1)2395>. Similar annulations have been performed using tetrathiafulvalene as the additional reagent <1997J(P1)1549>, which has been employed in a total synthesis of ()-aspidospermidine <1999TL161, 1999J(P1)995>. Aryl radical annulations of suitable o-iodoaniline derivatives providing indolines have also been achieved employing N-ethylpiperidine hypophosphite <2000TL1833>, or tris(trimethylsilyl)silane and 2,29-azobisisobutyronitrile (AIBN) <1999JOC7856>. In addition, radical cyclizations involving a solid-supported copper catalyst have been used in annulations of N-allyl-2-halopropionamide derivatives to structurally interesting substituted pyrrolidines <1999JOC8954> or pyrrolidine-2-ones <2006TL6263>.
ð75Þ
Other means for generation and annulation of aryl radicals involve treatment of N-(o-bromophenyl)propylamides with Bu3SnH/AIBN, which gives 3-alkylideneoxindoles <2000J(P1)763>, or exposure of N-allyl(o-iodoanilines) to fluorous tin hydride reagents, affording indolines <1999JA6607>. A set of indolines, for instance 239, have been obtained by radical cyclization of precursors such as 240, which were derived from N-allylanilines (Equation 76) <1999TL2533>.
ð76Þ
Photocyclization of N-methyl-(p-methoxyphenyl)anilines in the presence of aqueous hydrochloric acid gave a set of carbazolones, as illustrated by the conversion of the diarylamine 241 into the system 242 (Equation 77) <2002CC270>. In addition, it has been reported previously that photocyclization of fluorine-substituted diphenylamines leads to formation of carbazoles <1996J(P1)669>.
Pyrroles and their Benzo Derivatives: Synthesis
ð77Þ
3.03.5 Category IIab Cyclizations Treatment of the aminoketone 243 with lithium trimethylsilyldiazomethane gave the 3-pyrroline 244 (Equation 78). Annulation of related amides provided a corresponding series of 3-pyrroline-2-ones <1996H(42)75>. Likewise, pyrroles may also be obtained upon exposure of N-substituted -aminoketones to lithium trimethylsilyldiazomethane <1997SL1063>.
ð78Þ
A series of N-protected substituted prolines have been prepared from -aminoaldehydes, as illustrated by the stereoselective conversion of 245 into the heterocycle 246 using benzyl diazoacetate as a source of the final required carbon atom (Equation 79) <2004JOC4361>.
ð79Þ
The thermally generated carbene 247 participates in a cyclization reaction with the imine 248, providing the pyrrole 249 in a moderate yield after elimination of hydrogen chloride (Scheme 27). A number of similar 1,2,3trisubstituted pyrroles were prepared in this manner <1999CC447>. The required carbenes may also be generated under irradiation, giving comparable yields of pyrroles <1999TL7163, 1999CC447>.
Scheme 27
It has been shown that the electron-deficient cyclopropane 250 reacts with aniline forming the 2-pyrroline 251 in excellent yield. An ensuing dehydrogenation with DDQ afforded the pyrrole 252 (Scheme 28). Similar reactions were observed for some related cyclopropanes bearing two electron-withdrawing groups <2005OL2313>. Another route to pyrroles involving ring opening of small rings relies on palladium-catalyzed reactions of acetylpyridines with methyleneaziridines <2004JA13898>.
299
300
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 28
Treatment of the ketene-N,S-acetal 253 with ethyl bromoacetate in the presence of potassium carbonate gave the pyrrole 254 in excellent yield (Equation 80). In contrast, similar reactions performed under somewhat different conditions gave instead thiophene derivatives <2003T1557>.
ð80Þ
A microwave-assisted variant of the Batcho–Leimgruber reaction has been employed for the preparation of a number of indoles. For example, homologation of the o-nitrotoluene derivative 255 to the enamine 256, followed by reductive cyclization, provided 4-fluoroindole 257 (Scheme 29). This route was also extended to the preparation of azaindoles and pyrroloquinolines <2004OBC160>. Batcho–Leimgruber conditions have also been employed in syntheses of ethyl 6-aminoindole-7-carboxylate <1996JOC1155>, 6-chloro-5-fluoroindole <2004SC2295>, 6-fluoroindole <2006EJO2956>, a masked 5-formylindole <2005JHC137>, a pyrrolo[2,3-b]xanthone system <2005SC2695>, and an indole possessing a Weinreb amide moiety at C-4 <1996TL3067>. Likewise, a synthesis of 6-iodo-4-trifluoromethylindole has been performed according to the Batcho–Leimgruber route, using a TiCl3induced reductive cyclization of the appropriate enamine precursor <2002T3605>.
Scheme 29
In a modified version, the aniline 258, which is readily available from the corresponding o-nitrotoluene, was subjected to reductive amination with the ketone 259 providing 260, which gave the target indole 261 after a final acid-induced cyclization (Scheme 30) <1996TL6045>. Additional applications of this approach have emerged later <2003T7215>.
Scheme 30
Pyrroles and their Benzo Derivatives: Synthesis
The toluidine 262 has been shown to undergo double lithiation to provide the intermediate 263, which may be subsequently reacted with ethyl trifluoroacetate to provide the target heterocycle 264 (Scheme 31) <1996H(43)1471>.
Scheme 31
An elegant route to unusual indoles has been developed, illustrated here by conversion of the 2-aminostyrene derivative 265 into the pyrrole 266 (Equation 81). Replacement of DMF by nitriles in this procedure gives access to the corresponding series of 2,3,5-substituted indoles <2003JA4054, 2004JOC7836>.
ð81Þ
A cyclization reaction involving the sulfonamide 267 finalized an efficient synthetic approach to the COX-inhibitor 268 after subsequent simultaneous ester hydrolysis and detosylation (Equation 82) <2003JOC4104>. Indoles have also been prepared by reaction of (2-aminobenzyl)triphenylphosphonium salts with carboxylic acid anhydrides in the presence of a base <2002TL2885>. Exposure of o-(benzoylamino)benzonitriles to -bromoketones under basic conditions gives 3-aminoindole derivatives <2001BML2169>.
ð82Þ
Indoles have also been accessed by reactions of 2-aminobenzophenone derivatives or related compounds and onecarbon synthons, as treatment of the starting materials 269 with, for instance, the -diazophosphonate 270 in the presence of Rh2(OAc)4 gave the target heterocycles 271 (Equation 83) <2002OL2317>. Likewise, indoles may be prepared by exposure of N-tosylbenzophenones to lithium trimethylsilyldiazomethane, followed by treatment with t-BuLi and subsequent introduction of electrophiles <2006S1249>. Rhodium-catalyzed carbonylation of 2-alkynylanilines has been reported to give 3-alkylideneoxindoles <1995TL6243>. A titanium-induced synthesis of indoles by annulation of amides derived from molecules related to 269 and carboxylic acid chlorides has also been elaborated <1995T773>.
ð83Þ
301
302
Pyrroles and their Benzo Derivatives: Synthesis
3.03.6 Category IIac Cyclizations The Knorr synthesis offers a valuable and practical route to a number of pyrrolecarboxylates, as illustrated by preparation of ethyl 4-acetyl-5-methyl-3-propyl-1H-pyrrole-2-carboxylate by reaction of an oxime derived from a 3-oxohexanoate with acetylacetone <1998JOC8769>, new porphobilinogen analogues as inhibitors of hydroxymethylbilane synthase <2003OBC21>, or scale synthesis of the -opioid antagonist SB-342219 featuring generation of an aminoketone intermediate <2004OPD279>. A regioselective variant has been described, involving use of 1,3-dicarbonyl compounds bearing sterically demanding substituents, providing for instance access to the product 272 (Equation 84). Reactions starting from related diketones incorporating groups less bulky than isopropyl gave mixtures of regioisomeric pyrroles <1997TL1427>. A study of the Knorr reaction involving diethyl oximinomalonate and 2,4-pentanedione revealed formation of a 2,29-bipyrrole impurity in 0.4% yield along with the target pyrrole <2004JHC777>. In addition, a related route allowing preparation of pyrrole-2-carboxylates from enaminones and 2-oximinoacetoacetate under Knorr conditions has been reported <2002SC897>.
ð84Þ
In an example illustrating a modification of the Knorr synthesis, the Weinreb amide derivative 273 was converted to the -enaminoketone 274, and annulated to the target pyrrole 275 (Scheme 32). An extensive set of pyrrole derivatives were prepared using variations of this approach <1999T6555>.
Scheme 32
Enamines are also involved in the classical Hantzsch synthesis, which is usually performed by annulation of an enamine intermediate derived from ammonia and a suitable -ketoester or an equivalent 1,3-diketo synthon, with an -haloketone. A new development is the adaptation of this reaction to solid-phase conditions <1998TL2381>. Heating of the -aminoacrylonitrile 276 with the ketone 277 gave a decent yield of the pyrrole 278 (Equation 85), a member of a series of similar compounds which were synthesized using this approach <1997S530>. An additional solid-phase variant of the Hantzsch synthesis provided a set of pyrrole--carboxamide derivatives <1998BML2381>.
ð85Þ
An approach based on samarium diiodide-promoted reactions of the iminoketone 279 with aldehydes provides access to a series of substituted or fused pyrroles bearing at least two phenyl groups, for instance, the system 280 (Equation 86) <2001T4881>. In an alternative lanthanide-catalyzed route, a series of pyrroles were constructed from imines and nitroalkenes in the presence of Sm(i-PrO)3 <1999T13957>. A set of 1-dimethylaminopyrroles have also been obtained by TiCl4-induced reactions between 2-acetoxypropanal hydrazones with silyl enol ethers <1995TL8007>.
Pyrroles and their Benzo Derivatives: Synthesis
ð86Þ
A number of 1-methoxypyrroles has been prepared by reactions of -keto O-methyloximes with the alkyne 281 under basic conditions. For example, initial alkylation of the substrate 282 produced the intermediate 283, which underwent subsequent annulation followed by a proton shift to afford the final product 284 (Equation 87) <2004TL3953>.
ð87Þ
Heating of the dihydroisoquinoline 285 with the nitrostyrene 286 allowed practical preparation of the system 287 en route to the natural product lamellarin K <2004AGE866>. Reactions between nitroalkenes and enaminones have also been employed as the key step in a solid-phase approach to pyrrole-3-carboxamide derivatives (Equation 88) <1998TL8263>.
ð88Þ
The use of imine precursors has also been implemented in a route to 1-aminopyrrole derivatives. In a representative example, addition of the enolate of diphenylacetaldehyde to the diazocompound 288 gave the intermediate 289, which could be cyclized to 290, followed by rearrangement to the final product 291 (Scheme 33) <2002JOC8178>.
Scheme 33
303
304
Pyrroles and their Benzo Derivatives: Synthesis
A variant of this procedure has been performed on solid phase <2001T5855>. An alternative route to 1-aminopyrrole derivatives published previously involved annulation of precursors derived from reactions of -halohydrazones with -dicarbonyl compounds <1996H(43)1447>. A route to pyrroles illustrated by the preparation of 292 involves initial treatment of the nitroketene-S,S-acetal 293 with an organometallic reagent, followed by conversion of the resulting alkene 294 to the enamine 295, and final annulation to the target heterocycle (Scheme 34) <1998T12973>. A related approach featuring construction of -hydroxyenamines from 1,3-dicarbonyl compounds and -amino alcohols, and subsequent palladium-catalyzed cyclization to pyrroles, has been reported <1996TL9203>.
Scheme 34
Condensation of benzaldehyde with aminoacetaldehyde dimethyl acetal, followed by reduction of the resulting imine, gives the precursor 296, which could be further reacted with malonitrile providing the pyrrole 297 in 35% overall yield (Equation 89) <2004OL2857>.
ð89Þ
Exposure of the substrate 298 to the azide 299 in the presence of TMSOTf gave the intermediate 300, which was subjected to an intramolecular aza-Wittig reaction to afford the pyrrole 301 (Scheme 35). Reactions involving related 1,3-bis-silyl enol ethers gave access to a series of interesting pyrrolidine derivatives <2005JOC4751>. Likewise, pyrrole derivatives have also been constructed by reactions of anions derived from 1,3-dicarbonyl compounds with -azidoketones, and subsequent annulation of the resulting intermediates under aza-Wittig conditions, which constitutes a route to 2-alkylidenepyrrolines <2006JOC4965>.
Scheme 35
It has been found that upon treatment with SmI2, phenacyl azides will undergo reduction and ensuing dimerization producing pyrroles, as illustrated by the efficient conversion of the substrate 302 to 2,4-diphenylpyrrole 303 (Equation 90) <2002TL1863>. Pyrroles may also be obtained by dimerization of -aminocinnamates using tetrabutylammonium cerium(IV) nitrate via a radical pathway <2006T2235>. Cerium(IV)-induced radical reactions between 2-amino-1,4-naphthoquinones and 1,3-dicarbonyl compounds have led to a series of benzo[ f ]indole-4,9diones <2002T7625>. In addition, it has also been demonstrated that 2,3,4,5-tetrasubstituted pyrroles are formed upon treatment of aryl alkyl ketoximes with TiCl4/Et3N <2004MI270>.
Pyrroles and their Benzo Derivatives: Synthesis
ð90Þ
Exposure of the xanthate 304 to AIBN generates an acetonyl radical, which will subsequently react with the enesulfonamide 305 to provide the pyrrole 306 via the intermediate 307 (Equation 91) <2002CC2214>.
ð91Þ The hydrazone 308 underwent carbozincation and stannylation providing the intermediate 309, which was subsequently annulated to the 1-aminopyrrole derivative 310 (Scheme 36) <1999OL1505>.
Scheme 36
It has also been demonstrated that ketimines may participate in reactions with nitrostyrenes providing fused pyrroles, as shown by the preparation of the system 311. The series of events leading to this outcome were suggested to involve a Michael-type addition of the enamine tautomer of the substrate 312 to the olefin, followed by annulation with concomitant elimination of the nitro functionality (Equation 92) <1999TL4177>. In addition, solid-state reactions of enamine esters or ketones with (E)-1,2-dibenzoylethene induced by milling gave excellent yields of pyrroles <1999AGE2896>.
ð92Þ
A copper-catalyzed reaction between the propargylamine 313 and the vinyl sulfone 314 provided the pyrrolidine 315 (Equation 93). Extension of this procedure with a palladium-catalyzed allylic substitution with phenols afforded a series of 4-(phenoxymethyl)-3-pyrrolines or their isomers <2002EJO1493>.
ð93Þ
305
306
Pyrroles and their Benzo Derivatives: Synthesis
Taking advantage of an intramolecular Wittig reaction, the -amidoketones 316 underwent annulation to the 3-pyrrolines 317 upon treatment with the ylide 318 <1995S1151>. These intermediates could be further elaborated to the pyrroles 319 by base-induced elimination of benzenesulfinic acid (Scheme 37) <2000TL8969>. It should also be mentioned that a set of unusual 3-pyrroline-2-ones have been synthesized by Ugi’s four-component reactions from phenacylamine hydrochloride, cyanoacetic acid, cyclohexyl isocyanide, and aldehydes, involving final formation of the C(3)–C(4) bond <1999H(50)463>.
Scheme 37
A series of substituted pyrroles 320 have been accessed by reactions of the tin enamine 321 and -haloaldehydes 322 (Equation 94), whereas similar annulations involving -haloketones gave mixtures of isomers. This procedure may be performed even in aqueous medium <1997TL3265>.
ð94Þ
The Fischer indole synthesis is commonly recognized as one of the most powerful and versatile tools for construction of indoles, as reflected by the amount of recent publications in which it has been used successfully. The usual approach involves initial preparation of a phenylhydrazone 323 from a suitable phenylhydrazine and an enolizable carbonyl compound, followed by an acid-induced cyclization to the target indole 324, featuring a [3,3]sigmatropic rearrangement as the key step (Scheme 38). Some selected new examples of indoles prepared using ‘standard’ Fischer conditions are collected in Table 2.
Scheme 38
As is evident from the references cited in Table 2, a variety of substituted indoles may be prepared using this route. However, there are examples where alternative mechanistic sequences are in operation, giving rise to mixtures of products. This is sometimes the case when the starting hydrazine contains an ortho-substituent, as in the precursor 325, which may undergo cyclization to indoles of type 326 (general structure shown), as outlined in Scheme 39 <1997T8853>. The desired 7-hydroxy-4-nitroindole system could instead be accessed by a Fischer indolization of a constrained 4-aminobenzoxazine precursor <1997T8853>. Related side reactions involving loss of a –OMs group
Pyrroles and their Benzo Derivatives: Synthesis
Table 2 Selected examples of indoles prepared using the Fischer indole synthesis
R2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 a
H Ph CO2Me CO2Et Me Me Ph H C(Me)2CHTCH2 CO2Et CO2Me 2-BrC6H4 CO2Et Ph
R3 (CH2)3OH (CH2)2NHAc H H CH2CO2Et CH2CO2Et NHCOPh 1-Phenyl-1H-tetrazol-5-yl H H Me H H (CH2)4NH2
R4 H H H H H H H H H H CO2H H Cl H
R5 CH2SO2NHMe OMe NO2 H NHCOMe H F F H Br H H H OMe
R6 H H H H H NHCOMe H H OMe H H H Cl H
R7 H H OMe OTs H H H F H OTs Cl H H H
Yield (%) a
50 85a 64b 54b 45a 52a 44b 42b 25a 41b 87b 78a 97b 80b
Reference 1997JOC9192 2004T11719 2003EJO562 1999J(P1)1717 2002CHC539 2002CHC904 2003CHC161 1995JHC1557 2002TL2149 1998T45 2004OBC701 2003JA4240 2000OPD477 2002TL8449
Overall from the corresponding hydrazine or hydrazine salt. From the corresponding hydrazone.
b
Scheme 39
have also been observed <1998T45>. In addition, Fischer indolizations of some 2,4,6-trimethylphenylhydrazones have been reported to give 5,7-dimethylindoles as a result of the elimination of an ortho-methyl group <2003TL5665>. Mixtures of products may also be encountered during Fischer cyclizations of various diphenylhydrazones <1995CPB1281, 1995CPB1287>. Moreover, additional examples have shown that the process may be halted at the 2-aminoindoline stage preceding the final elimination of ammonia by choosing carefully designed substrates <1998T3745>. Formation of several types of basic compounds has been observed in connection with studies of Fischer indolization of phenylhydrazones derived from bulky ketones <1998JHC853>. The mechanism leading to abnormal indole products from the reaction of naltrexone hydrochloride with N-alkyl-N-(5,6,7,8-tetrahydro-1-naphthyl)hydrazine mesitylene sulfonate has been discussed <1997H(45)2109>. Several modern adaptations of the Fischer indole synthesis have been devised, employing for instance solid-phase<1996TL4869, 2005TL911> or dendrimer- <1996PNA10012> supported ketones, as well as immobilized hydrazines
307
308
Pyrroles and their Benzo Derivatives: Synthesis
<2003CC1822, 2005JCO130>, or hydrazones <2005JME1179, 2004AGE224>. A specific approach has been used for solid-phase preparation of spiroindolines <1997TL1497>. Examples of microwave-assisted Fischer indolizations have also been reported <2004TL8831, 2002TL9565>. Interestingly, it has been demonstrated that the Fischer indole synthesis may be performed under microwave irradiation in near-critical water even without the presence of an acid <1997JOC2505, 2005EJO3672>. A new one-pot approach features construction of hydrazones by treatment of nitriles with organometallic reagents, followed by introduction of hydrazines, and final cyclization to the target indoles, giving for instance the product 327 (Scheme 40). The intermediate hydrazones may also be obtained by addition of 2 equiv of an organolithium reagent to suitable carboxylic acids, followed by treatment of the intermediate dialkoxides with hydrazine hydrochlorides <2005T11374>. Phenylhydrazones are also available by treatment of -diazoesters with phenyllithium <2006TL743>. In addition, it should also be mentioned that efficient Fischer indolizations have been carried out in a chloroaluminate ionic liquid consisting of 1-butylpyridinium chloride/AlCl3 (molar ratio 23:67) <2001S370>, or using montmorillonite K10/ZnCl2 under microwave irradiation <1999SC1349>.
Scheme 40
The ketone component may be replaced by cyclic enol ethers, which will react with phenylhydrazines to give phenylhydrazones, as has been demonstrated by a large-scale synthesis of 5-fluorohomotryptophol derivatives from 4-fluorophenylhydrazine hydrochloride and tetrahydropyran (THP) <1997OPD300>. Further developments have broadened the scope of this approach, allowing for instance preparation of indomethacin 328 from the hydrazine derivative 329 and angelicalactone 330 (Equation 95) <2004OL79>. The application of 2-hydroxypyrrolidine-1carbamates in the Fischer reaction provided a new entry to melatonin and related compounds <1998SC3681>. Derivatives of L-tryptophan have been prepared by Fischer indolization of optically active N,N-diprotected L-glutamic acid -aldehydes and appropriate hydrazines <2003SL1411>. Furthermore, it should also be noted that the Gandberg modification of the Fischer synthesis, which involves the use of an acetal as the ketone equivalent, has also found some new applications <2001T1041, 1997JME3497, 1997JME3501>.
ð95Þ
The use of branched ketones enables preparation of 3H-indolium salts. For instance, condensation of the ketone 331 with the hydrazine 332, followed by Fischer indolization of the resulting hydrazone 333 with perchloric acid, afforded the product 334 (Equation 96) <2000JHC1571>. The hydrazine components may also be generated from anilines in a one-pot variant of this route <2004JHC103>.
ð96Þ
Pyrroles and their Benzo Derivatives: Synthesis
Some additional new extensions involve transition metal-catalyzed generation of the required hydrazones, which has for instance been exploited by Eilbracht in a tandem hydroformylation/Fischer route, as illustrated by the conversion of methallylic phthalimide 335 to the tryptamine derivative 336 (Equation 97) <2003OL3213>. Variations of this approach have allowed preparation of a variety of other tryptamines and homotryptamines <2005JOC5528>, 2,3-disubstituted indoles <2006OBC302>, as well as tryptophols <2003OL3213>, in addition to a wider range of tryptamides <2005OBC2333>. Related hydroformylation reactions eventually leading to indoles have also been studied by Beller <2004TL869>. A variant involving hydroformylation of N-allylacetamide as one of the steps for construction of hydrazones has been described, allowing a short synthesis of melatonin <2000CC1363>.
ð97Þ
An elegant synthesis of 4,6-dibromoindole derivatives has been developed, involving a copper-catalyzed coupling of dibromoaryl iodides with t-butyl carbazate. In a representative example, the iodoarene derivative 337 was converted to the intermediate 338, which was thereafter subjected to Fischer conditions rendering the indole 339 in a good overall yield (Scheme 41) <2004JOC3336>. A study on the Fischer indolization of N-BOC arylhydrazines has also been published <2004TL1857>. Palladium-catalyzed coupling of benzophenone hydrazone with aryl bromides, followed by exposure of the resulting N-aryl benzophenone hydrazones to in situ hydrolysis/Fischer indolization, provides a new variation of this classical synthesis <1998JA6621, 1999JA10251>, which has later been applied to the preparation of 5-substituted 3-(1H-indol-2-yl)-1H-quinolin-2-ones <2005JOC2555> and indoloparacyclophanes <2001AGE1283>.
Scheme 41
It has also been demonstrated that the system TiCl4/t-BuNH2 can catalyze hydroamination of alkenes with hydrazines, as well as the ensuing Fischer indolization of the resulting intermediate hydrazones <2004TL9541>. Similar hydroamination/Fischer sequences employing bis(2,6-di-t-butyl-4-methylphenoxo)-bisdimethylamide titanium as the catalyst leading for instance to tryptamines <2004TL3123> or tryptophols <2005T7622> have been described. In addition, there are several other titanium complexes for hydroamination of alkenes to hydrazones available <2002OL2853, 2004CEJ2409>. Synthesis of carbazoles and related indoles fused to carbocyclic rings is yet another fruitful field for application of the Fischer indolization, which has for example resulted in routes to indeno[2,1-b]indoles <2004OM344>, diarylcarbazoles <1999HC451>, tetrahydrocarbazole derivatives <2000JOC3387, 2003BMC3413, 1999CAL93, 1997J(P1)1699>, and benzo[a]carbazoles <2006SL1021>. The last example involved the use of zeolites as catalysts. Other notable extensions encompass preparation of pyrrolo[2,3-a]carbazoles <2004JHC349>, indolo[3,2-b]carbazoles, for example, 340 <2003T1265>, 341 <1999T12577>, and 342 <1999T12595>, as well as the naturally occurring indolo[2,3-a]carbazole alkaloid arcyriaflavin A 343 (Figure 3) <2005TL4839>. In addition, Fischer indolization has been utilized for preparation of methanocycloocta[b]indoles <2000JOC1353, 2003OBC391>, and aza derivatives thereof <2004JOC5196>. It is also possible to use the Fischer synthesis for crafting indoles fused to other heterocyclic rings. This has been nicely demonstrated by initial formation of the enehydrazines 344, which were subsequently cyclized to the -carboline derivatives 345 (Scheme 42). An additional dehydrogenation step provided access to the corresponding
309
310
Pyrroles and their Benzo Derivatives: Synthesis
Figure 3
Scheme 42
4-methoxy--carbolines <2005TL3831>. In addition, the Fischer indolization has also served as a tool for preparation of pyrido[ 29,39:2,3]thiopyrano[4,3-b]indoles <2000JHC379>, benzo[4,5]indolo[3,2-c]quinolines <1998JA2501>, benzofuroindoles as potent BKCa channel openers <2005CBC1745>, as well as a series of sulfur-containing compounds related to indolocarbazoles <1998SC1239>. Likewise, the Fischer indole synthesis is a very useful method for the construction of even more complex fused indole derivatives, provided that suitable ketone or hydrazone precursors are available, and has, for example, been utilized in approaches to the alkaloids rutaecarpine <2004T3417>, as well as its 3-aza- <1996T7789>, 7-aza<2000T7987>, and debenzoanalogues <1996JHC799>, tubifolidine <1998JOC7547>, ()-deethylibophyllidine <1996JOC7106>, (þ)-aspidospermidine <2005JOC10645, 2000OL1625>, other Aspidosperma alkaloids <2002JA4628>, and the skeleton of isogeissoschizine <2002OL615>. Some studies of related interest encompass preparation of indoles fused to the steroid framework <1997J(P1)2329>, and naltrindole derivatives under standard conditions <1998JME2872>, or on solid phase <2003OL1159>. In addition, an application to the synthesis of a 2,49biindolyl system has also been reported <1995JA1485>. A related strategy is based on application of the Japp–Klingemann reaction as an alternative means for preparation of the required hydrazones. For example, the the diazonium salt 346 was reacted with the ketone 347 affording the hydrazone 348, which was subsequently cyclized to the tryptamine derivative 349 (Scheme 43) <2000H(53)665>. The Japp– Klingemann reaction has also been employed as a key step in syntheses of cyclopenta[b]indoles <2005JOC8385,
Scheme 43
Pyrroles and their Benzo Derivatives: Synthesis
2002HCO65>, carbazole structures <2004JA3534>, various tryptamine derivatives and related molecules <2004SC1791, 1999OPD155, 2006SC1515, 1999BML1055, 2004BML2681>, numerous useful substituted indole-2-carboxylates <2005JHC615, 1998OPD214, 2005SC1359, 2004T8829, 2003JOC6279, 1997JOC9298, 1995TL7411, 1997JOC7447>, indole-3-acetic acid derivatives <1999JME638>, and pyrido[ 39,29:5,6]thiopyrano[3,2-b]indoles <2002JHC1001>. Treatment of the aldehyde 350 with phenylhydrazine in the presence of trifluoroacetic acid (TFA), followed by reduction of the intermediate, gave the system 351 (Equation 98), providing yet another illustration of the impressive versatility of the Fischer indole synthesis <1997T10983>.
ð98Þ
Similar indole ring formation may also proceed under nonacidic conditions <1999TL3601>. This has been demonstrated, for instance, by condensation of the hydrazine 352 with cyclohexanone, followed by treatment with trifluoroacetic anhydride (TFAA), which gives the intermediate N-trifluoroacetyl enehydrazine 353. An ensuing thermally induced rearrangement gave the final product 354 (Scheme 44). Some reactions were also performed in the presence of triethylamine <2001S1635>. A mechanistic study of the thermal annulation step involving o-substituted substrates revealed the intermediacy of dienylimines <1999CC2429>. Further studies of this approach involving m-substituted hydrazines showed that the corresponding 4-substituted indoles are usually the major products, along with smaller amounts of the 6-substituted isomers <2002H(57)1101>.
Scheme 44
An interesting extension of the Grandberg synthesis was utilized in reaction of the hydrazines 355 with the aldehyde 356, followed by N-functionalization, to provide the systems 357, via the conceivable intermediates 358 (Equation 99) <2002H(58)587>.
ð99Þ
311
312
Pyrroles and their Benzo Derivatives: Synthesis
The Bartoli indole synthesis relies on cyclization of 2-substituted nitrobenzenes 359 with vinyl Grignard reagents 360, and provides a convenient route to 7-substituted indoles 361 (Equation 100) <2005COR163>. Although the yields are in most cases only moderate, this approach may in some cases be a powerful tool for preparation of unusual indoles in one simple operation. Selected examples of indoles prepared using the Bartoli reaction are given in Table 3. A solid-phase version starting from suitable nitrobenzoic acids linked to the Merrifield resin has also been reported <2003OL2829>.
ð100Þ
Table 3 Examples of indoles prepared according to the Bartoli route
1 2 3 4
R3
R4
R7
Yield (%)
Reference
H H H Me
CH2Br H H H
Br CH2Ph CF3 Cl
48 53 56 53
2001JOC638 2002SL143 1999SL1594 2004JOC7875
The Gassmann synthesis has been utilized for preparation of a 6,7-dihydroxyoxindole unit of the natural product paraherquamide A. The starting aniline 362 was exposed to the chlorosufonium salt generated by treatment of ethyl methylthioacetate with sulfuryl chloride, followed by annulation to the 3-(methylthio)-6,7-dimethoxyoxindole 363 (Equation 101), which could be futher desulfurized and demethylated <1996JOC8696>. The chlorosulfonium salt may alternatively be formed by reacting ethyl methylthioacetate with oxalyl chloride <1996TL4631>.
ð101Þ
Another useful route involving formation of two bonds is based on palladium-catalyzed annulation of 2-iodoanilines with alkynes. As the use of trimethylsilyl acetylenes leads to regioselective formation of indoles bearing a TMS group at C-2 <1998JOC7652>, this approach has proven to be useful in the synthesis of optically active tryptophans <1999TL657>. In a typical example, the substituted o-iodoaniline 364 and the acetylene 365 were efficiently converted to the indole 366 (Equation 102), which could thereafter be transformed into 5,6-dimethyl-L-tryptophan <2001JOC4525>.
ð102Þ
Similar tryptophan syntheses may also be performed starting from suitable triethylsilyl (TES)-substituted alkyne components, which gives indolic intermediates bearing the readily removable TES functionality at C-2 as illustrated by the sequence featuring coupling of the aniline 367 with the alkyne 368, and conversion of the resulting
Pyrroles and their Benzo Derivatives: Synthesis
intermediate 369 into 7-methoxy-D-tryptophan ethyl ester 370 (Scheme 45) <2004OL249>. The generality of this strategy has been proven in numerous applications <2001JOC4525, 2002OL3339, 2003OL3611, 2005JOC3963>. Variants of this procedure have also been employed for the preparation of 4-hydroxytryptamine derivatives, for instance, the alkaloid psilocin <2003OL921>, as well as some indoles containing masked alcohols <2001T5233>.
Scheme 45
The tremendous potential of this approach is further manifested in a number of new applications, and has for instance been extended to the preparation of fluoroalkylindoles from suitable 2-iodoanilines and fluorine-containing alkynes <2004JOC8258, 2004CL314>, the indole-2-carboxylate 372, which was accessed from the precursor 371 under Negishi coupling conditions en route to the natural product duocarmycin SA (Equation 103) <2004OL2953>, or in the construction of pyrrolo[2,3-b]pyrazines from 2-amino-3-chloropyrazine derivatives <2004TL8087, 2004TL8631>. Reactions between N-tosyl-o-iodoanilines and terminal alkynes involving Pd(OAc)2/Bu4NOAc give rise to N-tosylindoles avoiding the use of amine bases and ligands <2006T5109>. Several other catalytic systems have been used in reactions between o-iodoaniline derivatives or related systems and alkynes, for instance, [Cu(phen)(PPh3)2]NO3/ K3PO4 <2003OL3843>, CuI/PPh3/K2CO3 <2004SL287>, Pd/C(10%)/CuI/PPh3/HO(CH2)2NH2 <2004SL1965>, a palladium-modified zeolite <2004TL693>, as well as Pd/CuI/PPh3/KF–Al2O3 under microwave irradiation <2001T8017>. In addition, several palladium-catalyzed solid-phase variants of this approach have been reported, employing o-iodoanilines immobilized via an amide linkage para to the amino group <1997TL2439, 2001TL4751>, or using N-THP<1998TL8317> or N-sulfonyl-linked aniline substrates <2000OL89, 2001OL3827>. Generation of benzynes from o-trimethylsilylaryl triflates followed by palladium-catalyzed coupling and cyclization with o-iodoanilines constitutes a new route to carbazoles <2004OL3739>.
ð103Þ
A number of additional cyclizations involving alkynes have been reported. For instance, it has been shown that indoles may also be accessed from 2-bromo- or 2-chloroanilines, as illustrated by the regioselective preparation of the carbinol 373 in the presence of the ferrocene 374 (Equation 104) <2004OL4129>, whereas a one-pot sequence featuring titanium catalyzed hydroamination of 2-chloroanilines with acetylenes, followed by intramolecular Heck cyclization in the presence of an imidazol-2-ylidene palladium complex, has also been reported <2004CC2824>. A set of aryl-2-indolyl carbinols have been prepared in high enantiomeric purity by palladium-catalyzed annulation of
313
314
Pyrroles and their Benzo Derivatives: Synthesis
chiral arylpropargylic alcohols with N-methanesulfonyl-o-iodoaniline <1996TA1263>. One-pot hydroamination of diphenylacetylene with 2-bromoaniline assisted by TiCl4/t-BuNH2, followed by a palladium-catalyzed cyclization gave 2,3-diphenylindole in 85% overall yield <2003OM4367>. Additional examples of indole syntheses from nitrosobenzene derivatives with alkynes encompass C–H functionalization at the ortho-position of the arene in the presence of a ruthenium catalyst under carbon monoxide <2002OL699>, whereas reactions of nitrosobenzenes with terminal acetylenes in the presence of dimethyl sulfate and potassium carbonate give 1-methoxyindoles <2006JOC823>. Some related ruthenium- <2002CC484> or palladium-catalyzed reactions involving nitroarenes under carbon monoxide atmosphere give indoles or azaindoles <2006JOC3748>. Indoles have also been accessed from Ru3(CO)12mediated <2001TL3865> or Zn(OTf)2-catalyzed reactions of anilines with propargyl alcohols <2006JOC4951>. In addition, indoles are also formed from anilines in ruthenium-catalyzed reactions with triethanolamine derivatives at elevated temperature <2000TL1811, 2001T3321>, or annulations involving epoxides <2003TL2975>. Such ruthenium-catalyzed reactions may also be performed in the presence of tin(II) chloride <1998CC995>.
ð104Þ
It has been demonstrated that the palladium-catalyzed reaction between the protected o-iodoaniline 375 and the diene 376 provides a route to the indoline 377 (Equation 105) <1998TL5463, 2001JOC8599>, which may be subsequently dehydrogenated to the corresponding indole, a partner for Diels–Alder cycloadditions leading to carbazoles <2001JOC8599>. Palladium-catalyzed annulation of o-iodoanilines with 1,3-dienes has also been used in a solid-phase approach to 2-alkenylindolines <1998TL9605>, whereas cyclizations involving vinylic cyclopropanes have previously been reported to give for instance 2,2-disubstituted indolines <1996T2743>. Moreover, it has been reported that palladium-catalyzed reactions of N-acyl-2-iodoanilines with vinylene carbonate give N-acyl-2hydroxyindolines <1995H(41)1627>.
ð105Þ
There are also examples of annulations involving allenes, which has been exploited in the conversion of the o-iodoaniline 378 into the system 379 involving a chiral ligand 380 (Equation 106) <1995JOC482, 1999JOC7312>. A palladiumcatalyzed sequence involving 2-iodo-N-tosylaniline, allenes, aryl iodides, and boronic acids offers access to a variety of 3,3disubstituted indoline derivatives <2001TL8677>. Indoles have been prepared by palladium-catalyzed reactions between N-(t-butoxycarbonyl)-2-iodoaniline derivatives and 1-(tributylstannyl)-1-substituted allenes <2005OL5793>.
ð106Þ
Pyrroles and their Benzo Derivatives: Synthesis
Hydroxyindoles may be accessed using the Nenitzescu reaction, as illustrated by preparation of the indole 381 from the enamine 382 and 1,4-benzoquinone (Equation 107) <1996JOC9055>. Additional applications of this strategy encompass syntheses of 19-alkyl-59-hydroxynaltrindole derivatives <2005JME635>, and 10-hydroxy-5,6dihydroindolo[2,1-a]isoquinolines <2001JOC4457>. An alternative approach to 5-hydroxyindole derivatives involves Lewis acid-mediated reactions of benzoquinone monoimines with enol ethers <1997TL6135>.
ð107Þ
The use of 1,1-diamines, for instance 383, allows direct preparation of 2-aminoindole derivatives such as the system 384 in modest yields (Equation 108) <2005S2414>. An extension of this approach has been employed in preparation of an extended set of related 2-aminoindoles for evaluation as inhibitors of human 5-lipoxygenase <2006JME4327>.
ð108Þ
The Bischler indole synthesis has been known for over a century, but continues to be used occasionally, and has for instance been applied in the preparation of a 2-arylindole during development of promising new selective indolebased estrogens <2001JME1654>, indole-3-acetic acid derivatives en route to new tryptamines <2006JME3509>, or construction of estrieno[2,3-b]indoles <2003TL3071>. A solvent-free version assisted by microwave irradiation has recently been presented <2006SL91>, and it has also been shown that tetrahydrocarbazoles are produced directly by reactions of 2-bromocyclohexanones and anilines under microwave irradiation <2006SC1485>. An interesting extension has been employed in the construction of the 3-phosphorylated indole 385 (Equation 109) <2003CHC1521>.
ð109Þ
Indoles have also been accessed by annulation of cyclic ketones with o-chloroaniline derivatives, as illustrated by the transformation of the precursor 386 to the functionalized tetrahydrocarbazole 387 (Equation 110) <2004AGE4526>. Similar palladium-catalyzed annulations involving o-iodoanilines and ketones leading mainly to fused indoles have been described previously <1997JOC2676>.
315
316
Pyrroles and their Benzo Derivatives: Synthesis
ð110Þ
Sequential amination and C–H activation constitutes the key to a palladium-catalyzed synthesis of carbazoles, which enabled, for instance, efficient assembly of the compound 388 (Equation 111) <2002CC2310>.
ð111Þ
Ma˛ kosza has elaborated an approach to 4-nitroindoles featuring oxidative nucleophilic substitution of hydrogen <1999TL5395>, wherein, for instance, treatment of 3-nitroaniline 389 with the ketone 390 provided the product 391 (Equation 112). However, the formation of 4-nitroindoles is in many cases accompanied by a competing annulation rendering the corresponding 6-nitroindoles <2004T347>.
ð112Þ
Nucleophilic substitution of chlorine is a key feature of a synthetic approach to a series of indole-6-carboxylic acids. For example, conversion of the starting nitrobenzene 392 using an SNAr reaction followed by reductive cyclization into the indole 393 was concluded by treatment with base to afford the final product 394 (Scheme 46) <2004SL883>.
Scheme 46
The cyclization step in this approach resembles the Reissert indole synthesis, which relies on treatment of an oxalic ester with an o-nitrotoluene in the presence of a base, followed by reductive cyclization of the resulting intermediate. For example, reaction of the nitrobenzene 395 with dimethyl oxalate under basic conditions gave the intermediate 396, which was subjected to subsequent annulation using SnCl2 as the reducing agent, providing the N-hydroxyindole 397 (Scheme 47) <1999JOC2520>. The conventional reductive conditions employing Zn/HCl have also been used for conversion of compound 395 to methyl 4-amino-5-methoxy-6-methylindole-2-carboxylate <1996JOC816>. Cyclizations with SnCl2 may also be followed by catalytic hydrogenation <1999JOC2520>, or treatment with TiCl3 <2001JOC3474>, which gives products lacking the N-hydroxy group. Likewise, the annulation step may be accomplished efficiently by catalytic hydrogenation only <1996H(43)891>. It should also be mentioned that formation of quinolone products has been encountered under Reissert conditions <2000SL1196>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 47
A variation on this theme has been used to synthesize 2-substituted indole derivatives, as shown by the preparation of the precursor 398, and its acid-induced conversion into the indole 399 (Scheme 48) <2006TL4113>. A related approach has previously been studied in connection with syntheses of 2-substituted indoles having a longer side chain <2001TL2031>.
Scheme 48
It has also been demonstrated that carbanions may react with o-iodoaniline under irradiation to give indoles. This approach has for instance been used for the construction of the fused indole 400 (Equation 113) <2003JOC2807>.
ð113Þ
Taking advantage of an N–H insertion reaction of rhodium carbenoids, N-alkylanilines may be converted to the intermediates 401, which can undergo subsequent cyclization to the indoles 402 (Scheme 49). Such methodology allowed preparation of a variety of indoles substituted in the benzene ring with either electron-withdrawing or -releasing groups <1998SL135, 2002J(P1)1672>. In similarity to many other indole syntheses, a variant of this procedure has also been performed on solid phase <2003JCO188>.
Scheme 49
Treatment of N,N-dimethylanilines with oxalyl chloride in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) provides a route to 1-methylisatins, as illustrated by the preparation of 5-fluoro-1-methylisatin 403 (Equation 114) <2001S904>. This procedure has also been extended to substrates possessing a cyclic amino substituent <2002S34>.
317
318
Pyrroles and their Benzo Derivatives: Synthesis
Similarly, formation of isatins has also been observed upon treatment of 4-N-(methylformamido)pyridine with oxalyl chloride, which generates an intermediate Vilsmeier reagent, followed by reactions with 4-substituted N,N-dimethylanilines <2000TL3475>.
ð114Þ
The Kno¨lker group has elaborated a very productive iron-mediated approach to carbazoles. A representative example affording the natural product furostifoline 404 involved an electrophilic substitution reaction between the aminobenzofuran derivative 405 and the tricarbonyl(4-1,3-cyclohexadiene)iron complex 406 rendering the intermediate 407, which could be subsequently cyclized under oxidative conditions to the target molecule 404 (Scheme 50) <1996TL9183>. Similar strategy has been employed as the key step in total syntheses of the carbazole alkaloids 7-methoxy-O-methylmukonal, clausine H, clausine K, clausine O <2005OBC3099>, furoclausine- A <2004SL528>, as well as the extended heterocyclic system indolo[2,3-b]carbazole <1998TL4007, 2000T4733>. The mechanistic aspects of this carbazole synthesis have been discussed, focusing on regio- and stereoselectivity <1996SL587>. A closely related molybdenum-mediated version of this chemistry has also been studied <1996SL737, 1996TL7947>.
Scheme 50
Oxidative cyclization of intermediates such as 407 may also be accomplished by ferricenium hexafluorophosphate followed by subsequent treatment with trimethylamine-N-oxide. This variant has served as a tool in preparation of the naturally occurring carbazoles carazostatin, O-methylcarazostatin <2002T8937>, as well as hyellazole and 6-chlorohyellazole <2004SL2705>. Alternative reagents for conversion of similar complexes to carbazoles are very active manganese dioxide <1997J(P1)349, 1997TL4051, 2003EJO740>, and NBS in the presence of sodium carbonate <2004SL2705>. Prolonged reactions of suitable anilines, for instance 408, with the complex 406 in the presence of air will eventually lead to formation of carbazole complexes, as illustrated by the preparation of 409, an intermediate en route to ()-carquinostatin A (Equation 115) <1997SL1108>. Such systems may thereafter be converted to the corresponding carbazoles by demetalation with trimethylamine-N-oxide, followed by dehydrogenation with Pd/C <1997SL1108, 1997TL1535, 1998TL2947, 1999TL6915, 2000TL1171>. Likewise, cyclizations yielding similar tricarbonyl(4a,9a-dihydrocarbazole)iron complexes do also occur in the presence of TFA and air <1997TL533, 2003T5317>, or Cp2FePF6 in CH2Cl2 <1996T7345>.
ð115Þ
Pyrroles and their Benzo Derivatives: Synthesis
3.03.7 Category IIad Cyclizations Vinylogous iminium salts, which were generated by treatment of the enaminones 410 with POCl3, undergo cyclization reactions with glycinates, providing the pyrroles 411 (Equation 116) <1998T5075>. Such strategy has been employed in preparation of 2,3- and 2,5-disubstituted pyrroles <1996T6879, 1998H(47)689>, as well as the natural products lukianol A <1999T14515>, rigidin, and rigidin E <2006T8243>.
ð116Þ
It has been demonstrated that reactions of ketene dithioacetals with suitable glycine derivatives provides convenient access to a variety of densely substituted pyrroles, as illustrated for instance by conversion of the readily available substrate 412 into the product 413 (Equation 117) <2005SC693>.
ð117Þ
Conversion of the -cyanoketone 414 to the tosylate 415, and subsequent cyclization using diethyl aminomalonate in the presence of ethoxide, provided the aminopyrrole 416 (Scheme 51). This approach was used for the preparation of a set of related derivatives in moderate yields <2000JOC2603>.
Scheme 51
A related route to 3-aminopyrroles is also available, as illustrated by conversion of the precursor 417 to the intermediate 418, which was subsequently cyclized to the target pyrrole 419 (Scheme 52) <2004T2267>. Precursors similar to 417 bearing, for instance, a benzyl group adjacent to the nitrile functionality have previously been annulated to a structurally related set of pyrroles en route to pyrrolo[3,2-d]pyrimidines <1997JOC8071>. A series of 5-amino-3H-pyrroles has been obtained from reactions of substituted 2,2-dicyano- or 2-cyano-2-ethoxycarbonylethenes with aromatic nitriles in the presence of the combination Sm/I2 in refluxing tetrahydrofuran (THF) <2002SC2643>.
Scheme 52
319
320
Pyrroles and their Benzo Derivatives: Synthesis
Reactions between nitriles and donor–acceptor cyclopropane derivatives have provided a route to a variety of pyrroles. For example, exposure of the nitrile 420 to the cyclopropane 421 in the presence of TMSOTf gave the product 422 in excellent yield (Equation 118) <2003OL5099>. Application of pyrrole-2-carbonitriles gives access to 2,29-bipyrroles <2004OL1057>, whereas inclusion of bi- or polycyclic cyclopropane components leads to formation of fused pyrroles <2003OL5099>, or 1-pyrroline derivatives <2003JA8122>. Pyrroles have also been prepared by gallium(III)- or indium(III)-mediated reactions of cyclopropenes and nitriles <2003OBC4025>. Moreover, heating of imines with diphenylcyclopropenone in ethanol has been reported to furnish 1,2-dihydropyrrol-3-one systems <2002J(P1)341>.
ð118Þ
A base-induced cyclization involving the substituted nitrobenzene 423 and the imine 424 gave the fused pyrrole 425, a crucial intermediate in a total synthesis of ()-rhazinilam (Equation 119) <2001T8647>.
ð119Þ
Exposure of the alkyne 426 to BuLi in the presence of t-BuOK, followed by reaction with ethyl isothiocyanate, gave the intermediate 427, which was subsequently alkylated and cyclized to the pyrrole 428 (Scheme 53) <1999EJO2663>.
Scheme 53
The Katritzky group has developed a pyrrole synthesis based on the benzotriazole derivative 429, which was subjected to lithiation, followed by introduction of imines. The resulting intermediates 430 could thereafter be annulated to the 1,2-diarylpyrroles 431 with concomitant elimination of morpholine and benzotriazole (Scheme 54) <1995TL343>.
Scheme 54
Pyrroles and their Benzo Derivatives: Synthesis
A one-pot approach giving a series of 1-(2-naphthyl)methylene- or 1-(3,4-dimethoxybenzyl)pyrrolidines 432 has been developed, as illustrated by the reductive cyclization of the four-carbon precursor 433, which was prepared by conjugate addition of the -(alkylideneamino)nitrile 434 to methyl vinyl ketone (Scheme 55) <2005S945>.
Scheme 55
The transformation of the benzonitrile 435 to the 1-pyrroline 436 illustrates an approach based on addition of but3-enylmagnesium bromide to nitriles (Equation 120), followed by trapping of the resulting intermediates with NBS <1995S242>. Similarly, the use of N-chlorosuccinimide (NCS) gives instead the related chloromethyl-substituted 1-pyrrolines <2005T4631>. A related well-established synthesis of 1-pyrrolines by addition of Grignard reagents to -bromobutyronitrile has also found new applications during development of a route to the trail pheromone of the ant Atta texana <1999T4133>.
ð120Þ
A synthesis of a set of 2-pyridylpyrroles has been described, involving annulation of 1,3-dicarbonyl compounds with 2-(aminomethyl)pyridine under acidic conditions, as illustrated by the construction of compound 437 (Equation 121) <2002OL435>. Likewise, pyrroles have also been obtained from reactions between 1,3-diaryl-1,3-dicarbonyl compounds and imines or oximes promoted by the TiCl4/Zn-system <2004SL2239>. Yet another approach involves rhodium-catalyzed reactions of isonitriles with 1,3-dicarbonyl synthons, which enables for instance preparation of fluorinated pyrroles <2001OL421>.
ð121Þ
Based on observations during a related study <1999TL5009>, the hydrazone 438 was reacted with the lithiated methoxyallene 439, providing the 3-pyrroline derivative 440 (Equation 122). However, several similar reactions gave substantial amounts of products with four-membered rings. Nevertheless, products of type 440 appear to be useful for further elaboration to 3-amino- or 3-alkoxypyrroles <1999TL8789>.
ð122Þ
321
322
Pyrroles and their Benzo Derivatives: Synthesis
Imines have been employed in [3þ2] cycloaddition reactions with Fischer carbene complexes leading to 3-pyrroline derivatives, as shown by the conversion of the reactants 441 and 442 to the product 443 (Equation 123). The preferred stereochemistry of the resulting 3-pyrrolines is trans, with minor amounts of the cis-isomers <2000JA11741>.
ð123Þ
On the other hand, the Fischer carbene complex 444 was converted to the pyrrole 445 upon treatment with cinnamaldehyde, illustrating an alternative heteroannulation method (Equation 124) <2006CC2271>.
ð124Þ
3.03.8 Category IIae Cyclizations The great synthetic utility of the Paal–Knorr condensation has been demonstrated by a considerable number of successful applications over the years. Consequently, this reaction is recognized as one of the most powerful tools for the preparation of pyrroles. In a modern example involving a new synthesis of the requisite 1,4-dicarbonyl compounds 446 by conjugate addition of benzylzinc chloride to methyl vinyl ketone under carbon monoxide atmosphere, access was gained to the pyrrole 447 (Scheme 56) <2004JOC908>. Classical Paal–Knorr conditions have recently been applied in syntheses of 1-aryl-2,5-di(2-thienyl)pyrroles by condensation of suitable 1,4-di(2-thienyl)-1,4-butanedione precursors with appropriate aniline derivatives <1999TL8887, 2002T3467>, or 1-(pyrrol-3-yl)pyrroles from 3-aminopyrroles and 1,4-dicarbonyl compounds <2001T10147>. Likewise, treatment of 2-(49-oxopentanoyl)indene with aqueous methylamine in refluxing ethanol gave the expected 2-(59-methyl-29-N-methylpyrrolyl)indene in 47% yield, en route to new 2-heteroaryl-substituted bis(indenyl)zirconium complexes <2000OM4095>. A variation involving generation of monosubstituted succinaldehydes giving access to 3-substituted pyrroles has been reported <1996TL4099>. This well-established reaction has also been used in the preparation of a series of 1,2-diarylpyrroles which displayed potency as selective inhibitors of cyclooxygenase-2 <1997JME1619>, and has moreover been adopted to a solution-phase combinatorial approach giving a variety of 1,2-disubstituted and 1,2,5-trisubstituted pyrroles <2004JCO893>. Solid-phase variants have also become available <2002BML1747, 2003SL711>. It has recently also been demonstrated that the Paal–Knorr reaction is a reversible process under certain conditions, which allows exchange of N-substituents in pyrroles via ring opening to a 1,4-dicarbonyl compound, and subsequent ring closure involving a new amine component <2006SL1428>.
Scheme 56
Pyrroles and their Benzo Derivatives: Synthesis
The Paal–Knorr synthesis may also offer practical routes to more complex, fused pyrrole derivatives. This may be illustrated by the transformation of the bicyclic precursor 448 into the compound 449 (Equation 125) <2005JOC1745>, or some additional recent approaches to the tricyclic core of the antitumor antibiotic roseophilin <1999OL649, 1999CC1455, 2000JA3801, 2000J(P1)3389, 2005OL4443>, as well as metacycloprodigiosin <1999JOC8281>. An application giving rise to pyrrolopyrroles has also been reported <2004JOC4656>.
ð125Þ
Although the standard Paal–Knorr procedure, which is often performed in acetic acid solution, is usually satisfactory for the preparation of a wide variety of targets, several modifications have appeared allowing shorter reaction times, milder conditions, or the use of rather unreactive substrates. The application of titanium isopropoxide as the catalyst permits the use of sterically hindered amines and 1,4-diketones <1995TL6205, 1999JOC2657, 2004JOC1475>. Other modified variants have been performed in the presence of layered zirconium phosphate <2003TL3923> or basic Al2O3 <2000SL391> under solvent-free conditions, and employing Bi(NO3)3?5H2O in CH2Cl2 <2005TL2643>, montmorillonite KSF-clay <2001H(55)1019, 2004JOC213>, or Fe3þ-montmorillonite clay <2005SC1051>, as the catalysts. A catalytic system consisting of Bi(OTf)3 immobilized in 1-butyl-3-methylimidazolium tetrafluoroborate has also been used successfully <2004TL5873>. The use of hexamethyldisilazane as the amine component in the presence of Al2O3 appears to be a useful path to pyrroles unsubstituted at the nitrogen atom <1996S1336>. It has been shown that 1-aminopyrroles are produced upon treatment of 1,4-diketo compounds with monoprotected hydrazines <1996JOC1180, 1997JOC2894>. An interesting extension featuring fixation of nitrogen by the TiCl4/Li/TMSCl system has also been presented <1998AGE636, 1998JOC4832, 2004BCJ1655>. Efficient Paal–Knorr syntheses have also been performed in ionic liquids <2004TL3417>, or under microwave heating <1999TL3957, 2005SL1405>, also involving substituted but-2-ene-1,4-diones <2001TL6595> or but-2-yne-1,4diones <2004T1625> as the precursors. A thorough study on the microwave-assisted Paal–Knorr reaction has resulted in efficient preparation of a library of pyrroles (40 members), here represented by 450, from the substrates 451, which were in turn derived from -keto esters, such as 452 (Scheme 57) <2004OL389, 2005EJO5277>. This frequently used reaction may also proceed without the presence of an acid catalyst, as demonstrated by construction of a pyrrole key intermediate in a synthesis of lamellarin L from a 1,4-diketo precursor derived by coupling of two different arylpyruvic acid fragments <2000TL9477, 2000CEJ1147>. Further applications of this approach in syntheses of related natural products have emerged recently <2006S3043, 2006S3048>.
Scheme 57
The Paal–Knorr synthesis has also been utilized as the key step in modern multicomponent approaches to pyrrole derivatives. This has, for example, been demonstrated by the development of a one-pot procedure, where the requisite 1,4-dicarbonyl compound 453 is generated using a sila-Stetter reaction from an acylsilane and an ,-unsaturated ketone in the presence of the thiazolium salt 454 as the catalyst. The sequence is eventually completed by Paal–Knorr cyclization using, for instance, various anilines, yielding the target pyrroles 455 (Scheme 58) <2004OL2465>. An alternative one-pot synthesis relies on the construction of the 1,4-diketone precursors employing a palladium-catalyzed coupling of aryl halides with propargylic alcohols rendering ,-unsaturated ketones, which thereafter undergo a similar thiazolium salt-catalyzed Stetter reaction with aldehydes <2001OL3297>. As demonstrated previously, useful 1,4dicarbonyl synthons may also be accessed via ozonolysis of cyclohexene derivatives <2001JOC2515>.
323
324
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 58
The 1,4-dicarbonyl component in the Paal–Knorr reaction may be replaced with a synthon possessing one or two masked carbonyl functionalities. A new development in this direction involves initial preparation of, for example, the precursor 456 by radical addition of the -xanthyl ketone 457 to vinyl pivaloate, followed by cyclization with amines yielding the pyrroles 458 (Scheme 59) <2003SL75>. In an application of a well-known variant, namely the reaction of primary amines with 2,5-dimethoxytetrahydrofuran, a N-substituted pyrrole-3-carboxaldehyde was prepared in excellent yield from 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde <1999BML3143>. Likewise, an extended set of 1-arylpyrroles for nuclear magnetic resonance (NMR) studies have been prepared by heating of 2,5-dimethoxytetrahydrofuran with suitable anilines in acetic acid <2000JHC15>, whereas the use of amides in a variant involving thionyl chloride as the reagent gives access to N-acylpyrroles <2003S1959>. The scope of this approach has also been extended using acid–base catalysis (AcOH/pyridine) <1998JOC6715>, or P2O5 as the acidic catalyst <1995SC1857>. In contrast, exposure of the related 2,5-dimethoxy-2,5-dihydrofuran to amine derivatives under acidic conditions is known to give 3-pyrroline-2-ones <1996TL1213>. Moreover, treatment of for instance 4-acetyl-2-butoxy-5-methyl2,3-dihydrofuran with primary amines gave a set of 3-acetylpyrrole derivatives <2000SC3215>. An example of a process featuring a heteroatom exchange in a fused furan leading to a pyrrole has been discussed, with emphasis on the mechanistic aspects concerning formation of an impurity <2002OPD64>. It has also been demonstrated that treatment of 3,5-disubstituted 3,5-dihydro-1,2-dioxines with amines gives pyrroles, presumably involving rearrangement of the starting compounds to the isomeric 1,4-diketones <2002TL3199>.
Scheme 59
2-Pentynones may also serve as four-carbon precursors to pyrroles, as illustrated by the conversion of compound 459 to the tetrahydroindole system 460 (Equation 126). This route presumably involves initial formation of an imine, which undergoes subsequent cyclization and isomerization to the target heterocycle <1997SL667, 1998T15253>. Similar products are available by heating of 2-(2-bromoallyl)cyclohexanone with appropriate amines <2004TL9627>. A pyrrole ring formation involving treatment of a similar acyclic substrate with ammonium chloride in the presence of Cu2Cl2 and oxygen has also been reported <2002CHC616>. In addition, -alkynylketones have been transformed to pyrroles by reactions with amines catalyzed by AgOTf or cationic Au(I) complexes <2006JOC4525>. A zinc perchlorate-catalyzed sequence involving amination and annulation of -cyanomethyl--ketoesters with primary amines in water leading to 2-aminopyrrole-4-carboxylates has been reported <2006T1452>. Useful yields of 1,2,5substituted pyrroles have also been obtained by annulation of 1,6-dioxo-2,4-dienes with amines <1998JOC9131>.
Pyrroles and their Benzo Derivatives: Synthesis
ð126Þ
Treatment of the substrate 461 with 4-chloroaniline in the presence of a dibutyliodotin hydride complex caused initial reductive amination of the aldehyde functionality to provide an intermediate which underwent annulation to the pyrrole 462 (Equation 127) <2004SL137>. Access to -fluoropyrrole derivatives has been gained by reactions of ,-difluoro--iodo--trimethylsilyl ketones with aqueous ammonia, followed by treatment with potassium fluoride <1995TL5119>.
ð127Þ
The substrate 463, which is available from 1,4-dichlorobut-2-yne, gives the 3-pyrrolines 464 upon treatment with appropriate amines. Subsequent dehydrogenation with DDQ provides access to the boronates 465 (Scheme 60), useful partners for Suzuki couplings <2002SL829>.
Scheme 60
A palladium-catalyzed reaction has also been utilized during construction of the pyrroles 466 from the diacetates 467 and methyl glycinate (Equation 128). Similar annulations could also be performed using benzylamine <2002SL619>.
ð128Þ
The silica gel-mediated reaction of a primary amine with the alkynoate 468, which was prepared from 2 equivalents of ethyl propiolate and one of propionaldehyde, resulted in the pyrrole 469 (Equation 129). This outcome was rationalized in terms of a sequence featuring a rearrangement of a 1,3-oxazolidine intermediate. A one-pot variant of this route involving generation of the required precursors gave moderate overall yields of a set of similar polysubstituted pyrroles <2004JA8390>. A silver/gold-catalyzed route to pyrroles involving similar precursors and primary
325
326
Pyrroles and their Benzo Derivatives: Synthesis
amines has also been reported, but followed a different mechanistic path via allene intermediates <2006OL2151>. It has also been reported that an unusual reaction occurs upon heating of 1-nitronaphalene with weakly or moderately activated dienes at elevated temperatures in a sealed system, rendering N-naphthylpyrroles <2003TL2943>.
ð129Þ
Titanium-catalyzed hydroamination of the diyne 470 has been demonstrated to proceed via a 5-endo-dig-cyclization affording the pyrrole 471 (Equation 130). Pyrroles have also been isolated as products from similar reactions involving related 1,5-diynes, which resulted from 5-exo-dig-annulations <2004OL2957>.
ð130Þ
A sequence involving a titanium-catalyzed hydroamination of alkynes, followed by an intramolecular N-arylation of the resulting imines, has been implemented in an approach to indoles, allowing, for example, efficient conversion of the substrate 472 into the indole 473, which incorporates a masked amine functionality (Equation 131) <2003AGE3042>.
ð131Þ
Several routes featuring formation of two C–N bonds rely on transition metal-catalyzed amination reactions. A neat example of such a methodology has been employed in the conversion of the biphenyl 475 into the carbazole 476 (Equation 132). Variation of the amine and biphenyl components allowed preparation of a series of similar unusual carbazole derivatives bearing either electron-withdrawing or -releasing substituents <2003AGE2051>. Palladiumcatalyzed amination of 2-(o-bromoaryl)-1-bromoethane derivatives <1998JA3068>, or base-induced reactions involving o-chlorostyrenes and amines <1998AGE3389, 2001JOC1403>, constitute new routes to indolines. Catalytic
Pyrroles and their Benzo Derivatives: Synthesis
amination of o-alkynylchloroarenes in the presence of palladium acetate and an imidazolium salt provided access to a series of indoles bearing various alkyl or aryl substituents <2005OL439>.
ð132Þ
Tetrahydrocarbazoles and related fused systems have been accessed by a route relying on palladium-catalyzed tandem formation of alkenyl and aryl C–N bonds. For instance, the starting triflate 477 could be efficiently transformed into the target system 478 by amination with aniline (Equation 133) <2005AGE403>. Annulation of (2-triflyloxy)phenethyl carbonates with amides in the presence of a palladium catalyst has been used as a route to various N-substituted indoline derivatives <2005OL4777>.
ð133Þ
3.03.9 Category IIbd Cyclizations The versatile van Leusen synthesis has been widely used during the reporting period of this chapter, as it involves the use of the readily available reactants TosMIC and, in most cases, electron-deficient alkenes. In an illustrative example, the diene 479 was converted to the pyrrole 480 in a good yield (Equation 134). Related reactions starting from nitroalkenes or nitrotrienes gave rise to a series of -nitropyrroles <1996S871>. A similar strategy has also been used to prepare 3-aryl-4-nitropyrroles en route to 2,7,12,17-tetraaryl-3,8,13,18-tetranitroporphyrins <1998J(P1)3819>. Likewise, application of 3-(arylsulfonyl)acrylates gave access to 4-(arylsulfonyl)pyrrole-3-carboxylates <1998SC1801>, whereas inclusion of alkene precursors derived from amino acids led to formation of chiral -(aminomethyl)pyrrole derivatives <2003H(60)791>. Variants involving diethyl glutaconate <1996JOC8730, 1997T7731> and the ethylene acetals of -nitroenones <1997S1451> as the alkene components have also been reported, as well as reactions employing a stannylated tosylmethyl isocyanide <1998JOC5332>, or BetMIC (benzotriazol-1-yl-methyl isocyanide) <1997H(44)67>. Additional uses of the van Leusen approach encompass preparation of 3-nitro- or 3-carbethoxypyrrole C-nucleosides <2003SL1619>, 3-(glycosyl)pyrroles <1995JHC899>, transformation of 2-tropanones to 3,4-disubstituted pyrroles <2002JOC5019>, and construction of indolylpyrroles <1997T8565>. Addition of anions of TosMIC or t-butyl isocyanoacetate to 2,3-dinitro-1,3-butadienes resulted in formation of 2,3-disubstituted 4-ethynylpyrroles <1995T5181>. The van Leusen method has also been used for construction of an intermediate in a total synthesis of dictyodendrin B <2005JA11620>, as well as a 3-aroyl-4-naphthylpyrrole en route to new antifungal agents <2005JME5140>. It has been demonstrated that 3-arylpyrroles are readily available by saponification and decarboxylation of methyl 4-aryl-3-carboxylates, which may be conveniently prepared using the van Leusen approach <1997JOC2649>.
ð134Þ
This route is also useful for the preparation of fused pyrrole derivatives, for instance 481, which was obtained in good yield upon treatment of the lactam 482 with TosMIC in the presence of DBU (Equation 135) <2003BML1939>. Exposure of 1,4-naphthoquinone to the van Leusen conditions gave benzo[ f ]isoindole-4,9-dione in 49% yield
327
328
Pyrroles and their Benzo Derivatives: Synthesis
<1996SC1839>, whereas the use of an ,-unsaturated lactam derived from L-glutamic acid did also give access to a fused pyrrole system <2001H(55)2099>. The method has also been used in construction of isoindole derivatives <1997H(45)1989>.
ð135Þ
A conceptually related approach is the Barton–Zard pyrrole synthesis and its modifications, which rely on a baseinduced reaction between an alkyl isocyanoacetate and a suitable electron-deficient alkene, and has for example been employed in construction of the -(perfluoroaryl)pyrrole 483 from the precursor 484 (Equation 136) <2001S2255>, as well as a number of related pyrroles featuring electron-withdrawing groups at C-4 <1999S471>. New extensions of this excellent procedure involve syntheses of carboranylpyrroles <2001TL7759>, 2,39-bipyrrole-based systems <1995JHC1703, 1997JHC13>, 3-(4,5-dihydroisoxazol-5-yl)pyrroles <2002TL53>, a 3-(9-anthryl)pyrrole derivative <1995TL8457>, and optically active 4-methyl-3-(19-naphthyl)pyrrole-2-carboxylates <1996J(P1)183>. The use of -nitrostilbenes as the alkene components gives access to the corresponding alkyl 3,4-diarylpyrrole-2-carboxylates, which may thereafter be converted to 3,4-diarylpyrroles by heating with KOH in ethylene glycol <1998J(P1)1595>, whereas reactions of similar -cyanostilbene precursors provide a regioselective route to methyl 3,4-diarylpyrrole-2carboxylates <2002JOC9439>. A useful variant featuring reactions of vic-nitroacetates and isocyanides in the presence of potassium carbonate as the base has also appeared <2001JHC527>. It should also be mentioned that application of benzyl isocyanoacetate leads to formation of benzyl pyrrole-2-carboxylates <1995SC379>. A solidphase version of this reaction <2004JCO142> as well as an adaptation involving solid-phase-supported reagents <1999J(P1)107> have also been reported.
ð136Þ
As with the van Leusen synthesis, there are also examples demonstrating the applicability of the Barton–Zard reaction in the construction of fused pyrrole systems. For example, treatment of the 9-nitrophenanthrene 485 with ethyl- or t-butyl isocyanoacetate gave the fused pyrroles 486a and 486b, respectively (Equation 137) <1998JOC3998>. Such methodology starting from suitable nitroaromatics has been applied in syntheses of several closely related systems <1996JA8767, 1997TL2031, 2000J(P1)995>, and it has also been demonstrated that reactions involving less reactive substrates may give better yields when performed in the presence of a phosphazene superbase <2000SL213>. Additional fused pyrrole derivatives have been accessed from Barton–Zard reactions between cyclic ,-unsaturated sulfones and alkyl isocyanoacetates <1997TL1745, 1997TL3639, 1998HCA1978, 2003JA6870>.
ð137Þ
Yet another variant which has found some use features -nitroacetate precursors <1999JOC6518, 2000J(P1)2977>. An example of this approach has been employed in the preparation of the pyrrole 487 from the nitroacetate 488 during a synthesis of (þ)-deoxypyrrololine (Equation 138) <2001JOC11>. Similarly, pyrroles are also formed upon treatment of -sulfonylnitroalkane derivatives with ethyl isocyanoacetate <1997J(P1)3161, 2003TL5163>.
Pyrroles and their Benzo Derivatives: Synthesis
ð138Þ
An elegant pyrrole synthesis involving isocyanides and electron-deficient acetylenes gave the pyrrole 489 by exposure of ethyl isocyanoacetate to the alkyne 490 in the presence of dppp <2005TL2563>. A reversal of the regioselectivity leading to the product 491 could be accomplished by using the catalyst Cu2O (Scheme 61) <2005JA9260>. Pyrroles have also been prepared by addition of -metalated isocyanides to acetylenes, involving an intramolecular cycloaddition of an alkene unit to an isocyanide functionality <2005AGE5664>.
Scheme 61
An additional number of routes to pyrroles depend on the formation of the C(2)–C(3) and C(4)–C(5) bonds. This may be, for instance, accomplished by dipolar cycloadditions between appropriate azomethine ylides and acetylenes, as illustrated by the conversion of the reactants 492 and 493 into the fluoropyrrole derivative 494 (Scheme 62). The required intermediate of type 492 was generated from the corresponding imines and difluorocarbene <1998JFC(90)117>. Reactions involving unsymmetrical alkynes may lead to regioselective formation of a single 2-fluoropyrrole isomer <2000J(P1)231>. Similar reactions giving 2-fluoropyrroles occur when azomethine ylides generated from imines and fluorocarbene are employed as one of the reactants <2005TL8337>. Syntheses of pyrrole derivatives have also been performed by cycloaddition of azomethine ylides generated from -silylamides or -silylimidates with dimethyl acetylenedicarboxylate (DMAD) 493 or N-phenylmaleimide <1999T12969>, whereas an intramolecular reaction between an azomethine ylide and an acetylene moiety constituted one of the key steps in an enantiocontrolled synthesis of (1S,2S)-6-desmethyl-(methylaziridino)mitosene <2000JA5401>.
Scheme 62
Pyrroles may also be constructed from mu¨nchnones. An interesting application of this strategy was demonstrated by initial four-component Ugi condensations involving a carboxylic acid, and amine, an aldehyde, and 1-isocyanohexene, which afforded precursors such as 495. This substrate, like many related compounds, underwent acidinduced conversion to the assumed intermediate, the mu¨nchnone 496, which eventually gave the pyrrole 497 upon cyclization with DMAD 493 in a one-pot operation (Scheme 63) <1996JA2574>. This approach could also be realized on solid phase <1996TL1149>, in similarity to a related route <1996TL2943>. However, the yields of pyrroles prepared using these routes were at best moderate. A pyrrole synthesis that has been suggested to involve palladium-catalyzed assembly of mu¨nchnones from imines, acid chlorides, and carbon monoxide is also available
329
330
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 63
<2004JA468>. Formation of mu¨nchnones as key intermediates toward pyrroles has also been suggested to occur upon insertion of carbon monoxide into acylamino chromium carbene complexes under irradiation <2000JA7398>. Additional studies involving mu¨nchnones have resulted in preparations of a pyrrole-3-carboxamide <2004BML129>, pyrrolo[3,4-b]indoles <1998SL1061>, 4-oxotetrahydroindoles <1996TL2887, 1997JOC982>, a 3-benzoylpyrrole derivative <1995JOC4947>, and 4-(perfluoroalkyl)pyrrole-3-carboxylates <1995JFC(71)5>. Dipolar cycloadditions between 5-aminothiazolium salts and electron-deficient acetylenes have also been shown to give pyrroles <1995T7019>. Application of azomethine ylides in dipolar cycloaddition reactions with alkenes provides a route to pyrrolidine derivatives, as illustrated by the generation of the intermediate 498, and its subsequent conversion to the target system 499 (Scheme 64) <1995TL9409>. The use of alkynes as dipolarophiles instead gives rise to 3-pyrrolines, which has been exploited in a route to indoloquinones <1997JOC4763>.
Scheme 64
Generation of a dipole from 2-cyano-1-trimethylsilylaziridine 500 and reaction thereof with bis(trimethylsilyl)acetylene gave the intermediate product 501, which could be N-desilylated to provide the target pyrrole 502 (Scheme 65) <1999JOC1630>. A series of related 3,4-bis(trimethylsilyl)pyrroles with various N-substituents is also available via this methodology <1997CC1515>.
Scheme 65
Katritzky has developed a pyrrole synthesis which relies on base-mediated reactions of a thioimidate with alkenes. For example, treatment of the thioamide 503 with butyllithium, followed by introduction of iodomethane, gave the key intermediate 504, which was reacted with a set of alkenes in the presence of a base providing the pyrroles 505 in good yields (Scheme 66) <1995T13271>. Construction of more substituted pyrroles may be achieved starting from thioamides bearing a substituent at the methylene unit <2000JOC8819>. Related thioimidates have previously been shown to give pyrroles upon reactions with alkenes in the presence of a base <1995BCJ2735>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 66
The photoinduced cycloaddition of the carbene complex 506 with methyl vinylketone provided the 1-pyrroline 507 (Equation 139) <2002OM4076, 2000OM3082>.
ð139Þ
Heating of diethyl acetamidomalonate 508 with 1,4-dichloro-2-butyne 509 in the presence of an excess of sodium ethoxide gave the pyrrole 510 (Equation 140), possibly via the intermediacy of a butatriene intermediate <1996JOC9068>.
ð140Þ
3.03.10 Syntheses by Contraction or Fragmentation of Existing Rings Pyrroles may also be accessed by transformation of existing heterocyclic rings. This topic has been recently reviewed <2005COR261>, and only a few representative examples are included in this section. Treatment of the substrate 511 with 1,3-dicarbonyl compounds under basic conditions is followed by an acidinduced rearrangement, producing a set of pyrroles, as illustrated by the synthesis of the system 512 via the 2,3dihydrofuran intermediate 513 (Scheme 67) <2002TL4491, 2003EJO2635>.
Scheme 67
The precursor 514 has been shown to undergo anodic oxidation to produce the 5-amino-1,2-thiazolium salt 515, which rearranged to the pyrrole 516 upon treatment with triethylamine (Scheme 68) <1995JPR310>. The mechanistic aspects of this approach have also been discussed <1996J(P1)2339>. Cycloaddition of nitrones with acetylenes has been used to generate 4-isoxazolines, which underwent thermal rearrangement to pyrroles fused to the isoquinoline framework <1996T12049>.
331
332
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 68
Conversion of the isoxazole 517 bearing a tethered amino functionality into the pyrrole 518 (Equation 141) illustrates an approach which was used for the preparation of a series of related derivatives in moderate yields <2006S1021>.
ð141Þ
Boger has reported several applications of the 1,2-diazine to pyrrole ring contraction protocol. For example, Diels– Alder cycloaddition involving the alkyne 519 and the 1,2,4,5-tetrazine 520 resulted in the intermediate diazine 521, which was converted to the densely substituted pyrrole 522 by treatment with zinc in acetic acid (Scheme 69) en route to the natural product ningalin A <1999JA54>. The methodology also proved efficient in total syntheses of ningalin B <2000JOC2479>, and isochrysohermidin–distamycin hybrids <2003JOC5249>.
Scheme 69
Another route to pyrroles relies on ring contraction of 3,6-dihydro-1,2-oxazines under rather harsh conditions <2003JOC460>. In an example illustrating a more practical approach, the 1,2-oxazine 523, which was generated by Diels–Alder reaction between the appropriate butadiene derivative and the nitroso species derived by oxidation of BOCNHOH, was ring-opened to the intermediate 524, followed by cyclization to the target heterocycle 525 (Scheme 70) <2005S3346>. Pyrroles are also formed in moderate to good yields by treatment of N-substituted 3,6-dihydro-1,2-thiazine-1-oxides with Et3N and P(OEt)3 <2003T9669>.
Pyrroles and their Benzo Derivatives: Synthesis
Scheme 70
The quinoline 526 has been transformed to the intermediate 527, which was subsequently ring-opened by ozonolysis, followed by base-induced ring closure to the indole-2-carboxaldehyde 528 (Scheme 71) <2002TL5295>. Several useful 4-substituted indoles have also been prepared by ring contraction of N-alkyl-5aminoisoquinolinium salts with the system NaHSO3/Na2SO3 <2000JHC1293>.
Scheme 71
3.03.11 Miscellaneous Methods for Pyrrole and Indole Synthesis A number of pyrrole ring syntheses depend on formation of more than two bonds and involve three or more components. Some of these processes involve well-studied principles for ring formation, and are included in appropriate sections above. This emerging field in pyrrole synthesis has been discussed in a short survey <2004AGE6238>. For example, the pyrroles 529 are formed by three-component reactions involving primary amines, aldehydes, and nitroalkanes (Equation 142). It should be noted that two aldehyde units are incorporated in the products <1998JOC6234>. There are also approaches available based on three-component reactions between ,-unsaturated carbonyl compounds, amines, and nitroalkanes <2000SL75, 2001T4767>, or carbonyl compounds, amines, and nitroalkenes <2003TL2865>.
ð142Þ
Densely substituted pyrroles have also been constructed from reactions of imines, isocyanides, and DMAD, as illustrated by the preparation of compound 530 (Equation 143) <2001JOC4427>. Isocyanides may also be combined with DMAD and maleimide or succinimide, yielding pyrroles substituted with two nitrogen-containing moieties <2004TL8409>, whereas a route involving secondary amines, DMAD, and arylsulfonyl isocyanate leads to formation of fully substituted maleimides <2006TL4469>. Titanium-mediated reactions of alkynes, imines, and carbon dioxide <1997TL6849>, or carbon monoxide <1996TL7787>, provide 3-pyrrolin-2-ones or pyrroles, respectively. In addition, a few pyrroles have been prepared by ruthenium- and platinum-catalyzed reactions featuring a propargylic alcohol, a ketone, and a suitable aniline derivative <2003AGE2681>. A set of fused pyrroles were also obtained by intramolecular [3þ2] cycloadditions of azomethine ylides formed from o-propargylsalicylaldehydes and appropriate sarcosine derivatives, followed by dehydrogenation <2003TL8417>. Reactions involving isoquinoline, diaroylacetylenes, and ethyl bromopyruvate give a set of pyrrolo[1,2-a]isoquinoline systems <2006TL6037>.
333
334
Pyrroles and their Benzo Derivatives: Synthesis
ð143Þ
A series of oxygenated pyrrole derivatives have been obtained in moderate yields in an approach involving sodium diethyl oxalacetate, amines, and aromatic aldehydes, as illustrated by the preparation of the product 531 (Equation 144) <2006T6018>.
ð144Þ
There are also a few examples of reactions that involve formation of the C(2)–C(3) and C(3)–C(4) bonds. A set of isatins 532 have been prepared by a route involving dilithiation of the starting ureas 533, followed by introduction of carbon monoxide, which serves as a source for the carbon atom at the 3-position (Equation 145) <2003S2047>. A related route starting from N-pivaloylaniline enabled preparation of 3-hydroxyoxindoles <1999J(P1)2299>. Isatins have also been accessed via reactions between formanilides and oxalyl chloride in the presence of Hu¨nig’s base <1996TL9381>, whereas somewhat different conditions may lead to formation of 3-arylamino-2-chloroindoles. Both processes involve aminochlorocarbene intermediates <2002S2426>.
ð145Þ
3.03.12 Further Developments During the production time of this chapter, numerous new advances have been disclosed. A few selected examples are included in this short section, with the goal to illustrate some of the current directions in ring synthesis leading to pyrrole and indole derivatives. It is clear that transition metal-mediated reactions will occupy a strong position in this field, giving opportunities for construction of targets with substitution patterns which are otherwise difficult to access. Nevertheless, further development and refinement of the already well-established methods will provide new versatile tools for crafting new important indoles and pyrroles. Likewise, some of the novel multi-component strategies will constitute a useful addition to the synthetic repertoire. Several new routes involve formation of one carbon–carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of -hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahydroindoles with multiple substituents by formation of the C-3–C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of -cyanomethyl--ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable N-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoanilines) <2006OL4473>.
Pyrroles and their Benzo Derivatives: Synthesis
ð146Þ
A new synthesis of 3-alkoxyindoles, for example compound 535, has been elaborated involving a Stille-coupling and a reductive annulation as outlined in Scheme 72 <2006T10829>. It has also been shown that related methodology may be useful for preparation of tetrahydrocarbazoles and related tricyclic indole systems <2007T1183>.
Scheme 72
The old methods are subject to many new modifications and applications. A variant of the Fischer indole synthesis has been carried out in Brønsted acid ionic liquids with excellent results <2007EJO1007>, and the use of branched aldehydes in a Fischer synthesis, followed by treatment of the resulting 3H-indoles with MCPBA, provided a new approach to 3,3-disubstituted oxindoles <2007TL461>. Rearrangement of 3H-indoles derived from Fischer cyclizations may also be used in some cases as a selective synthesis of 2,3-substituted indoles <2006OL5769>. Moreover, the Bartoli reaction has been implemented in a route to 7-(3-pyridyl)indole <2006JOC7611>, whereas the Barton– Zard pyrrole synthesis has been utilized for preparation of pyrrole Weinreb amides en route to pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones <2006JOC6678>. Generation of intermediate symmetrical azines from aldehydes and hydrazine, followed by microwave-assisted cyclization in the presence of aroyl chlorides and pyridine afforded a set of 3,4-disubstituted pyrroles in moderate yields <2007JOC3941>. Annulation of 2-iodoanilines with aldehydes in the presence of a palladium catalyst has been demonstrated to constitute a useful route to various 3-substituted indoles or tryptophans, giving for example the protected amino acid 536 (Equation 147). Similar cyclizations involving 2-bromo- or 2-chloroanilines have also been performed successfully using an alternative catalytic system <2006JOC7826>. An additional indole synthesis was based on Zn(OTf)2catalyzed reactions between propargyl alcohols and anilines <2006JOC4951>. Exposure of 1,3-diketones to methyleneaziridines in the presence of Pd(PPh3)4 (25 mol%) afforded a set of 1,2,3,4-tetrasubstituted pyrroles <2007TL2267>. It has also been shown that a palladium-catalyzed sequence featuring amination of aryl bromides with 2-chloroanilines and subsequent annulation of the intermediates by C–H activation provided a one-pot entry into a series of useful carbazoles <2006JOC9403>. There is also a report available detailing a pyrrole synthesis by palladium-catalyzed cyclization of alkynes with 2-amino-3-iodoacrylate derivatives <2006OL5837>.
ð147Þ
335
336
Pyrroles and their Benzo Derivatives: Synthesis
The recent interest in gold and silver chemistry has exerted some impact on the field of indoles and pyrroles. For example, cyclization of the substrate 537 with benzylamine in the presence of AgOTf gave the pyrrole 538 (Equation 148). Similar results were observed when the reaction was catalyzed by the system AuCl/AgOTf/PPh3 <2006JOC4525>. Further pyrroles have been prepared by copper-catalyzed reactions of ,-unsaturated -bromoketones with primary amines <2007S1242>, or platinum-catalyzed cyclization of homopropargylic azides <2006OL5349>.
ð148Þ
In an extension of a route to indoles based on palladium-catalyzed reactions of o-dihalobenzenes with azaallylic anions derived from imines, a three component process was developed involving primary amines, bromoalkenes, and dihalobenzenes, furnishing for example the indole 539 (Equation 149) <2007AGE1529>. It should also be mentioned in this context that 2,3-dihalophenols have served as starting materials for construction of 4- or 7-alkoxyindoles by a sequence involving directed ortho-metalation, followed by Sonogashira coupling and a tandem amination/ cyclization in the presence of a palladium catalyst <2007JOC5113>. There is also a new direct approach to pyrroles available, which relies on isocyanide mediated reactions of imines, alkynes, and carboxylic acid chlorides <2007OL449>. Finally, it has been demonstrated that copper(I)-catalyzed reactions involving N-protected 2-(alkynyl)anilines, formaldehyde, and secondary amines give excellent yields of 2-(aminomethyl)indoles <2007AGE2295>.
ð149Þ
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Pyrroles and their Benzo Derivatives: Synthesis
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Pyrroles and their Benzo Derivatives: Synthesis
Biographical Sketch
Professor Jan Bergman obtained his Ph.D. in 1971 at the Royal Institute of Technology, Stockholm, Sweden, under the direction of Professor Holger Erdtman. The title of the thesis ‘‘Synthetic Studies of Indole Derivatives’’ is a good indicator of his continued interest in nitrogen heterocycles. After a spell in Canada at the University of Waterloo during the Olympic year 1976, he returned to Sweden, and since 1989 he is head of the Organic Chemistry unit at the Karolinska Institute, Huddinge, Sweden.
Dr. Tomasz Janosik received his M.Sc. degree in chemical engineering from the Royal Institute of Technology in Stockholm in 1996. After completing his Ph.D. studies (2002) at the laboratory of Professor Bergman at the Karolinska Institute working in the field of bisindole and indolocarbazole chemistry, he pursued a postdoctoral period (2002–03) at Dartmouth College (New Hampshire, USA) in the group of Professor Gordon W. Gribble, where he was involved in a project toward development of new biologically active synthetic triterpenoids. He thereafter returned to the Karolinska Institute, where he is currently working as a senior scientist. The research interests of Dr. Janosik are focused on indoles, with extensions to natural products and the chemistry of sulfur-containing heterocycles.
351
3.04 Pyrroles and their Benzo Derivatives: Applications M. d’Ischia, A. Napolitano, and A. Pezzella University of Naples ‘‘Federico II’’, Naples, Italy ª 2008 Elsevier Ltd. All rights reserved. 3.04.1
Introduction
353
3.04.2
Polymers
354
3.04.2.1
Pyrroles
354
3.04.2.2
Indoles
355
3.04.2.3
Carbazole
356
3.04.3
Drugs
356
3.04.4
Medicinal Compounds
357
3.04.4.1
Antibacterial Agents
357
3.04.4.2
Antitumor Agents
359
3.04.4.3
Anti-HIV and Antiviral Agents
363
3.04.4.4
Anti-Inflammatory Agents
364
Miscellaneous Medicinal Compounds
365
3.04.4.5 3.04.5
Dyes
365
3.04.6
Natural Products
367
3.04.6.1
Bacterial Products
367
3.04.6.2
Fungal Products
368
3.04.6.3
Plant Products
369
Marine Products
375
3.04.6.4 3.04.7
Agrochemicals
377
3.04.8
Calixpyrroles
377
3.04.9
Other Applications
380
3.04.10
Further Developments
381
3.04.10.1
Polymers
381
3.04.10.2
Medicinal Compounds
381
3.04.10.3
Natural Products
381
3.04.10.4
Calixpyrroles
382
References
382
3.04.1 Introduction This section highlights the most significant applications of pyrroles, indoles, and carbazoles in the areas covered in CHEC-II(1996) <1996CHEC-II(2)207> and in related fields where substantial advances have been made since 1995. While sections on polymers, dyes, drugs, and medicinal compounds deal with novel applications of both old and new compounds, the survey of natural products has been restricted to those new structures that have been discovered during the past decade.
353
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Pyrroles and their Benzo Derivatives: Applications
3.04.2 Polymers 3.04.2.1 Pyrroles Interest in polypyrrole and other conducting polymers has increased tremendously during the last decade and especially following the awarding of the 2000 Nobel Prize for the discovery and development of electrically conductive polymers (see, for example, <2001AGE2581>). Polypyrrole is by far the most extensively studied conducting polymer, since monomer pyrrole is easily oxidized, water soluble, commercially available, and possesses environmental stability, good redox properties, and high electrical conductivity, and is promising for application in batteries, supercapacitors, electrochemical (bio)sensors, conductive textiles and fabrics, mechanical actuators, electromagnetic interference shielding, antistatic coating, and drug delivery systems. The literature on polypyrrole applications is so vast that only highlights are reported here, and the interested reader is referred to available reviews <2000SCI1540>. Several studies have focused on the mode of formation and properties of polypyrrole polymers. Studies of the effects of temperature on polypyrrole conductivity have shown that the polymer formed by electropolymerization of pyrrole and camphor sulfonate as dopant at low temperature has higher conductivity and is stronger than that formed at higher temperatures. X-ray scattering shows that interlayer distance increases with increasing temperature <2002IAS155>. Scanning electron microscopy, polarizing optical microscopy, and wide-angle X ray scattering analysis has been used to investigate the morphology and mode of growth of polypyrrole <1995PLM1849>. Polypyrrole p-toluenesulfonate specimens obtained by electrochemical polymerization from aqueous and methanolic solutions develop as compact films, which exhibit considerable molecular anisotropy, highly birefringent cross sections, and local molecular orientation correlate with the nodular surface features. Samples prepared from methanolic solutions, on the other hand, appear very different with lack of molecular anisotropy or internal subdivision, and they are massively voided as a result of extensive internal delamination, which occurs after the polypyrrole is deposited onto the work electrode. It is proposed that polymerization in solution is followed by a degree of further chain development after precipitation. A 1,3,4-alkyl-substituted polypyrrole polymer soluble (>1%) in acetone, acetonitrile, and chlorinated solvents has been reported by electrochemical and oxidative polymerization of N-hexylcyclopenta[c]pyrrole <2004MI2026>. Its in situ conductivity as a function of potential and doping charge has the typical features of redox conductivity with a maximum value of ca. 1 103 S cm1. Oxidative polymerization of 1-substituted pyrroles such as 1-(hydroxymethyl)pyrrole, 1-(3-hydroxypropyl)pyrrole, 1H-1-pyrrolylmethyl 4-methyl-1-benzenesulfonate, 1H-1-pyrrolylpropyl-4-methyl-1-benzenesulfonate, and 1H-pyrrolylmethyloctanoate, and copolymerization with pyrrole using (NH4)2Ce(NO3)6 and FeCl3 has led to conductive polymers with slight solubility in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) <2005MI1830>. Electrochemical copolymerization of pyrrole and indole in acetonitrile containing lithium perchlorate as supporting electrolyte has led to a range of copolymers that have been characterized by conductivity measurements and other techniques <2001JMA4107>. Polypyrrole field effect transistors have been produced by an electrochemical method in which conducting polymer nanostructures are directly grown between metal electrodes with the geometry controlled by hydrophilic/hydrophobic patterns <2006JA3760>. Devices grown with a high concentration of dopant show metallic behavior, while those with less doping behave as p-type semiconductors. Several studies have investigated the effects of dopants such as dodecylbenzenesulfonate <2003MI143>, dodecylbenzenesulfonic acid and tetraethylammonium tetrafluoroborate as codopant, <2002MI2583>, tetrafluoroborate or perchlorate and tetrasulfonated metallophthalocyanines <1997JCF131>, several alkylsulfonates <2001MI33>, and anions <1999JEC211> on the properties of polypyrrole polymers. Electrochemically synthesized polypyrrole film on a gold electrode surface was used as a novel support for bilayer lipid membranes and was found to be potentially useful for studies of biomimetic membranes, as suggested by a preliminary application using horseradish peroxidase <2005MI1373>. Evaluation of polypyrrole potential as sensor and biosensor figures prominently in the literature on the applications of polypyrroles. A systematic study of the effect of humidity and temperature on polypyrrole sensor has been carried out and has shown increased sensitivity at low temperature and humidity values <2005MI389>. A methodology for producing cheap, disposable, and highly sensitive ammonia/amine sensors with particular regard to detecting ammonia in mouth air from patients and/or amines in headspace urine from patients involves chemical polymerization of pyrrole on poly(etheretherketone) (PEEK) with ferric nitrate nonahydrate as the oxidant <2002SM301>. The resulting films were used as gas sensors and tested on a range of amines including ammonia, exhibiting high sensitivity with reproducible and reversible resistance changes. A new gas sensor using a polypyrrole film grown on the surface of an interdigitated-capacitor substrate has been proposed for the detection of carbon monoxide (CO) <1997MI203>. The patterning of polypyrrole structures
Pyrroles and their Benzo Derivatives: Applications
by a scalable and site-specific approach with individual addressability and the chemical sensing to ethanol vapor and ammonia gas have been described <2004MI828>. Several biosensors based on polypyrroles have been developed for detection of phenolic compounds <2004MI927>, glucose <2003MI141>, primary amines <2000ANC2211>, antidepressant drugs <2003MI133>, and wood infection by Serpula lacrymans <2006MI989>. In order to improve the surface properties of carbon fibers without affecting the mechanical properties of the reinforcing fibers, various monomers, including pyrrole and carbazole, were used to electrograft conjugated copolymers and produce homogeneous and continuously coated carbon fiber surfaces <2001SM391>. Polypyrroles are extensively investigated in the preparation of capacitor devices and considerable efforts are being spent to improve the properties and overcome limitations. Several strategies are investigated for activating polypyrrole electrodes for use in electrochemical supercapacitors, including the development of columnar morphologies by micellar deposition, self-doping by attachment of anions, and the use of aryl sulfonates to promote cross-linking and hydrophilicity. Improved performance is expected with the coupling of doping processes to structural relaxations that encourage solvent uptake by the polymer and ready access for dopant ions to all available sites <2004MI51>. Ta/ Ta2O5-based capacitors, in which polypyrrole is used as a solid electrolyte coating, have been prepared using aromatic sulfonate salts as the charge-compensating dopant ions, and have shown excellent high-frequency performance up to 100 kHz and stability <1996SM229>. In polypyrrole devices, charging times appear to be limited by rates of ionic mass transport and RC charging times. Investigation of the impedance of a highly porous polypyrrole/carbon composite has shown that increasing the polypyrrole content of the film increases capacitance up to 60 Fg1, but also increases the charging time constant <2005SM129>. Analysis of rate limiting factors is essential to devise methods of optimizing capacitor geometry in order to maximize rates. The electrochromic properties of polypyrrole film and composite film have been characterized <2001EPJ915>. The preparation of electrochromic conjugated N-salicylideneaniline-functionalized pyrrole-based polymers has been described. These change from yellow in the neutral form to a light green intermediate state at low levels of oxidation, and finally to a dark gray-blue upon oxidation <2005NJC1128>. Other electrochromic pyrrole-based polymers include poly(3,4-alkylenedioxypyrrole) electronically conducting polymers, which exhibit unique combinations of multicolor electrochromism, switching from a red or orange neutral state to a light blue/Gy-doped state, passing through a darker intermediate state (brown) <2000MM7051>, and polymers produced by electrochemical polymerization of -linked dipyrrole monomers <2004T7141>. These latter are electroactive, robust electrochromic materials that are highly delocalized in their oxidized forms.
3.04.2.2 Indoles Studies of indole polymers have increased steadily, though at a slower pace than those on polypyrroles. Controlled potential electrolysis of indole in tetraethylammonium perchlorate acetonitrile solution yields a black polymeric film of polyindole at a Pt electrode which appears to derive from the involvement of the C-2 and C-3 positions in the indole monomer as the active sites during electropolymerization <2001MI231>. This conclusion is in accord with a spectroscopic study on polymers obtained by oxidative coupling of indole, in the doped [ClO4] and undoped states, showing that the change from the doped to the dedoped state of polyindole is accompanied by a reordering of the p-bonds of the system with the disappearance of CTN bonds and the reappearance of N–H bonds <1997PLM2099>. A polyindole-based aqueous polymer rechargeable battery has been developed, including poly(5-nitroindole) as the anode active material and polyaniline as the cathode active material, and attaining 65 mA hg1 at charge–discharge of 103 A ¼ m2, which is approximately 77% of its theoretical capacity <2004JMA4001>. Polyindole films have been shown to be useful for prevention of copper corrosion <2006MI4802>. Electrochemical co-oxidation of pyrrole and indole in 99/1 v/v acetonitrile/water gives copolymers which show improved electrochemical activities as the incorporation of pyrrole units increases <2002MI814>. Electropolymerization of 5-cyanoindole (CI), indole-5-carboxylic acid (ICA), 5-chloroindole, 5-bromoindole, and 5-methoxyindole results in a redox-active film consisting of a cyclic trimer and chains of linked cyclic trimer (polymer) with marked fluorescence properties <1998JCF3619>. Electroactive polymer films are obtained by electropolymerization of indole and CI through coupling at the C-2 and C-3 positions <1998SM105>. The polymers exhibit similar redox reactions in aprotic media (LiClO4–acetonitrile) but quite different electrochemical behavior when cycled in HCl or HClO4 solutions. In the latter case, two types of redox-reversible processes are observed with different pH dependence. The synthesis, characterization, and optical properties of new sensing systems made by attaching different polyamine chains functionalized with an indole fluorophore to a boehmite matrix has been carried out <2005MI2920>.
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Steady-state fluorescence emission studies showed that these materials present a very efficient sensing behavior for hydrogen ions, metal ions such as Cu2þ and Zn2þ, and for the anionic nucleotides ATP, ADP, and AMP. Electropolymerization of ICA gives electroactive polymer films that have been characterized both in the oxidized and reduced forms <2003SAA163, 2001SAA423>. In the oxidized form of the polymer, the NH group of the pyrrole ring is deprotonated and a quinonoid form is present between the pyrrole rings. Self-doped poly(indole-5-carboxylic acid) electrodeposited from acetonitrile containing 0.1 M LiClO4 has been evaluated as cathode-active material with a Zn anode in a rechargeable cell containing 1 M ZnSO4 at pH 5. The cell had an open-circuit voltage of 1.36 V and a specific capacity of 67 A h kg1 <2005MI917>. A conducting, polymeric film of poly(indole-5-carboxylic acid) has been employed for covalent immobilization of tyrosinase, which retains catalytic activity and catalyzes oxidation of catechol to the quinone <2006MI41>. Poly(1-vinylpyrrole), poly(1-vinylindole), and some methyl-substituted compounds of poly(1-vinylindole) are of potential interest as photorefractive materials with a relatively low glass-transition temperature and requiring a lower quantity of plasticizer in the final photorefractive blend <2001MI253>. Polymers of 5,6-dihydroxyindoles fall within the peculiar class of pigments known as eumelanins and their chemistry has been reviewed <2005AHC(89)1>. Electrochemical copolymerization of pyrrole and indole has been investigated <2001JMA4107> and shown in some cases to give a product with increasing electrochemical activity at higher levels of incorporation of pyrrole units <2002MI814>. Copolymers with good thermal stability, good electrochemical behavior, high conductivity, and excellent ambient stability have been prepared by copolymerization of indole and 3,4-ethylenedioxythiophene <2005JMA2867>. Studies of the electrochemical behavior of electrodeposited redox-active indole trimer films, CI, and ICA, showed high electronic conduction for both films <1999PCP5169>. CI films show, however, a relatively large, potential-dependent barrier to ion insertion, consistent with a compact, poorly solvated structure, whereas ICA films display a higher film capacitance and a lower barrier to ion insertion, indicating a more open and solvated film. Polymerization mechanisms of unsubstituted indoles have been studied by accurate density functional theory (DFT) calculations <2002PLM6019>. The time and temperature dependence of conduction of polyindole, poly(indole-5-carboxylic acid), polycarbazole, and poly(N-vinylcarbazole) have been investigated to elucidate the aging process and conduction mechanisms <2004MI25>.
3.04.2.3 Carbazole Carbazole-based oligomeric and polymeric materials attract unabated interest for their electrical, electrochemical, and optical properties, and a number of reviews are available <2005MI303>. Studies on polycarbazole comprise work on the polymer properties as a function of the mode of polymerization and on applications. Carbazole units can be linked in two different ways leading to either poly(3,6-carbazole) or poly(2,7-carbazole) derivatives. The former seem to be of interest for electrochemical and phosphorescence applications, while the latter show promising optical properties in the visible range for light emitting diodes. Polycarbazole has been prepared by electropolymerization of solid carbazole crystals immobilized on the surface of Pt or Au electrodes in the presence of aqueous acidic media and has been shown to undergo redox transformations that have been explained by potential- and time-dependent sorption/desorption of Hþ and ClO4 ions <2003MI503>. Families of carbazole polymers have been synthesized by electrochemical oxidation of either carbazole in solution in the electrolyte or of carbazole deposited as thin film onto the working electrode and have been studied by various techniques. The polycarbazole films obtained with carbazole deposited in the thin film form exhibit a better polymerization efficiency and an electrical conductivity 1 order of magnitude higher <2000MI1561>. The main applications of polycarbazoles are in the field of sensors, for example, for ammonia <2005MI277> and potassium and copper ions <2000MI1749>; as cathode active materials for secondary batteries <1999MI145>; for use in dye-sensitized solar cells with p-conducting polymers <2004SM159>; and in the preparation of photoluminescent materials <2002SM1>. Electrochemical polymerization of polycarbazole on chemical-vapor depositiongrown, single-wall carbon nanotubes results in a polymer with spectroscopic characteristics similar to those of polycarbazole produced on conducting glass electrodes, but with significant differences at the near-infrared (IR) spectral range, a general ohmic behavior, and a substantial increase in the sample conductivity <2005SM202>.
3.04.3 Drugs Atorvastatin 1 is a synthetic lipid-lowering drug that lowers both cholesterol and triglyceride levels in the blood <2006MI95>. It acts as inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Pyrroles and their Benzo Derivatives: Applications
2-[(5-Hydroxy-1H-indol-3-yl)methylene]hydrazinecarboximidamide are a class of agonists of the serotonin 5-HT4 receptor <1995JMC2331> and Zelnorm (tegaserod maleate) (3-(5-methoxy-1H-indol-3-ylmethylene)-N-pentylcarbazimidamide hydrogen maleate) 2, one of the most potent members of the series, is used as a drug against irritable bowel syndrome.
3.04.4 Medicinal Compounds A huge number of synthetic or semisynthetic pyrrole, indole, and carbazole compounds with significant biological or pharmacological activities have been described. Therefore present coverage is restricted to those instances which appear to be of interest as candidate drugs.
3.04.4.1 Antibacterial Agents The copper complex of the thiosemicarbazone of pyrrole-2-carbaldehyde shows a broad-spectrum antibacterial activity inhibiting the growth of a range of Gram-positive bacteria and fungi at concentrations of 12–50 mg ml1, whereas the nickel and cobalt complexes are only moderately active <2005JIB2231, 2004ICA2543>. The copper complex of the thiosemicarbazone of indole-3-carbaldehyde is selective against Gram-positive bacteria. Potential antimicrobial derivatives possessing bioisosteric replacements of the central oxazolidinone ring found in oxazolidinone antibacterials, such as the pyrrole derivative 3, have been prepared <2004BML4735>.
(2-Pyrimidinyl)pyrrole inhibits at 200 mg ml1 concentration two plant pathogenic bacteria, Xanthomanus phaseoli (pathogenic on the bean plant) and Xanthomanus malvacearum (pathogenic on the cotton plant) <2004JHC343>. Potent DNA minor-groove binding antibacterials with a polypyrrole structure based on the natural product distamycin A have been synthesized and shown to target A/T-rich sites within the bacterial genome <2003JME3914>. Compound 4 showed in vivo efficacy in a mouse peritonitis model against methicillin-sensitive Staphylococcus aureus infection with an ED50 value of 30 mg kg1.
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A new series of short pyrrole tetraamides are described whose submicromolar DNA binding affinity is an essential component for their strong antibacterial activity <2002JME805>. The antibacterial activity is critically linked to the size of the N-alkyl substituent of the pyrrole unit. Two pyrrole analogues of chloramphenicol 5 and 6 have been synthesized and tested for antibacterial activity <1999JAN1140>. The pyrrole derivative 7 (X, Y ¼ H, Cl; Z ¼ S, NMe) showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria <1999BML2983>.
Cephalosporin derivatives containing a pyrrole ring in the N-acyl chain, such as compound 8, show significant antibacterial activity, similar to that of cefalexin <2000PHA568>. 1-Butyl-4-(2-phenyl-1H-indol-3-yl)-2-azetidinones of the type 9 <2004HAC494> and several new spiro indoline-based heterocycles 10 <2004BMC2483> show interesting antibacterial activity.
A series of indole-naphthyridinone inhibitors 11 of bacterial enoyl-ACP reductases FabI and FabK, attractive targets for the development of novel antibacterial agents, have been developed with greatly increased potency against multidrug resistant strains of S. aureus and the FabK-containing pathogens Streptococcus pneumoniae and Enterococcus faecalis (ACP ¼ acyl carrier protein) <2003JME1627>.
Pyrroles and their Benzo Derivatives: Applications
The indole derivative 12, a synthetic analogue of the antimicrobial natural product chuangxinmycin, is an inhibitor of bacterial tryptophanyl tRNA synthetase and displays antibacterial activity <2002BML3171>.
2-(1H-Indol-3-yl)quinoline derivatives (e.g., 13) effective against methicillin-resistant S. aureus have been prepared that have minimum inhibitory concentrations (<1.0 mg ml1) and retain activity against two strains of glycopeptide intermediate-resistant S. aureus <2000BML2675>. Carbazole-linked cyclic and acyclic peptoids, such as 14 and 15, have been synthesized and shown to exhibit antibacterial activity against S. aureus (ATCC 6538P) <2003T8741, 2002SL219>.
3.04.4.2 Antitumor Agents The antitumor properties of hybrid molecules based on distamycin A, for example, 16, have been reviewed <2006ARK20>. A number of novel substances containing a pyrrole ring have been investigated for their antitumor activity. Aroylpyrrolylhydroxyamides such as 17 and 18, which are analogues of the lead compound 3-(1-methyl-4phenylacetyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide, are a new class of synthetic histone deacetylase inhibitors <2006CMC225, 2004JME1098>. Compound 17 shows interesting, dose-dependent antiproliferative and cytodifferentiation properties against human acute promyelocytic leukemia HL-60 cells.
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Pyrrole-2-carboxamides, for example, 19, have been identified as novel scaffolds for developing androgen receptor antagonists, with inhibitory effects against the androgen-dependent growth of Shionogi carcinoma cells <2005BMC2837>. Water-soluble pyrrolo[2,1][1,4]benzodiazepine-glycosylated pyrrole and imidazole polyamide conjugates of the type 20 are highly cytotoxic against many human cancer cell lines <2003OBC3327>. A new series of N-phenylpyrrole-carbothioamides, for example, 21, has been prepared, and some compounds demonstrated inhibitory effects on the growth of a wide range of cancer cell lines, in some cases at 108 M concentrations <2003BMC495>.
Checkpoint 1 (Chk 1) inhibitors emerged as a novel class of neoplastic agents for abrogating the G2 DNA damage checkpoint arrest. An analogue of the Chk 1 inhibitor 3-ethylidene-1,3-dihydro-indol-2-one, compound 22, possesses potent inhibitory activities <2006BML421>. The potent VEGFR-2 kinase inhibitor 23 displays cellular efficacy, antiangiogenic activity ex vivo in rat aortic ring explant cultures, and oral antitumor efficacy in nude mice (VEGFR ¼ vascular endothelial growth factor receptor) <2006BML2158>.
Pyrroles and their Benzo Derivatives: Applications
Pyrrolo[2,1-c][1,4]benzodiazepine hybrids linked with indolecarboxylate and indolecarboxamides of the type 24 (X ¼ O, N(CH2)nO; n ¼ 36) have potent antitumor activity and induce apoptosis in human melanoma A2058 cells <2006JME1442>. Arylthioindoles of the type 25 are potent tubulin polymerization inhibitors <2006JME947, 2004JME6120>. Derivatives bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety inhibit MCF-7 cell growth at nanomolar concentration and show potency comparable to colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. A new class of protein kinase C inhibitors with 2-arylindolylmaleimide structures has been described, including the lead compound 26, which shows good selectivity in relation to other kinases, and possess antitumor activity in several in vitro and in vivo models <1995BML67>. 3-Formyl-6-methoxy-2-(4-methoxyphenyl)indole is a potent cytostatic agent with IC50 values of 35 nM (cell growth inhibition) and 1.5 mM (tubulin polymerization) <1998JME4965>.
Prodigiosin analogues such as 27 inhibit cancer cell proliferation at 50 nM to 50 mM concentrations <2006BML701>. Hybrids of -methylene--lactones and 2-phenylindoles, for example, 28, are potent inhibitors of the AKT–mTOR signaling pathway <2005BML4799>. N-Hydroxy-3-phenyl-2-propenamides, for example 29, are potent inhibitors of human histone deacetylase. One of them showed significant dose-related activity in the HCT116 colon and A549 lung tumor models with low gross toxicity, and entered human clinical trials in 2002 <2003JME4609>.
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Indolo[6,7-a]pyrrolo[3,4-c]carbazoles such as compound 30 have potent cyclin D1/CDK4 inhibitory properties and display antiproliferative activity against two human cancer cell lines (CDK4 ¼ cyclin-dependent kinase 4) <2003BML2261>. A-289099 31 is an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype <2002BML465>. Other studies have shown that 2,4-bis(39-indolyl)thiazoles, 3,5-bis(39-indolyl)-2(1H )pyrazinone, and 3,6-bis[39-(N-methyl-indolyl)] pyrazine offer potential as lead compounds for the discovery of anticancer agents <2000BMC363>. The lead candidate from a series of fluoroglycosylated fluoroindolocarbazoles, BMS-250749 32, displays broad spectrum antitumor activity against some preclinical xenograft models, including curative activity against Lewis lung carcinoma <2005JME2258>.
9-Isopropoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-one 33, a member of a series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors, displays IC50 values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, exhibits good selectivity against numerous tyrosine and serine/threonine kinases, including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK, has significant in vivo antitumor activity in tumor models, and has entered phase I clinical trials as its water-soluble N,N-dimethylglycine ester prodrug <2003JME5375>.
Pyrroles and their Benzo Derivatives: Applications
3.04.4.3 Anti-HIV and Antiviral Agents A group of substituted pyrrole derivatives, in particular compounds 34 and 35, are of considerable interest as novel human immunodeficiency virus (HIV) type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. They are under scrutiny as novel anti-HIV agents <2004AAC4349>.
Pyrrole 36 is a potent inhibitor of HIV-1 reverse transcriptase and is active against a strain of HIV-1 resistant to AZT (strain G9106) <1995MI98>. Aryl pyrrolyl and aryl indolyl sulfones of the type 37 and 38 are active against both wild-type and AZT-resistant HIV-1, but not against HIV-2 <1996JME522>. Substituted indole--diketo acids 39 and 40 (R ¼ H; RR1 ¼ OCH2O; R2 ¼ Me, Et, Bn) show anti-HIV-1 integrase activity at low micromolar concentrations with varied selectivity against the strand-transfer process <2004JME5298>.
The isatin -thiosemicarbazone derivative 41 shows significant anti-HIV activity in the HTLV-IIIB strain in the CEM cell line with an EC50 of 2.62 mM and a selectivity index of 17.41, and is not cytotoxic to the cell line at a CC50 of 44.90 mM <2005BML4451>. Lamivudine prodrugs involving N-4 substitution with isatin derivatives possess antiHIV and antitubercular activities <2005EJM1373>. Carbazole derivatives have been proposed as novel lead compounds in the development of integrase inhibitors <2005MI363>. In addition to potential anti-HIV agents, a number of antiviral compounds containing an indole moiety have been prepared. Antihepatitis B and C activities have been demonstrated for ethyl 5-hydroxy-1H-indole-3-carboxylates <2006BML2552> and indole-N-acetamide derivatives <2005JME4547>. Chlorinated indole nucleosides, for example, 42, are active against human cytomegalovirus and herpes simplex virus type 1 <2004JME5773>, whereas the indolocarbazole derivative 43 (R ¼ Et) is a potent inhibitor of human cytomegalovirus (IC50 19 nM), retaining activity against a range of strains including ganciclovir-resistant isolates <2001BML1993>.
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3.04.4.4 Anti-Inflammatory Agents Because of the broad range of biological activities that are relevant to the mode of action of anti-inflammatory agents, and the myriad patents on the subject, the present coverage of the topic has been restricted to those compounds that have been found to be active in specific biological models of inflammation and are therefore explicitly referred to as anti-inflammatory agents in research papers. Diarylpyrrole 44 (R1 ¼ MeO2S, R2 ¼ F, R3 ¼ Me) is a very potent and selective inhibitor of cyclooxygenase-2 (IC50 60 nM) <1997JME1619>. Tetrasubstituted pyrroles containing COCF3, SO2CF3, or CH2OAr groups at position 3 in the pyrrole ring are excellent COX-2 inhibitors, (IC50 30-120 nM). In vivo testing in the carrageenan-induced paw edema model in the rat establishes that the 1,2-diarylpyrroles are orally active anti-inflammatory agents, with compound 44 (R1 ¼ F, R2 ¼ MeO2S, R3 ¼ H) the most potent inhibitor of edema (ED50 4.7 mg kg1).
Aroyl- and thiophene-substituted pyrrole derivatives, for example, 45 (R4 ¼ H, Me, Et; Ar1 ¼ Ph, 2-thienyl, 4-ClC6H4, etc.; Ar2 ¼ Ph, 5-chloro-2-thienyl, 4-ClC6H4, etc.) have been synthesized as a new class of COX-1/COX2 inhibitors <2000EJM499>. N-(Pyridin-3-ylmethyl)-3-[5-chloro-1-(4-chlorobenzyl)indol-3-yl]propanamide 46 represents one of the most potent compounds evaluated in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone <2004BML5441>. A review of two patents claiming structurally novel 4-(2-arylindol-3-yl) butanoic acid derivative that are active as CXC chemokine receptor 2 (CXCR2) antagonists and claimed to be useful in the treatment of a broad range of inflammatory diseases has been published <2003MI721>. 3-[1-Acetyl-5-(p-hydroxyphenyl)-2-pyrazolin-3-yl]indole 47 shows marked inhibitory effects on carrageenan-induced edema in albino rats at an oral dose of 50 mg kg1, and lower ulcerogenic liability and acute toxicity than the standard drug phenylbutazone <2004EJM449>. 9-(2-Chlorobenzyl)-9H-carbazole-3-carbaldehyde (LCY-2-CHO 48) is a potent anti-inflammatory agent acting as an inhibitor of neutrophil degranulation, superoxide anion formation <2002MI35>, and lipopolysaccharide-stimulated nitric oxide generation in RAW 264.7 macrophages (IC50 1.3 0.4 mM) <2002MI1961>. It induces apoptotic effects mediated through activation of caspase and mitochondrial pathways <2005MI102>.
Pyrroles and their Benzo Derivatives: Applications
3.04.4.5 Miscellaneous Medicinal Compounds A series of 2,7- and 3,6-bis-cationic carbazoles, for example, 49, shows activity against a rat model of Pneumocystis carinii pneumonia (PCP), and some are more potent and less toxic than the standard anti-PCP drug pentamidine <1997EJM781>. While no quantitative correlation was seen between anti-PCP activity, topoisomerase inhibition, and DNA binding, a minimal level of DNA binding was found to be necessary for antimicrobial activity.
3.04.5 Dyes Several papers and patents deal with the preparation of pyrrole-, indole-, and carbazole-derived dyes for application in organic laser device production, coloring of textiles and other materials, photography, analytical chemistry and physiological and organ function monitoring. Sulfonyl-substituted 2-[4-(dialkylamino)phenyliminomethyl]pyrrole dyes have been prepared, for example, 50–53, and their ultraviolet–visible (UV–Vis) absorptions, second-order nonlinear optical properties, and thermal stabilities have been described <1999TL2157>.
2-(2-Pyrrolylidene)indolin-3-one (both (E)- and (Z)-isomers) are weakly fluorescent in protic solvents such as ethanol and water, but the fluorescence intensity of the (E)-isomer 54 increases upon addition of bovine serum
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albumin in water, indicating that the isomer binds to a hydrophobic site of the protein <2005MCL445>. Indole cyanine dyes, for example, 55 and 56 have been spectroscopically characterized and tested as green-sensitizing dyes in photographic emulsions <1996JMC559>.
A series of heptamethine 5-sulfo-3H-indocyanine dyes (e.g., 57–60) have been synthesized and their spectral properties and photostability have been determined for perspective biological applications <2004JPH53>. The photostability of the compounds was found to be influenced to a significant extent by the substituents: better photostability was obtained with an N-benzyl group on the 3H-indole ring and with electron-donor groups, such as 4-methoxylanilino, on the chlorocyclohexenyl bridge in the heptamethine chain. Near-IR absorbing heptamethine cyanine dyes 61–63 have been synthesized as sensitizers for a zinc oxide solar cell <2005SM147>.
Pyrroles and their Benzo Derivatives: Applications
The novel water-soluble dye 64 shows sufficient stability for potential application in molecular-based beacons for cancer detection using optical imaging <2005BCC735>. An optochemical ozone sensor with a quantitation limit of 0.03 ppm and accuracy exceeding 8% has been obtained by immobilization of the novel soluble indigo derivative 65 in permeable transparent polymeric films of polydimethylsiloxane-polycarbonate <2005MI1628>.
3.04.6 Natural Products The number of new natural products containing pyrroles and their benzo derivatives has increased considerably during the past decade. Due to space restrictions, only the most representative examples are included, and these witness the variety of structures and biological functions of natural products containing pyrroles, indoles, carbazoles, and related skeletons.
3.04.6.1 Bacterial Products An orange-brown indole derivative, sphestrin 66, is produced by Rhodobacter sphaeroides OU5 grown in the presence of 2-aminobenzoate <2005MI41>. The indole derivative 67 has been isolated from the culture broth of the symbiotic bacterium Xenorhabdus nematophilus <1996JNP1157>.
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3.04.6.2 Fungal Products Few of the novel fungal products that have been discovered contain the pyrrole ring as distinguishing structural feature. Of chemical interest is the metabolite 68 from the ethyl acetate extract of a static culture of Aspergillus niger isolated from the Mediterranean sponge Axinella damicornis, which contains the hitherto unprecedented pyrano[3,2-b]pyrrole skeleton <2004JNP1532>. Investigations of metabolites from Streptomyces continues to disclose interesting indole derivatives. Three new 3,6disubstituted indoles have been isolated from the mycelium of a strain identified as Streptomyces sp. (BL-49-58-005), which was separated from a Mexican marine invertebrate <2003JNP863>. Two of these, including oxime 69, have been found to exhibit cytotoxicity against a panel of 14 different tumor cell lines. Another indole compound, (S)-acetylamino--(3-indole)propanol 70, has been isolated from the culture broth of a streptomycete strain YIM33176 (Streptococcus pleomorphus) <2005CCL613>.
Species of Penicillium fungi are rich sources of indole metabolites, such as thomitrem A 71 and thomitrem E 72, isolated from Penicillium crustosum <2002P979>. They are structurally similar to previously described penitrem derivatives <1996CHEC-II(2)207> but lack the characteristic penitrem 17(18)-ether linkage.
A compound related to paspaline, paspaline B 73, has been obtained from Penicillium paxilli <1996P327>. Several indole diterpenoids can be found in extracts of Penicillium thiersii NRRL 28147, including the novel compound thiersinine A 74, which displays antiinsectan activity against the fall armyworm (Spodoptera frugiperda) <2002OL3095>. A 6-hydroxyindole moiety is the characteristic feature of compound 75, and a related aldehyde derivative with inhibitory activity on lipid peroxidation, identified in the poplar mushroom Agrocybe cylindracea <1997JNP721>.
The lipophilic yeast Malassezia furfur, when grown with tryptophan as the sole nitrogen source, produces a series of indole alkaloids, such as pityriarubin A 76, which may be of importance for the pathogenesis of the common skin disease pityriasis versicolor, as well as some tryptophan metabolites including some carbazole-containing derivatives, for example, 77 <2004AGE1098>. Additional indole alkaloids isolated from fungi include: brasilidine A 78, containing an isonitrile group, from the actinomycete Nocardia brasiliensis IFM 0089 <1997JNP719>; five new quinone pigments, with inhibitory properties on serine proteases of the coagulation pathway, viz. asterriquinones CT1, CT2,
Pyrroles and their Benzo Derivatives: Applications
CT3, CT4, and CT5 79, from the fermentation broth of Aspergillus, Humicola, and Botryotrichum spp. <1996JAN854>; an antifungal isatin, named prenisatin (5-(3-methyl-2-butenyl)indole-2,3-dione, 80), from submerged fermentations of Chaetomium globosum active in vitro against the growth of Botrytis cinerea <1996ACS443>; and the indole alkaloid L,L-cyclo(tryptophanylprolyl) 81 from the culture broth of Microbispora aerata subsp. nov. IMBAS-IIA, a strain isolated from penguin excrements collected on the Antarctic Livingstone Island <2003MI128>.
3.04.6.3 Plant Products Although an impressive number of alkaloids have been isolated from plant sources, only a few contain simple pyrrole rings. These include a series of tropane alkaloids from the bark of Erythroxylum vacciniifolium, for example, 82, that share as common structural features a methylpyrrole moiety <2005JNP1153>; methyl-(5-formyl-1H-pyrrole-2-yl)-4hydroxybutyrate 83 from sweet chestnut seeds <2002MI22>; and solsodomine A 84 and B 85 from the fresh berries of Solanum sodomaeum L. <1998JNP848>. The latter are the first pyrrole alkaloids from the genus Solanum. Indole derivatives cover the vast majority of the natural products reported in this section. A sulfur-containing indole alkaloid, glypetelotine 86, featuring an S-methyl-N-methylthiocarbamate moiety, has been isolated from the leaves of the endemic Vietnamese plant Glycosmis petelotii (Rutaceae) <1999P1711>.
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The seeds of Centaurea moschata contain alkaloids with a 5-hydroxyindole structural unit, namely moschamine 87, moschamindole 88, and moschaminindolol 89 <1997MI189>. Ervatamine-type indole alkaloids, for example, 6-oxo16,20-episilicine 90, 16,20-episilicine, and 6,16-didehydro-20-episilicine have been isolated from Ervatamia officinalis <2005HCA2537>.
An interesting example of N-oxygenated alkaloid, polyneuridine-N-oxide 91, occurs in the roots of Ochrosia acuminata along with 17-hydroxy-10-methoxy-yohimbane 92 <2004JNP1719>. One additional yohimbane 93 and five new sarpagine-type indole alkaloids, for example, 94, are found in the radix of Gelsemium sempervirens Ait. f. <2005TL5857>.
Indole-type glucosinolates, for example, 95 and 96, are present in the seeds of Isatis tinctoria L. <2001TL9015> whereas the roots of Isatis indigotica Fort contain the nitrile derivative 97 <2001CCL501>. The diprenylated indoles 29,39-epoxyasteranthine 98 and 29,39-hydroxyasteranthine, with antimycotic activity, occur in the stem bark and the root bark of Asteranthe asterias (Annonceae) <1996MI71>.
Pyrroles and their Benzo Derivatives: Applications
Lolicines A 99 and B 100 have been isolated as their 11-O-propionates from extracts of perennial ryegrass (Lolium perenne) seeds infected with the endophytic fungus Neotyphodium lolii <1998MI590>. The structures of lolicines A and B are similar to those of paspaline and paspaline B, which are known to be biosynthetic precursors of several groups of more complex indole-diterpenoids. From the same source, terpendole M 101, an indole-diterpenoid, has been isolated <1999MI1092>. These findings provide clues to the biogenesis of the lolitrem group of indolediterpenoid neurotoxins and yield information on the structure–activity relationships within the indole-diterpenoids.
Complex terpenoid indole alkaloid glucosides have been described, including a disaccharide-carrying strictosidinic acid alkaloid, hunterioside B 102, from Hunteria zeylanica <1998H(47)87>; bahienoside A 103 and bahienoside B, together with carboxystrictosidine, strictosamide, and other compounds, from the aerial parts of Psychotria bahiensis <2003JNP752>.
The aerial parts of Ophiorrhiza bracteata Bl. (Rubiaceae) contain a quaternary glucoalkaloid, bracteatine 104 <1997AJC1111>. Examples of monoterpene indole alkaloids that have been isolated include croceaines A 105 and B 106 from the leaves of Palicourea crocea <2004JNP1886>, and 16-hydroxymethylpleiocarpamine 107, 16-epideacetylakuammiline, and 14-hydroxycondylocarpine from the stem bark of Kopsia deverrei (Apocyanaceae) <1995MI275>.
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The bisindole alkaloids alstomacrophylline 108 and alstomacroline 109 have been isolated from the root bark of Alstonia macrophylla, along with the monomeric indole alkaloid 20-epi-antirhine <1997P757>. A dimeric indole alkaloid, schischkiniin 110, was isolated from the seeds of Centaurea schischkinii <2005T9001>.
The caulindoles (e.g., 111, 112), which are dimeric prenylindoles occurring in diastereomeric pairs, have been isolated from the stem and root barks of Isolona cauliflora. Biogenetically, the caulindoles are considered as Diels– Alder-type products derived from mono- and/or bis-prenylindoles acting as dienes and dienophiles <2004P227>. Dimeric indole alkaloids containing the 4-(indol-1-yl)-5-hydroxyindole system, for example, arundanine 113 <2003RCB745> and arundacine 114, have been isolated from the roots of Arundo donax L. (Poaceae) <2002KPS280>. A furanobisindole alkaloid, phalarine 115, has been obtained from Phalaris coerulescens <1999P153>. The leaves of Psychotria rostrata have been shown to contain two tryptamine-related alkaloids, psychotrimine 116 and psychopentamine 117, which feature unprecedented trimeric and pentameric indole skeletons <2004OL2945>.
Pyrroles and their Benzo Derivatives: Applications
Stem bark and roots of plants of the Strychnos species contain a series of bisindole alkaloids, several of which have been isolated. These include: the colored quaternary bisindole alkaloid guiaflavine 118 <1999JNP898>; a zwitterionic asymmetric bisindole compound named guianensine 119 <1995P1557> from Strychnos guianensis; a tertiary phenolic bisindole alkaloid, 109-hydroxyusambarensine 120, with moderate activity against two strains of Plasmodium falciparum <1999JNP619>; and a relatively rare zwitterionic indoloquinolizine alkaloid, tetradehydrolongicaudatine Y 121 from Strychnos usambarensis <1998P1263>. The structures of the three main tertiary indole alkaloids of Strychnos atlantica have been confirmed <1997MI115>.
Carbazole alkaloids occupy an important position among plant-derived alkaloids, and several of them exhibit interesting biological activities. Noticeably rich sources of carbazole alkaloids are Clausena, Glycosmis, and Murraya, from which additional examples have been reported. Clausine Z, 122, has been isolated from the stems and leaves of Clausena excavata Burm. (Rutaceae) and has been found to exhibit inhibitory activity against cyclin-dependent kinase 5 (CDK5) and protective effects on cerebellar granule neurones in vitro <2005PHA637>. From the same plant,
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several other new compounds have been isolated, including 10 alkaloids, clausine-M 123, -N, -O, -P, -Q, -R, -S, -U, and -V, and clausenatine-A from the root bark <1999P523>, four lactonic carbazole alkaloids, viz. clausenatine-D 124 and -G <1998CPB1459>; clauszoline-H 125, -I 126, and -J 127 from the roots, clauszoline-K 128 and -L 129 from the stem bark, and clauszoline-M 130 from the leaves <1997CPB48>, the carbazole-pyranocoumarin carbazomarin A 131, and the dimeric clausenamine A 132 <1996TL7819>. Additional lactonic carbazole alkaloids, clausamine-A 133, -B, and -C have been obtained from Clausena anisata <1998CPB344>.
Carbazole alkaloids from Glycosmis arborea include glycoborinine 134 <1999P1263> and 7-methoxyglycomaurin 135 <1998MI780>. A dimeric alkaloid, bisisomahanine 136, has been isolated from the roots of Glycosmis stenocarpa <2004CPB1175>. Bisisomahanine features an unusual dimeric prenylated pyranocarbazole structure with a 1,19linkage.
Carbazole alkaloids isolated from Murraya species include murrayamines O 137 and P 138 with a cannabinoid moiety from the root barks of Murraya euchrestifolia <1995TL5385> and the dimeric bismurrayafoline E 139 from Murraya koenigii <1999MI130>.
Pyrroles and their Benzo Derivatives: Applications
3.04.6.4 Marine Products Marine organisms, chiefly sponges, tunicates, and algae, have provided conspicuous examples of novel pyrrole and indole derivatives. Chemical investigation of the sponge Mycale cecilia has led to the isolation of 14 new pyrrole metabolites, namely mycalazals 3–13 (e.g., 140), a series of pyrrole-2-carbaldehydes possessing hydrocarbon side chains of different lengths and/or at differing degree of unsaturation, and mycalenitriles 1–3 (e.g., 141) with a 5-cyanoalkylpyrrole-2-carbaldehyde structure <2004T2517>. Mycalazals have shown activity as growth inhibitors of several tumor cell lines, in particular the LNcaP cell line. The Caribbean marine sponge Axinella sp. is another source of pyrrole alkaloids, such as axinellamines A 142 and B; the latter is a structurally modified dimer of axinellamine A <1998H(48)1461>.
Sponges also furnish a variety of indole alkaloids: Rhaphisia pallida contains pallidin 143 <1996JNP504>; Plakortis simplex, a Caribbean sponge, produces interesting iodinated tryptophan derivatives, plakohypaphorines D, E 144, the first naturally occurring triiodinated indole, and F 145, possessing both chlorine and iodine atoms on the indole nucleus <2004EJO3227>; Hamigera hamigera (Anchinoideae), a Mediterranean sponge with deterrent activity in a fish-feeding assay, contains hamigeramide 146 along with steroids and phenolics in the bioactive fraction <2004MI88>. Bisindole alkaloids are also commonly found in sponges. Okinawan marine sponge Dictyodendrilla sp. produces dendridine A, 147, an antibacterial and antifungal compound with a 4,49-biindolyl skeleton and a 7-hydroxyindole moiety <2005JNP1277>.
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Spongosorites genitrix has been found to contain the new brominated metabolites 148 and 149 (R1 ¼ Br, R2 ¼ H; R ¼ H, R2 ¼ Br), exhibiting moderate cytotoxicity against a human leukemia cell line (K-562) <1999JNP647>, and isobromotopsentin 150 which is a related brominated alkaloid with a 7-hydroxyindole unit <1995AJC2053>. Sponges from Cape Town, South Africa, have afforded three indole alkaloids: dilemmaones A 151, B, and C <1998JNP699>, which are named after the dilemma caused by faulty differentiation of similar specimens in the field. 1
Marine tunicates have afforded a variety of indole alkaloids with potential biological activities. Extracts of the Caribbean ascidian Didemnum conchyliatum contain the cyclized alkaloid 152 of the didemnimide class formed via condensation of the indole ring with the imidazole nitrogen of didemnimide A 153 <1999JNP389>. Aplidium meridianum has afforded novel pyrimidine-containing indole alkaloids (the meridianins; e.g., 154) with cytotoxic properties toward murine tumor cell lines <1998JNP1130>. Dendrodoa grossularia and the Okinawan marine tunicate Rhopalaea sp. contain the indole alkaloids 155 <1998JNP519> and rhopaladins A 156 to D <1998T8687>, which feature a modified imidazole ring. A specimen of Distaplia regina from Palau has been found to produce 3,6dibromoindole with antibacterial properties <1999MI59>.
Seaweeds represent an important source of indolic metabolites. An oxazole-containing indole alkaloid, martefragin A 157, has been isolated from the red algae Martensia fragilis <1996MI53>. The compound shows inhibitory activity on NADPH-dependent lipid peroxidation in rat liver microsomes (IC50 2.8 mM) <1998CPB1527>. Bindolyls and bisindole alkaloids have also been isolated from red and green algae. Representative examples include: chondriamide C 158, a bisindole amide with anthelmintic activity from Chondria atropurpurea <1998JNP1560>; a remarkable halogenated 3,39-biindolyl 159 from the green algae Chaetomorpha basiretorsa Sethcell <2005CCL777>; and a bisindole derivative, caulersin 160, from Caulerpa serrulata <1997JNP1043>. Prenylated 6-bromoindole alkaloids are found in the North Sea bryozoan Flustra foliacea <2002JNP1633>. Representative examples include compounds 161 and 162, with a 1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-7-ol skeleton.
Pyrroles and their Benzo Derivatives: Applications
3.04.7 Agrochemicals Synthetic agrochemicals incorporating pyrrole, indole, and carbazole structures are described mainly in patents and are not covered here. 2-(1-Ethoxymethyl-1H-pyrrol-2-yl)-5-phenyl-1,3-oxazole 163 is a novel analogue of the broadspectrum insecticide ‘pirate’ and of potential practical interest (LD50 1.13 mg ml1) <2004AJC227>. Compound 164, which is structurally related to 1-[1-(3,5-dichlorophenyl)-1-methylethyl]-4-methyl-3-phenyl-3-pyrrolin-2-one and which is an excellent herbicide against paddy weeds, is active against Echinochloa oryzicola and Scirpus juncoides and compatible with transplanted rice even under harsh conditions <2004JPES339>.
3.04.8 Calixpyrroles Calixpyrroles are macrocycles that consist of pyrrole rings linked through the pyrrolic 2- and 5-positions by sp3 hybridized carbon atoms. Their binding properties toward anions have been recognised recently. Selectivity toward a particular anion depends on how many pyrrole units are present and on the presence of other functional groups. For instance, calix[4]pyrroles (with four pyrrole units) are over 2 orders of magnitude more selective toward fluoride anion than other halide anions or phosphates. On the other hand, calix[6]pyrroles selectively bind the iodide anion. Such selectivity allows the use of calixpyrrole structures in chromatography or analytical chemistry for fast and simple determination or separation of anions <1996JA5140, 2003PCB6462>. Chromogenic octamethyl calix[4]pyrrole-based sensors (e.g., 165–167) for antipyretic carboxylates such as naproxen, ibuprofen, and salicylate, without bias by bicarbonate or carboxy termini of blood plasma proteins, have been described <2005JA8270>. The formation of a sensor–anion complex results in partial charge transfer and a dramatic change in color.
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Other calix[4]pyrroles for anion sensing include the mono-tetrathiafulvalene 168 <2003AGE187> and the mesosubstituted 3,4,5-tribromopyrrole derivative 169 <2003CC1810>.
The strapped calix[4]pyrrole-metalloporphyrin conjugate 170 shows strong binding with fluoride ion in organic solvents but no appreciable binding with Cl, Br, or I <2004OL671, 2005JOC3148>.
Pyrroles and their Benzo Derivatives: Applications
cis-Strapped calix[4]pyrrole derivatives and trans-strapped systems bearing isophthalate-derived diamide spacers linked to the tetrapyrrolic core display enhanced affinities for halide anions compared to normal, unstrapped calix[4]pyrrole, but show no size-dependent selectivity for anions as the length of the bridging strap is varied. The occurrence of anion-binding processes outside the central pocket defined by the strap, but which still favor strong associations as the result of hydrogen-bonding donors provided by the the amide groups, is proposed <2005JOC2067>. Calix[4]pyrrole[2]carbazole 171, an expanded calixpyrrole containing two carbazole subunits in lieu of two of the four Me2C bridging elements normally found in calix[4]pyrrole, has a winglike structure in the solid state and exhibits a slight preference for acetate relative to other carboxylate anions (e.g., benzoate, oxalate, succinate), as well as for various anionic substrates (i.e., chloride and dihydrogen phosphate), but no binding of bromide, nitrate, and hydrogen sulfate <2004JA16073>.
Bipyrrole, furan, and thiophene have been used to construct a series of calixpyrrole-like anion receptors, for example, 172 and 173 <2003JA13646, 2005JOC1511>. Some of these hybrid calixpyrrole systems show a selectivity for Y-shaped anions such as benzoate, over spherical ones such as chloride. Calix[6]pyrrole 174 encapsulates halide ions within the macroring cavity via six N–H X– hydrogen bonds and is a dramatically stronger chloride ion complexing agent than the smaller calix[4]pyrrole <2000CC1207>.
A strapped calix[4]pyrrole with enhanced affinity and selectivity for halide anions has been prepared <2002AGE1757>. The fluoride complex exhibits a binding constant of 3.87 106 M. The encapsulated binding site differentiates the anions on the basis of size and exhibits hydrogen-bonding interactions between the aromatic nitrogen proton and halide anions, as evidenced by 1H nuclear magnetic resonance (NMR) spectroscopy. Calix[3]bipyrrole 175 displays an affinity for bromide anions in dry acetonitrile that is greater than that of either the corresponding calix[4]pyrrole or calix[4]bipyrrole 176 for bromide and chloride anions <2003AGE2278>.
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A new calix[4]pyrrole containing a ferrocene moiety attached to one of the meso-positions has been prepared and shown to bind fluoride, chloride, and dihydrogen phosphate, acting as a new electrochemical sensor <2001TL6759>. Calix[4]pyrrole-modified silica gels have been designed to study the binding characteristics of calix[4]pyrroles with anionic and neutral substrates, and to provide a new solid support for the high-performance liquid chromatography (HPLC) separation of nucleotides, oligonucleotides, N-protected amino acids, and perfluorinated biphenyls <1998CEJ1095>.
3.04.9 Other Applications Literature on other structures containing pyrroles, indoles, and carbazoles and their applications is so vast that a detailed coverage is not possible, and accordingly only a bird’s-eye view is provided here. The space allocated cannot fully demonstrate interest in these topics, and the reader is encouraged to refer to the relevant papers. Pyrrole-based structures have been employed in the design and preparation of chemosensors and biosensors. N-(3-Aminopropyl)pyrrole was covalently coupled with alginate to provide a pyrrole-alginate conjugate for use in biosensor applications <2005MI3313>. 1,3,5-Tris(pyrrolyl)benzene 177 functions as a receptor with high selectivity for acetylcholine (ACh), exhibiting a binding free energy with ACh in chloroform of 3.65 kcal mol1 in the presence of chloride anion and 6 kcal mol1 in water <2003OL471>.
5-(N-Pyrrolyl)pentanethiol-modified monolayer-protected gold clusters have been synthesized and characterized by several techniques <2002MI201>. Indole-based foldamers and macrocycles have been described with potential applications in several fields exploiting molecular recognition and supramolecular interactions. Oligoindoles containing four, six, and eight indole rings have been prepared and shown to adopt a helical conformation when complexed with chloride ions by hydrogen-bonding interactions <2005JA12214>. 1H NMR analysis indicates that in the presence of chloride, the NH signals of the oligoindoles are shifted downfield following hydrogen-bond formation, while the aromatic signals are shifted upfield by stacking between indoles moieties. A number of studies deal with the preparation of indole based macrocycles as receptors for anions <2005AGE7926, 2005T10781, 2005TL4467>. An indole-terminated tris(macrocycle) designed to be a channel-former and which is an effective carrier in bulk membranes but fails to function in a lipid bilayer owing to hydrogen-bond formation has been described <1996CC2147>. Tryptophan- and tryptamine-derived tetraazacyclooctadecane macrocycles have been synthesized <1996J(P1)2427>. Transannular hydrogen bonding stabilizes a left-handed double-helical conformation of the
Pyrroles and their Benzo Derivatives: Applications
former macrocycle both in solution and in the solid state, whereas the latter shows less tendency toward intramolecular hydrogen bonding and does not exist as a helix in the crystal. Three indolyl-containing -cyclodextrin derivatives have been synthesized by the condensation of indol-3-ylbutyric acid with the corresponding oligo(aminoethylamino)--cyclodextrin and their molecular recognition behavior with some representative dye guests has been described <2002J(P2)463>. Pyridylindoles have been investigated together with other related systems as matrices for UV matrix-assisted laser desorption/ionization (UV-MALDI) mass spectrometry <2001RCM2354>. Fluorinated indole derivatives have been evaluated for application in electroncapture negative ionization mass spectrometry <1996JMP1228>.
3.04.10 Further Developments In 2006 and early 2007 research on applications of pyrroles and their benzo derivatives has continued steadily, and only a few highlights will be provided in the following.
3.04.10.1 Polymers A polypyrrole containing ferrocyanide ions as doping anions has been prepared by anodic electropolymerization and has been evaluated for the electroanalytical determination of ascorbic acid <2007MI1083>. Magnetic polypyrrole/ Fe3O4 nanospheres have also been described using hyaluronic acid as surfactant and have been functionalized with a cancer antibody, herceptin, resulting in high specific uptake by cancer cells <2007MI816>. Research on polyindole include the synthesis of long, electroactive fibers by interfacial polymerization performed at a stationary interface of aqueous FeCl3/dichloromethane biphasic system <2007MI595>, and a study of the electrorheological and dielectric properties of polyindole and polyindole/kaolinite composite obtained by free radical polymerization induced by FeCl3 as an initiator as a function of different parameters <2007MI3484>.
3.04.10.2 Medicinal Compounds A brominated pyrrole-imidazole alkaloid, rac-dibromophakellstatin, has been shown to display selective antitumor activity in vitro with the highest activity on the ovarian cancer cell line OVXF 899L <2007BMCL346>. The chemistry and bioactivity of anti-tubulin agents, either natural or synthetic, having an indole as core nucleus have been reviewed <2007MI209>. Exceptionally potent anti-HIV indolyl aryl sulfones characterized by the presence of either a pyrrolidin-2-one nucleus at the indole-2-carboxamide or some substituents at the indole-2-carbohydrazide have been discovered by molecular modeling studies and an updated highly predictive 3-D QSAR model <2006JME3172>.
3.04.10.3 Natural Products The construction of pyrrole structures during secondary metabolite biosyntheses has been overviewed along with relevant enzymological and mechanistic details <2006MI517>. A number of new indole-containing alkaloids have been described from different sources, including as representative instances: a novel azepino-indole-type derivative, hyrtiazepine <2006JNP1676> and a cytotoxic bis-indole, hyrtinadine A, bearing a pyrimidine moiety <2007JNP423>, from an Okinawan marine sponge Hyrtios sp; two unusual regioisomeric tetracyclic indoles, arboricine and arboricinine <2007TL1143>, and arboflorine, possessing a novel pentacyclic carbon skeleton <2006OL1733>, from the Malayan Kopsia arborea, as well as three indole metabolites from Kopsia officinalis <2006HCA515>; cephalinones A–D and cephalandoles A–C from Cephalanceropsis gracilis <2006JNP1467>; three new terpenoid derivatives, N(4)-demethyl-12-methoxyalstogustine, 17-carboxyl-N(4)-methylechitamidine chloride, and 17-carboxyl-12-methoxy-N(4)-methylechitamidine chloride, from the stem bark of Winchia calophylla <2006JNP18>; a unique dimeric derivative, Montamine, with significant in vitro activity against the CaCo2 colon cancer cells from the seeds of Centaurea montana (Asteraceae) <2006T11172>. A new carbazole alkaloid, streptoverticillin, has been isolated from Streptoverticillium morookaense, and has been shown to exhibit antifungal activity against Peronophythora litchii <2007JAN179>.
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3.04.10.4 Calixpyrroles Recent literature in the chemistry of calixpyrroles comprises the syntheses, characterization and complexation reactions of a series of binucleating Schiff-base calixpyrrole macrocycles <2007CEJ(A)3707>; a study of the dynamics of calix[4]pyrrole and octafluorocalix[4]pyrrole as a function of the solvent and fluorine substitution <2007CEJ(A)1108> and oxygen reduction at dicobalt complexes of a Schiff base calixpyrrole ligand <2007AGE584>.
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Pyrroles and their Benzo Derivatives: Applications
Biographical Sketch
Marco d’Ischia was born in 1958 and studied chemistry at the University of Naples Federico II, Italy, where he was appointed assistant professor in 1983. He was then made associate professor in 1992 and full professor of organic chemistry in 2001. His main research interests focus on the chemistry of natural products and heterocyclic compounds. Specific interests include the melanins and melanogenesis, the oxidative chemistry of catecholamines in relation to neuronal degeneration and other oxidative stress diseases; the chemistry of nitric oxide and biological nitrations; lipid peroxidation; the mechanism of action of phenolic antioxidants and antinitrosating agents. He has been on the Scientific Board of the European Society for Pigment Cell Research and the Board of Editors of the journal, Pigment Cell Research.
Alessandra Napolitano graduated in chemistry in 1984 at the University of Naples Federico II under the guidance of Professor G. Prota. In 2001, she was made associate professor of organic chemistry. Her main research interests lie in the field of heterocyclic compounds, with special reference to hydroxyindoles and benzothiazines, oxidative chemistry of phenolic natural products, food chemistry, lipid peroxidation, and analytical chemistry. Currently, she is involved in several research projects dealing with the chemistry of natural pigments, including pheomelanins, and the chemical bases of diseases.
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Alessandro Pezzella received his Ph.D. in 1997 under the direction of Professor G. Prota at the University of Naples Federico II. Since 1999, he holds a permanent position as researcher in the Department of Organic Chemistry and Biochemistry of the University of Naples. He has carried out research mainly in the field of 5,6-dihydroxyindole polymerisation and oxidative behavior of phenolic compounds. More recently, his research interests have concentrated on applications of heterocyclic compounds in materials science. He is the author and co-author of some 30 scientific publications, including reviews and book chapters.
3.05 Furans and their Benzo Derivatives: Structure A. Senning Technical University of Denmark, Kgs. Lyngby, Denmark ª 2008 Elsevier Ltd. All rights reserved. 3.05.1
Introduction
389
3.05.2
Theoretical Methods
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3.05.2.1
Quantum-mechanical Methods
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3.05.2.2
Semi-empirical Methods
390
3.05.2.3
Molecular Mechanics
391
3.05.3
Molecular Structure
391
3.05.3.1
The Furan Nucleus
391
3.05.3.2
Rotational Isomerism
394
3.05.3.3
Structure and Conformation in Hydrofurans
395
3.05.3.4
Furans with Exocyclic Double Bonds
395
3.05.3.5
Oligo- and Polyfurans
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3.05.4
Dipole Moments and Related Properties
397
3.05.5
Spectroscopic Characterization
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3.05.5.1
Proton and
13
3.05.5.2
Proton and
13
3.05.5.2.1 3.05.5.2.2 3.05.5.2.3
C NMR Spectroscopy of Furans
397
C NMR Spectroscopy of Modified Furans
397
Hydrofurans and their benzo derivatives THF derivatives Furans with exocyclic double bonds
397 397 397
3.05.5.3
Oxygen-17 NMR Spectroscopy of Furans
3.05.5.4
Mass Spectrometry
399
3.05.5.5
Photoelectron Spectroscopy
399
3.05.5.6
Electronic Spectra
399
3.05.5.7
IR Spectra
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3.05.6
Thermodynamic Aspects
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3.05.6.1
Aromaticity
3.05.6.2
Tautomerism
401
3.05.6.3
Linear Free Energy Relationships
402
Gas Chromatography
402
Further Developments
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3.05.6.4 3.05.7
400
References
403
3.05.1 Introduction This chapter, covering the literature of the period 1995–2006, surveys the structure of furans and their benzo derivatives in continuation of chapter 2.05 of CHEC-II(1996) <1996CHEC-II(2)259>. A fairly recent review of, mostly synthetic, furan chemistry also contains a useful bibliography of spectroscopic data <2001SOS(9)183>. Structural aspects are included in a recent review of aminofurans <2006AHC1>.
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Furans and their Benzo Derivatives: Structure
3.05.2 Theoretical Methods 3.05.2.1 Quantum-mechanical Methods A systematic theoretical analysis (Q-Chem 2.0 with 6-31G basis set B3LYP) of substituted oligofurans as well as of oligobenzo[c]furans (comprising two to six furan units) has explored the importance of the energy of the polaroninduced molecular reorganization for the charge-transfer rates of a variety of semiconducting or conducting furan oligomers 1 and, by inference, furan polymers 1 <2005JA2339>. The same authors subsequently also investigated the relative usefulness of, inter alia, MP2 and B3LYP calculations to chart the dependence of bandwidths upon furan oligomer 1 inter- and intramolecular stacking and tilting based on crystallographic data obtained with the corresponding thiophene oligomers <2005JA16866>. The Diels–Alder reactions of cyclobutano[b]furan, cyclobuteno[b]furan, and benzo[b]furan with ethene and ethyne, respectively, have been analyzed and compared with those of the corresponding [c]-fused compounds by means of B3LYP/6-31G* calculations. It was found that product stability is the controlling factor in these reactions with ethyne being slightly more reactive than ethene <2004JPO152>. A corresponding B3LYP/6-31G* study of the addition of ethene to benzo[c]furan and benzo-annulated derivatives including chryseno[2,3-c]furan 2 revealed a linear correlation between activation energies and structure count ratios <2002MI87>.
H
O
H
O
n
1
2
The standard enthalpies of formation Hf of all fluoro- and chlorofurans have been derived by isodesmic G3 calculations with an assumed precision of 2.0 kcal mol1 (see Table 1). In both series of compounds the 2-halofuran is more stable than the 3-halofuran, the 2,5-dihalofuran more stable than its isomers, and the 2,3,5-trihalofuran more stable than the 2,3,4-trihalofuran <2001JOC9041>. Following up the experimental observation that 2-azidofuran suffers thermal decomposition (to ring-opened products) at a rate approximately 103 times faster than that of phenyl azide, MP2/6-31G(d,p) calculations showed that the furan ring is intact in the transition state where a certain charge transfer from the furan ring to the azido group has taken place. The closed-shell 2-furylnitrene could be dismissed as an intermediate in the process <1997T9647>.
3.05.2.2 Semi-empirical Methods The enthalpies of formation for 2,3-dihydrofuran (23.52 kcal mol1) and 2,5-dihydrofuran (20.90 kcal mol1) have been calculated with the PM3 method <1997PCA2471>. The photochemical behavior of five-membered aromatic heterocycles, including furan, has been described in terms of PM3–RHF–CI semi-empirical calculations (RHF ¼ restricted Hartree–Fock; CI ¼ configuration interaction) <1998MI233, 1999H(50)1115>. Table 1 Calculated standard enthalpies of formation of fluoro- and chlorofurans Halofuran
Hf (kcal mol 1)
Halofuran
Hf (kcal mol 1)
2-Fluorofuran 3-Fluorofuran 2,3-Difluorofuran 2,4-Difluorofuran 2,5-Difluorofuran 3,4-Difluorofuran 2,3,4-Trifluorofuran 2,3,5-Trifluorofuran Tetrafluorofuran
52.2 48.7 89.3 92.6 94.4 86.1 126.9 131.3 165.4
2-Chlorofuran 3-Chlorofuran 2,3-Dichlorofuran 2,4-Dichlorofuran 2,5-Dichlorofuran 3,4-Dichlorofuran 2,3,4-Trichlorofuran 2,3,5-Trichlorofuran Tetrachlorofuran
12.6 12.0 15.9 16.0 16.2 15.0 18.9 19.4 22.2
Furans and their Benzo Derivatives: Structure
Modified neglect of diatomic overlap (MNDO) calculations have been shown to accurately predict the isomer distribution of polychlorinated dibenzo-1,4-dioxins and polychlorinated dibenzofurans in industrial combustion processes, an indication of thermodynamic control in these processes <2002MI1287>.
3.05.2.3 Molecular Mechanics The state of the art has been reviewed as has the incorporation of carbohydrates into macromolecular force fields <2006MI235>. 3-Chloro-4-(dichloromethyl)-5-hydroxyfuran-2(5H)-one 3, a mutagenic chlorinated-water pollutant, has been the subject of detailed molecular mechanics calculations <2004MI129>. Cl2HC HO
Cl O
O
3
3.05.3 Molecular Structure 3.05.3.1 The Furan Nucleus It has been noted that the Csp3Csp2 bonds in tetrakis(2-furyl)methane 4 have a length of 1.514 A˚ and are thus ˚ This relative bond shortening significantly shorter than the corresponding bonds in tetraphenylmethane (1.553 A). has been explained in terms of the slighter bulk of a 2-furyl group compared to a phenyl group <2005CL910>. A corresponding relative bond shortening has been observed for the Psp3Csp2 bonds in triaryl(ethyl)phosphonium iodides containing 2-furyl groups <2006JA8434>. 4,7-Dimethoxybenzo[c]furan 5, subject to rapid room temperature polymerization, was the first 1,3-unsubstituted benzo[c]furan to be examined by X-ray crystallography. The molecule is practically planar, nonaromatic, and consists of two independent 1,3-diene systems. The average length of the C–C single bonds is 1.437 A˚ and that of the CTC bonds 1.354 A˚ <1995AXC780>. OMe
O O
O O O
OMe
4
5
It has been shown by B3LYP/6-311G* calculations that the characteristic bowl shape of corannulene 6 is flattened in the corresponding fully furo[c]-annelated derivative 7, which thus is by and large analogous to the decamethylidene derivative 8 <2004JOC8111>.
6
8 7
The packing energies in crystalline tetrahydrofuran-3,4-dione 9 and (2S,3S)-tetrahydro-3-acetoxy-5-oxofuran-2,3dicarboxylic anhydride 10 have been calculated from the corresponding crystallographic data <2002JA225>.
391
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Furans and their Benzo Derivatives: Structure
As could be expected from its chemical reactivity and predicted by DZ calculations, ethyl 3-hydroxybenzo[b]furan2-carboxylate 11 is fully enolized as a benzo[b]furanol and forms strongly hydrogen-bonded dimers in the solid state <1998AXC1951>. The heterosumanene triphenyleno[1,12-bcd;4,5-b9c9d9;8,9-b0c0d 0]trifuran 12, with a 6p hub and 18p rim electron count, has been examined by B3LYP/6-311þG** calculations and found to be bowl-shaped with a bowl depth of ˚ The C–C bonds of the central benzene ring alternate in length (1.399 and 1.428 A). ˚ Compound 12 complexes 1.486 A. lithium and sodium ions, respectively, on both the convex and the concave side, more strongly in the former case. The less extended ring system 13, benzo[1,2-c;3,4-c9;5,6-c0]trifuran, was found to be planar, the length of the formal ˚ <2004T3037>. In another theoretical study C–C single bonds alternating only marginally (1.452 and 1.453 A) (density functional theory (DFT) calculations of the type B3LYP/cc-pVDZ) of compound 13, a uniform formal C– C single bond length of 1.454 A˚ and a uniform formal CTC bond length of 1.369 A˚ were found <2001JOC6523>. O Ac O
O
O
O
O
9
O
O
O
OH O
H
10
O O
O
O
OEt
11
13
12
Table 2 summarizes characteristic structural data of a number of 2-elemento-substituted furans. Tris(2-furyl)phosphine 23, tris(2-furyl)arsine 14, and pentakis(2-furyl)arsorane 15 have been examined by X-ray crystallography. Interestingly, 23 and 14 are not isomorphous. Compound 23 is propeller-shaped with approximate C3v symmetry. All three oxygen atoms occupy anti-periplanar positions relative to the lone electron pair on phosphorus. Compound 14 is likewise propeller-shaped, but with approximate Cs symmetry due to one 2-furyl group being rotated 180 relative to the corresponding 2-furyl group in 23. In both compounds, all three 2-furyl groups are nuclear magnetic resonance (NMR)-equivalent in the temperature range 20 to 50 C. Compound 15 with crystallographically imposed C2 symmetry is a rare example of a pentavinylarsorane. It forms a slightly distorted trigonal bipyramid, the twofold axis passing through one of the equatorial As–C bonds. This symmetry requires the corresponding 2-furyl group to be disordered over two orientations related by a 180 rotation about this As–C bond. ˚ are As predicted by VSEPR (¼ valence shell electron pair repulsion), the axial As–C bond lengths (2.054(2) A) ˚ significantly larger than the equatorial As–C bond lengths (1.936(2)–1.937(3) A) <2004JCD1610>.
Table 2 Carbon–element bond lengths in 2-elemento-substituted furans Compound
Element (E)
˚ C(2)–E (A)
Reference
14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
As As Au Au B Bi Ge Hg Ir P P P Pd Se Si Te Y
1.933, 1.933, 1.937 1.936, 1.936, 1.937, 2.054, 2.054 2.032(3) 2.117(3) 1.537 2.205, 2.212, 2.224 1.976 2.058 1.988 1.800, 1.802, 1.805 1.778 1.762, 1.763, 1.771 2.089(2) 1.887, 1.890 1.825 2.081, 2.084 2.436
2004JCD1610 2004JCD1610 2003OM4922 2003OM4922 2002EJI2942 2001MI3 2002MI183 1982AXB926 1994JOM(476)93 2004JCD1610 1997AXB317 2003ZNB751 1998JA11016 2000ZNB361 2000ZNB913 2000ZNB361 2002OM1759
Furans and their Benzo Derivatives: Structure
O As
O
AuPPh3
O
As
O
5
BF 4
O AuPPh3
15
14
AuPPh3
O
16
17
The crystal structures of 2-mono- and 2,2-diaurated furan derivatives have been examined in the light of the isolobal ˚ C(3)–C(4) analogy of [AuPR3]þ with Hþ. Compound 16 has the following bond lengths: C(2)–C(3) 1.358(5) A, ˚ C(4)–C(5) 1.330(6) A, ˚ C(5)–O 1.371(4) A, ˚ O–C(2) 1.401(4) A, ˚ C(2)–Au 2.032(3) A. ˚ For the corresponding 1.431(5) A, ˚ C(3)–C(4) 1.413(6) A, ˚ C(4)–C(5) 1.332(7) A, ˚ diaurated salt 17, the following values were found: C(2)–C(3) 1.379(6) A, ˚ ˚ ˚ ˚ ˚ C(5)–O 1.353(6) A, O–C(2) 1.415(5) A, C(2)–Au(1) 2.117(3) A, C(2)–Au(2) 2.117(3) A, Au(1)–Au(2) 2.8461(2) A. Thus, ˚ <2003OM4922>. the Au–Au distance in 17 is smaller than the interatomic distance in metallic gold (2.884 A) Tris(2-furyl)boron 18 is virtually planar unlike the propeller-shaped triphenylboron <2002EJI2942>. O
O
O
B
Bi
O
O
O Ge(tea)
O
18
19
O
20
O
O Se
P
22 O
Ph2P
P
Pd
PPh2 O
CH3 O
O
Ir(C6H8)2
O
O
O
O O
Hg
21
O P
O
24
25
26
O
cp*
O
Te
Si O O
O
27
I
23
Se Se
O
Te
Y O
O
O
29
cp*
30
O
NTs 2
31
28 In 2-(ditosylamino)furan 31, the symmetry of the furan nucleus is considerably distorted as evident from the bond ˚ C(2)–C(3) 1.334(4) A, ˚ C(3)–C(4) 1.447(5) A, ˚ C(4)–C(5) 1.290(6) A, ˚ C(5)–O 1.362(4) A. ˚ lengths: O–C(2) 1.347(3) A, <2004OL2405>. The C(4)–C(5) distance of 1.290(6) A˚ appears remarkably short and lies outside the range for corresponding bonds reported in data compilations for furan derivatives <1996CHEC-II(2.05)259>. In the crystalline state, N,N-dimethylbenzo[b]furan-2-carboselenoamide 32 displays a 44.4 dihedral angle between the aromatic plane and the selenoamide plane. The selenium atom occupies an approximately cisoid position relative to the oxygen atom <1994ICA(215)91>. For the analogous N,N-dimethylselenobenzamide, the corresponding dihedral angle is significantly larger, that is, 55–60 or 85–97 , depending on the particular solid-state conformation <1999POL3391>. NMe2 O
Se
32 As expected, solid furan-3-carboxylic acid consists of hydrogen-bonded dimers, but with an additional hydrogen bond linking the C(5)–H group of one dimer to a furan ring oxygen atom of a neighboring one <1996AXC342>.
393
394
Furans and their Benzo Derivatives: Structure
The crystal structure of dicyclohexyl furan-3,4-dicarboxylate is remarkable with regard to its less than perfect molecular symmetry. Thus, the lengths of formally equivalent bonds can vary, such as C(2)–C(3) 1.335 A˚ versus C(4)–C(5) 1.392 A˚ <1997JMT(403)1>. Not unexpectedly, 3-oxabicyclo[3.2.0]hepta-1,4-diene 33 is virtually planar. In both crystal modifications examined, symmetrically placed C–C bonds vary slightly in length <2000AXB697>. O
33 A test of the prediction of experimental crystal structures of 50 compounds with rigid molecules from calculated lattice energies obtained either by considering atomic charges (method A) or atomic multipoles (method B) has been carried out, the latter procedure giving the overall more satisfactory results. The four furan derivatives examined gave the following results. Compound 33: method A found no and method B one crystal lattice of lower energy than the experimental one; succinic anhydride: neither method found crystal lattices of lower energy than the experimentally found; phthalide: method A found two and method B no crystal lattices of lower energy than the experimental one; 3-nitrobenzo[b]furan: method A found no and method B two crystal lattices of lower energy than the experimental one <2005CGD1023>. The structural and chemical properties of furan-derived calixarenes such as 34 (n ¼ 1–6) have been reviewed <1999CEJ356>. Me Me
Me Me
O O
O O
Me Me
Me Me n
34 The O-bonded furan complexes [Cu(C4H4O)]þ, [Ag(C4H4O)]þ, and [Au(C4H4O)]þ have been generated and studied by a laser vaporization technique combined with a supersonic beam expansion in a time-of-flight (TOF) mass spectrometer. The ground-state binding energies were found as 37, 28, and 62 kcal mol1, respectively, and could be rationalized in terms of MP2/CCSD(T) single-point calculations <2001PCA9643>. Also, the analogous [Na(C4H4O)]þ, the 2,3,4,5-–bonded [Al(C4H4O)]þ, [Mg(C4H4O)]þ, [Sc(C4H4O)]þ, and [Ti(C4H4O)]þ, the 2,3,4,5-,O-bonded [Mn(C4H4O)]þ and [V(C4H4O)]þ, the 3,4--bonded [Cr(C4H4O)]þ and [Ni(C4H4O)]þ as well as the C3-bonded [Co(C4H4O)]þ and [Fe(C4H4O)]þ have been studied by radiative dissociation kinetics in a Fourier tranform ion cyclotron resonance (FT-ICR) spectrometer. The structures and binding energies of the complexes were also calculated by the DFT method. Furan was found to be a better p-binding ligand than benzene (by 5 kcal mol1), but inferior to pyrrole <2004PCA10897>. A binding energy of 0.13 eV has been found by coupled cluster and MP2 calculations for the Mulliken outer p-complex [(2,3,4,5-)-furan-O]mercury, Hg(C4H4O) <2005CPL(409)322>. Two clathrates of 2,2,6,6-tetraphenylhexa-2,4-diyne-1,6-diol with furan are unexpectedly dissimilar. In the case of ˚ the clathrated furan 2C30H22O2?C4H4O, where the guest molecules are placed in cavities of 5.2 5.5 6.0 A, ˚ ˚ ˚ C(4)–C(5) 1.234 A, ˚ molecules are dramatically distorted: O–C(2) 1.302 A, C(2)–C(3) 1.541 A, C(3)–C(4) 1.303 A, ˚ C(5)–O 1.412 A. In C30H22O2?2C4H4O, where the guest molecules are accommodated in channels formed by host molecules, the furan molecules are much more symmetric, but with substantially shortened formal single bonds: ˚ C(2)–C(3) 1.304 A. ˚ C(3)–C(4) 1.365 A, ˚ C(4)–C(5) 1.334 A, ˚ C(5)–O 1.357 A˚ <2001J(P2)2119>. O–C(2) 1.355 A, Somewhat distorted furan molecules are also seen in the clathrates [C29H23AsF3O4W]þ[PF6]?C4H4O <1999JOM120> and (C12H12Mn6O24)n?2nC4H4O (prepared from manganese(II) formate and furan) <2004CC416>.
3.05.3.2 Rotational Isomerism Calculations of the CIS, TD-B3LYP, and ZINDO type have shown that 2,29-bifuran 1 (n ¼ 2) and 2,29,20terfuran 1 (n ¼ 3) have both planar and distorted stable conformers in their S0 states, but planar structures in
Furans and their Benzo Derivatives: Structure
their S1 states <2005JMT189>. Similar conclusions were obtained by HF/6-31G and MP2/6-31-G calculations <2001JMT(572)141>. The rotational conformations of furfurylamine (furan-2-methanamine) have been examined by gas-phase electron diffraction, microwave spectroscopy, and theoretical calculations. At 298 K, an 87:13 ratio between a gauche- and a synisomer is found <1999PCA11460>. The equilibria between the OO-cis- and OO-trans-conformers of 3-, 4-, and 5-substituted furfurals have been examined by MP2/6-31G(d,p) calculations. The geometry of the furan nucleus appears little disturbed by the substitution pattern <2003JCC429>. In dimethyl sulfoxide (DMSO) solution, both C–C and C–N rotational isomerism was observed in 3-aminofuran-2carbaldehyde 35 (E/Z ratio 57:43), 3-aminofuran-2-thiocarbaldehyde 36 (E/Z ratio 78:22), 3-aminobenzo[b]furan-2thiocarbaldehyde 37 (E/Z ratio 72:28), and 2-aminobenzo[b]furan-3-thiocarbaldehyde 38 (E/Z ratio 55:45). Depending on the solvent the C–C rotational barriers of 35–38 were found at 16.2–22.2 kcal mol1 and the corresponding C–N rotational barriers at 8.4–13.0 kcal mol1 <1997JOC2263>. NH2
O
35
CHO
O
CHS
NH2
NH2
NH2
CHS
CHS
O
O
36
37
38
3.05.3.3 Structure and Conformation in Hydrofurans The manifest evolutionary advantages of -D-ribose over other potential nucleic acid sugar building blocks have been related to its unique stereochemical features in a review <2006MI189>. The hydrogen-bonded heterodimer THF?HCl has been investigated by molecular-beam Fourier transform (FT) microwave spectroscopy as well as by MP2/6-31G** calculations (THF ¼ tetrahydrofuran). Its three conformations are interrelated by one inversion movement and two pseudorotation movements <1999JCP6363>. The chiral cis-dihydrohelicene 39 has been found to lack a mirror plane, both in the gas phase (as calculated by MM in a CFF91 force field) and in the solid phase (as found by X-ray crystallography) <2001JOC200>. Br
O H
H O
Br
39 A clathrate with remarkably distorted 2,5-dihydrofuran guest molecules has been reported, that is, ˚ C(2)–C(3) 1.613 A, ˚ C(3)–C(4) 1.138 A, ˚ C(4)–C(5) [C24H14N2S9]þ[PF6]?C24H14N2S9?C4H6O: O–C(2) 1.450 A, ˚ ˚ 1.526 A, C(5)–O 1.616 A <2000JMA2716>. On the other hand, the 2,5-dihydrofuran guest molecules of the clathrate C20H20N2O4S2?C4H6O (prepared from N,N9-bis(p-tosyl)-p-phenylendiamine and 2,5-dihydrofuran) are fully sym˚ C(2)–C(3) 1.440 A, ˚ C(3)–C(4) 1.292 A˚ <1998ZNB1401>. metric with O–C(2) 1.434 A, The structures of mixed H2–THF clathrate hydrates, of possible relevance for medium-pressure hydrogen fuel storage, have been reviewed <2006AGE2011>.
3.05.3.4 Furans with Exocyclic Double Bonds Indigoid compounds such as (Z)-2-(3-thioxo-2(3H)-benzo[b]furanylidene)benzo[b]furan-3(2H)-thione 40 have been searched for for a long time. It has been shown that formal syntheses of compound 40 lead to the valence isomer [1,2]dithio[4,3-b:5,6-b9]bisbenzofuran 41, which in turn is in equilibrium with a bisdisulfide, the dimer [1,2,7,8]tetrathiacyclododecino[4,3-b:5,6-b9:10,9-b011,12-b-]tetrakisbenzofuran 42 (cf. Scheme 1).
395
396
Furans and their Benzo Derivatives: Structure
O
O
S
S
S
O
O
O S
O
40
S
S
S
S O
O
41
42
Scheme 1
In the solid state, as shown by X-ray crystallography, the dimer 42 is the only species present. This solid-state structure of compound 42 is characterized by an angle of 24 between the two C–C-linked benzo[b]furan planes in each half of the molecule (most likely due to O–O repulsions in the enforced cisoid configuration) and the two C–C ˚ single bonds of two nonequivalent molecules of compound 42 in the unit cell have lengths of 1.440 and 1.444 A, respectively <1995T8853>. These characteristic data can be compared with the structure of the parent 2,29bibenzo[b]furanyl 43, where the two corresponding rings are coplanar and the C(2)–C(29) bond length is 1.434 A˚ <2004OM3276>, that is, the twisting of the two ring planes of compound 42 leads to a marginal lengthening of the C(2)–C(29) single bond relative to the corresponding bond of the parent compound 43. O O
43 The structure of difluoromaleic anhydride (3,4-difluorofuran-2,5-dione) has been examined by microwave spectroscopy and found to be planar with C2v symmetry. The structural parameters show excellent agreement with those obtained by MP2/6-311þG* (2df) ab initio calculations <1999PCA1758>. In a crystallographic study of dichloromaleic anhydride (3,4-dichlorofuran-2,5-dione), the noncrystallographic molecular symmetry was determined as approximately C2v, the two chlorine atoms deviating slightly, that is, 0.0356(17) and 0.0167(17) , respectively, from the ring plane <2000AXCe273>.
3.05.3.5 Oligo- and Polyfurans The building block aromaticity of oligofurans 1 (n ¼ 2–8) as judged by NICS has been explored in, inter alia, DFT calculations <2002PCP1522, 2005JMT(726)189>. The calculated (B3LYP/6-31G* ) reorganization energy of the oligofurans 1, 44, 45, and 46 (all with n ¼ 2–6) appears to determine the intrinsic hole-transfer rate responsible for the semiconducting/conducting properties. With the exception of the oligobenzo[c]furans 46, the reorganization energy correlates linearly with the square root of n <2005JA2339>. R H
O
O H n
44
H
O
O
45
H n
H
O
H n
46
R = CF3, CN, F, NH 2
While oxidation of furan yields ill-defined polymers with severely interrupted p-conjugation, oxidation of 2,29,59,20-terfuran 1 (n ¼ 3) does produce fully p-conjugated polyfuran films. These films, when doped with trifluoromethanesulfonate ions, exhibit conductivities of up to 2 103 S cm1 and a gap of 2.35 eV between the
Furans and their Benzo Derivatives: Structure
valence band (highest occupied molecular orbital, HOMO) and the conduction band (lowest unoccupied molecular orbital, LUMO) <1993JA12519>.
3.05.4 Dipole Moments and Related Properties As determined with Stark effect measurements, difluoromaleic anhydride (3,4-difluorofuran-2,5-dione) possesses a dipole moment of 1.867(3) D <1999PCA1758>. The calculated dipole moment of the heterosumanene 12 amounts to 1.97 D, low compared to other heterosumanenes with less electronegative heteroatoms because of the opposite directions of the dipole vector due to the oxygen atoms and the one due to the carbon skeleton <2001JOC6523>.
3.05.5 Spectroscopic Characterization 3.05.5.1 Proton and 13C NMR Spectroscopy of Furans A protocol combining molecular dynamics and NMR spectroscopy gave excellent agreement between calculated and experimental nuclear Overhauser effect (NOE) buildup curves of 2,5-oligo(2-thienyl)furans <2002PCA1277>. A 1H and 13C NMR study of 45 substituted furans, combined with PM3 molecular orbital (MO) semi-empirical calculations, has been employed to establish a consistent pattern of substituent-induced chemical shifts <1998J(P2)679>.
3.05.5.2 Proton and 13C NMR Spectroscopy of Modified Furans 3.05.5.2.1
Hydrofurans and their benzo derivatives
The absolute configurations of the natural butenolides 47 and 48 <2003T3237> as well as 49 <2000CPB559> have been determined by elaborate NMR spectroscopy as well as X-ray crystallography.
O
Et Me
HO
O
OH
Me
Pri
R
Me
HO O
O
Me
O
R
47
48
R = H, OH
R = H, OH
Me
COOMe O O
OH
OH
49
3.05.5.2.2
THF derivatives
The structure elucidation of carbohydrates, including furanoses, by, inter alia, NMR methods has been reviewed <2001MI3, 2001MI312, 2002MI334, 2003MI749>. The envelope conformation of a series of D-aldofuranoses has been established by comparison of experimental and calculated intermediate neglect of differential overlap (INDO) 13C–13C NMR coupling constants <2003RJO1764>.
3.05.5.2.3
Furans with exocyclic double bonds
The (E)-structure of the natural antioxidant marginalin 50 has been established by comparison with analogous synthetic isoaurones as well as by 1H and 13C NMR spectroscopy <2006T9855>. The characteristic H(4)–H(5) 1H NMR coupling constants of the 3-oxabicyclo[3.2.0]heptane derivatives anti-51 3 ( JH,H ¼ 1.3 Hz) and syn-51 (3JH,H ¼ 5.6 Hz) have been used to establish the structural assignments for these isomers <2006OL491>. The structure of the rearranged cembrane derivative ciereszkolide 52 has been elucidated by onedimensional (1-D) and 2-D NMR spectra, high-resolution fast atom bombardment mass spectrometry (HRFAB-MS), infrared (IR), and ultraviolet (UV) as well as by single crystal X-ray analysis <2004EJO3909>.
397
398
Furans and their Benzo Derivatives: Structure
The structure of tornabeatin A 53 could be determined by means of 1-D and 2-D NMR, UV, IR, and MS spectroscopy <2004P2605>. The structure of isopestacin (3-(2,6-dihydroxyphenyl)-7-hydroxy-5-methylbenzo[c]furan-1(3H)-one) 54 has been derived by 1H and 13C NMR spectroscopy and further confirmed by X-ray crystallography <2002P179>. HO
O
HO O
O
O
O
O
HO
anti-51
syn-51
HO
50 Me O O
OMe O
Me
OH
CH 2
Me
O
H H
O
O
OAc
Me
O
52
OH HO
Me
54 O
O
HO
53
3.05.5.3 Oxygen-17 NMR Spectroscopy of Furans Three fluorinated analogs of the herbicide endothall 55, that is, compounds 57–59, have been characterized by 17O NMR spectroscopy (cf. Table 3). 1
O
1
O
O
3
O
1
1
1
O
O
COOH
COOH
COOH O2
COOH
55
O3
56
O2
F COOH
F F COOH
F
57
58
59
Table 3 17O NMR data for endothall 55, the anhydride 56, and the fluorinated analogs 57–59 ( in ppm; 49 MHz, 333 K, CH3CN, external standard: 1,4-dioxane) Compound
O1
55 56 57 58 59
83.4 81.6 87.7 72.1 79.2
O
O2
O3
304.1
371.8
COOH 260.0 257.3 259.9
302.2
377.0
O3
3
Furans and their Benzo Derivatives: Structure
It could be concluded that the difluoro compound 58, contrary to the monofluoro compound 57, possesses an increased electron density at O1 relative to the parent compound 55, tantamount to an electron-donating -effect of the fluorine substituents. On the other hand, the fluorine substituent of compound 59 appears to cause a decrease of the electron density at O3 relative to that in 56 <2003TL5429>. In a study of the density-dependent 17O NMR magnetic shielding in 33 inorganic and organic oxygen compounds, data for furan and 2-methylfuran are provided (at 333 K, H2O as external standard). The gas-to-liquid shifts GL for these two compounds are rather small, 2.4 and 3.2 ppm, respectively. The negative signs are characteristic for dicoordinate oxygen <2003JMT(651–653)265>.
3.05.5.4 Mass Spectrometry The use of MS in food analysis has been reviewed <1997MI239>. Time-of-flight (TOF) mass spectra of furan and furan-d4 have been recorded and interpreted <1998CPH(236)365>.
3.05.5.5 Photoelectron Spectroscopy An examination of the photoelectron (PE) spectra of 42 five-membered heteroaromatics and simple derivatives thereof, including furan and furan derivatives, showed only minor perturbations of the aromatic structures by the substituents <1993MI811>. Threshold PE spectra as well as photoabsorption and photoion spectra of furan and furan-d4 have been measured and interpreted <1998CPH(236)365, 2001CPH(263)149>. Furan adsorbed on a Si(111) 7 7 surface has been examined by X-ray photoelectron (XPE) spectroscopy. A surface-parallel p-bonded geometry in the preferred state and a -bonded geometry through the oxygen atoms in the less preferred state were found <2000MI212>. Furan and 2-methylfuran <2003JCP3670> as well as furfuryl alcohol (furan-2-methanol) <2003JCP7282> have been thoroughly examined by PE spectroscopy. It could be concluded that both the methyl group and the hydroxymethyl group affect the frontier molecular orbitals of furan only slightly. A theoretical study has established the usefulness of the NDDO-G approximation for the calculation of the excitation energies of a large number of heterocycles including furan and compared the results with those of INDO/S, AM1, and PM3 calculations as well as with the experimental values <1999PCA4553>.
3.05.5.6 Electronic Spectra Furan and 2-methylfuran <2003JCP3670> as well as furfuryl alcohol (furan-2-methanol) <2003JCP7282> have been thoroughly examined by UV spectroscopy. It was concluded that both the methyl group and the hydroxymethyl group affect the frontier molecular orbitals of furan only slightly. The 2,5-linked bi- to quinquefurans 1 (n ¼ 2–5) (together with their thiophene analogs) have been thoroughly examined with regard to their photophysical behavior. In acetonitrile solution at 273 K, the UV absorption max increases regularly from 209 nm for furan to 382 nm for 2,29:59,20:50,2-:5-,2--quinquefuran 1 (n ¼ 5) <2000PCA6907>. A theoretical study has confirmed the usefulness of the NDDO-G approximation for the calculation of vertical transitions in the ultraviolet–visible (UV–Vis) spectra of a large number of heterocycles including furan and compared the results with those of INDO/S, AM1, and PM3 calculations as well as with the experimental values <1999PCA4553>. Inner-shell electron energy loss spectroscopy (ISEELS) has been used to record the K-shell spectra of gaseous furan <2003JCP8946> and of 2,5-dihydrofuran <2005CPH(310)67> at the carbon and oxygen thresholds. Differential cross sections for elastic scattering of electrons from THF have been determined together with vibrational and electronic energy loss spectra. Band assignments were verified by CI calculations <2005MI411>. The vacuum UV absorption spectrum of 2-vinylfuran has been recorded and interpreted. The electronically excited molecule was found to behave like a linear polyene rather than like furan <2004JCP10972>.
3.05.5.7 IR Spectra Scaled quantum-mechanical force fields for furan (and thiophene) and its isotopomers have been calculated with the B3LYP/6-31G** method. Corresponding MP2 and HF calculations gave less satisfactory results. Excellent agreement
399
400
Furans and their Benzo Derivatives: Structure
between calculated and experimental IR absorption intensities was observed with the exception of the C–H and C–D stretching modes <1997SAA1365>. Theoretical IR intensities of the fundamental, overtone, and combination transitions in furan (as well as pyrrole and thiophene), obtained by MULTIMODE and second-order perturbation calculations, have been compared with experimental data <2004PCP340>. IR and FT-Raman spectra, combined with BPW91/6-311þG* calculations, show that the anti-forms of 5-(4-bromophenyl)furan-2-carbaldehyde <2003MI213> and 5-(4-fluorophenyl)furan-2carbaldehyde <2002MI235> are preferred over the respective syn-forms. Time-resolved IR spectroscopy has been used to study the equilibria between 1- and 2-bound pentacarbonylchromium and pentcarbonylmolybdenum complexes with 2,3-dihydrofuran and 2,5-dihydrofuran, respectively <2002OM5657>.
3.05.6 Thermodynamic Aspects 3.05.6.1 Aromaticity The popular, but not uncontested, ring current concept which links a diamagnetic ring current to aromaticity and a paramagnetic ring current to antiaromaticity of planar ring systems has been reviewed <2001CRV1349>. The alternative, and likewise controversial, nucleus-independent chemical shift (NICS) approach which uses nuclear magnetic shielding/deshielding criteria as a measure of planar ring aromaticity has also been updated in a review <2005CRV3842>. The merits of NICS, obtained by an upgraded computational protocol, as a measure of the aromaticity, nonaromaticity, or antiaromaticity of, inter alia, planar five-membered heterocycles (including furan) have been discussed. The subtypes NICS(0)pzz and NICS(1)zz appear to perform most reliably in providing a linear relationship with aromatic stabilization energies (ASEs) <2006OL863>. Quantum-chemical calculations (MP2, HF) concerning the aromaticity of 15 five-membered heterocycles, including furan, have been performed based on both semihomodesmic (SEH) and superhomodesmic (SUH) reactions, the former being preferable. The double-bond character index for furan was found to be 0.553 versus 0.475 for cyclopenta-1,3-diene and 0.627 for thiophene <1995JMT(358)55>. Furan, benzo[b]furan, benzo[c]furan, and the isomeric furofurans 60–63 have been the subject of detailed B3LYP/ 6-311G** calculations. The oxygen atoms could be shown to prefer positions corresponding to the positions of maximal negative charge in the parent compounds indenyl anion (C9H7) and pentalene dianion (C8H62), respectively. The relative thermodynamic energies were found as follows: benzo[b]furan (0.0 kcal mol1), benzo[c]furan (14.2 kcal mol1) and furo[3,2-b]furan 60 (0.0 kcal mol1), furo[2,3-b]furan 61 (0.7 kcal mol1), furo[3,4-b]furan 62 (2.5 kcal mol1), 1H-furo[3,4-c]furylium ylide 63 (22.6 kcal mol1). At the same time, it was concluded from the calculated magnetic susceptibilities that all furan rings in this series possess considerable aromaticity regardless of the variations in relative thermodynamic energy <1996AGE2638>. The heteropentalenes 60–63 have also been shown by near-HF estimates to exhibit intense diamagnetic circulation of the p-electrons in a magnetic field normal to the molecular plane. A diatropicity matrix could be established <2004JCP6542>. O O O
O
60
O
O
O
O
62
61
63
The benzo[c]furan derivative 64 has been shown to be only marginally diatropic, another indication of furan being the least aromatic of the simple five-membered heterocycles <1996JOC935>.
Me
Me
O Me
Me
64
Furans and their Benzo Derivatives: Structure
3.05.6.2 Tautomerism The tautomeric equlibrium between naphtho[2,3-c]furan-4(9H)-one 65 and naphtho[2,3-c]furan-9-ol 66 (together with that of related systems) has been briefly reviewed <2005T9929> and exemplified in the case of 5,8-dihydroxynaphtho[2,3-c]furan-4,9-dione <2005AJC600>. O
OH O
O
65
66
The two potential glutaric anhydride enols, the monoenol 67 and the dienol 68, are disfavored by 24.1 and 41.1 kcal mol1, respectively, as shown by B3LYP/6-31G** calculations. This is in spite of the aromatic stabilization of 68 and in line with the general instability of anhydride enols <2001HCA1405>.
O
OH
O
HO
67
OH
O
68
Quantum-chemical (DFT, B3LYP/6-31G* ) calculations have been performed to determine the relative stabilities of the tautomer pairs 69/70 (gas-phase reaction enthalpy: calculated 1.2 kcal mol1, experimental value in diethyl ether 1.1 0.1 kcal mol1), 71/72 (gas-phase reaction enthalpy: calculated 2.1 kcal mol1), and 73/74 (gas-phase reaction enthalpy: calculated 2.6 kcal mol1, experimental value in dipentyl ether 1.9 0.1 kcal mol1). In all cases, the tautomer with the endo CTC bond is strongly favored over the one with the exo CTC bond. Because of the overwhelming stability of 2,5-dimethylfuran versus tetrahydro-2,5-bismethylenefuran 71 and 2,3-dihydro-5-methyl2-methylenefuran 72, the equilibrium 71 ! 72 cannot be observed experimentally <2001STC405>.
O
CH2
O
70
69
CH 2
O
CH2
CH2
71
O
O
Me
O
Me
72
CH 2
O
O
Me
74
73
It has been demonstrated that the racemic natural product 4-hydroxy-2,5-dimethylfuran-3(2H)-one (HDMF, furaneol, pineapple ketone) 75 probably is formed by in vivo racemization of a biosynthetically formed enantiomer. Biosynthesis at pH 5 leads to enantiomerically enriched 75. At pH 7.2, 50% of the C-2 hydrogen atoms are exchanged with D2O within 1 h <2003CH573>. HO Me
O
O
75
Me
401
402
Furans and their Benzo Derivatives: Structure
3.05.6.3 Linear Free Energy Relationships The 2-furyl group has been characterized as a substituent in classical Hammett-type studies involving the ionization of substituted benzoic acids, the ionization of substituted phenols, and the solvolysis of 1-arylethyl acetates. The values found (m þ0.06, p þ0.02; m þ0.11, p þ0.21; mþ þ0.10, pþ 0.39) show that the 2-furyl group is inductively electron withdrawing, while its resonance effect allows electron donation as well as electron withdrawal (the former effect being significantly stronger than the latter). By and large, the 2-furyl substituent behaves very much like 2-thienyl <1971JCB2304>. Corresponding studies of 5-substituted 2-furoic acids 76 <1964T1913> and 5-substituted 3-furoic acids 77 <1976JOC2350> have shown that the furan nucleus is a better transmitter of substituent effects than the benzene ring. COOH R
O
76
COOH
R
O
77
The two triarylphosphine series Ph3P, Ph2(2-C4H3O)P, Ph(2-C4H3O)2P, (2-C4H3O)3P 23 (a transition metal catalysis ligand superior to Ph3P) and Ph3P, Ph2(3-C4H3O)P, Ph(3-C4H3O)2P, (3-C4H3O)3P have been investigated spectroscopically (IR, 31P NMR), crystallographically, and by B3LYP/TZ2P quantum-chemical calculations. It could be concluded that both 2-furyl and 3-furyl groups are more electron-withdrawing than phenyl groups. The counterintuitive concomitant 31P NMR deshielding of the phosphorus atom by furyl groups relative to phenyl groups could ˚ compared to P–C(phenyl) bonds (1.79 A) ˚ in the corresponding be correlated to shorter P–C(2-furyl) bonds (1.76 A) ethylphosphonium iodides EtR3PI <2006JA8434>.
3.05.6.4 Gas Chromatography Quantitative structure–retention relationships (QSSRs) have been established for polychlorinated dibenzofurans to assist their determination by gas chromatography (GC) <2002MI7, 2003ANC1049, 2005MI1683>.
3.05.7 Further Developments The intriguing cationic system 78, the benzo[a]furan 3a-oxonia-3aH-indene, has so far neither received experimental nor theoretical attention, but was in 2007 recognized by Chemical Abstracts as a ring parent and assigned RN 92176232-5 <2007MI1>.
The crystal structure of 1-(-D-erythrofuranosyl)cytidine, the des(hydroxymethyl) analog of -cytidine, has been determined and used to correlate the preferred conformations of furanoses in solution with those in the solid state. Conformational similarities and differences of tetrofuranoses vs. pentofuranoses have been charted as well <2007AXCo137>. Gloriosaol A and gloriosaol B, two isomeric spirobibenzo[b]furans found in the plant Yucca gloriosa, could be shown to be diastereoisomers rather than atropisomers by comparison of their experimental 1H NMR data with computed NMR data (MPW91PW91 with a 6-31G-(d) basis set) <2007T148>. Fluorophores containing the dicyanomethylenedihydrofuran moiety such as 79 have been investigated with regard to their value as single-molecule fluorescence imaging agents. Their X-ray crystal structures were correlated with their absorption and fluorescence emission wavelengths as well as the corresponding quantum yields <2007T103>.
Furans and their Benzo Derivatives: Structure
Smaragdyrin–azobenzene conjugates of the type 80 have been crystal structure determined and studied with respect to their photochemical and electrochemical behavior. It could be concluded that the relatively electronwithdrawing azobenzene moiety is responsible for a corresponding energy transfer to the smaragdyrin p-system <2007EJO191>.
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405
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Biographical Sketch
Alexander Senning was born in 1936 in Riga, Latvia. He studied chemistry at Munich, Germany (1954–59), and Uppsala, Sweden (1960–62). He obtained a Ph.D. in organic chemistry from Uppsala University (1962), joined the Department of Chemistry, Aarhus University, Denmark, as assistant professor (1962–65) and served as associate professor during 1965–93. During a sabbatical leave (1973–75), he was head of the research laboratory of the drug company A/S Alfred Benzon, Copenhagen, Denmark. He joined the Danish Engineering Academy (DIA), Lyngby, Denmark, later part of the Technical University of Denmark (DTU), Kgs. Lyngby, Denmark, as professor of organic chemistry in 1993, until his retirement in 2003. Alexander Senning is also the author of Elsevier’s Dictionary of Chemoetymology, published in 2006. Research interests include organic sulfur chemistry and medicinal chemistry. He has been intensively involved as a book and journal editor.
3.06 Furans and their Benzo Derivatives: Reactivity H. N. C. Wong The Chinese University of Hong Kong, Hong Kong, People’s Republic of China K.-S. Yeung Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA Z. Yang Peking University, Beijing, People’s Republic of China ª 2008 Elsevier Ltd. All rights reserved. 3.06.1
Introduction
408
3.06.2
Reactivity of Fully Conjugated Rings
408
3.06.2.1
Reactivities of Furans
3.06.2.1.1 3.06.2.1.2 3.06.2.1.3 3.06.2.1.4 3.06.2.1.5 3.06.2.1.6 3.06.2.1.7 3.06.2.1.8 3.06.2.1.9
3.06.2.2
Reactivity of Fully Conjugated Benzo[b]furans
3.06.2.2.1 3.06.2.2.2 3.06.2.2.3 3.06.2.2.4 3.06.2.2.5 3.06.2.2.6 3.06.2.2.7 3.06.2.2.8
3.06.2.3
3.06.3.1
Reactions with electrophiles Reactions with oxidants Reactions with reductants Reactions as nuclear anion equivalents Reactions catalyzed by metals and metallic derivatives Reaction involving free radicals Cycloaddition reactions Photochemical reactions
Reactivity of Fully Conjugated Benzo[c]furans
3.06.2.3.1 3.06.2.3.2
3.06.3
408
Reactions with electrophiles Reactions with nucleophiles Reactions with oxidants Reactions with reductants Reactions as nuclear anion equivalents Reactions catalyzed by metals and metallic derivatives Reactions involving free radicals Cycloaddition reactions Photochemical reactions
Cycloaddition reactions Miscellaneous reactions
439 439 443 444 444 446 449 450 452
454 455 462
Reactivity of Nonconjugated Rings
462
Reactivity of Dihydrofurans and Tetrahydrofurans
3.06.3.1.1 3.06.3.1.2
408 417 418 422 423 424 428 429 437
Reactions of 2,3-dihydrofurans and 2,5-dihydrofurans Reactions of tetrahydrofurans
462 462 468
3.06.3.2
Reactivity of Dihydrobenzo[b]furans
472
3.06.3.3
Reactivity of Dihydrobenzo[c]furans
473
3.06.4
Reactivity of Substituents Attached to Ring Carbons
478
3.06.4.1
Alkyl and Substituted Alkyl Substituents
478
3.06.4.2
Carboxylic Acids and Their Reactions
480
3.06.4.3
Acyl Substituents and Their Reactions
480
Heteroatom-Linked Substituents and Their Reactions
481
3.06.4.4 3.06.5
Further Developments
483
References
485
407
408
Furans and their Benzo Derivatives: Reactivity
3.06.1 Introduction The chemistry of furans, their benzologs, and their derivatives was covered in CHEC(1984) <1984CHEC(3)599> and in CHEC-II(1996) <1996CHEC-II(2)297>. This chapter is intended to update the previous work concentrating on major new reactions published in 1996–2006. Attention is placed on the more interesting reactivities of these compounds, instead of executing an exhaustive literature search of all relevant articles that were recorded in 1996– 2006. A number of books , book chapters <1997PHC117, 1998PHC129, 1999PHC144, 2000PHC134, 2001PHC130, 2002PHC139, 2003PHC167, 2004PHC156, 2005PHC142>, and reviews were published which are concerned with the chemistry of furans, benzofurans, and their derivatives.
3.06.2 Reactivity of Fully Conjugated Rings 3.06.2.1 Reactivities of Furans 3.06.2.1.1
Reactions with electrophiles
3.06.2.1.1(i) Protonation Interesting intra- and intermolecular transformations involving oxonium ions formed by protonation of furan rings were shown to lead to elaborated ring systems. As shown in Scheme 1, interception of a transient cation by the pendant hydroxyl group led to the ketone intermediate 1, which further cyclized to provide the tetracyclic isochromene product <2005TL8439>.
OH
MeO
MeO
MeO
O
O
HCl
O
O
EtOH reflux 70%
O
O
O
1 Scheme 1
As exemplified in Scheme 2, a one-pot C-5-benzylation/eliminative cyclization of N-tosylfurfurylamine with electron-rich benzyl alcohols in strong acids under refluxing conditions provided indole derivatives in modest yield <2005TL8443>. Presumably, the indole ring was formed via trapping of the cation 2, generated by the loss of the furan N-tosyl group in the benzylated intermediate, by the aniline nitrogen.
MeO MeO
NHTs OH
O NHTs
MeO
Ts N O
MeO Scheme 2
H3PO4
MeO
AcOH reflux 46%
MeO
NHTs
+ O +
2
Furans and their Benzo Derivatives: Reactivity
3.06.2.1.1(ii) Alkylation As illustrated in Equation (1), a Lewis acid-promoted intramolecular conjugate addition of a furan to a dienone was used to generate the seven-membered ring of the fused tricyclic framework of sesquiterpene echinofuran <2003T1877>. The use of Et2AlCl provided the best result, minimizing undesired polymerization of the furan substrate 3. O
O Et2AlCl O
PhMe 0 °C, 10 h 65%
3
ð1Þ O
An intramolecular Friedel–Crafts alkylation of a furan was employed to construct the unusual bicyclo[6.1.0]nonane skeleton of the crenulide diterpenoids. As shown in Equation (2), the formation of the eight-membered ring under the Lewis-acidic conditions proceeded in high yield and without resorting to high dilution <2003JOC9487>. O
HO2C
O H
Me2AlOTf
R
H
H
R
ð2Þ
ClCH2CH2Cl 85 °C, 24 h R = H, 86% R = Me, 83%
O
O
Asymmetric carboselenenylation of furans was achieved by using the C2-symmetric selenenyl triflate 4, as shown in Equation (3). The reaction was only effective for styrene derivatives <2005AGE3588>.
O
OMe SeOTf
+
Ph (10 equiv)
+
Ph 4 Å MS CH2Cl2 −78 °C, 2 h 73%
O
OMe
4
OMe
ð3Þ
Se MeO
dr = 91:9
Kinetic investigations of the electrophilic substitution of 2-(trialkylsilyl)furans <2001OL1629> and 2-(tri-n-butylstannyl)furan <2001OL1633> with benzhydryl cations suggested that 2-organometallic groups activate the 5-position to a much greater extent than the 2-position. Therefore, the apparent electrophilic ipso-substitution was the net result of electrophilic substitution at the 5-position followed by protodemetallation.
3.06.2.1.1(iii) Reactions with aldehydes and ketones Electron-rich furans were found to condense with aryl aldehydes under mild AuCl3-catalyzed conditions, forming triheteroarylmethanes as exemplified in Equation (4) <2005OL5857>. This reaction was applied to the synthesis of dendritic structures.
CHO AuCl3 (1 mol%)
+ O
N H
MeCN rt 77%
O
O
ð4Þ HN
409
410
Furans and their Benzo Derivatives: Reactivity
1-(3-Furanyl)ethanol derivatives participated in acid-catalyzed oxa-Pictet–Spengler reaction with aldehydes to give cis-5,7-disubstituted 4,5-dihydro-7H-furano[2,3-c]pyrans under kinetic control, as illustrated in Equation (5) <2002S1541>. p-TsOH (1 mol%) MgSO4
O
O
OH
+
O
O
H
ð5Þ
MeCN rt, 2 h 76%
The syn-selective vinylogous Mukaiyama aldol addition of 2-trimethylsilyloxyfuran to aldehydes, and the corresponding anti-selective addition to aldimines as well as their synthetic applications were extensively reviewed <1999SL1333, 2000CSR109, 2000CRV1929>. The aldol addition of 2-trimethylsilyloxyfuran to achiral aldehydes in the presence of a catalytic amount of BINOL–titanium complex was discovered to undergo asymmetric autoinduction by the -hydroxy--butenolide products formed, leading to higher yields and better enantioselectivity (BINOL ¼ 1,19-bi-2-naphthol) <2000AGE1799>. This reaction, when catalyzed by the C2-symmetric chromium(salen) complex 5, produced an enantiomeric excess (ee) of up to 97% for the major syn-isomer in the presence of isopropanol (salen ¼ N,N9-bis(salicylaldehydo) ethylenediamine) <2003CL974>. A typical example of this process is shown in Equation (6). However, these catalytic systems for the enantioselective addition to aldehydes have not been shown to be generally applicable, and the syn/anti-diastereoselectivity would require further improvement. The less well studied 3-trimethylsilyloxyfurans were also shown to react with aldehydes at the 2-position in an aldol addition manner under Lewis-acidic conditions. High syn-diastereoselectivity was obtained with bulky aldehydes as shown in Equation (7) <2005OL387>.
– SbF6 N + Cr
N
O
O Ph Ph
ð6Þ
5 (2.5 mol%) PriOH
O + Me3SiO
O
H
Ph
HO O
CH2Cl2 0 °C, 24 h 86%
Ph
O
+
HO O
Ph syn: 93% ee syn:anti = 85:15
O
anti
O OSiMe3 + CH3(CH2)5
O
O
BF3·Et2O
H CH2Cl2 −78 °C 99%
OH CH3(CH2)5
O
ð7Þ
syn:anti = >95:5
Furfurylamine derivatives could be prepared, via an in situ-generated aldimine intermediate, by treatment of an aldehyde and N-sulfinyl-p-toluenesulfonamide with furan in the presence of ZnCl2 <2003T4939>. As shown in Equation (8), enantioselective addition of 2-methoxyfuran to aldimines was achieved using the chiral C2-symmetric phosphoric acid 6 as an organocatalyst <2004JA11804>. This reaction uniformly provided 94% ee irrespective of the substitution pattern on the aldimine phenyl ring.
Furans and their Benzo Derivatives: Reactivity
Ar O
O P
O
OH
Ar
ð8Þ
6 BOC +
(Ar = 3, 5-dimesitylphenyl) (2 mol%)
N
O
MeO
H
NHBOC O
MeO
ClCH2CH2Cl −35 °C, 24 h 96%
97% ee
The Lewis acid-catalyzed addition of 2-trimethylsilyloxyfuran to N-gulosylnitrones was shown to be diasteroeselective <2002OL1111, 1997T11721>. In particular, the reaction with the D-glyceraldehyde-derived gulosylnitrone 7, shown in Equation (9), provided tetrahydrofuro[2,3-d]isoxazol-5(2H)one 8 as the predominant product, which was converted into a ribofuranosylglycine precursor to polyocin C <2002OL1111>.
O O
H
O
H H
OSiMe3 + O
O
H Me3SiOTf (10 mol%)
O
CH2Cl2 −78 °C 72%
O
O
O
7
O
HH O
O
O N + O –
O
O O H N O
H
ð9Þ
O
8 dr > 97:3
Structural characterizations of reaction intermediates and products of the addition of 2-trimethylsilyloxyfuran to naphthoquinones <1998TA1257> and benzoquinones <1999TA4357> to form furanofuranones indicated that the reaction proceeded via Michael addition, rather than Diels–Alder cycloaddition, in which the type of intermediate 9 shown in Scheme 3 was observed by proton nuclear magnetic resonance (NMR) spectroscopy.
MeO
MeO
HO
O S + Me3SiO
S O
H CHCl3 –20 °C, 3 h 90% dr = 90:10
O O MeO
O O O
OH
9
HO S
O
H O O H
O
Scheme 3
A syn-selective, organocatalytic, enantioselective vinylogous Mukaiyama–Michael addition of 2-trimethylsilyloxyfuran to ,-unsaturated aldehydes to produce -butenolides was achieved by using a chiral amine catalyst
411
412
Furans and their Benzo Derivatives: Reactivity
<2003JA1192>. The methodology was adopted to prepare the key intermediate 11 using the catalyst 10 in a formal total synthesis of campactin <2006OL597>, as depicted in Scheme 4. This type of reaction was extended to incorporate a chlorination reaction of the enamine intermediate in the reaction cycle as shown in Equation (10). Furans also function as effective nucleophiles in such catalytic organocascade reactions <2005JA15051>. Me
O N Ph N H
+ Me3SiO
CHO
Me3Si
O
Me3Si
H2O–CHCl3 –40 °C 95%
OH HO
O H O
10
H
CHO
11
syn:anti = >30:1 82% ee
Scheme 4
Me
O
Bn N
N
Me3SiO
O
Cl
Cl Cl
O
O Cl
O
(10 mol%)
Cl
+
H
N H
O
Me
ð10Þ O
EtOAc −55 °C 71%
Cl Cl
Me
H
dr > 24:1 >99% ee
3.06.2.1.1(iv) Reactions with diazonium salts and diazo compounds The copper(I)-catalyzed asymmetric cyclopropanation of methyl furan-2-carboxylate with ethyl diazoacetate was achieved by the use of the bisoxazoline ligand 12 to provide the exo-isomer of 2-oxa[3.0.1]bicyclohexene 13, as shown in Scheme 5 <2003CEJ260>. The product was transformed into 1,2,3-trisubstituted cyclopropane by ozonolysis
O
O N But
N
12
But
(2.5 mol%) Cu(OTf)2 (2 mol%) PhNHNH2 (2 mol%)
EtO2C + O
N2
CO2Me
CH2Cl2 0 °C
OCOCO2Et
2 steps O
CHO Scheme 5
O
EtO2C H
O
CO2Me
13 CHO
EtO2C
O3 DMS
H
91% ee recrystallization 53%, >99% ee
CH2Cl2 –78 °C 94%
Furans and their Benzo Derivatives: Reactivity
<2000EJO2955>, and then elaborated to -butyrolactones by a two-step sequence comprising of allylsilane addition and retro-aldol lactonization <2003CEJ260>. This methodology was applied to the asymmetric synthesis of paraconic acids <2003CEJ260>, (–)-roccellaric acid <2001OL1315>, the fused cyclic ring systems of xanthanolides, guaianolides, and eudesmanolides <2003OL941>, and the cis-fused 5-oxofuro[2,3-b]furan core of spongiane diterpenoids <2005OL5353>. Rh2(OAc)4-catalyzed intermolecular addition of ethyl diazoacetate to 2-methylfuran proceeded on the 4,5-double bond of the furan ring, leading to ethyl 6-oxo-2,4-heptadienoate, with a 19:1 regioselectivity. The corresponding reaction with 3-methylfuran gave a low 2:1 regioselectivity, although still favoring the unsubstituted side. Consistently, reaction with 2,4-dimethylfuran predominantly occurred at the 4-methyl side of the furan nucleus, as shown in Equation (11) <1999TL5171>. These results are in accord with a mechanism involving nucleophilic attack on the carbenoid carbon by the more nucleophilic furan C-2-position. The reactions of other 2-methyl analogs of furan also exhibited similar regioselectivity <1999TL5439>. These types of reactions were also performed on 2-methoxy- and 2-trimethylsilyloxyfurans using aryl diazoketones to give 6-aryl-6-oxo-(2Z,4E)-hexadienoates and 6-aryl-6-oxo-(2Z,4E)-hexadienoic acids, respectively, using Rh2(OAc)4 as catalyst <2001T7303>, as well as with diazoarylacetates using pentacarbonyl(2-cis-cyclooctene)chromium(0) as a catalyst <2004JOM2662>. O Rh2(OAc)4
+
OEt
O
+ O
O
CH2Cl2 rt, 10 h
N2
CO2Et
ð11Þ
H
CO2Et
Trace
>80%
1-Diazo-3-(3-furanyl)-2-propanone underwent intramolecular metal carbenoid addition and, subsequently, the typical rearrangement to provide a 1,6-dicarbonyl product. However, as shown in Scheme 6, the cyclopropane intermediate 15 formed during the reaction of the isomeric 1-diazo-3-(2-furanyl)-2-propanone 14 underwent a Wolff-type rearrangement to give 2-(2-methylfuranyl)acetic acid as the major product in the presence of water <1998JOC9828>. When the tether was constrained by the introduction of a fused ring, the usual rearrangement occurred and was exploited for the synthesis of [6,6], [6,5], and even [6,4]-fused ring systems, as exemplified in Scheme 7 <2005HCA330>.
CO2H
O
N2
Rh2(OAc)4
O
CH2Cl2 H2O rt, 1 h
O
14
O
•
O O
60% + O
O O
15
O 15%
Scheme 6
O
N2
O
Rh2(OAc)4 O
CH2Cl2 15 min CHO
O I2 CH2Cl2 rt, 1 h 83%, 2 steps
O
Scheme 7
Intramolecular addition of more elaborated diazoacetates and diazoketones to a pendant furan moiety are more complex <1997TL5623>. 2-Substituted substrates uniformly provided the 2,4-diene-1,6-dicarbonyl products. Products of 3-substituted substrates depended on the structure of the diazocarbonyl and the rhodium catalyst used. For example,
413
414
Furans and their Benzo Derivatives: Reactivity
in contrast to the reaction of diazomalonate 16 (Scheme 8), reaction of the diazoacetoacetate 17 produced the fused tricycle 19, presumably as a result of [3þ2] annulation of the intermediate 18. This type of transformation was exploited in the construction of the [6,7]-fused ring system of guanacastepenes, as shown in Equation (12) <2003OL4113>. Furans tethered with diazocarbonyl moieties to the 2-position were also used for generating macrocyclic rings <1999OL1327>. Regioselectivity with respect to addition to furan 2,3-double bond was dependent on the metal catalyst, as well as the inherent selectivity differences between diazoacetates and diazoketones used. O
O
O Rh2(O2CC9H19)4
N2 O
R O
R = OEt 62%
O EtO2C
CH2Cl2
16: R = OEt 17: R = Me
R = Me 78%
O
+
O
O
H O
O
O
O
18
O
O
19
Scheme 8
O
Me
Me
EtO2C
Rh2(OAc)4 O
N2
OSiButPh2 O
CH2Cl2 rt 50%
OSiButPh2
EtO O
H
O
ð12Þ
Ruthenium and platinum carbenoids, derived from tertiary propargyl carboxylates, also reacted with furans in a similar manner, leading to triene systems (as represented in Scheme 9) <2006OL1741>. The initially formed mixture of (2Z,4E) and (2Z,4Z) isomers 20 and 21, respectively, could be isomerized completely to a single (2E,4E) isomer. OAc
[RuCl2(CO)2]2 (2.5 mol%)
OAc
+ ClCH2CH2Cl 50 °C, 18 h 86%
OAc
OAc
CO2Me
OMe
OAc
+ 20
O
[Ru]
CO2Me
CO2Me
21
43:58
Scheme 9
The feasibility of intramolecular type II annulations between furans and vinylcarbenoids to give highly strained molecular frameworks that contained anti-Bredt alkenes is depicted in Equation (13) <1997TL1737>. O O Rh2(O2CC9H19)4 N2 Me2ButSiO
O O
hexanes 83%
O Me2
ButSiO
O
ð13Þ
Furans and their Benzo Derivatives: Reactivity
3.06.2.1.1(v) Reactions with other electrophiles An intramolecular Mannich-type cyclization of the functionalized furan 22, shown in Equation (14), to the cyclic iminium cation that was generated from the aminal was the key step in the construction of the strained ABCD ring system during the total synthesis of nakadomarin A. The fused tetracyclic advanced intermediate 23 was obtained as a single isomer <2003JA7484>. As illustrated in Equation (15), when the furan was tethered at the 2-position, a novel spirocyclization occurred, giving the spiro-2,5-dihydrofuran derivative 24 as the sole diastereoisomer. This spirocyclization proceeded irrespective of the length of the carbon linker <2006OL27>.
OAc O
H
H
i, p-TsOH CH2Cl2
O
OAc
BsN
ð14Þ
ii, 1 N HCl THF 87%
NBOC
NBOC OH
OTHP
22
TBDMSO
23
OTBDMS
O
O HOAc
OH
BsN
OAc
BsN
NBOC
OH
ð15Þ
BsN
PhMe rt, 72 h 80%
NBOC
24
An interesting example concerning hydrolytic cleavage of furan rings that occurred following the addition to N-acyliminium ions to give dicarbonyl compounds is shown in Scheme 10. This reaction presumably occurred via the oxonium ion intermediates 25 that were generated from a 1,5-proton shift of the initially formed oxonium ions <1998JOC6914>.
O
O n
N OH
O
O N
N
HCO2H
n
n C6H12 rt, 30 min
O
O + O
25
n = 1 (75%) n = 2 (64%)
Scheme 10
The synthetic utility of vinylogous Mannich additions of 2-silyloxyfurans to cyclic iminum ions <2001T3221> that provided threo-products predominantly was demonstrated by the assembly of the complete carbon framework during the total synthesis of the plant alkaloid, crommine, as shown in Scheme 11 <1996JA3299, 1999JA6990>. Vinylogous Mukaiyama–Michael additions of 2-trimethylsilyloxyfuran to 3-alkenoyl-2-oxazolidinones to provide -butenolides were shown to be anti-selective. The reaction could be rendered enantioselective in the presence of a C2-symmetric copper–bisoxazoline complex <1997T17015, 1997SL568> or a 1,19-binaphthyl-2,29-diamine-nickel(II) complex as catalyst, as depicted in Equation (16) <2004CC1414>.
415
416
Furans and their Benzo Derivatives: Reactivity
Br Pri3SiO
BOC
Br MeO
O
N
5% Pri3SiOTf
CO2Me
+
H
O
O
BOC N
CO 2 Me
CH2Cl2 0 °C 32% Pri3SiO
H
O
O
POCl3 N
O
CO2H
O
DMF 31%
H2 10% Pd/C O
10% HCl–EtOH 85%
H
H H
N
O
O
O
O
O
H
N
H H
O
O
O
Crommine Scheme 11
O
O + Me3SiO
Ni(ClO4)2•6H2O (10 mol%) BINIM-2QN (10 mol%) (CF3)2CHOH molecular seives
N
O
O
CHCl3 −25 °C, 87 h 82%
N
O
O O
anti:syn = 99:1 93% ee
ð16Þ N
N
N
N
BINIM-2QN
As shown in Equation (17), 2-trimethylsilyloxyfuran also participated in a triphenylphosphine-catalyzed substitution reaction with Morita–Baylis–Hillman acetates to provide interesting -butenolides regio- and diastereoselectively <2004AGE6689>. However, the reaction mechanism (vinylogous Michael vs. Diels–Alder) has not been distinguished. O O Me3SiO
+ O
OAc
O PPh3 (20 mol%)
R
THF 25 °C R = Me, 80% R = OMe, 86%
O
H
H
R dr > 95:5
ð17Þ
Furans and their Benzo Derivatives: Reactivity
2-Trimethylsilyloxyfuran reacted stereoselectively with chiral tungsten carbene complexes in a Mukaiyama– Michael addition fashion to provide anti-products, as shown in Equation (18) <2005AGE6583>. The metal carbene in the butenolide product serves as a useful functional group for further transformations. MeO W(CO)5 Me3SiO
O
W(CO)5
O
+ O
O
OMe
O
PhMe −60 °C 92%
O
ð18Þ
O anti:syn = 11:1 face selectivity = 38:1
Reaction of 2,5-disubstituted and 2,3,5-trisubstituted furans with the cyclic trithiazyl trichloride 26, which was in thermal equilibrium with the monomeric thiazyl chloride, in boiling solvents resulted in the regiospecific formation of isothiazoles, as shown in Scheme 12 <1997CC367, 1997J(P1)1617, 1997J(P1)2247>. Electrophilic thiazylation that occurred at the more nucleophilic C-3 position of the furan ring was favored as the mechanism. This reaction could also be performed using a premixed mixture of ethyl carbamate, thionyl chloride, and pyridine. Furans having electron-withdrawing groups directly at the 2-position are poor substrates <2001J(P1)1304, 1999S757>. 4-Chloro- and 3-chloromethylisothiazole side products were obtained with substituted 2-methylfurans <1997J(P1)2247>.
NO2
NO2
THF reflux, 30 min 85%
Cl
R
N
+
O
Cl
MeO
R=H
S
S N
N S
O OMe
Cl
26
O2N
R = Br THF reflux, 1 h 64%
OMe 3N
N S
S Cl
Br
S
N
O
Scheme 12
Aminomethylation of furans that directly delivered primary furfurylamine products was realized using N-silyl-N,Oacetal 27 under Lewis acid-catalyzed conditions, as illustrated in Equation (19). However, furans are less nucleophilic toward 27 than pyrroles <2003JOC483>. Hf(OTf)4 (20 mol%) NHSiMe3
TMSCl
NH2
+ O
Me3SiO
CCl3
27
3.06.2.1.2
CH2Cl2 rt, 6 h 89%
ð19Þ
O CCl3
Reactions with nucleophiles
The addition of Grignard reagents to 2-nitrofuran provided trans-2,3-disubstituted 2,3-dihydrofurans as the predominant isomers <2003TL3167>. 2- and 3-(Phenylsulfinyl)furans underwent Pummerer-type reaction-initiated regioselective nucleophilic additions, as shown in Equation (20) and Scheme 13, respectively <2004OL3793>.
417
418
Furans and their Benzo Derivatives: Reactivity
The sulfinyl group in the products enables further substitution of the furan ring, for example, via sulfoxide–lithium exchange (as illustrated in Scheme 13). O O O
SOPh
O
(CF3CO)2O
+
ð20Þ MeCN 0 °C, 30 min 54%
SOPh
O
MeCN 0 °C, 30 min 73%
O
i, MCPBA ii, PhLi (2 equiv) PhMe –78 °C, 10 min
SPh
SPh
(CF3CO)2O
SnBun3
+
H O
O
CO2Me
iii, ClCO2Me –78 °C to rt 71%
O
Scheme 13
The chiral Fischer-type chromium carbene complex of furan 28, shown in Scheme 14, participated in nucleophilic 1,4-addition with organolithium reagents followed by alkylation in a regioselective and diastereoselective manner, creating a quaternary C-3 stereocenter in the 2,3-trisubstituted 2,3-dihydrofuran products after oxidative decomplexation and reductive cleavage of the chiral auxiliary <2003CEJ5725>.
i, PhLi Et2O –80 °C
O (OC)5Cr
O
ii, MeOTf –80 °C to rt 78%
28
O (OC)4Cr Ph
3 steps 90%
O dr = 84:16
HO Ph
O 78% ee
Scheme 14
3.06.2.1.3
Reactions with oxidants
Useful new procedures for the oxidation of furans were reported. Mono-, di-, and trisubstituted furans were oxidized to (Z)-enediones by methyltrioxorhenium/urea hydrogen peroxide <1998TL5651>. Mo(CO)6-catalyzed oxidation of 2,5-dialkyl furans by cumyl hydroperoxide provided (E)-enediones selectively. In the presence of Na2CO3, the corresponding (Z)-isomers were obtained <2003TL835>. Sodium chlorite in acidic aqueous medium was found to be an efficient oxidation system for the conversion of symmetrical 3,4-disubstituted furans to -hydroxybutenolides <2005JOC3318>, and 2-substituted and 2,5-disubstituted furans to ,-unsaturated 1,4-dicarbonyl compounds <2005SL1468>. As shown in Scheme 15, a regioselective oxidation of 3-substituted furans (except 3-carboxylate) to -substituted -butenolides was achieved by using N-bromosuccinimide (NBS), followed by elimination of the more acidic C-2 proton of the 2,5-diethoxy intermediate under acidic hydrolytic conditions <2005SL1575>.
Furans and their Benzo Derivatives: Reactivity
HO
O
NBS NaHCO3
HO
EtOH−CHCl3 rt
EtO
HO
HCl 2
O
H2O−acetone rt 75%
OEt
O
O
Scheme 15
The useful synthetic utilities of photosensitized oxidation of furans were demonstrated. A notable example was the oxidation of the trisubstituted furan 29 shown in Scheme 16 to the (Z)--keto-,-unsaturated ester intermediate 30, a crucial step for the construction of the ABC ring system of the complex heptacyclic marine alkaloid norzoanthamine <2004SCI495>.
i, O2, hν Rose Bengal CH2Cl2 0 °C, 12 h
AcO
O
29
SiButMe2
AcO O CO2Me
ii, MeI Bun4NF THF rt, 1 h 97%, 2 steps
O
AcO
30
H
O
3 steps
H
O
H
CO2Me
O Scheme 16
Another novel example as generalized in Scheme 17 is the photooxidation of the furan moiety in the presence of two trisubstituted alkenes in the side chain during the total synthesis of litseaverticillols <2005CEJ5899, 2003AGE5465, 2004OL2039>.
O
O
O2, hν MB
R
Me2S
Pri
2NEt
R O R
MeOH 0 °C 0.5–1 min 97%
MeO H
O
OOH
CHCl3 25 °C 5–8 h
R H
O
CHCl3 25 °C, 5–6 h 51–55%, 2 steps
OH
MB = methylene blue R = Scheme 17
Photosensitized oxidation of a bis(2-trimethylsilylfuran) followed by spirocyclization of the intermediate bis(-hydroxybutenolide) was employed to construct the tricyclic bis(spiroketal) core of prunolides. As shown in
419
420
Furans and their Benzo Derivatives: Reactivity
Equation (21), both the (Z)- and (E)-isomers of 31 provided the same 2:1 mixture of the trans- and cis-products <2005OL2357>. SiMe3
Me3Si O
i, O2, h ν Rose Bengal MeOH 2 min
O
O
O O
O
O
ð21Þ
ii, silica gel 80% MeO
MeO
OMe
OMe
31 The oxidation of 2,5-disubstituted furans by NBS <2005OL27> and singlet oxygen <2006OL1945> was adopted for the synthesis of [5,5,5]- and [6,5,6]-bis(spiroketals). An interesting example is depicted in Scheme 18.
i, O2, hν methylene blue 5 min CH2Cl2 O
OH
O O
ii, DMS
HO
HO
OH
O
O
p-TsOH 80% 1:1 mixture
O
Scheme 18
The aza-Achmatowicz oxidative ring expansion of furans and its synthetic application were reviewed <1998SL105>. An interesting example of performing the Achmatowicz oxidation of furfuryl alcohol and its aza variant simultaneously on the bisfuran-containing 1,3-amino alcohol 32 in the synthesis of aza-C-linked disaccharides is depicted in Scheme 19 <2005CC1646>.
i, NBS NaOAc THF–H2O O Tol
O S O
NH
O
NTs O
ii, (MeO)3CH
OH
BF3•Et2O CH2Cl2 34%
32
OAc
O
OMe
OMe
OAc
AcO
OAc NT s O
AcO
OAc OMe
AcO OAc Scheme 19
Annulation of furans via electrochemical oxidation at the anode has become an important process for the synthesis of complex polycycles, and was covered in a review <2000T9527>. Furans tethered at the 3-position to electron-rich alkenes, enol ethers, or vinyl sulfides were converted to [6,5] and [7,5]-fused ring systems <1996JOC1578, 2002OL3763, 2004JOC3726, 2005JA8034>, as illustrated in Scheme 20. Analysis of crude reaction mixtures and side
Furans and their Benzo Derivatives: Reactivity
products indicated that the furan moiety tethered to alkenes was oxidized to radical cation (initiator), while when tethered to methyl enol ether, it served as terminator to capture the enol ether radical cation <1996JOC1578>. Studies using cyclic voltammetry and probe molecules also suggested that in reaction involving furans tethered to silyl enol ether, the silyl enol ether was preferentially oxidized according to its lower oxidation potential to give a radical cation (e.g., 33) <2004JOC3726>. In contrast to the six-membered ring formation (Scheme 20), annulations to form sevenmembered rings were influenced by the gem-dialkyl effect, as evidenced by Equation (22) <2005JA8034>. carbon anode LiClO4 2,6-lutidine
R
R
R
H
+ Me3SiO
MeCN–PriOH 2 F mol–1 rt
O
Me3SiO
H
O
O
O
33
OPri
R 1 N HCl rt H
O
O
R = H, 70% R = Me, 78% Scheme 20
carbon anode LiClO4
R
R
2,6-lutidine
Me3SiO
MeCN−PriOH 2 F mol–1 rt acidic workup
O
O
ð22Þ
H O
R = H, 0% R = Me, 61%
The anodic cyclization reaction of furans was applied as a key step to construct the [5-6-7]-fused tricyclic core of cyathins <1999OL1535>, and the [5-6-5]-fused tricyclic core of alliacol A using the acyclic silyl enol ether tethered furan 34 during its total synthesis (Scheme 21) <2004JA9106, 2003JA36>. RVC anode carbon cathode 2,6-lutidine 0.4 M LiClO4
Me2ButSiO
Me2ButSiO
O
O
MeOH–CH2Cl2 (1:4) 15–20 mA, 2.2 F mol–1 rt
Me2ButSiO
O
O
34
MeO H
TsOH rt 88%
HO
O O O Alliacol A
Scheme 21
O
OH
H
421
422
Furans and their Benzo Derivatives: Reactivity
Another example is the assembly of the complex [6-7-5]-fused tricyclic core 35 of guanacastepenes, obtained as a single diastereoisomer, as shown in Scheme 22 <2005OL3425>. The efficiency of this reaction is consistent with the gem-dialkyl effect that is required for the seven-membered ring formation in this type of electron-transfer reaction. RVC anode (0.2 mA) 2,6-lutidine 0.06 M LiClO4
Ph2ButSiO
O Me2ButSiO
OSiButMe2
Ph2ButSiO H
20% MeOH–CH2Cl2 2.44 F mol–1 rt, 17 h 70%
M eO
O
H O
OSiButMe2
Ph2ButSiO HCl H2O, THF rt 85%
O
H OSiButMe2
O
35 Scheme 22
When furans were tethered at the 2-position to silyl enol ethers, an electrochemical spiroannulation occurred at the 2-position, as exemplified in Equation (23) <2006CC194>. This reaction pathway is a manifestation of the higher nucleophilicity of the furan C-2 position, resulting in the isolation of the kinetic products. carbon anode LiClO4 2,6-lutidine O
MeOH−PriOH
Me3SiO
O
+
O
H
O
OPri
OPri
69%
3.06.2.1.4
ð23Þ
HO
23%
Reactions with reductants
The reduction of furans was reviewed in an article concerning the reduction of aromatic heterocycles <1996TA317>. Birch reduction of 2-silyl-3-furoic acids provided 2-silyl-2,3-dihydrofuran-3-carboxylic acids as mixtures of cis- and trans-isomers <1996TL9119>. Stereoselective reduction of chiral 2-furoic amides to form dihydrofuran derivatives was accomplished under Birch-type reductive alkylation conditions. Methyl <1998TL3071, 2000J(P1)3724> and trimethylsilyl <2001TL5841, 2002J(P1)1748> substituents at the 3-position of the furan moiety are essential for achieving high diastereoselectivity in the alkylation step as illustrated in Equation (24), presumably by controlling the enolate geometry. This methodology was applied as a key step in the synthesis of (þ)-nemorensic acid <2000CC465, 2002J(P1)1369>, (–)-cis- and (–)-trans-crobarbatic acids <1999TA1315>, eight- and nine-membered cyclic ethers <2001OL861>, dihydropyranones <2002OL3059>, and 2,5-dihydrofuran 36 for a formal total synthesis of ()-secosyrin 1, as illustrated in Scheme 23 <2004OL465>. OMe R N
THF −78 °C
O O OMe
OMe
Na, NH3 then MeI
R N O
ð24Þ
O OMe R = H (45%, dr = 41:59) R = Me (98%, dr = 30:1) R = SiMe3 (94%, dr = 97:3)
Furans and their Benzo Derivatives: Reactivity
SiMe3
OMe
SiMe3
OMe Na, NH3 p-MeOC6H4CH2Br
O
2 steps
N
OH
O
N 68% dr > 20 : 1
O O
O OMe
42% 90% ee MeO
OMe
MeO
36 OCO(CH2)4CH3
HO
O O O (–)-Secosyrin 1 Scheme 23
Hydrogenation of dimethyl 2-phenylfuran-3,4-dicarboxylates using Pd/C at 100 C provided tetrahydrofuran (THF) products without undesired reduction of the phenyl ring. A 2:1 mixture of 2,3-cis-3,4-cis- and 2,3-cis-3,4trans-diastereoisomers was obtained from 2-alkoxyphenyl substrates <2000S2069>. Hydrogenation of furfuryl alcohol derivatives to tetrahydrofuranylcarbinols using Raney nickel provided much higher erythro- (anti-)selectivity than using Pd/C or rhodium on alumina. Moreover, as illustrated in Equation (25), the erythro-selectivity in the formation of 37 and 38 was decreased by increasing the polarity of the alcohol solvent used, presumably by influencing the substrate conformation through the disruption of the intramolecular hydrogen bonding between the hydroxyl and the furan oxygen atom <1996S349>. H2 (80 b) Raney nickel OH O C12H25
3.06.2.1.5
OH PriOH, 37:38 = 81:19 EtOH, 37:38 = 69:31 MeOH, 37:38 = 53:47
O
37
OH
+ O
C12H25
38
ð25Þ
C12H25
Reactions as nuclear anion equivalents
Applications of furanyl anion equivalents in stereoselective manner have been increased. An example of asymmetric conjugate addition of a furanyllithium to 1-nitrocyclohexene induced by a chiral amino alcohol derivative is shown in Equation (26). The 2-trityloxymethyl group was essential for obtaining the selectivity in the product, which was used as an entry to prepare arene-fused piperidine analogs <2004JA1954>. Ph Me2N
Li
NO2 OTr
O MeO
+ O
Ph
PhMe −78 to −95 °C 99%
NO2
ð26Þ
OTr O cis:trans = 89:11 91% ee
3-Furanylmagnesium bromide reacted with chiral N-[p-tolylsulfinyl]-bornane-10,2-sultam to provide 3-furanylsulfoxide with 99% ee <1997TL2825>, and with chiral N-tert-butanesulfinimines (e.g., 39) to provide diarylmethylamines diastereoselectively <2002TA303>. The diastereoselectivity observed for the reaction indicated in Equation (27) is consistent with a six-membered magnesium chelate transition state. Di(2-furanyl)zinc added to a chiral glycal epoxide in the presence of trifluoracetic acid (TFA) to provide -C-furanylglycoside selectively. Addition using 2-furanylzinc chloride also provided the product with similar efficiency <2003SL870>.
423
424
Furans and their Benzo Derivatives: Reactivity
MgBr
i, PhMe −45 °C, 4 h
H +
O
O
S
N
O
ð27Þ
ii, 4 N HCl MeOH 25 °C, 30 min 76%
39
NH3Cl dr = 97:3
Furanyltitanium reagents were shown to add readily to aliphatic aldehydes in the absence of any promoter, providing more desirable yields and stereoselectivity than furanyllithium, magnesium, and zinc reagents. They were employed as key steps in the total syntheses of (þ)-dysidiolide <1998JOC228> and (þ)-ricciocarpins A and B <2004OL1749>, as depicted in Scheme 24. H
(Pri)3Ti
CO2Me +
O H
H
i, Et2O −78 °C OSi(Pri)3
O
ii, dilute HCl rt, 12 h 78%
CHO
O
H O
O Ricciocarpin B
Scheme 24
The furanylcerium that was generated from lithiation/transmetallation of furan 40 as shown in Equation (28) was a highly nucleophilic species that added readily to the sterically hindered ketopyrrole to provide the penultimate intermediate during the total synthesis of roseophilin <1998JA2817>. MeO O
+
i N SiPr 3
Cl
BunLi CeCl3 THF −50 °C then −78 °C to rt 62%
N O
SEM
40
N
MeO OH
SEM
ð28Þ
O Cl
N
SiPri3
The lithiation of 3-(N-tert-butoxycarbonylamino)furan occurred regioselectively at the 2-position as a result of the apparent ortho-directing effect of the NHBOC group, providing 2-substituted-3-aminofurans after subsequent reactions with electrophiles, as represented in Scheme 25 <2006SL789>. In contrast, the lithiation of 2-(N-tertbutoxycarbonylamino)furan took place exclusively at the 5-position instead of the 3-position <2003T5831>.
NHBOC
ButLi TMEDA
NHBOC
NHBOC
O
+ O
THF –90 to –70 °C 1–2 h
O
Li
Cl
OEt
THF −70 °C to rt overnight 97%
O
CO2Et
Scheme 25
3.06.2.1.6
Reactions catalyzed by metals and metallic derivatives
The electrophilic propargylation at the C-2-position of furans with propargylic alcohols can be effected by using 5 mol% of the cationic methanethiolate diruthenium complex 41 as a catalyst (Equation 29). Substrates are limited to 1-phenyl-substituted secondary propargylic alcohols <2003AGE1495>.
Furans and their Benzo Derivatives: Reactivity
Cp* MeS
Cp* Ru
Ru
Cl
Cl
SMe Ph
41 O
Ph +
Ph
ð29Þ
(5 mol%)
Ph ClCH2CH2Cl 60 °C, 1 h 88%
OH
O
As shown in Equation (30), furan reacted with ethyl acetylenecarboxylate under gold-catalyzed conditions to form the hydroarylation product that contained a (Z)-alkene selectively <2003EJO3485>. Ph3PAuCl (1 mol%) AgSbF6 (1 mol%)
+
CO2Et
CO2Et MeNO2 40 °C, 3 h 82%
O
ð30Þ
O
Palladium catalysts were able to catalyze the allylation of furans with alkylidenecyclopropanes, presumably via an allylpalladium intermediate, to furnish 2-allylated products, as illustrated in Equation (31) <2000JA2661>. Pd(PPh3)4 (5 mol%) POBun3 (10 mol%)
Bun + Bun
O
Bun O
no solvent 120 °C 77%
CO2Et
CO2Et
ð31Þ
Bun
The diorganozinc 42 and the high-order zincates, 43 and 44, of 2-furaldehyde diethyl acetal, as shown in Equation (32), participated in a Negishi-type cross-coupling reaction with 2-chloropyridines and bromobenzenes as effectively as the corresponding furanylzinc chloride. These reagents transfer all the organic groups during the reaction <2002OL375>. The synthetic utility of furanylzinc species is further illustrated by the elaborated coupling employed in the total synthesis of bipinnatin J, as shown in Equation (33) <2006OL543>. OEt
OEt
OEt O
Zn
EtO
O
O
ZnLi
EtO 2
4
3
42
43
44
OEt O
ZnLi
EtO
N
+
3
Cl
43
ClZn I
O i, Pd(dppf)Cl2 ii, 5 N HCl 85%
Cl
ð32Þ
H
O O
O
THF 0 °C, 2 h 100%
O OMOM O O
O
N O
Pd(dppf)Cl2
OMOM O
Cl
O O +
ZnLi2
EtO
ð33Þ
425
426
Furans and their Benzo Derivatives: Reactivity
The cross-coupling of sodium 2-furanylsilanolate with aryl iodides and aryl bromides as catalyzed by palladium species 45 was developed, as illustrated in Equation (34). Coupling with aryl iodides could be performed at room temperature, using Pd2(dba)3?CHCl3 as the catalyst <2006OL793>. O
Br i, NaH PhMe
+ O
OH
CO2Et
PdP(But)3
ð34Þ
ii, 45 (2.5 mol%) PhMe 50 °C, 3 h 60%
Si
Cl
(But)3PPd
45
CO2Et
A method of forming 2-furanylsilane in a regioselective manner involved iridium catalyzed silylation using (t-BuF2Si)2 in the presence of 2-tert-butyl-1,10-phenanthroline as a ligand. As shown in Equation (35), 3-methylfuran provided the 5-silylated product 46 as the predominant regioisomer <2005CC5065>.
N
N But
ð35Þ
(3 mol%) Ir[(OMe)COD]2 (1.5 mol%)
+ (ButF2Si)2
ButF2Si
octane 120 °C, 32 h 99%
O
+ O
SiF2But
O
46
47 88:12
Unsymmetrical 2,5-disubstituted alkynylfurans could be prepared from 2,5-bis(butyltelluro)furan by sequential palladium-catalyzed cross-couplings. As represented in Scheme 26, the use of THF, a less effective solvent than MeOH for the symmetrical bis-coupling to alkynes, enabled the first monocoupling to occur <2003TL1387>. PdCl2 Et3N BunTe
O
+
TeBun
OH Ph
BunTe
THF 25 °C, 6 h 82%
O OH
PdCl2 Et3N MeOH 25 °C, 5 h 65%
Ph
O OH
Scheme 26
A direct Heck-type coupling of 2-furaldehyde with various electron-rich and electron-deficient aryl iodides and bromides to provide 5-aryl-2-furaldehydes regioselectively was also developed <2001OL1677>. An interesting example is shown in Equation (36).
OHC
O
O
Br
CHO
PdCl2 (5 mol%) (c-C6H5)3P (10 mol%) KOAc Bun4NBr
+ DMF 110 °C, 10 h 64%
OHC
O
O
CHO
ð36Þ
Furans and their Benzo Derivatives: Reactivity
Regioselective palladium-catalyzed arylation of ethyl 3-furoate at either the 2- or the 5-position can be achieved by the judicious choice of solvent and palladium catalyst, as shown in Scheme 27. However, efficient arylation requires the use of aryl bromides substituted with electron-withdrawing groups (e.g., NO2) <2003OL301>. This method was applied to the synthesis of furo[3,2-c]quinolinone from 1-bromo-2-nitrobenzene.
EtO2C
Pd/C KOAc O
Pd(PPh3)4 KOAc
+
NMP 110 °C 42%
NO2
EtO2C
Br
EtO2C
O
PhMe 110 °C 73%
O2N
O
O2N
Scheme 27
As shown in Equation (37), 4,5-dibromo-2-furaldehyde and methyl 4,5-dibromo-2-furoate underwent regioselective cross-coupling reaction at the 5-position with alkynes under Sonogashira-type conditions, presumably due to the activation of the 5-position by the electron-withdrawing groups at the 2-position toward oxidative palladium insertion <1998TL1729, 1999EJO2045>.
CuI (10 mol%)
+
HO
Br
PdCl2(PPh3)2 (5 mol%)
Br Br
O
O
Et3N (solvent)
R
HO
rt, 48–96 h
R
ð37Þ
R = CHO, 71% R = CO2Me, 97%
Palladium-catalyzed Stille cross-coupling of furanylstannanes to an allyl bromide was also regioselective. An example, as employed in the total synthesis of 6-hydroxyeuryopsin, is depicted in Equation (38) <2004CC44>. This type of reaction could also be performed by using a catalytic amount of CuCl, rather than a palladium catalyst <1999SL1942>.
Br
Pd2(dba)3 (20 mol%) AsPh3 (80 mol%)
+ Bun3Sn
O
SiButMe2
SiButMe2
ð38Þ
THF rt, 48 h 85%
OSi(Pri)3
O
OSi(Pri)3
Analogous to 3,4-bis(trialkylsilyl)furans <1996PAC335, 1997LA459, 1998T1955, 1999CSR209>, the use of 2,4bis(trialkylsilyl)furans, in which the silyl groups served as blocking groups and ipso-directing groups, for the regioselective synthesis of substituted furans was also developed. An application to the preparation of differentially functionalized furans as useful intermediates is shown in Scheme 28 <1997T3497>.
i, BunLi THF 0.5 h
Me3Si
O
Scheme 28
SiMe3
ii, BnBr THF 0.5 h 82%
I2 AgO2CCF3
Me3Si Bn
O
SiMe3
THF –78 °C, 2 h 74%
Me3Si Bn
O
I
427
428
Furans and their Benzo Derivatives: Reactivity
2-Furanylcuprate 48 was discovered to undergo 1,2-metallate rearrangement, leading to ring opening to provide ,-unsaturated ketone 49, as shown in Scheme 29 <2003JOC4008>. i, ButLi THF −78 °C O
Bun
Bun CuLi2 O
O
ii, Bun2CuLi Et2O−Me2S −78 to 0 °C
Bun
Bun
CuBun2Li2
Bun
H 2O
O
68% Bun
Bun
48
49
Scheme 29
Furan was demonstrated to function as a 1,3-propene dipole when it was dihapto-coordinated to a rhenium p-base, which enhanced the nucleophilicity of the uncoordinated C-3-position. As represented in Scheme 30, the 2,5dimethylfuran complex 50 (Tp ¼ hydridotris(pyrazolyl)borate; MeIm ¼ 1-methylimidazole) reacted with Michael acceptors to form substituted cyclopentenes <2003JA14980, 2005OM2903>.
O MeIm
O
MeIm CO [Re]
BF3•Et2O
+
O
CH2Cl2 –40 °C 72%
Tp
50
O
CO H2O2
[Re] Tp O
O
Scheme 30
Fischer-type chromium carbene complexes of furans underwent Do¨tz benzannulation with alkynes to provide trisubstituted benzo[b]furan derivatives. An example used in the synthesis of isodityrosine is depicted in Equation (39) <2005JOC7422>. The efficiency of the reaction could be improved by ultrasound sonication <1999OL1721>. I I CO2Me O O
O
NHCOCF3
+ Cr(CO)5
60 °C then air 68%
ð39Þ
O
CO2Me NHCOCF3 OH
3.06.2.1.7
Reactions involving free radicals
Furans trapped aryl radicals, generated from the oxidation of arylboronic acids <2003JOC578> and from arylhydrazines <2002T8055> by Mn(OAc)3, to give 2-arylfuran derivatives. A perfluoroalkyl radical, produced by using sodium dithionite, initiated dimerization of furan derivatives via addition to the furan 2-position <2002TL443>. The ethoxycarbonylmethyl radical, generated from xanthate 51 by dilauroyl peroxide, added to the 5-position of 2-acetylfuran, giving the addition product as shown in Equation (40) <2003CC2316>. O S
OEt
EtO S
51
dilauroyl peroxide
+ O O
ClCH2CH2Cl reflux 65%
O EtO
ð40Þ
O O
Furans and their Benzo Derivatives: Reactivity
An intramolecular cascade reaction initiated by the addition of an alkenyl radical to a furan was used to synthesize an indene <1998SL1215>. As illustrated in Scheme 31, radical fragmentation in the spiro-dihydrofuran radical 52 provided the intermediate triene 53, which underwent Cope-type rearrangement to form the product. A related reaction with 1-bromocyclohexene that led to unsaturated ketone product was also developed <2003EJO1729>. OTHP O
H11C5
THPO Bun3SnH AIBN
I
H11C5
THPO
H11C5
•
PhMe reflux, 21 h 51%
SPh
O
O
SPh
53
52 O
OTHP
H11C5
Scheme 31
Similar methodology was employed to the synthesis of more complex polycyclic ring system, as shown in Scheme 32 <1997TL9069>. The initial alkenyl radical 54, formed by an intramolecular radical 13-endo-dig macrocyclization, initiated a radical cascade reaction by first reacting at the -position of the furan ring. Bun3SnH AIBN
O
O O
40%
I
O
O
O
54 Scheme 32
3.06.2.1.8
Cycloaddition reactions
3.06.2.1.8(i) Diels–Alder reactions The inter- and intramolecular Diels–Alder reactions of furans, and their applications to the synthesis of natural products as well as synthetic materials, were reviewed <1997T14179>. HfCl4 promoted the endo-selective intermolecular Diels–Alder cycloadditions of furans with ,-unsaturated esters <2002AGE4079>. The cycloaddition between furan and methacrylate was also achieved under these conditions, providing, however the exo-isomer as the major cycloadduct. A catalytic enantioselective Diels–Alder reaction between furan and acryloyl oxazolidinone to provide the endo-adduct in 97% ee was achieved by using the cationic bis(4-tert-butyloxazoline)copper(II) complex 55, as shown in Equation (41) <1997TL57>. O
O N
2+
N
Cu But O
But
O
2SbF6
O
O
55 (5 mol%) O +
N
O
–78 °C, 42 h 97% endo:exo = 80:20 97% ee
O
N
ð41Þ O
Recrystallization 67% 100% ee
429
430
Furans and their Benzo Derivatives: Reactivity
The presence of a halogen substituent at the 5-position of 2-furanyl amides markedly enhanced the rate of intramolecular Diels–Alder reaction. For example, 5-bromofuran 56 shown in Equation (42) provided the oxatricyclic adduct after heating for 90 min. In contrast, the 5-unsubstituted furan 57 required 1 week for the cycloaddition to be completed <2003OL3337>. The enhanced reaction rate and yield, as determined by CBS-QB3 calculations, were attributed to the decreased activation energy as well as a greater stabilization of the cycloadduct imparted by the halogen substitution. The computational results also suggested that substitution at the 2-position has a greater effect than that at the 3-position, and that a 2-methoxy group is as beneficial as a halogen <2006AGE1442>. O
X
O
X
O
O
PhMe 110 °C 90 min, 100% 1 week, 90%
NBn
56: X = Br 57: X = H
ð42Þ
NBn
An intramolecular Diels–Alder reaction of a furan with a strained and sterically hindered bicyclopropylidene that proceeded under high pressure to provide the acid-labile cycloadduct is shown in Equation (43) <1996T12185>. An apparent increase in the reaction rate was observed with the 5-methoxyfuran 58 compared to the 5-unsubstituted analog 59. R R
10 kb
O
O
58: THF, 85 °C, 20 h, >95% 59: C5H12, 90 °C, 43 h, 32%
ð43Þ
58: R = OMe 59: R = H Structural elements can also be incorporated into the furan starting materials so that intramolecular cycloadditions proceed at or below ambient temperature even with an unactivated dienophile, such as the example illustrated in Scheme 33 <2002OL473, 2002JOC3412>. Based on B3LYP/6-31G* calculations, the amidofuran substrate 60 was shown to be populated in a reactive conformation that was imparted by the amide carbonyl of the tether.
Me N
O
Me
SMe
N rt,12 h
O
O
O
Me N
SMe
SMe
O O
H
60 Scheme 33
A complexation-induced intramolecular Diels–Alder cycloaddition of furan is depicted in Scheme 34. Upon exposure to silica gel, the alkyne–Co2(CO)6 complex 61 was transformed to the cycloadduct that contained a seven-membered ring <2000OL871>. This facile process was supposed to be arisen from the bending of the linear triple bond to a structure with a 140 angle between the two carbon substituents in the cobalt complex 61. O O
O Co2(CO)8
O
PhMe
O Co2(CO)6
61
Scheme 34
i, silica gel 0 °C ii, H2 Pd/C EtOAc 0 °C 62%
O Co2(CO)6
Furans and their Benzo Derivatives: Reactivity
Introduction of hydrogen-bonding recognition elements into furans and dienophiles could also facilitate disfavored Diels–Alder reactions. For example, the pair of hydrogen bonds formed between the phenylfuran 62 and maleimide 63 shown in Equation (44) enhanced the rate of the cycloaddition, as well as stabilized the ground state of the exoproduct 64 <1999OL1087>. O N H O
O N
N H
H
O
O N
O
CDCl3
O
50 °C, 15 h
N H O
O N
62
O
O
ð44Þ
H O H
64
63
An interesting and rare example of inverse electron demand transannular Diels–Alder reaction of the furanophane 65 was employed for the synthesis of the chatancin core as depicted in Equation (45) <2003JOC6847>. The diastereoselectivity of this reaction was controlled by the macrocyclic conformation of 65 in the protic reaction medium.
O
O
ð45Þ
H2O−DMSO (1:2) 115 °C, 72 h 67%
OH CO2Me
65
OH
CO2Me
3.06.2.1.8(ii) Other cycloadditions The inter- and intramolecular [4þ3] cycloadditions between furans and oxyallyl cations to generate seven-membered rings were reviewed . Silyloxyacroleins <2000OL2703> and cyclopropanone hemiacetals <2001OL2891> were used as oxyallyl equivalents for the [4þ3] cycloaddition with furans. A theoretical study at the B3LYP/6-31G* level of the AlCl3-catalyzed intermolecular [4þ3] cycloaddition between 2-(trimethylsilyloxy)acrolein and furan showed that the reaction was a three-step process that involved an initial nucleophilic Michael-type attack of furan at the -conjugated position of acrolein, as illustrated in Scheme 35 <2003OL4117>. Similar calculations of a TiCl4-catalyzed intramolecular [4þ3] cycloaddition between furan and allyl p-toluenesulfone-derived oxyallyl cation also suggested a stepwise mechanism <2001OL3663>.
Me3SiO OSiMe3
O +
O
O O
Al
Al
OSiMe3 O
+ O
Scheme 35
The phenylalanine-derived chiral amine catalyst 10 was used to promote the asymmetric [4þ3] cycloaddition between 2,5-dialkylfurans and trialkylsilyloxypentadienals to generate seven-membered carbocycles with endo-selectivity and 81–90% ee, as represented in Equation (46) <2003JA2058>. However, the absolute configurations of the cycloadducts have not been determined.
431
432
Furans and their Benzo Derivatives: Reactivity
O
Me N
Ph N H OSiMe3
O +
O
ð46Þ
CHO
10 (20 mol%) O
CHO
CH2Cl2 −78 °C, 96 h 64%
89% ee
A [4þ3] cycloaddition between 2,5-bis((tert-butyldimethylsilyloxy)methyl)furan and the oxyallyl cation generated from 1,1,3-trichloroacetone was a pivotal step for the construction of phorbol B ring during a formal total synthesis of (þ)phorbol <2001JA5590>. This type of furan–oxyallyl cation cycloaddition was used as a unifying strategy for the synthesis of tropoloisoquinoline alkaloids <2001JA3243>, and a key step in the total synthesis of colchicine, as shown in Equation (47) <1998JOC2804, 2000T10175>. Regioselective coupling of the complex furan 66 with the -alkoxy-substituted oxyallyl cation generated from the silyl enol ether 67 provided the desired endo-adduct as a single diastereoisomer. Interestingly, the reaction of the N-acetyl analog of 66 gave the undesired regio- and diastereoselectivity. MeO MeO
OSiMe3
NHBOC
NHBOC Me3SiOTf
+
MeO
O
MeO
OMe
66
OMe
67
MeO
EtNO2
ð47Þ
O
MeO
−60 °C 45%
O OMe
The intermolecular [4þ3] cycloaddition between furan and the nitrogen-stabilized oxyallyl cation generated from N-(1,3-dibromoacetonyl)phthalimide 68 by LiClO4/Et3N, as represented in Equation (48), was predicted by frontier molecular orbital (FMO) calculations at the PM3 level to be a stepwise process <1996JOC1478>. The diastereoselective inter- and intramolecular [4þ3] cycloadditions of a furan with a nitrogen-stabilized chiral oxyallyl cation, generated by epoxidation of a chiral oxazolidinone-substituted allenamide using dimethyl dioxirane, to form complex polycyclic structures were developed <2001JA7174, 2003JA12694>. This reaction was further extended to the use of a furan tethered to either the - or -position of the allene, as demonstrated in Equation (49) <2004AGE615>. The catalytic enantioselective variant of this type of cycloaddition was also achieved by using a C2-symmetric copper(salen) complex, providing ee up to 99% <2005JA50>. O
LiClO4 Et3N
PhthN +
MeO
68
Ph
Br
MeCN rt 57%
O
Ph
H Et3SiO
CH2Cl2 −78 °C, 5−15 min 65%
ð48Þ
O N
dimethyl dioxirane
•
O
94:6 O
H
NPhth
Br + MeO
MeO
O N
NPhth O
Br
O
O
O
O Br
H
O
OSiEt3 H
O
ð49Þ
dr = 93:7
The [4þ3] cycloaddition between furan and amino-stabilized allyl cations has not been as actively studied. An intramolecular cycloaddition between a furan and a 2-aminoallyl cation, generated from methyleneaziridine under Lewis acid-promoted conditions, is shown in Equation (50) <2004AGE6517>. An AgBF4-promoted asymmetric intermolecular [4þ3] cycloaddition of 2-aminoallyl cations, derived from chiral -chloroimines, with furan to give cycloadducts of up to 60% ee was also reported <1997TL3353>.
Furans and their Benzo Derivatives: Reactivity
i, BF3•Et2O (150 mol%) CH2Cl2 −30 °C, 1 h; rt, 16 h
Bn N
H
O O
O
ð50Þ
ii, aq. H2SO4 (10%) MeOH rt, 16 h 70%
In contrast to the extensively developed type-I intramolecular [4þ3] cycloadditions as illustrated above, type-II intramolecular [4þ3] cycloadditions with cation moieties tethered to the 3-position of furans have not been shown to be versatile transformations. As shown in Equation (51), an attempt on the cycloaddition of furan 69 only resulted in a low yield of the fused tricycle product that resembled the BC ring of ingenol <2003JOC7899>. Et3N (2.2 equiv) (CF3)2CHOH
Cl Cl
O Cl O
rt, 7 d 14%
O O
ð51Þ
69 The intramolecular [5þ2] cycloaddition of oxidopyrylium ions, obtained from the Achmatowicz oxidative ring expansion of furfuryl alcohols, with alkenes was employed as a key strategy for the construction of the [6,7]-fused BC ring system of the daphnane diterpene phorbol <1997JA7897> and resiniferatoxin (Scheme 36) <1997JA12976> during their total synthesis, as well as for the assembly of the cyathin diterpene skeleton <1999T3553>. A version of this type of cycloaddition using a chiral sulfinyl auxiliary on the alkene component is shown in Scheme 37 <2002OL3683>.
i, MCPBA THF 0 °C ii, Ac2O DMAP C5H5N 96%
OSiButMe2 O OH
OBn OAc
iii, DBU MeCN 80 °C 84%
OSiButMe2
OSiButMe2
+ O
O
O OBn
H
OBn
O OAc
OAc
Scheme 36
CO2Et CO2Et
HO
O • •
+ S p-Tol O–
O i, NBS THF–H2O 0 °C ii, Ac2O
CO2Et
CO2Et O
CO2Et
O
CO2Et DBU
OAc • •
+ S p-Tol O–
PhMe 0 °C, 1 h 81%
H
O
H •
•
+S
O–
p-Tol dr = 100 : 0
Scheme 37
433
434
Furans and their Benzo Derivatives: Reactivity
As shown in Equation (52), the intramolecular [6þ4] cycloaddition between a furan and a tropone was successfully achieved for the first time during the construction of the highly functionalized ABC ring of ingenol <2005SL2501>.
O
O O MOMO
O SiButPh2 OSiButMe
2
H
ð52Þ
SiButPh2
C6H6 reflux 60%
MOMO OSiButMe2
Methyl 2-methyl-5-vinyl-3-furoate participated in intermolecular extraannular [4þ2] cycloadditions in which the 5vinyl group and the furan 2,3-p bond acts as the 4p-component with dienophiles to form tetrahydrobenzo[b]furans. However, the reaction was very sluggish under either thermal or high-pressure conditions <2002EJO3589>. Extraannular [4þ2] cycloadditions of 3-vinylfurans were also slow, except for reactions with phenylsulfinylated dienophiles, which occurred at room temperature with shorter reaction times. An application to the regioselective synthesis of substituted benzo[b]furan is illustrated in Scheme 38 <1996JOC1487>. A 5-trialkylsilyl substituent could enhance tendency of 2- and 3- vinylfurans toward the extraannular [4þ2] cycloadditions <1997H(45)1795>.
Me2ButSiO
O PhS
Me2ButSiO
OH i, PhMe reflux, 2 h
CO2Me
+ PhMe rt, 5 h 67%
O
O H
SOPh CO2Me
ii, 10% Pd/C Ph2O 160 °C, 70%
O CO2Me
Scheme 38
In contrast, the [8þ2] cycloaddition of 2-butadienylfurans, that participated as 8p-components, with dimethyl acetylenedicarboxylate (DMAD) was facile, giving oxygen-bridged 10-membered [8þ2] cycloadducts, as illustrated in Equation (53) <2005OL1665>.
CO2Me O
+ O CO2Me R
1,4-dioxane 80 °C, 10 h R = H, 84% R = Me, 77% R = OMe, 79%
ð53Þ R MeO2C
CO2Me
Gold(III) catalyzed the cycloisomerization of furans tethered via carbon, oxygen, and nitrogen linkages to a terminal alkyne to produce phenols, as depicted in Scheme 39 <2000JA11553>. This reaction was also catalyzed by PtCl2 <2001AGE4754>. Based on density functional theory (DFT) calculations and on the trapping of reaction intermediates, the mechanism was proposed to involve a cyclopropyl platinacarbene complex <2003JA5757> that led to
AuCl3 (2 mol%)
O NTs
Scheme 39
MeCN 20 °C 97%
NTs O
70
NTs OH
Furans and their Benzo Derivatives: Reactivity
an arene oxide intermediate (e.g., 70), which was observed experimentally for the first time under the gold-catalyzed conditions <2005AGE2798>. New gold(III)–pyridine-2-carboxylate complexes that provided higher reaction conversions than AuCl3 were developed <2004AGE6545>. This methodology was adapted to the synthesis of interesting spiroannulated dihydrobenzo[c]furans containing pentofuranosides, hexofuranosides, and hexopyranosides, as represented in Equation (54) <2006TL3307>. O
O Ph
O
OMe
OMe
O
O
O AuCl3 (3 mol%)
O BnO
Ph
O
O
ð54Þ BnO
MeCN rt,10 min 78%
OH
The furan 2,3-double bond was found to participate in regio- and stereoselective cyclization with masked o-benzoquinones <1998JA13254, 1999CC713>. An example of a diastereoselective cyclization involving (R)-furfuryl alcohol in which the -hydroxyl group controlled the facial selectivity to produce the ortho,endo-adduct is shown in Equation (55) <2003OL1637>. DFT <2002JOC959> and experimental <2003JOC7193> studies suggested a stepwise mechanism with the nucleophilic attack of furan to the conjugated dienone as the rate-determining step for this reaction. The 4,5-double bond of 2-methoxyfuran underwent inverse electron demand cycloaddition with pentacarbonylbenzopyranylidenetungsten(0) complexes in THF at room temperature. As illustrated in Scheme 40, subsequent elimination of W(CO)6 and rearrangement of the adduct provided intermediate 71, which was converted to naphthalene and benzonorcaradiene derivatives in the presence of TsOH and triethylamine, respectively <2002CL124>. OH HO O +
MeO MeO
O
CO2Me
O OMe
MeOH 40 °C, 1 h 60%
OMe
MeO2C
ð55Þ
OMe MeO
O
99% de
Ph O
Ph –W(CO)6
O
+ W(CO)5
O
OMe
OMe
THF rt
71
Ph TsOH CO2Me
2h 87%
Ph
Et3N H 0.5 h 86%
H CO2Me
Scheme 40
As depicted in Scheme 41, an intramolecular cycloaddition of the furan 2,3-double bond of a furan tethered to a cyano-substituted benzocyclobutene via an intermediate quinone dimethide was used for the synthesis of the tetracyclic core of halenaquinol and halenaquinone <2001SL1123, 2002T6097>. The reaction proceeded via an endo-transition state to produce the cycloadduct 72 exclusively. A related chemistry is shown in Equation (56), in
435
436
Furans and their Benzo Derivatives: Reactivity
which the furan 2,3-double bond of the furanylbenzocyclobutene participated in an efficient 6p-disrotatory electrocyclization with the intermediate quinone dimethide to form the fused tetracyclic ring system of the furanosteroid, viridin <2004AGE1998>. Additional examples of furan-substituted bicyclo[3.2.0]heptenones that participated in oxy-Cope transannular rearrangement involving the 2,3-double bond were reported <1996JOC7976>, demonstrating a feasible approach for the synthesis of poly [5,5]-fused ring systems.
O O
O CN
O CN O
MeO
1,2-dichlorobenzene reflux, 2 h 75%
O NC
O
MeO
O
H O
MeO
H
72 Scheme 41
OSiButMe2 OSiButMe2
i, Pri2NEt xylenes 140 °C, 3.5 h OSiEt3
ð56Þ
ii, DDQ rt, 15 min 83%
O
OSiEt3 O Me3Si
SiMe3
2,3-Dimethylene-2,3-dihydrofuran 73 was generated from 3-(acetoxymethyl)-2-(tributylstannylmethyl)furan by using BF3?Et2O and captured by dienophiles to form adducts in a regioselective manner <1996CC2251>. The reaction with methyl acrylate is illustrated in Scheme 42.
OAc
CO2Me
BF3•Et2O O
SnBun3
0 °C
O
73
dr = 91:9 92%
O
CO2Me
Scheme 42
Intermolecular [3þ2] 1,3-dipolar cycloaddition of a D-glyceraldehyde-derived nitrile oxide to the 4,5-double bond of 2-methylfuran gave a 60:40 diastereomeric ratio of the two furoisozaxoline isomers. This chemistry was employed in the synthesis of L-furanomycin <2005EJO3450>. As depicted in Scheme 43, an intramolecular cycloaddition of a furan with a carbonyl ylide dipole proceeded under rhodium-catalyzed microwave-promoted conditions to provide the cycloadduct in a modest yield <2004OL3241>.
Furans and their Benzo Derivatives: Reactivity
O
N
N
N Rh2((CH3)2CHCO2)4 O O
O
O
N2
+ O – O EtO2HC
C6H6 microwave 90 °C 35%
Et O CO2Et
O
Et O
O
Et
O CO2Et
Scheme 43
3.06.2.1.9
Photochemical reactions
` ¨ chi [2þ2] photocycloaddition of furans with carbonyl compounds The regio- and stereoselectivities of the Paterno–Bu are determined by the conformational stability of the triplet diradical intermediates <2004JA2838>. As illustrated in a study with 2-silyloxyfurans shown in Equation (57) <2000JOC3426>, reaction with ketones provided higher substituted products regioselectively (e.g., 74, R ¼ Me), while those with aldehydes were nonselective. As usual, exo-oxetanes were produced predominantly in both examples. exo/endo-Selectivity was, however, influenced by the substituents of the carbonyl compounds. For example, the exo-selectivity was completely reversed by electronegative substituents (e.g., OMe and CO2R), providing endo-isomers as the predominant products <1998JOC3847>. R + OSiButMe2
O
hν (>290 nm)
Ph
R O
Ph O
MeCN 0 °C
O
R = Me: 74:75 = 93:7 R = H: 74:75 = 60:40
74
R
Ph O
+
OSiButMe2
O
OSiButMe
2
ð57Þ
75
A remarkable example of [2þ2] photocycloaddition of furans with alkenes, as shown in Equation (58), is the pivotal intramolecular cyclization employed in the total synthesis of ginkgolide B <2000JA8453>. The stereochemical outcome of this triplet transformation was predominately influenced by the relative 1,3-stereochemistry of the substrate 76. O
EtO2C
O
Et2CO
O
O
hν (>350 nm)
ð58Þ
C6H14 100%
OSiEt3
OSiEt3
76 Furan underwent photocyclization reactions with 2-alkoxy-3-cyanopyridines <1999J(P1)171> and 2-alkoxynicotinic acid esters <2002TL6103>, forming cage-like adducts, as shown in Scheme 44, that presumably resulted from a singlet [4þ4] cycloaddition followed by a triplet [2þ2] cycloaddition. Reaction of 2-cyanofuran, however, provided the [4þ4] product as the major isomer <2004TL4437>.
O
O MeO2C
hν (>290 nm) +
MeO
Scheme 44
N
N
N O
benzene 73%
OMe MeO
O
MeO2C
OMe
437
438
Furans and their Benzo Derivatives: Reactivity
Photocyclization of N-alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic trans-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(p-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(1E)-butenyl)benzo[b]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>. O hν (350 nm) O
ð59Þ
CH2Cl2 96%
OEt
O
Unlike 2- and 3-furanylcarbenes <1997LA897>, 2- and 3-furanylchlorocarbenes could be characterized in a nitrogen matrix at low temperature. The syn-2-furanylchlorocarbene 77 was more photoreactive than its anti-isomer and rearranged to a mixture of conformers of 5-chloropent-2-en-4-yn-1-al (Scheme 45). It could also be trapped in solution by alkenes at room temperature <1998JA233>. The syn- and anti- isomers of 3-furanylchlorocarbene 78 and 79, respectively, could be photochemically interconverted. Both isomers rearranged to an isomeric mixture of methylenecyclopropenes 80 and 81 upon irradiation (Scheme 46) <1999OL1091>. The effect on the ring-opening rearrangement by the substituent on the carbene moiety was further investigated by ab initio calculations, which were found to be consistent with experimental results <1999JOC9170>. Substituents with a lone pair of electrons increased the energy barrier due to greater stabilization on the carbene reactant than on the transition state, suggesting that carbenes with this kind of substituents could be isolated experimentally. The predicted tendency of rearrangement is in the order: SiH3 > H > CHTCH2 > CH3 > Br > Cl > F > NH2 > OH. Substituents on the furan ring also affected the outcome of the photo-rearrangement. For example, photolysis of 2-diazomethyl-5trimethylsilylfuran and 2-diazomethyl-5-trimethylstannylfuran at >420 nm provided the (Z)-isomer of 1-(trimethylsilyl)pent-2-en-4-ynone and 1-(trimethylstannyl)pent-2-en-4-ynone, respectively (Equation 60). However, both were very stable and did not isomerize to the (E)-isomers on prolonged irradiation <2001EJO269>.
Cl hν (404 nm) Cl O
N2
N N
hν (>400 nm) • •
O
10 K
77
hν (<400 nm)
H O
H
Cl
Cl
O
Scheme 45
O
Cl Cl
H
••
••
hν (366 nm)
hν (313 nm)
O
H +
O
hν (578 nm)
O
78
79
80
Cl
81
Cl
Scheme 46
Me3X
N2 O X = Si X = Sn
H
hν (435 nm) Ar 30 K
Me3X O
ð60Þ
Furans and their Benzo Derivatives: Reactivity
3.06.2.2 Reactivity of Fully Conjugated Benzo[b]furans According to the frontier orbital theory, the frontier electron populations of the parent benzo[b]furan 82 are represented as illustrated . It should be noted that the more positive the numerical values, the more reactive is the corresponding carbon toward electrophiles. –0.38 –0.01
0.47 0.54
–0.38 –0.23
O
82
3.06.2.2.1
Reactions with electrophiles
3.06.2.2.1(i) Acylation Two types of 3-benzoylbenzo[b]furans were regioselectively prepared from their corresponding starting materials 2-methylbenzo[b]furan and 2-benzylbenzo[b]furan through a Friedel–Crafts reaction pathway, as shown in Scheme 47 <2002JME623>.
MeO
MeO p-MeOC6H4COCl SnCl4 O
p-MeOC6H4COCl SnCl4 R
CS2 rt 85% R = Bn
O
O
CH2CI2 63% R = Me
O
Me O
Scheme 47
Regioselective formylation was also achieved by treatment of a 3-phenylbenzo[b]furan with N,N-dimethylformamide and phosphoryl chloride (Vilsmeier reagent) at 0–25 C to give 2-carbaldehyde derivative in 90% yield (Equation 61). In addition, a variety of interesting 2-acylbenzo[b]furan derivatives were described in the same article <2002T5125>. Ph MeO
POCl3 DMF
O OMe
0–25 °C 90%
Ph MeO CHO
ð61Þ
O OMe
With 2-substituted benzo[b]furans, the regioselective electrophilic aromatic substitutions of formyl and nitro groups to C-3 of 2-aryl-7-methoxy-2-phenylbenzo[b]furans were achieved (Equation 62). Further synthetic transformations of the resulting formyl group into methyl, hydroxymethyl, 1-hydroxyethyl, and cyano groups were also reported <1992JOC7248>. i, Zn(CN)2, HCl Et2O, 0 °C
MeO2C
CHO MeO2C OH ð62Þ
OH O OMe
OMe
ii, H2O, EtOH 50 °C 62%
O OMe
OMe
439
440
Furans and their Benzo Derivatives: Reactivity
2-Lithiated benzo[b]furan was found to be a useful reagent in reactions with amides to give the corresponding 2-acylbenzo[b]furan product (Equation 63). The acylation yield was not reported <2002TL6937>. O +
O
n-BuLi
Me2N O
O
ð63Þ
THF–hexane – 78 °C
OEt
82
OEt
O
O
A key synthetic step to an unnatural nucleotide bearing benzo[b]furan by the reaction of 2-lithiated benzo[b]furan with lactone 83 is illustrated in Equation (64) <2003JA6134>.
+ O
OH
i, BuLi, THF, then 83 ii, BF3•Et2O, Et3SiH
H
O
O
OH
O
Pri
2Si
O
iii, TBAF, THF
82
ð64Þ
O
OH
83
3.06.2.2.1(ii) Halogenation Since halogen-substituted benzo[b]furans play an important role in the transition metal-catalyzed coupling of benzo[b]furans with other substrates, synthetic methods to regioselectively synthesize substituted benzo[b]furan halides have become very critical routes. Several syntheses of benzo[b]furan based aryl halides are described here. When benzo[b]furan derived polycyclic phenol 84 was allowed to react with bromine, tribromide 85 was formed in high yield (Equation 65) <1999JME3199>. Reaction of 2-methylbenzo[b]furan 86 with N-bromosuccinimide (NBS) at room temperature gives 3-bromo-2-methylbenzo[b]furan 87 as illustrated in Equation (66) <2005JOC10323>. HO
Br
HO Br
ð65Þ Br2 HOAc rt 83%
O
84
Br
O
85 Br
NBS Me
Me THF rt 85%
O
86
ð66Þ
O
87
Another interesting bromination strategy was developed to obtain 3,5-dibromobenzo[b]furan and 2,3,5-tribromobenzo[b]furan by sequential treatment of the corresponding benzo[b]furans with bromine followed by the basemediated elimination of HBr (Scheme 48) <2003S925>.
i, Br2 CH2Cl2
Br
Br
Br i, Br2 CH2Cl2
Br KOH Br
Br Br
Br O
Scheme 48
ii, NaHSO3 H2O 23%
O
EtOH
O
ii, NaHSO3 H2O 95%
Br O
Furans and their Benzo Derivatives: Reactivity
In a total synthesis of XH14 reported recently, the key intermediate 3-bromobenzo[b]furan was made by brominepromoted cyclization of an o-methoxy phenylacetylene, as depicted in Equation (67) <2002JOC6772>. OBn O
O OMe
O
Br O
Br2
ð67Þ OBn
CHCl3 92%
OMe OMe
O OMe
OMe
As depicted in Equation (68), anodic fluorination of ethyl 3-benzo[b]furanyl acetate was applied to the synthesis of a 2,3-difluoro-2,3-dihydrobenzo[b]furan derivative. A 2-fluoro-3-hydroxyl derivative was also obtained as a minor product <2003SL1631>. COOEt
COOEt
F
COOEt
HO
Et4NF•4HF +
F
MeCN–H2O 1.8 V, 4 F mol–1
O
F O
O
ð68Þ
40%
The C-2 trimethylsilyl-derived pyridino[b]furan was treated with the combined reagent NIS/KF to give 2-iodopyrido[b]furan, a key intermediate for the synthesis of sesquiterpenoid furanoeudesmanes (NIS ¼ N-iodosuccinimide) (Equation 69) <2003T325>. OH NIS KF SiMe3
N
O
THF 51%
OH I
N
Cl
ð69Þ
O Cl
3.06.2.2.1(iii) Reactions with aldehydes and ketones Due to the electronic richness of the C-3 of benzo[b]furan 82, the Yb-catalyzed electrophilic substitution of benzo[b]furan 82 with glyoxalate led to a 3--hydroxybenzo[b]furan ester in a regioselective manner, as depicted in Equation (70) <2000JOC4732>. HO CO2Et
Yb(OTf)3 +
EtO2CCHO
(5 mol%)
ð70Þ
CH2Cl2
O
O
rt, 24 h 76%
82
The C-2 proton of benzo[b]furan 82 underwent regioselective metallation by treatment with n-butyllithium to form 2-lithiated benzo[b]furan, which directly reacted with electrophiles, such as 1,4-cyclohexadienone to form 4-(benzo[b]furan-2-yl)-4-hydroxy-2,5-cyclohexadien-1-one in high yield, as shown in Equation (71) <2005TL7511>. n-BuLi THF –78 °C O
HO O O
O
82 96%
O
ð71Þ
441
442
Furans and their Benzo Derivatives: Reactivity
Another application of 2-lithiated benzo[b]furan to generate a structurally interesting benzo[b]furan derivative was realized by reaction of 2-lithiated benzo[b]furan with 4,4-dimethoxy-4H-naphthalen-1-one, followed by hydrolysis, as shown in Equation (72) <2003JME532>. i, n-BuLi THF–hexane –78 °C
O + MeO OMe
82
O
ii, HOAc H2O 82%
O
ð72Þ
O HO
A benzo[b]furan derived acetylenic alcohol was also prepared by reaction of 2-lithiated benzo[b]furan with a cyclopentanone (Equation 73) <2004SL2579>. n-BuLi
+ O
Et2O–hexane –78 °C 53%
O
82
ð73Þ
O HO
3.06.2.2.1(iv) Reactions with diazonium salts and diazo compounds Benzo[b]furan-based diazobutenoates were used as a substrate to make a cyclopropane in 89% yield via a rhodiumcatalyzed intramolecular process, as can be seen in Equation (74). Cyclopropane 88 was the key intermediate for the total synthesis of diazonamide A <2000OL3521>. N2
O O O O
Me
Rh2(cap)4
ð74Þ
Me
OMe CH2Cl2 89%
O
OMe
O
88 The rhodium-catalyzed intermolecular cyclopropanation of diazobutenoates with benzo[b]furan 82 resulted in the formation of a benzo[b]furan-derived cyclopropane in a diastereo- and enantioselective manner, as depicted in Equation (75) <1998JOC6586>. Ph H +
MeO2C
O
Ph
Rh2(S-DOSP)4
CO2Me
pentane 57%
N2
ð75Þ
O 96% ee
82 3.06.2.2.1(v) Reactions with other electrophiles Direct nitration of benzo[b]furan 82 is another important reaction to provide benzo[b]furan derivatives. Because of its electronic richness, benzo[b]furan 82 can undergo regioselective nitration to give 2-nitrobenzo[b]furan in 62% yield by using sodium nitrate and ceric ammonium nitrate under ultrasonic conditions (Equation 76) <1996OM499>. NaNO3 (NH4)2Ce(NO3)6 O
82
HOAc–CHCl3 62%
NO2 O
ð76Þ
Furans and their Benzo Derivatives: Reactivity
As illustrated in Equation (77), the regioselective nitration of 2-(trimethylstannyl)benzo[b]furan was also applied to the synthesis of 2-nitrobenzo[b]furan. The reaction proceeded by an initial treatment of benzo[b]furan 82 with n-BuLi/ Me3SnCl, and was then followed by reaction with tetranitromethane (TNM) or dinitrogen tetroxide <2003EJO1711>. i, n-BuLi Et2O–hexane then Me3SnCl O
ð77Þ
NO2
ii, C(NO2)4 DMSO
O
82
3.06.2.2.2
Reactions with oxidants
In contrast to furan, because of its large resonance energy, the benzene ring of benzo[b]furan 82 is dominant to such an extent that [4þ2] cycloadditions of the furan ring are not possible. On the other hand, photochemical [2þ2] cycloaddition occurs readily on the C-2/C-3 double bond. For example, photooxygenation of 2,3-dimethylbenzo[b]furan at 78 C produced dioxetane 89, which isomerized at room temperature to give 2-acetoxyacetophenone (as shown in Scheme 49) <1995ACR289>.
Me Me
O O
sensitizer
O
O
Me
O2 hν
O
Me
Me
O
89
O
Me
Scheme 49
3-Alkylbenzo[b]furans were oxidized by chloroperoxidase from Caldariomyces fumago to their trans-2,3-diols as major products, and these were all fully characterized because of their stability (Equation 78) <2001T8581>. CH2CO2Me
chloroperoxidase H2O2, NaCl pH 2.75
CH2CO2Me Cl
acetone
O
HO CH2CO2Me
+
OH
O
+
OH
ð78Þ
O
O
16%
HO CH2CO2Me
23%
24%
The ruthenium(II) porphyrin-catalyzed amidation of benzo[b]furan 82 was reported for the first time to make 2-Nnosylamide in 50% yield under mild conditions, as can be seen in Equation (79) <2004OL2405>. SO2NH2
[RuII(TTP)(CO)] PhI=NTs
+ O
NHSO2
CH2Cl2 50%
O2N
82
O
NO2
ð79Þ
The structurally interesting bis(benzo[4,5]-furo)[2,3-e:39,29-g][1,2,3,4]tetrathiocine was obtained by an oxidative coupling reaction of 2-lithiated benzo[b]furan with elemental sulfur (Equation 80) <2002JOC6220>. i, n-BuL THF –78 °C O
82
ii, S8 –78 °C to rt 6.5 h 35%
S S S O
S O
ð80Þ
443
444
Furans and their Benzo Derivatives: Reactivity
3.06.2.2.3
Reactions with reductants
At 0 C, the reduction of benzo[b]furan 82 with lithium in the presence of a catalytic amount of 4,49-di-tertbutylbiphenyl (DTBB, 5 mol%) in THF was observed to give 2-vinylphenol in high yield, as illustrated in Equation (81) <2002T4907>. Li DTBB (cat.)
ð81Þ
THF 0 °C 93%
O
82
OH
Another regioselectively reductive ring-opening of benzo[b]furan 82 was also utilized to afford the active vinyllithium species in the presence of a catalytic amount of DTBB (5 mol%) in THF at 0 C, and the formed vinyllithium was able to further react with electrophiles (such as t-BuCHO, PhCHO, Ph(CH2)2CHO, Me2CO, n-PrCOMe, PhCOMe, (CH2)4CO) at –78 C to give their corresponding (Z)-products. Further reaction of the diols led to substituted 2H-chromenes under acid-catalyzed cyclization, as depicted in Scheme 50 <2001EJO2809>. Li DTBB PhCOMe
OH H3PO4
THF 56%
O
Me
Ph
PhMe reflux 85%
OH
82
O
Ph Me
Scheme 50
3-Substituted-2-phenylbenzo[b]furans were able to undergo a palladium-catalyzed hydrogenation reaction to give their corresponding 2,3-dihydrobenzo[b]furans, but the yields are quite low (Scheme 51) <2002T4261>.
Me
H
O
Ph H
R
H2 Pd
CO2Me
H
H2 Pd Ph
MeOH 48% R = Me
O
Ph MeOH 11% R = CO2Me
O
H
Scheme 51
The surfactant-stabilized aqueous colloidal rhodium(0) was used to hydrogenate unsubstituted nitrogen-, oxygen-, or sulfur-derived heterocycles (such as benzo[b]furan 82) in quantitative yield, as can be seen in Equation (82) <2004ICA3099>. NaBH4 RhCl3 H2 (40 b) O
82
3.06.2.2.4
20 °C, 2.5 h 100%
ð82Þ O
Reactions as nuclear anion equivalents
2-Metallated benzo[b]furans play a very important role as nucleophiles in the quest for structurally diverse 2-substituted benzo[b]furans. For example, benzo[b]furan-2-sulfonamide 90 was synthesized by sequential reactions of a benzo[b]furan with n-BuLi/SO2, N-chlorosuccinimide (NCS), and NH4OH (Scheme 52) <1990JME749>.
Furans and their Benzo Derivatives: Reactivity
i, n-BuLi THF-hexanes MeO –78 °C
MeO
O
O
MeO
i, NCS
S OH ii, SO2 98%
O
S ii, NH4OH 34%
O
NH2
O
90
Scheme 52
As shown in Equation (83), 2-iodobenzo[b]furan was also prepared by reaction of benzo[b]furan 82 with tertbutyllithium in ether at –78 C, followed by reaction with iodine <2002JOC7048>. i, t-BuLi Et2O–hexane –78 °C O
82
ð83Þ
I
ii, I2 95%
O
An efficient approach for asymmetric syntheses of benzo[b]furan-1-alkylamines was developed by reaction of 2-lithiated benzo[b]furan with aldehyde–SAMP-derived hydrazones (SAMP ¼ (S)-()-1-amino-2-methoxymethylpyrolidine; Equation 84). In this way, an efficient synthesis of hydrazine 91 was achieved <2004TA747>. NH2 N OMe + EtCHO
+
HN N
n-BuLi Et2O –78 °C 85%
O
82
s
O
s Et
ð84Þ
OMe
91
A phenylacetylene-substituted benzo[b]furan was prepared by reaction of 2-lithiated benzo[b]furan with 1-(phenylethynyl)-1H-1,2,3-benzotriazole (Equation 85) <2002JOC7526>. N N
n-BuLi
N
+
Ph THF–hexane –78 °C 67%
O
82 Ph
O
ð85Þ
The synthesis of a novel compound 1,2-bis(2-methylbenzo[b]furan-3-yl)-perfluorocyclopentene 92 was realized by reaction of octafluorocyclopentene with 3-lithiated 2-methylbenzo[b]furan, which was generated by the treatment of 2-methyl-3-bromobenzo[b]furan with n-BuLi at 78 C in THF, as can be seen in Equation (86) <2005JOC10323>.
F
Br
F Me
O
O F
+ F F
F
F
n-BuLi
F
THF –78 °C 46%
Me F F F
ð86Þ O F
F F
Me
92 Benzo[b]furan 82 with sodium sand in the presence of 1-chlorooctane gave the 2-sodium salt of benzo[b]furan, which with CO2 gave the carboxylic acid 93 (Equation 87) <2002AGE340>.
445
446
Furans and their Benzo Derivatives: Reactivity
i, Na 1-chlorooctane PhMe O
O
85%
82
ð87Þ
COOH
ii, CO2
93
As can be seen in Equation (88), the 2-sodium salt of benzo[b]furan could also be formed by treatment of benzo[b]furan 82 with sodium dithionite in the presence of fluoroalkyl chlorides in dimethyl sulfoxide (DMSO), leading to the corresponding fluoroalkylated products in moderate yields <2001JFC107>. Na2(S2O4) Cl(CH2)7CF3
82
3.06.2.2.5
ð88Þ
(CH2)7CF3
DMSO 65%
O
O
Reactions catalyzed by metals and metallic derivatives
In the total synthesis of naturally occurring frondosin B, the palladium-catalyzed coupling reaction of C-3 stannylated benzo[b]furan 94 with the vinyl triflate 95 was employed as a key step to build up the framework of the final target, as depicted in Equation (89) <2001JA1878>.
SnBu3
OTf
MeO
Pd2(dba)3 LiCl, NMO
ð89Þ
MeO
+ O
94
95
THF 50 °C 23%
O
A palladium-catalyzed cyclization was applied to establish the skeleton of the benzo[b]furan derived tetracyclic ring in frondosin B (Equation 90) <2004T9675>. O Pd(OAc)2 Ph3P Et3N
TfO (CH2)3 O
MeO
O
MeCN reflux 54%
ð90Þ O
MeO
The regioselective coupling reaction of 2,3-dibromobenzo[b]furan with several terminal acetylenes was achieved using a palladium-catalyzed Sonogashira reaction, as exemplified in Equation (91) <2003S925>.
Br Br O
+
But
PdCl2(PPh3)2 CuI Et3N THF 84%
Br But
ð91Þ
O
Other regioselective C–C bond formation reactions were also reported by using palladium-catalyzed coupling of 2,3,5-tribromobenzo[b]furan 96 as a substrate. Thus, the palladium-catalyzed coupling between tribromide 96 and arylzinc 97 gave a dibromide 98, which underwent sequential Kumada coupling with a Grignard reagent and a
Furans and their Benzo Derivatives: Reactivity
Negishi coupling with methyl zinc chloride to regioselectively afford a trisubstituted benzo[b]furan 99, as illustrated in Scheme 53 <2002TL9125>.
OMe ClZn
Br
Br
OMe
97
Br
OMe
PdCl2(PPh3)2
O
OMe
Br
Br O
96
98 i, NiCl2(dppe) MeCH=CHMgBr THF rt 87%
Me
OMe OMe
ii, PdCl2(dppf) MeZnCl THF reflux 85%
O
99
Scheme 53
The palladium-catalyzed Suzuki–Miyaura reaction of 3,5-dibromo-2-pyrone 100 with benzo[b]furan-2-boronic acid 101 was applied to the synthesis of 3-(benzo[b]furan-2-yl)-5-bromo-pyrone 102 in 50% yield (Equation 92) <2004SL2197>.
O
B(OH)2
+ Br
Br
O
Pd(PPH3)4 K2CO3
O
O
O
100
101
PhMe 100 °C, 4 h 50%
ð92Þ
O Br
102
The C–H coupling of benzo[b]furan 82 with bis(pinacolato)diboron 103 was carried out in octane with [IrCl(COD)]2-(4,49-di-tert-butyl-2,29-bipyridine) as a catalyst (3 mol%), leading to the formation of the 2-borylated product 104, as can be seen in Equation (93) <2002TL5649>.
O +
O
[IrCl(COD)]2 dtbpy
O
B B O
O
82
B O
103
octane 80 °C 91%
O
O
ð93Þ
104
A highly regioselective borylation of arenes and heteroarenes (such as benzo[b]furan 82) was achieved by the iridium-catalyzed C–H activation reaction, as shown in Equation (94) <2003CC2924>.
O + O
82
[Ir(OMe)(COD)]2 dtbpy
O B
HB O
hexane 25 °C,1 h 90%
O
104
O
ð94Þ
447
448
Furans and their Benzo Derivatives: Reactivity
An additional method to prepare 2-aryl benzo[b]furan was realized by the palladium-catalyzed C–H activation of benzo[b]furan with aryldiazonium trifluoroacetate (Equation 95) <1999EJO1357>. N2+ + O
Pd(OAc)2
CF3CO2–
Me
Me
EtOH 43%
82
ð95Þ
O
The palladium-catalyzed hydrofuranylation of alkylidenecyclopropane 105 with unfunctionalized benzo[b]furan was utilized in the synthesis of a 2-allylbenzo[b]furan derivative 106, as illustrated in Equation (96) <2000JA2661>. Bun
Pd(OAc)2
Bun
EtOH 43%
+ O
82
CH(Bun)2
O
105
ð96Þ
106
As depicted in Equation (97), oxidative cross-coupling of -aryl-,-difluoroenol silyl ether with unfunctionalized benzo[b]furan 82 in the presence of Cu(OTf)2 in wet acetonitrile proceeded smoothly to give benzo[b]furan difluoromethyl aryl ketone in 50% yield <2004OL2733>. CF2 OSiMe3
+ O
F
Cu(CF3SO3)2 MeCN 0 °C, 3 h 50%
MeO
82
OMe F
O
ð97Þ O
3-Chloromercurio-benzo[b]furans 107 were key intermediates for the syntheses of natural product XH14 and its analogs. The synthesis proceeded by the palladium-catalyzed carbonylation reaction as a pivotal step. The 3-chloromercurio-benzo[b]furan 107 was also reduced to form its hydride derivative by NaBH4 reduction, as illustrated in Scheme 54 <2002JOC6772>.
HgCl
OMe
PdCl2 MgO–LiCl CO
OBn
R
MeOH 69%
O
107
CO2Me R
OMe OBn
O
NaBH4 KOH 85% H
CHO
OMe
OMe
HO R
OBn O
OH O XH 14
Scheme 54
A C2-symmetric benzo[b]furan-containing heterocycle 108 was constructed by the palladium-catalyzed coupling reaction between the lactam-derived vinyl phosphates and benzo[b]furan-2-boronic acid 101 (Equation 98) <2005TL3703>.
Furans and their Benzo Derivatives: Reactivity
OP(O)(OPh)2 N BOC
BOC
PdCl2(PPh3)2 Na2OC3
+
B(OH)2 O
OP(O)(OPh)2
101
N
O
THF-EtOH reflux 25%
O
ð98Þ
108
As can be seen in Equation (99), a platinum-catalyzed intramolecular cyclization was also utilized in the formation of benzo[b]furan-based tricycles. A platinum carbene was proposed as an intermediate in this reaction <2003JA5757>.
CH2Br
+
O
CO2Me
i, NaH DMF
CO2Me MeO2C C CH2 C CH H
CO2Me
ii, PtCl2 acetone reflux
ð99Þ
O
Triflates of 3-benzo[b]furans were prepared, and evaluated in the palladium-catalyzed Stille, Heck, Suzuki, and Sonogashira coupling reactions. As can be seen in Scheme 55, results demonstrated that benzo[b]furan-3-triflate 109 was a good coupling partner in the metal-catalyzed reactions, and good to excellent results were obtained <2002SL501>.
OMe
Pd(OAc)2 dppp Et3N CO
CO2Me
OMe
OTf
MeOH
O
CN
PdCl2(PPh3)2 Et3N CH2=CHCN
OMe
THF reflux
O
109
O
Scheme 55
3.06.2.2.6
Reaction involving free radicals
A regioselective addition of N,N-dichlorobenzenesulfonamide (dichloramine-B) 110 to benzo[b]furan 82 was achieved to make a pyrrolidine-derived tricyclic compound 111 at room temperature in good yield. Triethylborane was selected as a radical initiator in this reaction (Equation 100) <2003JOC3248>. Cl
Cl
+ CH2=CHCH=CH2 + Ph-SO2NCl2 O
82
110
Et3B
N
PhMe 25 °C 80%
O
O
S
Ph
ð100Þ
O
111
Under similar conditions, a radical-initiated [3þ2] cycloaddition of N-centered radical with benzo[b]furan 82 was examined. A benzo[b]furan-derived pyrrolidine 112 was obtained in good yield with again Et3B as a radical initiator (as depicted in Equation 101) <2001OL2709>. CH2Cl O S + O
82
Me
Me
H
O N
Et3B
Cl
C6H6 rt, 3 h 83%
N O H O
ð101Þ
S
112
O
449
450
Furans and their Benzo Derivatives: Reactivity
3.06.2.2.7
Cycloaddition reactions
Benzo[b]furan 82 is a very important building block in materials science and drug discovery. Because it is electronically rich at C-2 and C-3, many important synthetic transformations occur at these two positions. For example, o-benzoquinones oxidatively generated from the corresponding substituted 2-methoxyphenols reacted with benzo[b]furan 82 to form polycyclic molecules, as depicted in Scheme 56 <1999JA13254>.
CO2Me
MeOH
HO
O
CO2Me
PhI(OAc)2
82 reflux 64%
O MeO OMe
OMe
H
MeO OMe CO2Me O O
H
Scheme 56
A domino process for the construction of a tetracyclic ring was achieved by the gold-catalyzed formation of an isobenzopyrylium derived from a phenylacetylene-based benzaldehyde. This was followed by reaction with electronrich benzo[b]furan as a dienophile in a Diels–Alder reaction with inverse electron demand (Equation 102) <2003AGE4399>. O Ph Ph AuCl3
ð102Þ
+ O
MeCN 80 °C 61%
CHO
82
O
OH
The reaction of benzodifuran 113 with 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine 114 proved to be an efficient way to make pyridazino–psoralen-based aromatic polycycles such as 115 through a reaction sequence illustrated in Scheme 57 <2005T4805>.
CO2Me
CHO O
O +
N
N
–N2
N
N
dioxane reflux, 2 h
CO2Me
113
CHO O
CHO O
CO2Me
OH
CO2Me N
N N
N MeO2C
114
O
MeO2C
H
CHO O
O 65%
O N
115
N CO2Me
Scheme 57
3-Vinylbenzo[b]furans, 3-vinylfuropyridines, and 3-vinylindoles were employed as conjugated dienes in the Diels– Alder reaction with ethyl acrylate, affording tricyclic adducts in fair to good yields, as shown in Equation (103) <2002OL2791>.
Furans and their Benzo Derivatives: Reactivity
OEt
OEt
CO2Et
CO2Et
ð103Þ
PhMe 110 °C, 72 h 59%
O
O (endo:exo = 37:63)
The enol form of dihydrofuro[2,3-h]coumarin-9-one 116 was also employed as a dienophile in the Diels–Alder reaction with 3,6-bis(trifluoromethyl)1,2,4,5-tetrazine 117 to afford the desired tetracyclic product 118 in 54% yield (Equation 104) <2002S43>. N
N CF3
F3C
N N 117 O
O
O
dioxane reflux 54%
O O
O
O
F3C N N
116
ð104Þ CF3
118
As can be seen in Scheme 58, a new synthesis of -lactams was also achieved by reaction of benzo[b]furan-derived vinyl sulfilimines with dichloroketene, a reaction which proceeded through a [3,3] sigmatropic rearrangement <2005OL839>.
– + NTs S O
Et
Cl H
Cl
[3,3] Cl2C=C=O
O
Cl
Cl
O
– + NTs SEt
N O
O
Ts
SEt
Scheme 58
As illustrated in Equation (105), 6-(diethylamino)benzo[b]furan-2-carbaldehyde 119 reacted with 49-bromo-29hydroxyacetophenone 120 in dry dimethyl formamide (DMF) in the presence of an excess of sodium methoxide to afford a heterodimer of benzo[b]furan and flavone <2004TL8391>. O NaOMe H2O2
Br
HO
CHO + O
Et2N
OH
119
O
DMF–H2O–EtOH 21%
Et2N
O
O
Br ð105Þ
120
A regioselective lithiation was achieved by treatment of 3-substituted benzo[b]furan 121 with n-BuLi at 0 C in THF, and the 2-lithiated benzo[b]furan so generated was allowed to couple with quinone monoketal followed by a regioselective cyclization to give kushecarpin A’s analog 122 (Scheme 59) <2005TL7511>. Under microwave conditions, 5-nitro-substituted furfuryl amide 123 underwent an unusual isomerization– cyclization reaction pathway to give 1,4-dihydro-2H-benzo[4,5]-furo[2,3-c]pyridine-3-one 124 (Equation 106) <2003OL3337>.
451
452
Furans and their Benzo Derivatives: Reactivity
i, n-BuLi THF 0 °C
OEt CH2O
OMe OMe
Me +
O
OH O
ii, HOAc 80%
O
121
O HO
O NaH
O
THF 25 °C
O HO
122 Scheme 59
But N O O
MeO
N
O
15 min 36%
O
MeO
O NMP MW (300 W)
But
ð106Þ O
NO2 O2N
123
124
The palladium-catalyzed carbonylative annulation of 3-(2-iodophenyl)-benzo[b]furan 125 provided benzo[b]indeno[1,2-d]furan-6-one 126 in 81% yield, as can be seen in Equation (107) <2002JOC5616>.
I O
125
Pd(PCy3)2 (5 mol%) CsPiv CO (1 atm) DMF 110 °C, 7 h
ð107Þ
O O
126
81%
2-Benzo[b]furyl-4-chloromethyl-1,3-oxazole 127, an important intermediate for the synthesis of potent and highly selective D3 receptor ligands, was realized by a direct condensation of benzo[b]furan-2-carbamide and 1,3-dichloropropan-2-one (Equation 108) <2003JME3822>.
ClCH2C(O)CH2Cl CONH2 O
3.06.2.2.8
130 °C, 1 h 54%
N O
O
CH2Cl
ð108Þ
127
Photochemical reactions
As shown in Equation (109), irradiation of a benzene solution containing 3-cyano-2-ethoxypyridine (0.02 M) and benzo[b]furan 82 (0.5 M) resulted in the formation of two tetracyclic stereoisomeric adducts <2000CC1201>.
Furans and their Benzo Derivatives: Reactivity
EtO
EtO Me
N
EtO O
H
hν
+
N
H
Me
Me
ð109Þ
+
C6H6
NC
N
O
82
O
H CN
27%
H CN
34%
` ¨ chi reaction of benzoin 128 with benzo[b]furan 82 was utilized to stereoselecThe diastereoselective Paterno–Bu tively construct a [6-5-4] tricyclic heterocycle 129 (Equation 110). The observed diastereoselective excess was also explained <2004TL3877>. O hν
Ph
O
+
O
O
Et
n-hexane 2-propanol 20%
Me
82
O
128
H O O
H Ph
Et
ð110Þ
Me
O
129 58% de
` ¨ chi reaction of 1-acetylisatin 130 with benzo[b]furan 82 was employed to make a The photoinduced Paterno–Bu structurally interesting spiro-type molecule 131 in good yield, as depicted in Equation (111) <2002J(P1)345>.
Ac
H
+
O O
ð111Þ
N
C6H6 76%
O
82
O
hν
N
O H O
130
Ac
131
As shown in Equation (112), the photolytic reaction of benzoxazole-2-thione 132 with unsubstituted benzo[b]furan 82 was utilized to make 2-benzofuryl-benzoxazole 133, but the yield is relatively low <2003HCA3255>. Ac N O
O
82
N
hν
S
+
ð112Þ
C6H6 35%
132
O
O
133
A novel tandem photolysis was observed for the synthetic conversion of 2,3-diphenylbenzo[b]furan to benzo[b]phenanthro[9,10-d]furan 134. This process might involve sequential photochemical cyclization and aerial oxidation (Scheme 60) <2003TL3151>.
H H
hν O
Scheme 60
MeCN EtOH
[O] O
O
134
453
454
Furans and their Benzo Derivatives: Reactivity
3.06.2.3 Reactivity of Fully Conjugated Benzo[c]furans A review article summarizing various aspects of the chemistry of benzo[c]furans (isobenzofurans) bridging the gap between these theoretically interesting but usually fugitive molecules and natural products was published . Another review deals with the recent advances in the chemistry of these molecules <1999AHC1>. The main reactions of benzo[c]furans are cycloaddition reactions, which are summarized in Section 3.06.2.3.1. AM1 <1998JMT165>, FMO <1997T13285>, and DFT <2000J(P2)1767, 2004JMM87> computational studies concerning Diels–Alder reactions of benzo[c]furans, as well as their addition reactions with azulene-1,5-quinones and azulene-1,7-quinones <1999J(P1)2129>, have all been reported. The Bird’s aromaticity indexes (BAIs) of benzofurans have been reevaluated by Schleyer making use of Becke3LYP/6-311þG** geometries, and the results obtained show that the aromaticity of benzo[c]furan 135 is greater than that of benzo[b]furan 82 <1996AGE2638>. Moreover, Schleyer also discovered that the computed 1H NMR chemical shifts (GIAO-HF/6-31þG* //Becke3LYP/6-311þG** ) of 135 corresponded closely to those for furan and benzene, suggesting that 135 retains significant aromaticity. 7
1
6
O2 5
O
3
4
135
82
Although many research articles state that 135 and its derivatives are rather reactive and as a result are difficult to be isolated at room temperature unless electron-withdrawing or bulky groups are substituted at the C-1 or C-3 position, there are reports concerning the isolation of stable derivatives of 135. For example, as shown in Equation (113), attempts to purify 136 by flash chromatography led to the formation of 1-(diethylamino)-3-phenylbenzo[c]furan hydrochloride 137 in a yield as high as 81% <1997JME2936>. Ph
Ph
flash chromatography
Cl
O
NEt2
ð113Þ
NEt2 • HCl
O
136
137
Other intriguing observations were the identification of relatively stable 1-t-butyldimethylsilyl-4-methylbenzo[c]furan <1996JA10766>, and the preparation of the stable benzo[c]furan derivative 138 starting from dimethyl 3,4-furandicarboxylate and N-methyl succinimide via a base-promoted condensation reaction, as can be seen in Equation (114) <1996S1180>. i, NaH (2.2 equiv) THF, MeOH (cat.) reflux
O CO2Me O
+ CO2Me
NMe O
OH
NMe
O ii, H+ 73%
O
OH
ð114Þ
O
138 A novel crystalline benzo[c]furan 139 was also reported by Warrener, in which the 1,3-positions are linked with an alicyclophane <2001CC1550>. CF3
O
O
OF3C O N
O
139
O N
Furans and their Benzo Derivatives: Reactivity
In addition to being a very reactive Diels–Alder diene, 1,3,4,5,6,7-hexaphenylbenzo[c]furan was reported to be highly fluorescent in toluene solution, as well as in its solid state. This benzo[c]furan may therefore be used as electron transport material in an organic light-emitting diode <2002SM247>.
3.06.2.3.1
Cycloaddition reactions
Although being itself rather elusive, freshly generated 135 has been used time and again in trapping reactions. For example, its Diels–Alder cycloaddition with dienophiles such as quinone <1999AJC1123> and DMAD <2002SL1868, 2002OL3355> led to the formation of cycloaddition adducts. Benzo[c]furan 135 was also used to trap dienophiles 140 <2000J(P1)195>, 141 <2001SC1167>, 142 <2003CEJ2068>, and 143 <2003OL2639>.
O O
O O O
140
141
142
143
Several reviews summarized the use of benzo[c]furan derivatives in trapping reactions <1996BCJ1149, 1997SL145, 1998CC1417>. The most popular benzo[c]furan derivative used in trapping reactions must be the 1,3-diphenyl derivative 144, which is commercially available and is a crystalline compound. Ph O Ph
144 There is a plethora of reactive and/or unstable dienophiles 145 <1996TL7251, 2001J(P1)1929>, 146 <1998TL6529>, 147 <1996JOC3392, 1998T9175>, 148 <1996TL8605>, 149 <1997SL44>, 150 <1996J(P2)1233>, 151 <1996TL4907>, 152 <1996JOC6462>, 153 <1996T3409>, 154 <1996T10955>, 155 <1996JCCS297>, 156 <1996JOC764>, 157 <1997JOC3355>, 158 <1998JOM1>, 159 <2004JOC7220>, 160 <2000TL6611>, 161 <1997BCJ1935>, 162 <1997TL4125>, 163 <2001JOC3806>, 164, 165 <1996H(43)527, 1998BCJ711>, 166 <1997JOC1642>, 167 <1996CC1519>, 168 <1997JOM41>, and 169 <1998JCD755> that were successfully trapped by 144. Cl
Cl Cl
F
O
F F
145
Cl
Cl Cl
Fe SO2Ph
Cl Cl
147
146
148
149
150
Cl
151
Me Cl Br
Fe
CO2Me Br Cl
152
153
154
155
156
157
158
455
456
Furans and their Benzo Derivatives: Reactivity
CO2Me (CH2)6
159
160
O
O
161
162
163
O
O
O OC CO N
N CO2Et
O
164
165
166
O
167
168
169
Diels–Alder cycloaddition of 144 and its derivatives with singlet oxygen, leading eventually to the formation of 1,2dibenzoylbenzenes, has been employed to determine the presence of singlet oxygen <1996NJC571, 1996JPH49, 1997JPPA273, 1997JA5286, 1997OM4386>. An [8pþ8p] cycloaddition was observed for 144 and o-thiobenzoquinonemethide 170, as shown in Scheme 61 <1996JHC1727>.
Ph O
Ph S
S
144 Ph
S
O PhMe reflux, 5 h 84%
170
Ph
Scheme 61
Substituted benzo[c]furans played a very important role in the quest for natural as well as non-natural molecules. The schemes depicted here are examples showing the use of substituted benzo[c]furans in the synthesis of complex molecules. A short synthesis of ()-halenaquinone 173 was reported <2001JOC3639>, in which the pivotal step was the Diels–Alder cycloaddition of 4,7-dimethoxybenzo[c]furan 171 to 172, as illustrated in Scheme 62. In a similar manner, the total synthesis of ()-xestoquinone, ()-9-methoxyxestoquinone, ()-10-methoxyxestoquinone <2001T309>, and the naphtho[2,3-h]quinoline portion of dynemicin A <1997JA5591> was also achieved.
SPh OMe
H
SPh OMe
H
O +
OMe
171 Scheme 62
O
O OMe
172
PhMe reflux, 21 h 94%
H
H
O
O
O OMe
O
O OMe
O O
O
173
Furans and their Benzo Derivatives: Reactivity
Diels–Alder cycloaddition between 1,4,7-tris(trimethylsilyloxy)benzo[c]furan 174 and the dienophile 175 was also the key step in the total synthesis of (þ)-dynemicin A 176 reported by Myers <1997JA6072>, as can be seen in Scheme 63.
Me
H RO
N
OR O
Me
H CO2SiPri3
RO
O
N
H H
CO2SiPri3 O
OMe
+
OMe
H O
RO
174
O
THF –20 to 55 °C 5 min 75%
175
RO
RO
H H
O
R = Me3Si Me
H MnO2 3HF•NEt3 THF 23 °C, 9 min 53%
OH
O
CO2H
HN O
OMe H O
OH
OH
176 Scheme 63
Kelly reported a short synthesis of the CDEF fragment of lactonamycin 178 in eight steps. As can be seen in Scheme 64, the Diels–Alder reaction between the tricyclic 177 and 2,3-dimethylbenzoquinone was used for construction of the tetracyclic skeleton <2002OL1527>.
O Me Me
Me
N
OR
RO O
RO
O Me
RO
O
RO
N
Me
O
–60 °C
RO
Me O
177 R = SiMe2But Me N TFA
OH
O Me
O
Me
HO
178
O
Scheme 64
Two novel mono- and bisoxadisilole-fused benzo[c]furans were prepared and isolated. They were shown to undergo facile Diels–Alder cycloaddition reactions with dienophiles such as the oxadisilole-fused benzyne, as illustrated in Equations (115) and (116), to form acene precursors <2006JOC3512>.
457
458
Furans and their Benzo Derivatives: Reactivity
Si O Si
Si O
Si O Si
O CHCl3
Si
ð115Þ
Si O
O Si
85% Si
O Si Si
O Si
O
Si
Si
Si
O CHCl3 45%
Si O Si
ð116Þ
O
O Si
Si O Si
Many benzo[c]furan derivatives have been prepared and their intermolecular Diels–Alder cycloaddition reactions led to many intriguing structures. These benzo[c]furans are: 179 <1996JA9426, 1996TA1577>, 180–184 <1996AJC1263, 1997T3975>, 185–187 <1997LA663>, 188 <2000TL5957, 2002T9413>, 189 <2000OL923, 2001JOC3797>, 190 <2000IJB738>, 191 <2000OL1267>, 192 <1996TL6089>, 193 <1996TL6797>, 194 <1996TL5963>, 195 <1996JOC3706>, 196 <1996JOC6166>, 197, 198 <1996JOC3706>, 199–201 <1997JOC2786, 1997S1353>, 202 <1997SL47>, 203 <2004OM4121>, 204 <1996JA741, 1997AGE1531>, 205 <1998EJO99>, 206 <1996S77>, 207 <2001TL789>, and 208 <1996TL8845, 2003JOC8373, 2003JA2974>. Br
Me
O O
O O
Me
179
181
182
183
O Br
Ph O
O
O
Me3Si
Br C6H13
OC6H13
186
187 OMe
Bu OSiMe3
188
MeO
189
Ph
Me O
O
184
Me3Si
Br
O
185
OSiMe3 Me O
O
191
PO(OR)2 O
194
195
MeO
192
CN
193
SEt
SEt
SEt
O
O
O
Me
R = Me, Et, n-Pr, i-Pr
Ph
MeO
SiMe3
190
O
OC6H13
C6H13 Br
H13C6O
O
Br
180
H13C6O
O
O
Ph
(CH2)nCH=CH2
196 n = 3, 4
197
Furans and their Benzo Derivatives: Reactivity
SEt
SEt
SEt
SEt
O
O
O
O
NEt2
N
O
199
O
N Me
(CH2)nCH=CH2
Me
200
E (CH2)2CH=CHSO2Tol
201
n = 2, 3
198
O
Me
R
O
Ph O
O
O
O
O O
Re(CO)2Cp
R
Ph Ph
202
203
R = H, -p-C6H4But (CH2)4
O
H
204
R
O O
O
(CH2)4
Ph
C12H25
H
O
Ph
Ph
O
O
O
C12H25
205
206
207
208
Intramolecular Diels–Alder reactions involving in situ generation of benzo[c]furan species have also been a viable method in the construction of polycyclic molecules. As can be seen in Scheme 65, a nitrogen-containing heterocycle 210 was obtained via a sequence of Pummerer reaction and Diels–Alder cycloaddition, starting from the enesulfoxide 209, presumably via a benzo[c]furan intermediate <1997JOC2786>. A new entry into the erythrinane skeleton was achieved by employing a similar strategy, as illustrated in Scheme 66 <1996JOC4888, 1998JOC1144>.
O
SEt SOEt O N
Me O
209
OAc
p-TsOH Ac2O xylene 81%
O Me
N O
Me
+ N O
N
Me O
210
Scheme 65
The Hamaguchi–Ibata methodology was employed in the conversion of dizaoketone 211 to benzo[h]quinoline 212 <1999J(P1)59>, as depicted in Scheme 67, again via a benzo[c]furan. Benzo[c]phenanthridines can be obtained in a similar way <1998TL9785>.
459
460
Furans and their Benzo Derivatives: Reactivity
SEt SOEt
TFAA
O
CO2Me
MeO
N
MeO
O
MeO
CO2Me
O
Et3N
N O O
MeO SEt
CO2Me p-TsOH CO2Me
O
MeO
66%
N
MeO
N O
MeO O
MeO Scheme 66
O O
O MeN
MeN O N2
MeO
O O
O
MeN
Cu(hfa)2
H
PhMe reflux,12 h 52%
CO2Me
O
O
H
MeO
H
MeO
CO2Me
CO2Me
211 O O
MeN H MeO HO CO2Me
212 Scheme 67
A more structurally intriguing furanophane 216 was obtained by Herndon, who utilized an [8þ2] cycloaddition of dienylbenzo[c]furan 215 and DMAD (Scheme 68). The dienylbenzo[c]furan, in turn, was generated from a reaction between alkynylbenzophenone 213 and an alkenyl chromium carbene 214 <2003JA12720>.
Bu
OMe
Bu
OMe
Bu
Cr(CO)5
H
DMAD O
+
MeO dioxane 85 °C, 1 h 76%
Ph
213 Scheme 68
O
O
214
Ph
215
Ph
CO2Me CO2Me
216
Furans and their Benzo Derivatives: Reactivity
A similar one-pot synthesis as can be seen in Scheme 69 led to the formation of isoquinolines after spontaneous deoxygenation <2003OL4261>.
Bu
(CO)5Cr +
H
Me2N
CHO
O
NC
Me2N H Bu
NMe2 H
Bu
PhMe 100 °C 59%
H
N
H
N
H
Scheme 69
The syntheses of several nonbenzenoid and heterocyclic benzo[c]furans were reported in 1996–2005. These heterocycles undergo similar cycloaddition reactions as their benzenoid analogs. These molecules are: 217 <1996JOC6166>, 218 <1996H(43)1165>, 219 <1998H(48)853, 1998JOC7680>, 220 <1999TL397>, 221 <2003JOC6919>, 222 <2003AJC811>, 223 <1997HCA2520, 2005HCA1250>, 224 and 225 <2003OBC2383>.
SEt
OR1
Me
R2
OMe R1
N N
O S
O
Me
O
O CO2R2
Ph
217 R
CO2Me
218 1 = Me,
SPh
R1
R3
220
219
R1 = R2 = R3 = H 1 R = H; R2 = R3 = Me 1 = H; R2 = NPri ; R3 = H R 2 R1 = R2 = H; R3 = NEt2 R1 = H; R2 = CO2Me; R3 = NEt2 R1 = Cl; R2 = CO2Me; R3 = NEt2
Ph, -(CH2)3C CH, -(CH2)3C CCO2Me R2 = Me, -CH2C CH
N
Cl
O
N
S
O
OHC O
N
O
N
O
N
Cl
Cl
N
O
R
221
222
223
224
225
R=H R = Me R = OMe
An appropriate example to show the reactivity of a nonbenzenoid benzo[c]furan is the realization of a fused carbazole 228 from maleic anhydride and benzo[c]furan 227, which was generated from sulfoxide 226 through a Pummerer reaction as shown in Scheme 70 <1996JOC6166>.
461
462
Furans and their Benzo Derivatives: Reactivity
O EtS
O EtS
O
SOEt
O
O
Ac2O
O
O
CHO N
p-TsOH 78%
N PhSO2
N PhSO2
PhSO2
226
227
228
Scheme 70
3.06.2.3.2
Miscellaneous reactions
1,3-Dithienylbenzo[c]furan 229 was converted to benzo[c]selenophene 230 on interaction with Woollins reagent at room temperature, as can be seen in Equation (117) <2005TL7201>. S
S Woollins reagent (0.25 equiv)
O
Se
ð117Þ
CH2Cl2 67%
S
S
229
230
3.06.3 Reactivity of Nonconjugated Rings 3.06.3.1 Reactivity of Dihydrofurans and Tetrahydrofurans 3.06.3.1.1
Reactions of 2,3-dihydrofurans and 2,5-dihydrofurans
As depicted in Equation (118), the regioselective addition of an active methylene compound to 2,3-dihydrofuran was promoted by catalytic amounts of AuCl3–AgOTf, providing a 2-substituted THF as the product <2005OL673>. O O
O
AuCl3−AgOTf Ph
Ph
Ph
Ph
+
ð118Þ
CH2Cl2 rt 58%
O
O
O
Palladium-catalyzed regioselective hydroamination of 2,3-dihydrofuran under ligand-free and neutral conditions was found to be general with secondary alkyl amines, as exemplified in Equation (119) <2001T5445>. K2Pd(SCN)4 + O
HN
O
20 °C, 12 h 91%
O
N O
ð119Þ
Palladium-catalyzed enantioselective Heck reaction of 2,3-dihydrofuran to provide 2-substituted-2,5-dihydrofurans was achieved by using the chiral phosphinooxazoline ligand 231, as shown in Equation (120) <1996AGE200>. Analogous chiral phosphinooxazoline ligands 232 <2001OL161>, 233 <2003CEJ3073>, 234 <2004SL106>, as well as phosphite-oxazoline 235 <2005OL5597> were also effective for this reaction. This Heck coupling, in contrast to that using 2,2-bis(diphenyl-phosphanyl)-1,1-binaphthyl (BINAP) to obtain 2-substituted-2,3-dihydrofuran isomers, was reviewed <1997S1338, 2004S1879>. As indicated in Equation (121), a transient intermediate 236 that was probably formed by a double dyotropic rearrangement of the initial Pd arylation adduct for the BINAP–palladiumcatalyzed reaction was characterized spectroscopically at low temperature <2001HCA3043, 1997AGE984>.
Furans and their Benzo Derivatives: Reactivity
Pd(dba)2(3 mol%)
231 (6 mol%) TfO
O
PriNEt2
+
N O
C6H6 30 °C, 72 h 92%
O
231
>99% ee
O
O Ph
Ph N
N
O S
N PPh2
O Fe
O
O
O
Ph2P
ð120Þ
Ph2P
P
O
Me3Si
O
O
SiMe3
N PPh2
P(3,5-(CF3)2C6H3)2
232
233
234
PPh2 + Pd
235
Ph O
–OTf
O
PPh2 O
Ph
ð121Þ
236 As represented in Equation (122), a rhodium-catalyzed hydroformylation of 2,3- and 2,5-dihydrofuran using furanoside-derived chiral diphosphite ligands, for example, 237, provided 3-formyltetrahydrofuran as the major product with ee up to 75% <2005CC1221>.
O
CO/H2 Rh(acac)(CO)2
237 45 °C, 24 h 98% conversion
O
OPL*
O
But
But
OPL*
L* =
O
ð122Þ
O O
CHO 74% ee
O But
But
237 Platinum-catalyzed cyclization of a 2,3-dihydrofuran to the tethered alkyne provided the fused tricyclic compound 238, as shown in Scheme 71. Acid-promoted benzannulation of 238 then produced the dihydrobenzofuran, presumably via a retro-hetero-Diels–Alder opening of the dihydropyran ring <2004OL3191>. H PtCl2 (5 mol%)
p-TsOH
O Ph
Scheme 71
O
PhMe 50 °C, 24 h 58%
O O Ph
238
PhMe 70–110 °C 2–30 min 95%
O Ph
463
464
Furans and their Benzo Derivatives: Reactivity
Enantioselective [3þ2] cycloaddition between 2,3-dihydrofuran and 1,4-benzoquinones was performed using the oxazaborolidinium catalyst. As shown in Equation (123), reaction of unsymmetrical 1,4-benzoquinones gave a mixture of two regioisomers. This methodology was applied to a concise total synthesis of aflatoxin B2 <2005JA11958>. A Do¨tz benzannulation involving a dihydrofuran containing chromium carbene complex and an alkyne was also employed to form the aflatoxin B2 skeleton regioselectively <2006TL2299>. As depicted in Equation (124), annulated product 239 was the only regioisomer obtained. H + N
Ph
Ph
B
Tf2N– H
OH
OH
O
MeO
MeO
ð123Þ
(20 mol%)
H
+ O
CH2Cl2−MeCN (1:1) −78 °C, 2 h −78 to 23 °C, 5 h
O (1.5 equiv)
+
H MeO O
O O
H
H
65% 92% ee
O
32% 90% ee OSiButMe2
tMe
OSiBu
(CO)5Cr
2
H
+
HO OEt
OMe
H
O H
ð124Þ
OEt
THF 80 °C, 2 h 31%
O
OMe
O O
H
239 An example of enantioselective 1,3-dipolar cycloaddition of ethyl diazopyruvate to 2,3-dihydrofuran, catalyzed by a chiral ruthenium-PyBox complex, to provide a tetrahydrofurofuran was reported (Equation 125). However, the adduct 240 was only obtained in 74% ee, and its absolute configuration not determined <2004SL2573, 2005HCA1010>. As shown in Equation (126), 2,3-dihydrofuran also participated in 1,3-dipolar cycloaddition with dipoles derived from aziridines under Sc(OTf)3-catalyzed conditions, forming cis-fused furopyrrolidines <2001TL9089>.
O
N
N Pri O
O
O
N
PyBox RuCl2(p-cymene)
Pri
+
EtO2C
PhMe 0 °C 68%
N2
ð125Þ O
O
EtO2C
240 74% ee
H Sc(OTf)3 (3 mol%)
ð126Þ
+ N Ts
O
CH2Cl2 0 °C, 1.5 h 72%
N O Ts H dr = 50:50
Furans and their Benzo Derivatives: Reactivity
2,3-Dihydrofuran participated in Pauson–Khand reaction with alkyne–dicobalt complexes, giving furocyclopentenones regioselectively <2001JOM104>. An example of employing this reaction as a starting point for a total synthesis of terpestacin is shown in Equation (127) <2003JA11514>. SiMe3 O
O
NMO +
Co2(CO)6
H
O SiMe3
CH2Cl2
ð127Þ
H
51%
dr > 95:5
An interesting example of triple electrophilic aromatic substitution between a dihydrofuran derivative and phloroglucinol was exploited for the total synthesis of the C3-symmetric xyloketal A, as shown in Equation (128) <2006OL1427>. O OH
BF3•Et2O MgSO4
HO
O
H
H
+ O
Et2O −78 °C,20 min 79%
OH
HO
O
O O
H
O
ð128Þ
Xyloketal A
dr = 80:20
Two equivalents of 2,3-dihydrofuran, that served as two different reaction components, were coupled to anilines to form cis-fused furotetrahydroquinolines by using catalytic amounts of Dy(OTf)3 <2001TL7935> and InCl3 in water <2002JOC3969>, as illustrated in Scheme 72. Similar reactions making use of Sc(OTf)3 in 1-butyl-3-methylimidazolium hexafluorophosphate were also reported <2002S2537>. The isolation of a furo[2,3-b]oxepin side product 242 <2001TL7935>, which was the major product obtained in the InCl3-catalyzed coupling between 2,3-dihydrofuran and 2-methylindoles <2003TL2221>, suggested a stepwise pathway involving an oxonium intermediate 241 for the second reaction. InCl3 in water catalyzed the hydration of dihydrofuran to the corresponding lactol, which was the first reactive species in the reactions described above and also in an indium-promoted allylation with various allylic bromides to provide allylated 1,4-diols <2004SL829>. O
InCl3 (cat.) Cl
O
Cl
H2O
+ 45 °C, 10 h 77% cis:trans = 74:26
NH2
Dy(OTf)3 (5 mol%) MeCN 4 °C, 48 h
81% cis:trans = 76:24
+ O
Cl
Cl N H
241 Scheme 72
OH
N H
OH
10%
H N H
242
O H O H
465
466
Furans and their Benzo Derivatives: Reactivity
Dihydrofuran was used as a ketone equivalent in a Fischer-type indole synthesis with an aryl hydrazine under strongly acidic conditions to give a tryptophol. As shown in Equation (129), 5-methyl-2,3-dihydrofuran gave rise to 2-methyltryptophol regioselectively <2004OL79>. OH O
NH2
N H
4% H2SO4
+
ð129Þ
MeCONMe2 100 °C 80%
N H
Coupling of 2,3-dihydrofuran with alkene–zirconocene <2004AGE3932> or aryne–zirconocene <2005SL2513> complexes and subsequent addition of an electrophile provided cis-disubstituted homoallylic alcohols, as illustrated in Equation (130). An insertion/-elimination pathway that involved the formation of an oxazirconacyclooctene intermediate was proposed for the reaction mechanism. Et
O +
Cp2Zr
I
i, THF –78 to 25 °C
OH Et
ð130Þ
ii, I2 –20 to 25 °C, 1 h 75%
The dyotropic rearrangement of lithiodihydrofuran-derived dihydrofuranyl cuprate followed by electrophilic addition was further extended to the stereoselective preparation of differentially functionalized 1,1-disubstituted alkenes, as illustrated in Scheme 73 <2003SL955, 2003S2530>. This method was applied to the elaborated dihydrofuran 243 for the synthesis of the C-10–C-15 segment of tylosin II <1996SL1125, 1996T6613>, as depicted in Equation (131), as well as to the synthesis of the C(12)–C(15) segment of apoptolidin <2005T401>.
i, (Me3Si)2CuCNLi2 THF−Et2O (1:1) –5 °C, 1.5 h O
Li
ii, Bun3SnCl –40 to 20 °C, 5 h 87%
HO
HO I2
Bun3Sn
SiMe3
CH2Cl2 0 °C 91%
I
SiMe3
Scheme 73
i, ButLi THF –60 to −5 °C, 1 h ii, (Me3SiCHCH)2CuCNLi2 THF−Et2O (1:1) –10 to −5 °C, 2 h
HO
O
243
iii, MeI –60 to 20 °C, 4 h 76%
SiMe3
ð131Þ HO OH
As shown in Equation (132), dihydrofurans having a 3-acetyl group underwent benzannulation via photoinduced cleavage of the dihydrofuran ring to give naphthalene products <2001TL3351>. Helicene-type compounds and benzo[kl]xanthenes were also produced by this method <2005TL7303>.
Furans and their Benzo Derivatives: Reactivity
O Cl
Cl hν 2 M HCl
O
O Cl
ð132Þ
MeCN argon 23 °C, 3 h 96%
Cl
The diastereoselective and enantioselective [2þ2] cycloaddition of a 7-oxanorbornene with a chiral alkynyl acyl sultam was effected by using a ruthenium catalyst to provide the exo-cycloadduct as shown in Equation (133) <2004AGE610>. O
O
Xc O
MeO
CpRuCl(COD) +
MeO
Ph
O
MeO
Xc
MeO
THF 25 °C, 168 h 73%
Ph dr = 97:3 95% ee
Xc =
ð133Þ
N S O O
As demonstrated in Equation (134), a tandem ring opening/cross metathesis of endo-2-tosyl-7-oxanorbornene with vinyl ether or vinyl acetate as catalyzed by Grubbs’ second generation catalyst 244 afforded a 2,5-disubstituted THF as a single regioisomer. The same regioselectivity was obtained from the reaction of the 2-exo-isomer. 2-Carboxylate and benzoxymethyl groups could also exert a similar directing effect on this reaction as the tosyl group <2004OL1625, 2005OL131>. However, opposite regioselectivity (viz. the formation of 245 and 246) was observed with an acetate substituent (Equation 135) <1999JOC9739, 2000TL9777>. These reactions were reviewed <2003EJO611>.
OEt 244 (6 mol%)
O
Mes N
Ts
Cl EtO
CHCl3 55 °C, 4 h 94% E : Z = 55 : 45
Ts
Cl
O
N Ru
Mes Ph
ð134Þ
PCy3
244 Grubbs’ catalyst i, 244 (5 mol%)
O + OAc
OAc
CH2Cl2 rt, 2 h 75% ii, H2 (50 Psi) 10% Pd/C MeOH 245:246 = 81:19 75%
AcO R1
O
R2
245: R1 = Et; R2 = (CH2)3OAc 246: R1 = (CH2)3OAc; R2 = Et
ð135Þ
467
468
Furans and their Benzo Derivatives: Reactivity
The tandem ring-opening/ring-closing metathesis of 7-oxanorbornene derivatives as catalyzed by Grubbs’ catalyst 244 was applied to synthesize a key bicyclic cyclopentenone intermediate in a total synthesis of trans-kumausyne <2005OL3493>, bicyclic seven- and eight-membered sulfonamides <2006TL189>, a seven-membered ring in a spirotricyclic -lactam <2005HCA1387>, and the 9-oxabicyclo[4.2.1]nona-2,4-diene of mycoepoxydiene <2004JOC8789>. Equation (136) depicts an interesting example of this type of reaction in which the formation of new six-, seven-, and eight-membered rings in the polycyclic product was achieved in a single step, although a stoichiometric amount of the catalyst was used <2004OL3821>. O
O O O
244 (1 equiv)
O
TsN
25 °C to reflux, 24 h 10%
BOCN
TsN O
O
ð136Þ
BOCN
O
(0.5 mM in CH2Cl2)
The synthetic applications of 8-oxabicyclo[3.2.1]oct-6-en-3-ones as polyoxygenated building blocks were reviewed <2004AGE1934>. The reactivity of 8-oxabicyclo[3.2.1]octane toward the inter- and intramolecular ring-opening/ ring-closing metathesis could be modulated by substitution on the ring <2001OL4275, 2002AGE4560>. For example, the intramolecular formation of a spiro-seven-membered ring, as shown in Equation (137), was more effective in the substrate 247 that has an endo-hydroxyl group than in substrate 248 which has a keto group. R2 R1
R2 R1
244 O
CH2Cl2
O
ð137Þ
247: R1 = OSButMe2; R2 = H (80%) 248: R1 = R2 = O (<15%)
3.06.3.1.2
Reactions of tetrahydrofurans
It was found that the THF -radical was readily generated from THF by dimethylzinc and air. The THF -radical added to aldimines at room temperature to form threo THF-substituted benzylamine derivatives as major isomers <2002OL3509>. It was less reactive toward aldehydes, although reaction with aldehydes was made possible at 50 C to give -hydroxylated -substituted THFs, which were isolated as the keto-lactones in modest yields after Jones oxidation (Scheme 74). The initially generated THF -radical probably reacted with molecular oxygen to generate an -peroxygenated THF -radical as the key intermediate <2004TL795>. Generation of a THF oxonium ion by the oxidation of the initially formed THF -radical was proposed to account for the 4-tetrahydrofuranyl-4-aminobutanols obtained in the reaction of two THF molecules with anilines at room temperature under the dimethylzinc/air conditions, as indicated in Equation (138) <2005T379>.
O + Ph
O
Me2Zn (12 equiv) air
OH Ph
THF 50 °C, 2 d
H
OH O
CrO3 H2SO4
O Ph
acetone 0 °C,15 min 54%
O O
Scheme 74
NH2
Me2Zn (12 equiv) air +
Cl
O
Cl
ð138Þ
O rt, 20 h 87%
N H
OH
Furans and their Benzo Derivatives: Reactivity
Triethylborane together with air <1999CC1745> or tert-butylhydroperoxide <2003JOC625> also generated the THF -radical from THF at room temperature, and promoted its addition to aldehydes to provide the threo-adducts as the major isomers. This method was applied to the synthesis of the cytotoxin muricatacin <2003JOC7548>. As demonstrated in Equation (139), chemoselective addition of THF -radical to an aldimine or an aldehyde could therefore be achieved in a three-component reaction system, depending on the radical initiator used <2003OL1797>. O O + Ph
O
air
H2N
+
H
+
O rt
OMe
Ph
N H
Ph
OH
ð139Þ
OMe Me2Zn (12 equiv), 21 h Et3B (12 equiv), 16 h
0% 75%
74% 10%
Addition of the THF -radical, generated by using triethylborane or benzoyl peroxide, to styrylsulfimides produced 2-styryltetrahydrofurans <1996TL909>. As exemplified in Equation (140), THF was coupled to a variety of aryl- and alkyl-substituted terminal alkynes under microwave irradiation to provide a mixture of cis- and trans-2vinyltetrahydrofurans <2004TL7581>. It was proposed that the THF -radical was the reactive species that was generated by oxygen under the microwave conditions. alkyne/THF (1:200) microwave 300 W +
OH
200 °C, 40 min 56%
O
OH O cis:trans = 31:69
ð140Þ
Tetrahydrofuranyl ethers, which served as hydroxyl protecting groups, were prepared from the reaction between THF and alcohols via the THF -radical by using CrCl2/CCl4 <2000OL485>, or BrCCl3/2,4,6-collidine <2000TL6249>, or 1-tert-butylperoxy-1,2-benziodoxol-3(1H)-one/CCl4 <2004TL3557>. THF ethers can also be formed by the reaction of alcohols with THF using (diacetoxyiodo)benzene under microwave irradiation <2004SL2291>. The sole example of a reaction with a hindered tertiary alcohol <2000OL485> under these newly developed conditions is shown in Equation (141). CrCl2 CCl4
OH O solvent
O
O
+
ð141Þ
47%
The hydroxylation at the C-2 position of THF to form lactol by iodosylbenzene in the presence of an Mn(III)–salen complex was reported <1997SL836>. Selective oxidation of the C-3 methylene carbon of the tetrahydrofuran moiety over the C-7 methylene carbon of the bicyclic ketal of buergerinin F to form its lactone analog, buergerinin G, was performed by using ruthenium tetroxide (Equation 142) <2003JOC4117>. An unusual oxidation of hexahydrobenzofuran-3a-ol using a catalytic amount of in situ-generated RuO4 provided nine-membered keto-lactones as shown in Equation (143). The usual regioselectivity in RuO4-promoted oxidation of ethers was reversed in this example, with the tertiary C-7a proton oxidized selectively over the secondary C-2 proton <2003OL1337>.
O 3
RuCl3 NaIO4 NaHCO3
O O 7
Buergerinin F
H2O−CCl4−MeCN (1:1:1) rt, 22 h 77%
O O O Buergerinin G
O
ð142Þ
469
470
Furans and their Benzo Derivatives: Reactivity
RuCl3 (2.4 mol%) NaIO4 (4.1 equiv)
O
H2O−CCl4−MeCN (3:2:2) rt, 75 min 81%
O
OH 2 7a
O
ð143Þ
O
Similar regioselective hydroxylation of the C-16 tertiary -carbon of the tetrahydrofuran moiety in cephalostatinrelated steroids could also be achieved with retention of configuration by in situ-generated dioxoperoxy CrO4 (from a mixture of CrO3 and n-Bu4NIO4). Notably, alkenes and iodides were unaffected under these conditions <2004OL1437>. A remarkable example, as shown in Equation (144), is the preferential oxidation by this Cr(VI) oxidant at C-16 of the bis-THF containing substrate 249 to provide 250 as the major product.
O
CrO3 (3 equiv) Bun4NIO4 (3 equiv) O
AcO O O
O
16
AcO
O Cr
ð144Þ
O
O
OH AcO
249
MeCN−CH2Cl2 (3:1) −40 °C, 10 min 62%
AcO
250
Bicyclo[3.n.0]oxonium ions derived from THFs could produce either ring expansion, ring-switched, or non-rearranged products in the presence of protic nucleophiles <1996J(P1)413>. Tetrahydrofurfuryl monochlorates underwent a Zn(OAc)2-induced regio- and stereoselective 1,2-rearrangement/ring expansion via bicyclo[3.1.0]oxonium ions to provide tetrahydropyrans <1999TL2145>. Extension of this methodology to a novel stereoselective and stereospecific 1,4-rearrangement/ring expansion of 251 via bicyclo[3.3.0]oxonium ions 252 to form oxocanes 253 and 254 is depicted in Scheme 75 <2002OL675>. Related methodology in which the THF oxygen atom trapped a dicobalthexacarbonyl-stabilized cation to generate the bicyclo[3.3.0]oxonium and bicyclo[3.4.0]oxonium ions for the formation of oxocane and oxonane (Scheme 76) respectively was also developed <2000T2203>. Ring expansion of 2-(iodomethyl)tetrahydrofurans by p-iodotoluene difluoride/Et3N–HF to give 3-fluorotetrahydropyrans also involved bicyclo[3.1.0]oxonium intermediates (Scheme 77) <2003TL4117>.
OH
i, ClSO2CH2Cl 2,6-lutidine CH2Cl2 0 °C O OH
251
ii, 1:1 THF−H2O rt, 22 h 82% 253:254:251 = 85:8:7
O
253 H2O
H
+ OH
O +
O
254 +
252 O OH
251 Scheme 75
Furans and their Benzo Derivatives: Reactivity
SiMe3
O
+ O
O +
CH2Cl2 OH
SiMe3
SiMe3
MsCl Et3N rt
Co2(CO)6
Co2(CO)6
Co2(CO)6
Ph
Ph
Ph
CAN O Co2(CO)6
MeOH rt 52%
O
Ph
Ph Scheme 76
Ph
p-Tol-IF2 Et3N–5HF
O I
Ph
+ O
Ph
O
H
CH2Cl2 rt 66%
F
Scheme 77
As shown in Scheme 78, the transient bicyclo[3.3.0]oxonium ylide 255 that was generated from a THF-substituted diazoketone was first protonated by acetic acid to the corresponding bicyclo[3.3.0]oxonium ion, which then provided the ring expansion product <1996CC1077>. In the presence of the weakly acidic MeOH, the ylide underwent a concerted [3þ2] cycloreversion to a ketene intermediate to form the ring cleavage product <2004JOC1331>. OAc HOAc O O
N2
O + –
CH2Cl2 rt
O
>90%
Rh2(OAc)4
O
O
O
MeOH
255
O OMe
84%
Scheme 78
Transient oxonium ions could be generated from 2-tetrahydrofuranylsilanes <1996TL9119> and 2-tetrahydrofuranylstannanes <2006TL3607> by oxidation with cerium ammonium nitrate. Intramolecular capture of the cations by the hydroxyl group provided furo[2,3-b]pyrans, as depicted in Equation (145). O
O MeO2C
CAN (2 equiv)
MeO2C
MeCN 20 °C 54%
O
ð145Þ
OH O
SnBun3
H
O
471
472
Furans and their Benzo Derivatives: Reactivity
As illustrated in Equation (146), the C-2 hydrogen of 2-substituted THFs was found to undergo 1,5-hydride migration to pendant electron-deficient alkenes <2005JA12180> and aldehydes <2005OL5429> under Lewis acidpromoted conditions, providing spiro-carbocycles and spiro-ketals, respectively, after subsequent cyclization. Such a transformation occurred with 2-tetrahydrofuranylstannane 256 and in the absence of the Thorpe–Ingold effect, as shown in Equation (147) <2006TL3607>. CO2Et
CO2Et
Sc(OTf)3 (5 mol%)
CO2Et
O
O MeO2C
CH2Cl2 MeO2C
rt, <1 h 96%
CO2Me Ph
MeO2C
ð146Þ CO2Me
Ph CHO
MeO2C
BF3•Et2O CH2Cl2
SnBun3
O
CO2Et
O
20 °C 32%
256
ð147Þ O SnBun3
Regioselective acylative cleavage of 2-methyltetrahydrofuran to 4-halopentanoates could be achieved by using bismuth(III) halides as catalyst <2005T4447>. This methodology was applied to the synthesis of a tetralin, as shown in Equation (148). AcCl BiCl3
ð148Þ 87%
O
AcO
As illustrated in Equation (149), 2-alkyne-substituted THFs could be ring-opened via intramolecular transfer hydrogenation using TpRuPPh3(MeCN)2PF6 (Tp ¼ tris(1-pyrazolyl)borate) as a catalyst to provide dienyl ketones <2004JOC4692>. H Ph
O
H
O
TpRuPPh3(MeCN)2PF6 (10 mol%) ClCH2CH2Cl 80 °C, 12 h 93%
Ph
ð149Þ
3.06.3.2 Reactivity of Dihydrobenzo[b]furans The chemistry of 2,3-dihydrobenzo[b]furan 257 discussed herein is focused on the furan part, rather than on the phenyl part, where its chemistry is similar to that of benzenoid molecules. For the chemistry based on the furan part, the frequent reports are related to the C–O bond cleavage. For example, by using an electron-rich ligand-based PCy3/ Ni(acac)2 as a catalyst, 2,3-dihydrobenzo[b]furan 257 was employed to couple aryl groups to afford biaryl compounds, as can be seen in Equation (150) <2004AGE2428>. NiCl2PCy3 p-TolMgBr O
257
i-Pr2O
OH
ð150Þ
60 °C, 15 h 62%
As shown in Equation (151), in the presence of a catalytic amount of BF3, 2,3-dihydrobenzo[b]furan 257 was converted to its corresponding phenol iodide by treatment with SiCl4/LiI <2004TL3729>. o-2-Bromoethylphenol
Furans and their Benzo Derivatives: Reactivity
was also obtained by reaction of 2,3-dihydrobenzo[b]furan 257 using the high nucleophilicity of bromide ion in an ionic liquid, 1-n-butyl-3-methyl-imidazolium bromide ([bmim][Br], although the yield is low at 40% <2004JOC3340>. SiCl4 LiI BF3 O
257
I
ð151Þ
MeCN 70 °C, 45 min 90%
OH
The DTBB-catalyzed lithiation of 2,3-dihydrobenzo[b]furan 257 in THF at 20 C led to a suspension, which, after filtration of the excess of lithium, gave a solution of the corresponding functionalized organolithium compound. This intermediate was treated with zinc bromide (1:1 molar ratio), and then the generated organozinc reagent was successfully coupled with aryl bromide by the palladium-catalyzed Negishi reaction to yield the expected coupling product (Equation 152) <2002EJO1989, 2001TL5721>. The reaction of the organolithium compound derived from 2,3-dihydrobenzo[b]furan 257 with a variety of electrophiles was also reported <2002T4907, 1998TL7759>. Ar
i–iv O
OH
ð152Þ
257 i, Li, DTBB, THF, 20 °C; ii, ZnBr2, THF, 20 °C; iii, ArBr, Pd(PPh3)4, THF, 70 °C; iv, HCl–H2O
2,3-Dihydrobenzo[b]furan was reported to be reductively cleaved by treatment with hydrosilanes in the presence of catalytic amounts of B(C6F5)3 in high yield, as depicted in Equation (153) <2000JOC6179>. HSiEt3 OH
B(C6F5)3 O
257
ð153Þ
CH2Cl2 rt, 20 h 99%
3.06.3.3 Reactivity of Dihydrobenzo[c]furans The thermal reactions of dihydrobenzo[c]furan 258 were studied behind reflected shock waves in a single pulse shock tube over the temperature range 1050–1300 K to lead to products from a unimolecular cleavage of 258 <2001PCA3148>. Intriguingly, carbon monoxide and toluene were among the products of the highest concentration, while benzo[c]furan, benzene, ethylbenzene, styrene, ethylene, methane, and acetylene were the other products. Trace amounts of allene and propyne were also detected.
O
258 As depicted in Scheme 79, reductive ring opening of 258 using a small excess of Li and a substoichiometric amount of DTBB led to the organolithium species 259, which was quenched by the electrophile (–)-menthone to give diol 260 in 76% yield <2004S1115>. In a similar manner, lithiation reactions catalyzed by linear and cross-linked arene-based polymers generated the same organolithium species 259 that reacted with electrophiles such as 3-pentanone, cyclohexanone, tert-pentanal, benzaldehyde, and acetophenone to give diols of diversified structures <2004RJOC795>.
473
474
Furans and their Benzo Derivatives: Reactivity
Li
Li DTBB (3%) O
O i, –78 to –20 °C OLi
THF 0 °C, 6 h
258
OH
ii, H2O –20 °C 76%
259
OH
260
Scheme 79
Exhaustive cleavage of the carbon–silicon bond followed by treatment with an acid converted the complex benzo[c]furan 261 to phenol 262, as illustrated in Equation (154) <2003JA12994>. Villeneuve and Tam were able to interrupt this phenol formation by choosing Cp* Ru(COD)Cl as the catalyst. Thus, the reaction of 1,4-epoxy-1,4dihydronaphthalene 263 with a ruthenium catalyst in 1,2-dichloroethane at 60 C afforded the 1,2-naphthalene oxide 264 (Equation 155) <2006JA3514>. OBn
OBn OBn
SiMe2
O Cl
H
O MeO
i, n-Bu4NF DMF
O OBn
H O
OBn
OH
MeO Cl
O H
ii, TFA CH2Cl2 0 °C to rt 72%
ð154Þ
H
MeO O
OMe MeO
OBn
OMe MeO
OMe
OMe
261
262 O
O Cp*Ru(COD)Cl (5 mol%) CO2Et
263
ClCH2CH2Cl
CO2Et
60 °C, 2 h 82%
ð155Þ
264
Another way in which 1,4-epoxy-1,4-dihydronaphthalenes can react is via the deoxygenation reaction to form naphthalenes. For example, as shown in Equation (156), when 265 was allowed to react with 10 equiv of a commercially available Grignard reagent in refluxing THF, naphthalene 266 was obtained <1997TL4761>. Me
Me PhMgBr
O
265
THF reflux, 2 h 75%
ð156Þ
266
Ring opening of 1,4-epoxy-1,4-dihydronaphthalenes in general follows an exo-SN29 or SN29-like mechanism, leading to cis-alcohols. A review summarizing these conversions appeared in 1996 <1996S669>. An example depicting this transformation is shown in Equation (157) <2004OL3581>. Cheng also made use of nickel-catalyzed reactions to open 1,4-epoxy-1,4-dihydronaphthalenes by alkynyl <2002OL1679> and alkenyl groups <2004JOC8407>. Butyllithium was also used to open 1,4,5,8-diepoxy-1,4,5,8-tetrahydroanthracenes to give similar ring-opening products <1998H(47)977>. Most interestingly, an efficient ring closure of 2-iodophenoxyallene 267 catalyzed by palladium(0), followed by ring opening of 1,4-epoxy-1,4-dihydronaphthalene 268, led to the formation of 2-benzofuran-3-ylmethyl-1,2-dihydro-1-naphthalenol 269 in very good yield (Equation 158) <2006OL621>.
Furans and their Benzo Derivatives: Reactivity
O
O Me
OMe
Me
OMe OH
I O Pd(OAc)2 (5 mol%)
ð157Þ
PPh3 (11 mol%) PMP (0.5 equiv) Zn (10 equiv) DMF 95%
OMe
OMe
O
O
OH
PdCl2(PPh3)2 Zn
• +
ð158Þ
O THF 80 °C, 16 h 85%
I
267
268
269
Enantioselective ring opening of 1,4-epoxy-1,4-dihydronaphthalene remains a very active research area because the use of chiral catalysts to control the absolute stereochemistry of products could lead to optically active building blocks that can be employed in the quest for complex bioactive molecules. Lautens reported in 1997 that the oxygen bridge of 268 can be reductively opened, utilizing Ni(COD)2 as a catalyst and (R)-BINAP as a ligand to give alcohol 270 in good chemical and optical yields as depicted in Equation (159) <1997JOC5246, 1998T1107>. Ni(COD)2 (14 mol%) (R)-BINAP (21 mol%) O THF 2h 88%
268
ð159Þ HO
270 98% ee
Nickel- or palladium-catalyzed asymmetric reductive ring opening of 268 and its derivatives with organic acids and zinc powder under mild conditions also led to the formation of alcohols such as 270, as shown in Equation (160) <2003OL1621>. Pd(binap)Cl2 (5 mol%) Zn O (CH3CH2CH2)2CHCO2H
268
PhMe 2h 89%
ð160Þ
HO
270 90% ee
It is also known that the formation of trans-alcohols through a rhodium-catalyzed ring opening of 1,4-epoxy-1,4dihydronaphthalenes by amines can be achieved <2003CCL697>. This transformation is believed to involve the formation of a new carbon–nitrogen bond via an intermolecular highly regioselective allylic displacement of the bridgehead oxygen with a piperazine derivative. Another example for the formation of the trans-1,2-diol derivative 271 was reported by Lautens and co-workers <2000OL1677, 2001T5067, 2001JOM259, 2002JOC8043, 2004PNAS5455>, who treated 268 with a rhodium catalyst in the presence of phenols or carboxylates as nucleophiles, and (R)-(S)-PPF-PBut2 and other chiral ferrocenes as ligands. Good yields and high enantioselectivities were obtained, as can be seen in the example shown in Equation (161). Copper-catalyzed enantioselective ring opening of
475
476
Furans and their Benzo Derivatives: Reactivity
268 and its derivatives by dialkylzinc or Grignard reagents to form trans-alcohols was also reported by Feringa <2002OL2703> and Zhou <2005JOC3734>, making use of phosphoramidite catalysts 272 and 273, respectively. Salzer <2005JOM1166> also reported the optimized synthesis of a trans-alcohol in 59% yield and 97.5% ee using a rhodium-catalyzed reaction in the presence of the ‘Daniphos’-ligand 274. The formation of trans-alcohols can be explained by a rhodium-catalyzed mechanism, as outlined in Scheme 80 <2004PNAS5455>.
PBut2
[Rh(COD)Cl]2 (0.5 mol%) (R)-(S)-PPF-PBut2 (1 mol%)
Br
PPh2
O
268
Fe p-Br-C6H4OH THF 80 °C 94%
O
ð161Þ
HO (R)-(S)-PPF-PBut2
271 98% ee
Ph N P O O
Ph
OO
Ph P N
PBut2 Ph2P Me (CO)3Cr H
Ph
272
273
274
Cl L2*Rh
RhL2* Cl O
OR
Solvent L2*Rh
OH
Cl
H
L2* ⊕ Rh Cl O
O
RhL2* –
RO
Cl
OR
Cl O RhL2*
–
ROH Scheme 80
Rhodium-catalyzed nucleophilic ring opening of 1,4-epoxy-dihydronaphthalenes to form amino-alcohols was reported by Lautens <2002JOC8043>. An enantioselective rhodium-catalyzed version of this approach was recorded <2003JA14884> in which 268 was converted to an amino-alcohol 275, as illustrated in Equation (162). Biaryl and binaphthyl monodentate and bidentate catalysts have also been shown by Pregosin to provide similar results <2004OM2295>.
Furans and their Benzo Derivatives: Reactivity
[Rh(COD)Cl]2 (0.5 mol%) PPF-PBut2 (1.5 mol%) AgOTf (1.5 mol%) n-Bu4NI (2 mol%)
N
OH
Me
N
O
ð162Þ
N-methylpiperazine THF 80 °C 96%
268
275 99% ee
Sulfur nucleophiles are also able to afford 2-sulfanyl-1,2-dihydronaphthalen-1-ols such as 276 via rhodium catalyzed asymmetric ring-opening reactions, as shown in Equation (163) <2004JOC2194>. [Rh(COD)Cl]2 (2.5 mol%) (R)-(S)-PPF-PBut2 (6 mol%) AgOTf (7 mol%) NH4I (1.5 equiv)
OH S
O
ð163Þ
2,6-Me2C6H3SH galvinoxy (5 mol%) THF reflux 79%
268
276 98% ee
Palladium-catalyzed enantioselective alkylative ring opening of 277 and analogous molecules, on the other hand, was reported to lead to cis-alcohols such as 278 in good yields and high enantioselectivities. An example is shown in Equation (164) <2000JA1804, 2004JA1437>. Mechanistic studies <2001JA6834> and effects of halide ligands and protic additives <2001JA7170> have all been studied. The mechanism of the palladium-catalyzed ring opening of 1,4-epoxy-1,4-dihydronaphthalene 268 with dialkylzinc to form cis-alcohols was proposed to go through a carbopalladation pathway, as depicted in Scheme 81 <2001JA6834>. Pd(MeCN)2Cl2 (5 mol%)
OH
Et2Zn (R)-Tol-BINAP
O
O
O
ð164Þ CH2Cl2 91%
O
277
O
278 92% ee
O + R2Zn
268 R2Zn Cl2PdL2
O
X
⊕ PdL2
L2Pd
R2ZnX
–
carbopalladation
R
R X = R or Cl
X R2Zn
⊕ – PdL2 R2ZnX
O
L2Pd
R
R R R2Zn Scheme 81
OPdL2X
R OZnR
477
478
Furans and their Benzo Derivatives: Reactivity
Carretero and co-workers reported a similar palladium-catalyzed approach with the use of a ferrocene ligand 279 but the products are of opposite absolute structures <2002CC2512>. The same group also reported that in the presence of a Grignard reagent, the copper-catalyzed ring opening reaction of 268 and its derivatives afforded trans-alcohols as major products. Scheme 82 shows a plausible mechanism. As can be seen, the results are consistent with a copper-catalyzed endo SN29 attack of the organocuprate generated from a copper salt and a Grignard reagent, providing a trans-alcohol after a reductive elimination of the organocopper species and subsequent hydrolysis <2006S1205>.
SBut PCy2 Fe
279 OMgX R
OMgX CuR2
O R2Cu 2MgX2
268 Scheme 82
Lautens reported various limitations in rhodium-catalyzed cis-alcohol formation. As can be seen in Equation (165), the yield of 280 is only 16%, albeit with 96% ee <2003OL3695>. On the other hand, an identical reaction utilizing Pd(dppp)Cl2 as a catalyst gave 280 in 82% yield but only with 71% ee (dppp ¼ 1,3-bis(diphenylphosphino)propane) <2003OL3695>. B(OH)2 OH
O
O O [Rh(COD)Cl]2 (2.5 mol%) (R)-(S)-PPF-PBut2 (5 mol%) Cs2CO3 (0.5 equiv) THF 16%
268
ð165Þ
280 96% ee
3.06.4 Reactivity of Substituents Attached to Ring Carbons 3.06.4.1 Alkyl and Substituted Alkyl Substituents Treatment of tri-2-furylmethane with n-BuLi resulted in the unanticipated formation of 1,1-bisfuryl-1-[5-(tri-2furylmethyl)]furylmethane, as shown in Equation (166). Presumably, a tri-2-furylmethane anion was generated in preference to a 2-furyl anion. The same product could also be obtained using ButOK as the base <2004OL3513>. BunLi TMEDA THF –78 °C, 30 min 40%
O
O O
O
O O
tOK
or Bu THF rt, 30 min 50%
O
O
O
ð166Þ
Furans and their Benzo Derivatives: Reactivity
Deprotonation of allyl furfuryl ethers by t-BuLi occurred at the -position, as shown in Equation (167), whereas deprotonation of the corresponding propargyl furfuryl ethers occurred at the 9-position (Equation 168). The resultant anions then underwent a [2,3]-Wittig rearrangement preferentially over a [1,2]-Wittig rearrangement, giving homoallylic alcohols and a propargyl alcohol, respectively <1999CC2263>. ButLi α
O
O
THF −78 to −20 °C 58%
ð167Þ
O OH syn:anti = 90:10
HO ButLi
O
ð168Þ
THF −78 to −20 °C 43%
O α′
O
The double bond of the side chain in the benzo[b]furan as shown in Equation (169) was oxidized to an epoxide employing m-chloroperbenzoic acid (MCPBA), while the other double bonds in the molecule remained intact <2006OBC1604>. O
O
O
O
O
MCPBA CH2Cl2 rt 86%
O
O
ð169Þ
O
O
As can be seen in Equation (170), the dienophilic reactivity of the double bond in 1,4-epoxy-1,4-dihydronaphthalenes can further be illustrated by its reaction with bisepoxide 281, leading to the formation of the structurally intriguing 282 and 283 in 34% and 44% yield, respectively <2001T571>. E
O
O
O
E
O
sealed tube O
CF3 CF3
+ CH2Cl2 140 °C, 5 h
E = CO2Me
281
ð170Þ O
O
O
O
E O
O +
CF3 CF3
O
O
E
O CF3 CF3
E
282
E O
283
A new phosphine-functionalized N-heterocyclic carbene ligand as shown in Equation (171) for palladium-catalyzed hydroarylation reaction on 268 led to the formation of an aryl substituted compound 284 <2006SL1193>.
N + N O
268
Cl– Ph2P PhI, Pd(OAc)2, KOBut, Et3N DMSO, 120 °C 69%
O Ph
284
ð171Þ
479
480
Furans and their Benzo Derivatives: Reactivity
3.06.4.2 Carboxylic Acids and Their Reactions The ester moiety of methyl 2-methoxy-4-furoates underwent the usual addition reaction with Grignard reagents to provide tertiary alcohols, as exemplified in Equation (172). However, displacement of the 2-methoxy group of the corresponding 3-furoate isomers occurred under the same reaction conditions, presumably via a six-membered organomagnesium chelate, to give 2-substituted-3-furoates as the major products (Equation 173) <2003TL5781>. Et OH MeO2C Ph
EtMgBr OMe
O
OMe
O
HO Et Et
EtMgBr
OMe
O
ð172Þ
Ph
Et2O rt 90%
CO2Me
CO2Me Ph
Et
Et2O
Ph
ð173Þ
+
Et
O
Ph
rt 70%
O
Et
16%
Copper-mediated decarboxylation was observed to convert benzo[b]furan-2-carboxylic acid into its corresponding benzo[b]furan, albeit in low yield (Equation 174) <2002EJO1937>. Me
Me
Me
HO
Me
HO
Cu
ð174Þ
COOH quinoline 25%
O
O2N
O
O2N
3.06.4.3 Acyl Substituents and Their Reactions Furfural-derived 2-furylhydrazone underwent alkylated ring opening with phenyl Grignard reagents to produce dienal products, as shown in Equation (175). However, only reductive alkylation occurred with alkyl Grignard reagents (Equation 176) <2000TL2667>. Different elimination pathways of dinitrogen in the reaction intermediates, that is, [3,3]-sigmatropic rearrangement versus radical fragmentation, were probably responsible for the different products obtained. O
MgBr NNHTs
H
+
O OMe
NNHTs O
+
THF rt 70%
ð175Þ MeO
MgBr THF rt 80%
O
ð176Þ
2-Formyl and 2-acetylfuran underwent an unusual reaction with ethyl azodicarboxylate to form adducts 285 and 286, respectively, as depicted in Equation (177) <1997T9313, 1999J(P1)73>. Computational studies of the reaction suggested an initial Diels–Alder reaction between the furan and azodicarboxylate, followed by rearrangement of the cycloadducts. A similar transformation was observed for the reaction between furfurals and 1,4-phthalazinedione in the presence of Pb(OAc)4, as shown in Equation (178) <2002OL773>.
Furans and their Benzo Derivatives: Reactivity
O
CO2Et R O
+
O
N
sealed tube
N
R = H, CH2Cl2, 100 °C, 1 d R = Me, CHCl3, 70 °C, 9 d
CO2Et
O R
N
CO2Et
N CO2Et
ð177Þ
285 (40%) 286 (35%)
O + R
CHO
O
O
R Pb(OAc)4
HN HN
CH2Cl2 rt, 30 min R = H, 64% R = Me, 46%
O
N N HO2C
ð178Þ O
Biologically interesting benzo[b]furyl quinoxalines were prepared by sequential oxidation and condensation (Scheme 83) <2004T6063>.
O
SeO2 Ac O
dioxane
O
CHO
H 2N
Me
H2N
Me
Me N
56%
O
Me N
Scheme 83
Chou and co-workers discovered that flash vacuum pyrolysis (FVP) at 550 C and ca. 102 Torr converted 7-oxa-1naphthonorbornenyl)methyl benzoate 287 to isonaphthofuran 288, which led to a mixture of 289, 290, and 291 in 48%, 9%, and 28% yield, respectively, as illustrated in Scheme 84 <1998TL7381>. The same treatment of (1-benzo[c]furanyl)methyl benzoate led to a similar result <1997T17115>.
3.06.4.4 Heteroatom-Linked Substituents and Their Reactions As shown in Equation (179), a tandem Claisen rearrangement–lactonization involving the C-3 side chain of furan 292 was employed for a concise synthesis of hyperolactone C <2003JNP1039>. Although the product yield was low, the reaction created two contiguous quaternary carbon centers in one step.
O
O OH Ph
O
CO2Me
292
sealed tube PhMe 130 °C, 15 h 25%
Ph
O
ð179Þ O
O Hyperolactone C
Benzo[b]furan-based azide was also reported to undergo a 1,3-dipolar cycloaddition with norbornadiene as dipolarophile to give a triazole after extrusion of cyclopentadiene (Equation 180) <2001T7729>.
481
482
Furans and their Benzo Derivatives: Reactivity
Ph
O
O
O
O
O
Ph
FVP O
O –CH2=CH2
O
288
O Ph
287
ring contraction
O • •
O
289 [2+2]
O
ring expansion
–PhCO2H OH
••
• Ph
O O
• O
C–H insertion
[1,5]H
OHC O
290
291
Scheme 84
N
N3
N
N
norbornadiene C6H6
O
ð180Þ
O
reflux, 15 h 72%
Cycloaddition of the less-electrophilic azirine 293 and 1,3-diphenylbenzo[c]furan was carried out in the presence of ZnCl2, as shown in Scheme 85, which led to the formation of an adduct 294. Thermolysis of 294 in toluene was shown to give another adduct 295 <2005H(65)1329>.
Ph
Ph H
ZnCl2
N +
EtO2C
O
1.5 d Ph
NH Ph
Me
294 Scheme 85
O 4 Å MS
O
Me
293
OH
CO2Et
PhMe reflux, 16 h 55%
Ph
Ph N Me
295
H CO2Et
Furans and their Benzo Derivatives: Reactivity
3.06.5 Further Developments Reactions of furans, dihydrofurans, tetrahydrofurans and benzo[c]furans have been reviewed <2007PHC187>. Derivatives of new furan skeletons were synthesized from bicyclic azo compounds and nitriles in the presence of SbCl5 or AlCl3. An example is shown in Scheme 86 <2007S33>.
Scheme 86
Cinchonidine-derived quaternary ammonium phenoxides (e.g., 296) have been shown to catalyze vinylogous aldoltype reaction between benzaldehyde and 4-methyl-2-(trimethylsilyloxy)furan, leading to the formation of a 5-substituted butenolide in good yield and good ee% as can be seen in Equation (181) <2007CL8>.
ð181Þ
Singlet oxygen reaction with a furan provided a spiroketal that reacted further under acidic condition to give eventually a bis-spiroketal as shown in Scheme 87 <2007OBC772>.
483
484
Furans and their Benzo Derivatives: Reactivity
Scheme 87
An enantiopure Fischer carbene complex was able to react with 2-methoxyfuran in an intriguing manner that led to the formation of trisubstituted cyclopropane molecules in excellent diastereoselectivities. The relevant mechanism for the formation of a cyclopropane is depicted in Scheme 88 <2007CEJ1326>.
Scheme 88
As illustrated in Equation (182), a seven-membered lactam was formed by utilizing a ring closure reaction under Heck coupling conditions <2007OBC655>.
ð182Þ
The lithiation of the phthalan shown in Scheme 89 with an excess of lithium in the presence of a catalytic amount of 4,49-di-tert-butylbiphenyl (DTBB) afforded a dianionic species, which on treatment with tert-pentanal provided a diol <2007TL3379>.
Scheme 89
Furans and their Benzo Derivatives: Reactivity
Upon reaction of the benzobisoxadisilole shown in Equation (183) with 1.5 equivalents of BF3?OMe2 for 25 hours at room temperature, 50% yield of the dehydration product was obtained together with the recovery of 31% unreacted starting material <2007TL2421>.
ð183Þ
Reissig showed that when a variety of 3-alkoxy-2,5-dihydrofurans were subjected to manganese(III)-catalyzed allylic oxidation, -alkoxylbutenolides were obtained as can be seen in Equation (184). The total synthesis of ()annularin H was achieved employing this procedure as a pivotal step <2007SL1294>.
ð184Þ
Reissig also oxidatively cleaved the aforementioned 3-alkoxy-2,5-dihydrofurans to lead to the formation of ,unsaturated -ketoaldehydes, as can be seen in Equation (185) <2007AGE1634>.
ð185Þ
Immobilized box–Cu complexes were shown to efficiently catalyze the insertion of carbenes into the C–H bond of tetrahydrofuran with enantioselectivity of up to 88% ee. The use of immobilized catalysts allows their recovery and reuse. As can be seen in Equation (186), the major syn-isomer was shown to be of 2R,S absolute configuration by comparing its sign of optical rotation with that of an authentic sample <2007OL731>.
ð186Þ
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487
488
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2007CL8 2007OBC655 2007OBC772 2007OL731 2007PHC187 2007S33 2007SL1294 2007TL2421 2007TL3379
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Furans and their Benzo Derivatives: Reactivity
Biographical Sketch
Henry N. C. Wong was born in Hong Kong, and he studied at the Chinese University of Hong Kong, where he obtained a B.Sc. in 1973. He obtained his Ph.D. from University College London in 1976 under the mentorship of Professor Franz Sondheimer. After spending 1976–78 at Harvard University under the direction of Professor Robert B. Woodward, he returned to University College London as a Ramsay Memorial Fellow. Subsequently, he did research at Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences in 1980–82, and finally returned to The Chinese University of Hong Kong in 1983, where he is now professor of chemistry and head of New Asia College. His scientific interests include syntheses and studies of non-natural molecules and natural products.
Kap-Sun Yeung was born in Fujian, China, and he studied at the Chinese University of Hong Kong, where he conducted undergraduate research with Professor Henry N. C. Wong and received his B.Sc. in 1990. He then spent a year as a research assistant with Professor Chi-Ming Che at the University of Hong Kong. In 1991, he was awarded a Croucher Scholarship to study at the University of Cambridge, where he was involved in the total synthesis of swinholide A and scytophycin C under the guidance of Professor Ian Paterson. After obtaining his Ph.D. in 1994, he carried out postdoctoral research in Professor Chi-Huey Wong’s group at the Scripps Research Institute, California. In 1996, he joined the Bristol-Myers Squibb drug discovery chemistry group in Connecticut. His research interests include all aspects of synthetic organic chemistry, pharmaceutically important heterocycles, and drug design.
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Furans and their Benzo Derivatives: Reactivity
Zhen Yang was born in Liaoning, China, and got his B.Sc. in 1978 and M.Sc. in 1986 at the Shenyang College of Pharmacy. He spent three years as a graduate student at the Chinese University of Hong Kong, where he conducted his research under the guidance of Professor Henry N. C. Wong and received his Ph.D. in 1992. He carried out postdoctoral research with Professor K. C. Nicolaou at the Scripps Research Institute from 1992 to 1995, and was an assistant in Professor Nicolaou’s domain from 1995 to 1998, where he was involved in the total syntheses of taxol, epothilone A, and brevetoxin A. He then moved to the Institute of Chemistry and Cell Biology, Harvard University, in 1998 as an institute fellow to conduct his independent research in the field of chemical genetics. In 1998, he joined the College of Chemistry and Molecular Engineering, Peking University, as a Changjiang Professor, and founded VivoQuest Inc. His research interests include total synthesis of natural product, organometallic chemistry, chemical biology, and drug discovery.
3.07 Furans and their Benzo Derivatives: Synthesis T. Graening and F. Thrun TU Berlin, Berlin, Germany ª 2008 Elsevier Ltd. All rights reserved. 3.07.1
Introduction
3.07.2
Furans
3.07.2.1
3.07.2.4 3.07.3 3.07.3.1
Formation of a C–O bond Formation of a C–C bond
498 506
508
[3þ2] Cyclizations [4þ1] Cyclizations
508 512
Synthesis by Rearrangement or Ring Contraction
513
Multicomponent Reactions
514
Dihydrofurans
515
Synthesis by Monotopic Cyclization
3.07.3.1.1 3.07.3.1.2 3.07.3.1.3
3.07.3.2
498
Synthesis by Ditopic Cyclization
3.07.2.2.1 3.07.2.2.2
3.07.2.3
498
Synthesis by Monotopic Cyclization
3.07.2.1.1 3.07.2.1.2
3.07.2.2
498
515
Formation of a C–O bond Formation of the C(2)–C(3) bond Formation of the C(3)–C(4) bond
515 519 520
Synthesis by Ditopic Cyclization
522
3.07.3.2.1 3.07.3.2.2
[3þ2] Cyclizations [4þ1] Cyclizations
522 524
3.07.3.3
Synthesis by Rearrangement
525
3.07.3.4
Multicomponent Reactions
526
3.07.4 3.07.4.1
Tetrahydrofurans
3.07.4.1.1 3.07.4.1.2
3.07.4.2 3.07.5 3.07.5.1
Formation of a C–O bond Formation of a C–C bond
540 544
Synthesis by Monotopic Cyclization
544
Formation of a C–O bond Formation of a C–C bond
544 546
Synthesis by Ditopic Cyclization
548
Furoannulation Benzannulation
548 549
Synthesis by Rearrangement
3.07.6
Benzo[c]furans
3.07.7
Dihydrobenzofurans
3.07.7.1
527 534
Synthesis by Ditopic Cyclization
3.07.5.2.1 3.07.5.2.2
3.07.5.3
527
Benzo[b]furans
3.07.5.1.1 3.07.5.1.2
3.07.5.2
527
Synthesis by Monotopic Cyclization
549 551 553
Synthesis by Monotopic Cyclization
3.07.7.1.1 3.07.7.1.2
553
Formation of a C–O bond Formation of a C–C bond
553 555
497
498
Furans and their Benzo Derivatives: Synthesis
3.07.7.2
Synthesis by Ditopic Cyclization
557
3.07.7.3
Synthesis by Rearrangement
559
3.07.8
Further Developments
References
560 561
3.07.1 Introduction Furans, benzofurans, and their reduced forms are common structural motifs in naturally occurring compounds. Furan heterocycles are also found in synthetic materials, for example, in pharmaceuticals as well as fire retardants and polymer materials. Accordingly, chemists have paid considerable attention to the development of ring syntheses for this class of heterocycles. The development of novel metal-catalyzed methodology and the advent of asymmetric transformations has had a great impact on the synthetic accessibility of furans and related compounds. In this chapter, the most relevant ring syntheses are summarized, organized by parent heterocycle and according to the topology of ring formation. The nomenclature of the reduced forms of furan and their benzo-fused analogs is given in Scheme 1. Less common trivial names are given in parentheses.
Scheme 1
The chemistry of the class of furan heterocycles has been covered in Rodd ’s Chemistry of Carbon Compounds <1997RCC(4)283>, and the current literature has been reviewed annually since 1995 by Friedrichsen and more recently by Hou et al. in Progress in Heterocyclic Chemistry.
3.07.2 Furans Regioselective syntheses of polysubstituted furans organized according to substitution patterns have been reviewed by Hou and Wong <1998T1955>. A review on the synthetic aspects of furan has appeared in Science of Synthesis <2001SOS(9)183>. Newer developments in furan synthesis have been highlighted recently <2005AGE850, 2006OBC2076>. Reviews on the palladium-catalyzed transformation of acyclic precursors to furans <2002COR841> and on organometallic compounds of furans, thiophenes, and their benzo derivatives are available <2001AHC(78)1>. The role of the furan heterocycle as a building block in synthesis and its role in the synthesis of natural products has been treated in specialized reviews. Aminofuran derivatives are treated in a recent review by Ramsden and Milata <2006AHC(92)1>.
3.07.2.1 Synthesis by Monotopic Cyclization 3.07.2.1.1
Formation of a C–O bond
The widely applicable acid-catalyzed cyclization of 1,4-dicarbonyl compounds and their surrogates, known as the Paal–Knorr furan synthesis, is frequently used in the synthesis of furan-containing compounds (Equation 1).
Furans and their Benzo Derivatives: Synthesis
ð1Þ Mechanistic details have been disclosed which imply that the cyclization follows a pathway by rapid protonation of one of the carbonyl groups followed by attack of the forming enol at the other carbonyl group <1995JOC301>. The reaction can be carried out under milder conditions and with improved yields using catalysts other than Brønsted acids and the reaction has been greatly extended in substrate scope. The Paal–Knorr synthesis of furans as well as thiophenes and pyrroles has been carried out on solid support and a library of heterocyclic compounds has been prepared <2003SL711>. It has been shown that the acid-catalyzed synthesis of 2,3,4-substituted furans from 1,4-diketones can be assisted by microwave irradiation <2004OL389>. Rh-catalyzed 1,4-carbonylative addition to methyl vinyl ketone gives rapid access to the required 1,4-dicarbonyl compounds (Equation 2) <2006T11740>.
ð2Þ
2-Butene-1,4-diones and 2-butyne-1,4-diones can also serve as starting materials in furan syntheses according to the Paal–Knorr method. 2,5-Diaryl- and 2,3,5-triarylfurans are obtained in high yield in the presence of Pd/C and H2SO4 with formic acid as hydrogen source and poly(ethylene glycol)-200 as a solvent under microwave irradiation (Scheme 2) <2003JOC5392>.
Scheme 2
Electron-poor pentenediones of type 1, however, mainly yield bisfurylmethanes in the presence of BF3?OEt2 and water (Equation 3) <2003T755>.
ð3Þ
,-Unsaturated--hydroxyketones readily furnish furans by lactol formation followed by spontaneous dehydration (Scheme 3) <2002OL2413>. With (Z)- and (E)-,-unsaturated--hydroxyketones, it has been found that the acidcatalyzed cyclodehydration is accelerated by photochemical trans- to cis-alkene isomerization <1996TL6065>. 2-Butene-1,4-diols yield furans under Swern oxidation conditions. This method has been utilized in the synthesis of hibiscone C <2000SL363> and cristatic acid <2000OL2467>.
Scheme 3
499
500
Furans and their Benzo Derivatives: Synthesis
Upon treatment of the -hydroxyketone 2 with MsCl and 4-dimethylaminopyridine (DMAP), however, hemiacetal formation did not lead to a lactol, but the ansa-furan 3 was formed instead (Equation 4). Formation of this unexpected product is presumably initiated by a base-catalyzed retro-aldol reaction <2004TL6753>.
ð4Þ
,-Unsaturated ketones can be oxidatively cyclized to yield furans by employing a dihydroxylation reaction. According to the procedure in Equation (5), methylfurolabdanes, isolated from Nicotiana tabacum, were synthesized from (þ)-sclareolide <2002EJO4169>.
ð5Þ
,-Unsaturated -hydroxyketones can be liberated by acetal cleavage to yield 2,3,4-substituted furans. This route has been followed for the synthesis of compounds that serve as dimethylidenechromane-4-one equivalents (Equation 6). Utilizing a similar procedure, furo-[3,4-b]indoles as indole-2,3-quinodimethane equivalents can be synthesized <2002JOC1001>.
ð6Þ
The reaction conditions of the classical Paal–Knorr furan synthesis can be too harsh, when labile functionality has to be preserved. In the synthesis of the 3-oxa guaianolide 4, a five-step detour proved to be more efficient than direct cyclization (Scheme 4) <2000T6331>. Cyclic carbinol amides yield -trifluoromethyl-sulfonamido furans upon treatment with triflic anhydride (Equation 7) <2003OL189>.
Scheme 4
Furans and their Benzo Derivatives: Synthesis
ð7Þ
5-Oxoalkynes, 5-oxoalkynyl esters, and sulfones are versatile precursors for 2,5-disubstituted furans <1997TL8129, 1998T15253>. 5-Oxoalkynes can be conveniently prepared by Michael addition of alkynylborates to ,-unsaturated ketones <1999T14233>. With a strong base (KOBut, potassium hexamethyldisilazide (KHMDS), or KH), trimethylsilyl (TMS)-substituted alkynones yield annulated 2-methylene furans in moderate to good yields (Equation 8) <1999T2847>.
ð8Þ
In the total synthesis of (þ)-citreofuran, the transannular cyclization of a 5-oxoalkene was brought about by acid catalysis (Equation 9) <2003JOC1521>. para-Toluenesulfonic acid turned out to be optimal for this particular substrate. Mercury triflate is also an effective catalyst for the cyclization of 5-oxoalkynes. Through a protodemercuration, 2-methyl-5-substituted- and 2,4,5-trisubstituted furans can be prepared in high yields <2004OL3679>.
ð9Þ
The cyclization of 5-oxoalkynes can be facilitated by bringing an electron-withdrawing group in conjugation to the alkynyl group. Acid- or base-catalyzed enolization of a -ketoester group and intramolecular 1,4-addition to the alkynones of type 5 furnishes the 3-carboxy-2,5-disubstituted furans 6 in excellent yields (Equation 10) <2000TL1347>. This reactivity was exploited in a synthesis of ()-deoxypukalide, in which the cyclization to a 2,3,5-trisubstituted furan was accomplished in high yield on a late step of the synthetic scheme <2001JOC8037>.
ð10Þ
,-Acetylenic ketones can also undergo an SN9-type O-alkylation to yield 2-vinyl-3,5-substituted furans upon treatment with a strong base (Equation 11) <1998JOC7132>.
ð11Þ
501
502
Furans and their Benzo Derivatives: Synthesis
Using Pd-catalysts and incorporating a TMS group in the 9-propargyl position, 2-alkenylfurans can be obtained with high (E/Z)-selectivities (Scheme 5). The geometry of the double bond can be inverted with catalytic amounts of diphenyl diselenide <2002OL1787>.
Scheme 5
Cyclization of -propargyl--ketoesters can be combined with cross-coupling of aryl halides or triflates in an oxypalladation–reductive elimination reaction to yield arylfurylmethanes (Equation 12) <2003T4661>.
ð12Þ
Allenones are the classical substrates for the Marshall reaction as initially described with (PPh3)3RhCl, AgNO3, or AgBF4 as catalysts to furnish trisubstituted furans in excellent yields (Equation 13) <1990JOC3450, 1991JOC960>. The Marshall group has utilized this methodology in the total syntheses of ent-rubifolide <1997JOC4313> and entkallolide B <1996JOC5729>.
ð13Þ
Pd(II) catalysts can be employed as well. Compared to the standard Pd(II) catalysts, the palladacycle catalyst 7 shows a broader compatibility with functional groups. Terminal alkynes, alkyl halides, and -halogen ketones are tolerated <1997CB1449>. It is worth mentioning that other catalysts of Pd(II) preferentially give dimerization products.
The cycloisomerization of allenyl ketones can be exploited for the synthesis of 2,3,4- or 2,3,5-trisubstituted and tetrasubstituted furans, when the Pd(0)-catalyzed cyclization of ,-disubstituted substrates is combined with the coupling of an aryl halide or substituted allyl halide, as has been reported by Ma et al. (Equation 14) <2000OL941, 2000CC117, 2003CEJ2447>.
ð14Þ
Furans and their Benzo Derivatives: Synthesis
Hashmi et al. have found that terminal allenyl ketones give dimerization products when Pd(II)-catalysts are employed furnishing 2,4-disubstituted furans (Equation 15) <1995AGE1581, 1997JOC7295>. Tetrakis(2,2,2trifluoroethoxycarbonyl)palladacyclopentadiene proved to be the most effective catalyst to obtain predominantly dimerization instead of cycloisomerization.
ð15Þ
In the presence of 1 mol% AuCl3, allenyl ketones undergo a rapid cycloisomerization and can be reacted with a Michael acceptor. In a cross-dimerization of terminal allenyl ketones and ,-unsaturated ketones, 2,5-disubstituted furans can be obtained (Equation 16) <2000AGE2285>.
ð16Þ
Allenones can efficiently be generated in situ by base-assisted propargyl–allenyl isomerization in the presence of 5–10 mol% CuI to yield mono- and disubstituted furans under mild conditions, tolerating acid- and base-sensitive groups (Scheme 6) <2002JOC95>. 3-Thio-substituted furans can be prepared from propargyl sulfides <2003AGE98>. Similarly, 3-oxy-2,3,5-trisubstituted furans can be prepared. These reactions involve a 1,2-migration of the heteroatom. 3,39-Difurans with a 2,3,5-substitution pattern can be prepared in a dimerization of alkynones when PdCl2(PPh3)4 is used as catalyst <1999TL4841>. It is noteworthy that 2,5-disubstituted furans are obtained with Pd(PPh3)4 as the catalyst under similar reaction conditions. (Z)-3-Iodo-3-alkene-1-ones, on the other hand, also yield 2,5-substituted-3,39-difurans with Pd(PPh3)4 as the catalyst <1999JOC1738>. It is believed that both of these reactions proceed via an allenyl ketone intermediate and that a hydridopalladium halide is involved in the PdCl2(PPh3)4-catalyzed reaction <2001JOC6014>.
Scheme 6
3-Oxy-tetrasubstituted furans are obtained in a silver-catalyzed isomerization sequence involving an initial [3,3]sigmatropic rearrangement (Scheme 7). Phosphatyloxy and sulfonyloxy groups can be employed as well <2004AGE2280>.
Scheme 7
Using Pd(II) or Pd(0) catalysts in the presence of NaI, trisubstituted furans are formed from alkylidenecyclopropyl ketones in good to excellent yields (Equation 17) <2003AGE183, 2004JA9645>. In some cases, aqueous HCl needs
503
504
Furans and their Benzo Derivatives: Synthesis
to be added to drive the reaction to completion. The same reactions can be induced by NaI alone, although the reactions are not as clean as in the presence of the Pd-catalysts.
ð17Þ
From cyclopropenylketones, either 2,3,4- or 2,3,5-trisubstituted furans are available with high regioselectivities, depending on the choice of the catalyst <2003JA12386>. Pd(II)-catalysis leads to the formation of the 2,3,5-isomers, whereas with CuI as a catalyst 2,3,4-isomers are obtained (Scheme 8).
Scheme 8
A synthesis of [b]-fused furans involving a ring enlargement can be effected by the treatment of -alkynyl-cyclopropylcycloalkanones with an electron-rich Au(I) catalyst in the presence of a suitable nucleophile (Equation 18) <2006AGE6704>. The nucleophiles that can be used include alcohols, phenols, carboxylic acids, indole, and 2-pyrrolidone. Open-chain ketones as well as other ring sizes react with comparable yields. Silver and lanthanide triflates are also effective catalysts for this transformation.
ð18Þ
It has been shown by Marshall and Sehon that in the presence of AgNO3 absorbed on silica gel, -alkynyl allylic alcohols, which are more accessible than allenyl ketones, also undergo cycloisomerization to furans (Equation 19) <1995JOC5966>. Similarly, 3-trifluoromethylfurans can be prepared utilizing a Pd(II) catalyst <2000JOC2003>.
ð19Þ
,-Unsaturated -alkynyl ketones can be reacted with a variety of nucleophiles in the presence of Cu(I) or Au(III) catalysts to furnish trisubstituted furans (Equation 20) <2004JA11164, 2005JOC4531>. Bu4[AuCl4] is an air-stable recyclable catalyst that can be employed in ionic liquids <2006SL1962>. The range of nucleophiles includes alcohols, amines, 1,3-diketones, and indoles. These reactions can also be induced by electrophiles to yield tetrasubstituted furans <2005JOC7679>. N-Iodosuccinimide (NIS) and PhSeCl have proven successful as electrophiles in this process.
ð20Þ
A variety of metal catalysts, based on metals such as Mo, W, Ru, Rh, Pd, and Pt, are available to cyclize enyne ketones (Equation 21). Initially, furan intermediates with a metal carbenoid substituent in the 2-position are formed which can be subjected to subsequent reactions furnishing furans with vinyl ether- <1998JOC4564>,
Furans and their Benzo Derivatives: Synthesis
cyclopropyl- <2002JA5260, 2004JOC1557>, or homoallylthioether substituents <2003OL2619>. The cyclization can also be initiated by phosphines giving rise to the formation of phosphonium ylides that undergo Wittig reaction with aldehydes to form 2-vinyl furans <1999TL3753, 2004T1913>. Triethylamine can also induce cyclization of 2-alken-4-yn-1-ones in cis-geometry, in which case 2-ammoniomethyl furans are formed <2005JOC2576>.
ð21Þ
(Z)-Enynols can also be employed as substrates when ruthenium or iridium catalysts are used <2006ASC1671>. Furan-2-acetic esters are obtained by a Pd(II)-catalyzed oxidative cyclization–alkoxycarbonylation of (Z)-enynols <1999JOC7693>. In analogy, 2-furan-2-ylacetamides are obtained in an aminocarbonylation with secondary amines (Equation 22) <2006S4247>.
ð22Þ
2,3,5-Alkyl-substituted furans can be prepared in good yields by mercury-catalyzed rearrangement of tertiary alkynyl cycloalkylepoxy alcohols (Equation 23) <1998JOC9223>. The alkynyl group may be phenyl substituted. A fourth alkyl group on the epoxide is tolerated which then gives rise to the formation of a ketone instead of an aldehyde. Substrates with normal (n ¼ 3–5), medium (n ¼ 6), and large (n ¼ 10) ring sizes undergo this reaction with equally good yields.
ð23Þ
Han and Widenhoefer have developed a Pd-catalyzed alkoxidation protocol to furnish 2,3,5-trisubstituted furans from easily accessible 2-allyl-1,3-diketones (Equation 24). Electron-rich and electron-poor aromatic groups as well as heteroaryl substituents give comparable good results. Symmetric 1,3-diketones with two identical alkyl or aryl substituents performed equally well. The reactions of homoallyl and 4-hexenyl-substituted 1,3-diketones also gave rise to furans, albeit in moderate yields <2004JOC1738>.
ð24Þ
A modification of the Garst–Spencer furan annulation using dimethylsulfonium methylide gives improved yields of 3,4-disubstituted furans in which R1 and R2 need not be part of a ring annulation (Scheme 9) <1998TL8929>.
Scheme 9
505
506
Furans and their Benzo Derivatives: Synthesis
3.07.2.1.2
Formation of a C–C bond
An organophosphine-mediated cyclization of alkyl 3-aroyloxy-2-butynoates gives rise to the formation of 2,3- and 2,4disubstituted as well as 2,3,5-trisubstituted furans (Equation 25) <2004JA4118>. 3-Alkyne-1,2-diols undergo iodocyclization to give 3-iodofurans after subsequent dehydration <2001TL5945>.
ð25Þ
5-Substituted 3-aminofuran-2-carboxylate esters can be prepared following a simple two-step procedure (Scheme 10) <2000OL2061>. -Cyano ketones are coupled with ethyl glyoxylate under Mitsunobu conditions to provide -cyanovinyl ethers in good yield. Subsequent treatment of the vinyl ether with sodium hydride affords the 3-aminofuran. It was found that carrying out the reaction sequence in a one-pot procedure afforded the 3-aminofuran in comparable yields.
Scheme 10
Conjugate addition of -ketoesters or 1,3-diketones to ethyl propynoate leads to Michael adducts of type 8 which undergo radical cyclizations to furans in the presence of 2,29-azobisisobutyronitrile (AIBN)/tributyltinhydride (Equation 26) <2003TL2125>.
ð26Þ
Tetrasubstituted furans can be obtained in a one-pot, two-step sequence comprising SmI2-promoted reduction of readily available 4,5-epoxyalk-2-ynyl esters followed by Pd(0)-catalyzed cyclization of the resulting 2,3,4-trien-1-ol in the presence of an aryl halide or triflate (Scheme 11) <2001JOC564, 2004T4139>. In such a reaction, up to four carbon substituents are incorporated onto the furan ring, with the aryl group being introduced at the 3- or 4-position. Allyl electrophiles can also be employed in this reaction <2003TL3263>. The cumulated triene species 9, which is formed upon treatment with SmI2, has also been proposed as an intermediate in the cycloisomerization of alkynyl oxiranes to furans <1992JA1450>.
Scheme 11
Furans and their Benzo Derivatives: Synthesis
Reductive cyclization of trichloroethyl propargyl ethers using manganese and catalytic amounts of CrCl2 in the presence of TMSCl provided 3-substituted furans in high yields (Equation 27). The feasibility of this reaction has been demonstrated in the synthesis of the natural products perillene and dendrolasine <2002OL1387>.
ð27Þ
(E)--Propargyloxyenyne sulfones, which can be prepared by nucleophilic substitution of (E)--haloenyne sulfones with sodium alkoxides, are convenient precursors for 2-sulfonyl-3-alkynyl furans (Scheme 12) <1996TL7381>.
Scheme 12
2,3-Disubstituted-4-chlorofurans can be prepared in a three-step sequence using easily accessible 1-acetoxytrichloroethyl allyl ethers as starting materials <1999CC2267>. A regioselective Cu-catalyzed atom-transfer reaction is followed by dechloroacetoxylation and dehydrohalogenation/aromatization, furnishing furans in overall yields of 51–74% (Scheme 13).
Scheme 13
Regio- and stereoselective addition of carbon nucleophiles to trifluoromethyl phenylsulfanyl acetylene provides an expeditious approach to 3-trifluoromethyl furans. The addition products 10 can be cyclized in very good yields under thermal or mildly acidic oxidative conditions (Scheme 14) <2002TL665>.
Scheme 14
507
508
Furans and their Benzo Derivatives: Synthesis
2-Fluoromethyl- and 2-hydroxymethyl-4-alkylfurans are accessible from -alkylacroleins and 1-bromo-1-trimethylsilylethylene in a four-step sequence (Scheme 15) <1996TL7437>. Lithiation and carbonyl addition leads to diallylalcohols 11. Epoxidation and mesylation provides the bis-epoxides 12, which can be transformed into fluoromethylfurans (X ¼ F) upon treatment with tetrabutylammonium fluoride (TBAF). In the presence of water, hydroxymethylfurans are formed (X ¼ OH).
Scheme 15
1,4-Dioxene can be used to prepare trisubstituted annulated furans in a three-step sequence. By lithiation of 1,4dioxene, followed by carbonyl addition, an allylic alcohol 13 is obtained, which can be reacted with silyl enol ethers in the presence of a Lewis acid to furnish disubstituted dioxanes of type 14. These compounds rearrange to furans under mild conditions upon treatment with camphorsulfonic acid (Scheme 16) <1999TL2521>.
Scheme 16
Photochemical addition of alkenes to conjugated -diketones leads to biradicals of type 15 that form allyl carbene intermediates of type 16 which readily isomerize to furnish tetrasubstituted furans in good yields (Scheme 17) <1996JOC3388>.
Scheme 17
3.07.2.2 Synthesis by Ditopic Cyclization 3.07.2.2.1
[3þ2] Cyclizations
The synthesis of furans from -ketoesters and -halogenated aldehydes or ketones under basic conditions is known as the Feist–Be´nary furan synthesis (Equation 28). In most of the cases, the reaction is initiated by an aldol reaction. If the first step is alkylation, reversed regioselectivity is observed.
Furans and their Benzo Derivatives: Synthesis
ð28Þ
Condensation of 1,2-dielectrophiles with a component that serves as a 1,3-C,O-nucleophile is the underlying principle of a number of improved methods for furan synthesis. Bis-silyl enol ethers are suitable enol equivalents for the condensation with dielectrophiles to produce furans. Langer and co-workers have made use of this concept in the synthesis of annulated furans with 1-chloro-2,2-dimethoxyethane as electrophile <2005EJO2074>. In a stepwise reaction comprising TMS triflate-assisted aldol reaction and cyclization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, 3-methoxy exomethylene tetrahydrofurans are obtained, which finally yield the furan reaction products upon treatment with trifluoroacetic acid (Scheme 18).
Scheme 18
A convenient method for the synthesis of annulated 2-alkylthio-5-aminofurans has been described by Padwa et al. The reaction sequence involves the formation of a thionium group from readily available dithioacetals upon treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). The thionium ion undergoes cyclization with the -carbonyl group followed by an elimination step to yield the 2,3,5-trisubstituted furans in good to excellent yields (Equation 29) <2002JOC1595>. The alkylthioaminofuran reaction products can be utilized to construct polyclic frameworks of natural products in a subsequent Diels–Alder reaction.
ð29Þ
2,3-Disubstituted furans are available from ,-unsaturated enones in a two-step sequence. At first, conjugate addition of a cuprate generates an enolate, which undergoes an aldol reaction with (tetrahydropyranyloxy)acetaldehyde under zinc chloride catalysis (Scheme 19) <2000OL4095>. Treatment of the reaction product with acid affords the disubstituted furans in good yields.
Scheme 19
509
510
Furans and their Benzo Derivatives: Synthesis
The retro-Diels–Alder reaction is a valuable tool for the synthesis of heterocycles <2003COR1423>. The Diels–Alder/ retro-Diels–Alder reaction of oxazoles with acetylenedicarboxylates has been extensively applied for the synthesis of 3,4disubstituted furans. In a total synthesis of the alkaloid colchicine, such a reaction has been carried out in an intramolecular mode to yield a [b]-annulated furan, which served as a synthetic key intermediate (Equation 30) <2000T10175>.
ð30Þ
A one-pot synthesis of di- and trisubstituted furans from acyl isocyanates using trimethylsilyldiazomethane has been developed, which improves the synthesis of such oxazole intermediates (Scheme 20) <2004S1359>.
Scheme 20
Reductive cyclization of butynoates with PPh3 opens an easy access to 2,3,4-trisubstituted furans <2004JA4118>. Allenones of type 17 are proposed to be intermediates in this reaction (Scheme 21). One example for the reaction of a butynone is also given.
Scheme 21
Simple propargyl compounds react with -ketoesters using Pd(PPh3)4 as catalyst, and the furylpalladium intermediate can be utilized for the cross-coupling with an aryl iodide in order to introduce a substituent in the 2-position (Equation 31) <2005JOC6980, B-2002MI(2)1827>.
ð31Þ
In much the same way, but with improved yields, a gold(I)-catalyzed propargyl Claisen rearrangement affords triand tetrasubstituted furans in good to excellent yields (Equation 32) <2005OL3925>.
ð32Þ
Furans and their Benzo Derivatives: Synthesis
Pd(II)-catalyzed reaction of propargyl alcohols or propargyl amines with -sulfonyl-,-unsaturated ketones leads to the formation of furo[3,4-b] heterocyclic derivatives (Equation 33) <2000JOC3223>.
ð33Þ
In a ruthenium- and platinum-catalyzed sequential reaction, simple starting materials such as a propargyl alcohol and a ketone can be utilized for a synthesis of tri- and tetrasubstituted furans (Equation 34) <2003AGE2681>. With cyclic ketones, an easy access to annulated furans is given. Pyrroles are also available by this route. With 1,3dicarbonyl compounds utilizing a Ru-catalyst in the presence of trifluoroacetic acid, 3-acyl- or 3-carboxylfurans can be obtained in good yields <2007ASC382>.
ð34Þ
A Pd(0)-catalyzed three-component coupling of propargylic alcohols and aryl halides with a suitable Michaelacceptor to yield alkylidene tetrahydrofuran derivatives has been developed. Upon decarboethoxylation of these compounds with potassium tert-butoxide, 3-benzylfurans are eventually formed (Scheme 22) <2001JOC4069>. The reaction sequence can be carried out as a one-pot procedure with acceptable yields.
Scheme 22
A simple access to 4-aryl-3-furanols is provided by the condensation of bis(alkoxycarbonylmethyl)ethers with various arylglyoxylates (Equation 35) <2001TL6429>.
ð35Þ
The reaction of thioenol aryl ethers with 1,3-diketones mediated by Ag2CO3 on Celite leads to a facile construction of medium- and large-sized ring-substituted furans (Equation 36) <2000OL1387>. This method has been exploited in syntheses of dibenzofurans, coumestans, and 4-pyrones.
ð36Þ
Nicholas reaction of acetophenone silyl enol ether with the bis-acetal–alkynylcobalt complex 18 using an excess of Lewis acid affords a furyl--pyrone in quantitative yield (Equation 37) <2003EJO1652>.
511
512
Furans and their Benzo Derivatives: Synthesis
ð37Þ
Alkynyl(phenyl)iodonium salts allow for a direct synthesis of 2-substituted furotropones from tropolones <1996TL5539>.
3.07.2.2.2
[4þ1] Cyclizations
3-Substituted furans are obtained in one step from simple propargyl alcohols by hydroformylation (Equation 38) <2006ASC545>. However, the reported yields are only low.
ð38Þ
Luh and co-workers have developed a versatile furan synthesis based on propargylic dithiolan intermediates of type 19 (Scheme 23) <2000JA4992, 2005EJO3875>. The reaction products 20 resulting from reaction with butyllithium followed by addition of an aldehyde can be either treated with acid to give 2,3,5-trisubstituted furans or with Hg(OAc)2 and subsequently with iodine, to give iodofurans. The latter can be used in Sonogashira, Heck, and other cross-coupling reactions to furnish tetrasubstituted furans <2006SL1209>.
Scheme 23
Mu¨ller and co-workers have developed a reaction sequence comprising Sonogashira coupling with a carboxylic acid chloride and acid-mediated nucleophilic addition to the resulting ynone intermediate with concomitant deprotection and cyclocondensation. This one-pot procedure opens an easy access to 3-chloro- and 3-iodofurans in moderate to good yields (Scheme 24) <2006EJO2991>. The reaction can be carried out as a one-pot three-component reaction in which the initial halofuran products undergo a Suzuki cross-coupling reaction to furnish 2,3,5-trisubstituted furans, albeit in modest yields <2005CC2581>. 3-Chloro-4-iodofurans are obtained in the presence of ICl and NaCl in moderate yields.
Scheme 24
Furans and their Benzo Derivatives: Synthesis
Sequential treatment of 2-alkynal tetramethylethylene acetals with a divalent titanium reagent Ti(OPri)4/2PriMgX and aldehydes gives furans in good to excellent yields after acidic workup. This procedure is tolerating various functional groups and provides an efficient one-pot access to a variety of 2-substituted and 2,3-disubstituted furans (Scheme 25) <2001TL5501>.
Scheme 25
The addition of vinyl and aryl Grignard reagents to propargyl alcohols followed by reaction with a nitrile provides access to furans and butenolides in a one-pot procedure. These reactions are believed to involve a magnesium-chelate intermediate. Highly substituted furans can be prepared with control over the substitution pattern by the judicious choice of substrates and reagents (Scheme 26) <2000TL17>.
Scheme 26
A concise synthesis of highly substituted furans, pyrroles, butenolides, and 2-butene-4-lactam esters starts from alkynyl adducts of a Fischer carbene complex 21 (Scheme 27) <1998JOC3164>. Incorporation of an aldehyde yields a reactive vinyl tungstencarbonyl complex 22 that can be oxidatively transformed to an ester group, furnishing the furan carboxylic ester 23.
Scheme 27
3.07.2.3 Synthesis by Rearrangement or Ring Contraction A versatile synthesis of 2,3-di- and 2,3,4-trisubstituted furans utilizes 1,2-dioxines generated by an enyne-ring-closing metathesis (RCM)/Diels–Alder reaction sequence (Scheme 28) <2005JOC6995>. The well-known conversion of 1,2-dioxines to furans can be carried out in one step using FeSO4 or in a two-step procedure. Subsequent cleavage of the N–O bond gives rise to 3-hydroxymethyl furans with a tethered amino group. 6-Methylenebicyclo[3.1.0]hexanes 25, which can be obtained from diazoallenes 24, thermally rearrange to [c]-annulated 2-alkyloxyfurans (Scheme 29) <2006S3605>. A furoannulation protocol via dichlorocarbene adducts of alkyl enol ethers has been applied to the synthesis of the furanosesquiterpene pallescensin A (Equation 39) <2006TL6817>.
513
514
Furans and their Benzo Derivatives: Synthesis
Scheme 28
Scheme 29
ð39Þ
Ring expansion of oxanorbornene imines provides 2-substituted furans in high yields <2001HCA3667>.
3.07.2.4 Multicomponent Reactions The three-component reaction of isonitriles, aldehydes, and acetylenedicarboxylates gives high yields of tetrasubstituted 2-aminofuran derivatives (Equation 40). This reaction can also be performed in ionic liquids <2004S2376>. When carboxylic acids instead of aldehydes are employed in the reaction, 2,5-diaminofurans are formed <2006SL1592>. Vicinal tricarbonyl compounds also undergo reaction with the intially formed isocyanide–dimethyl acetylenedicarboxylate (DMAD) zwitterion <2006TL2037>. Furoannulated heterocycles are obtained when hydroxycoumarin <2002TL2293> or an aminopentynoate are employed as substrates <2004OL115>.
ð40Þ
An in situ-generated nucleophilic thiazole carbene has been shown to trigger a three-component reaction of thiazolium salts, aldehydes, and DMAD, constituting a facile synthesis of highly substituted 3-aminofurans (Scheme 30) <2005JOC8919>. The choice of the thiazolium salt has a pronounced effect on the outcome of the reaction, and moderate to good yields can be obtained. Employing ,-unsaturated aldehydes gives rise to the formation of 2-vinyl-3-aminofurans.
Furans and their Benzo Derivatives: Synthesis
Scheme 30
3.07.3 Dihydrofurans 2,3-Dihydrofurans and 2,5-dihydrofurans show different chemical behavior as the former resemble cyclic enol ethers. The synthesis of both these substructures is treated together in this section, organized according to the topology of ring closure. A review dealing with the role of hydrofurans in the synthesis of heterocyclic compounds has appeared <1997CHE625>. Furan-2(5H)-ones (3-butenolides, 26) form an important subclass of dihydrofurans, since they occur in a large number of natural products. The methodology for their synthesis and their applications in the total synthesis of natural products have been reviewed recently <2005MI139>.
3.07.3.1 Synthesis by Monotopic Cyclization 3.07.3.1.1
Formation of a C–O bond
Iodo-enol cyclization of 2-allyl-1,3-dicarbonyl compounds is a commonly encountered route for the diastereoselective synthesis of 4,5-dihydrofurans. A detailed study of the I2-induced cyclization of 2-allyl-1,3-dicarbonyl compounds (Equation 41) reveals that the stereochemical outcome of these reactions is strictly dependent on the dicarbonyl species and on substituents in the allylic position <2002T8825>.
ð41Þ
A high-yielding method for the synthesis of 2,3-dihydrofurans is provided by a ruthenium-catalyzed oxidative cyclization of 4-penten-1-ols (Equation 42). Treatment of 2-phenyl-5-hexen-2-ol gave the corresponding oxidative cyclization product, 2,5-dimethyl-2-phenyl-2,3-dihydrofuran, in quantitative yield <2003CL24>.
ð42Þ
A facile synthesis of substituted 2,3-dihydrofurans makes use of a palladium-catalyzed allylation reaction of a propargylic carbonate with either an external or an internal O-nucleophile (Equation 43) <2004TL1861>.
ð43Þ
515
516
Furans and their Benzo Derivatives: Synthesis
In the attempt to perform hydroacylation on 4-pentynoic acid using Wilkinson’s catalyst in the presence of various aminopyridines, a method for the stereoselective synthesis of (E)-alkylidene derivatives of (3H)furan-2-ones has been discovered (Equation 44) <2005SL1113>.
ð44Þ
A synthesis of -1,1,1-trifluoroethyl 3-butenolides starting from -ketothioesters by deprotonation with Hu¨nig’s base has been reported (Equation 45) <2006S1050>.
ð45Þ
The addition of p-toluenesulfinate to the silyl ether of 1-hydroxybut-3-yn-4-yl(phenyl)iodonium triflate triggers a sequence of reactions that ultimately delivers 2-substituted-3-(p-toluenesulfonyl)dihydrofuran products in variable yields (Scheme 31). A putative 1,2-group shift within an unsaturated oxonium ylide (Stevens rearrangement) accounts for the oxygen-to-carbon transfer of the ether substituent <2000JOC8659>.
Scheme 31
Allenyl sulfoxides and sulfones offer an efficient entry to dihydrofurans and other oxacycles via the base-catalyzed cyclization with a tethered hydroxy group (Equation 46) <2001OL3385>.
ð46Þ
Alkynyloxiranes are efficient allenone precursors under carbonylative conditions using a Pd(0) catalyst. They readily undergo cyclization to dihydrofurans (Scheme 32) <1997JOC8484>.
Scheme 32
Furans and their Benzo Derivatives: Synthesis
The metal-catalyzed conversion of 2,3-allenoates to 3-butenolides has proven to be superior to the acid-catalyzed cyclization of the corresponding carboxylic acids. The reaction of the esters can be effected by Au(III) catalysts in improved yields <2005TL7431>, and furan-2(5H)-ones functionalized in the 4-position can be prepared by iodo- or seleno-lactonization in moderate to good yields (Scheme 33) <2006T4444, 2005EJO3942>. The cycloisomerization of optically active 2,3-allenoic acids, on the other hand, can proceed with complete conservation of stereochemical information when copper(I) chloride is used as a catalyst <2006S3711>.
Scheme 33
Allenyl ketones can also be cross-coupled with allenoic acids to give 2,4-disubstituted furans <2002AGE1775> or with allenamides to yield 4-(39-furanyl)-2(5H)-furanimines <2005JOC6291>. With chiral allenoic acid derivatives, 4-(39furanyl)butenolides can be synthesized stereoselectively with complete chirality transfer (Equation 47) <2004CEJ2078>.
ð47Þ
The intermolecular reaction of 2,3-allenoates with propargyl electrophiles in the presence of catalytic amounts of Pd(II) affords -allenyl 3-butenolides, which are reactive enophiles with electron-deficient alkenes (Equation 48) <2006CC94>.
ð48Þ
Full details for the palladium-catalyzed cyclization of 3,4-alkadienoic acids to -methylene-3-butenolides have been given (Equation 49) <2005T9896>. -Substituted -alkylidene 3-butenolides are also available in good yield by palladium-catalyzed carbonylative cyclization of -iodo enones <2005TL8137>. In asymmetric de novo syntheses of D- and L-talose, iterative asymmetric dihydroxylation reactions of dienoates have been employed to furnish -substituted 3-butenolides <2005JOC10576>.
ð49Þ
Functionalized 2-hydroxy-3-allenoates can be converted into 2,5-dihydrofurans by using 5–10 mol% of gold(III) chloride as catalyst. This mild and efficient cyclization method can be applied to alkyl- and alkenyl-substituted allenes at room temperature, furnishing tri- and tetrasubstituted dihydrofurans in good to excellent yields and with complete axis-to-center chirality transfer (Equation 50) <2001OL2537>.
517
518
Furans and their Benzo Derivatives: Synthesis
ð50Þ
Examples for the transformation of 2-alkynyl-2-hydroxyalkanones to 3(2H)-furanones using either Pt(II) or Au(III) catalysts have been reported. This cycloisomerization process involves a 1,2-migration of an alkyl group. If cyclic substrates are employed, spirocyclic 3(2H)-furanones are obtained under ring contraction (Equation 51) <2006AGE5878>.
ð51Þ
Electrophilic cyclization of a wide variety of (Z)-enynols affords substituted (Z)-5-(1-iodoylidene)-2,5-dihydrofurans with high regio- and stereoselectivity under mild reaction conditions. To access the cyclization precursors 27, a zirconium-mediated cross-coupling reaction of three different components involving an alkyne, a ketone, an alkynyl bromide in a one-pot procedure has been developed (Scheme 34) <2005JOC6999>.
Scheme 34
-Hydroxy-,-alkynyl esters 28 in cyclic or acyclic form furnish 5,5-disubstituted tetronic acids (-hydroxy-,unsaturated--lactones) of type 29 in a simple one-pot procedure. At first, pyrrolidine is added as a base, and subsequent acid treatment effects lactonization to obtain the products in good yields (Scheme 35) <2006SL1607>.
Scheme 35
Enantiomerically enriched 2,5-dihydrofuran derivatives can be obtained from easily available enantiomerically enriched trisubstituted (acyloxy)butynols of type 30. These compounds were transformed into (acyloxy)dihydrofurans with complete stereospecificity by Ag(I)-mediated rearrangement to allenic intermediates 31, followed by Ag(I)-assisted cyclization (Scheme 36). This sequence was successfully applied to the formal synthesis of a differentiation-inducing antibiotic, (S)-()-ascofuranone <1999BCJ279>.
Furans and their Benzo Derivatives: Synthesis
Scheme 36
3.07.3.1.2
Formation of the C(2)–C(3) bond
Alkylidenecarbenes are valuable intermediates for intermolecular C–H insertion reactions. They allow for a stereocontrolled synthesis of 2,5-diyhdrofurans, since C–H insertion proceeds with retention of configuration at an existing stereocenter. Upon using the Seyferth method for alkylidene carbene formation with the ketoaldehyde 32, the alkylidene intermediate of the aldehyde underwent 1,2-hydride shift, whereas the alkylidene formed from the keto function underwent 1,5-C–H insertion to give the dihydrofuran product (Equation 52) <2005TL7483>.
ð52Þ
Vinyl radicals are another kind of reactive intermediates that can be trapped in an intramolecular reaction mode to afford dihydrofurans (Equation 53) <2001OL3583>.
ð53Þ
A one-pot synthesis of benzolactones and lactams via a cobalt-catalyzed regioselective [2þ2þ2] co-cyclotrimerization of alkynyl alcohols and amines with methyl propiolate has been described (Equation 54) <2005CC4955>.
ð54Þ
Several anionic metal carbonyls were used for intramolecular cyclization of 1-(3-bromo-1-propynyl)-ketones 33. Among these salts, CpW(CO)3Na was the most effective in yielding a metalated fused 1-2,5-dihydro-3-furyl complex 34. Demetalation of the organometallic product by (NH4)2Ce(NO3)6 in MeOH/CH2Cl2 under a CO atmosphere provided fused 3-(methoxycarbonyl)-2,5-dihydrofurans 35 in yields of 50–60% (Scheme 37) <1996JOC3245>.
Scheme 37
519
520
Furans and their Benzo Derivatives: Synthesis
3.07.3.1.3
Formation of the C(3)–C(4) bond
Ring-closing alkene metathesis has become the most frequently employed method in the synthesis of 2,5-dihydrofuran derivatives. Utilizing an RCM–alkene-isomerization sequence, a general method for the preparation of cyclic enol ethers has been developed (Scheme 38) <2002JA13390>. The initially formed 2,5-dihydrofuran 36 is isomerized to the less-substituted double-bond isomer 37 of the two possible enol ethers by treating Grubbs’ N-heterocycylic carbene catalyst with forming gas (N2/H2 95:5), which is believed to generate a Ru-hydrido complex.
Scheme 38
A stereodivergent approach to 2,5-disubstituted dihydrofurans that makes use of a stereoselective Ir-catalyzed allylic etherification of Cu-alkoxides followed by an RCM has been reported by Hartwig and Shu (Scheme 39). Due to the catalyst-controlled stereoselectivity in the allylic etherification step, both the cis- and the trans-epimer are made accessible depending on which enantiomer of the phosphoramidite ligand is employed <2004AGE4794>.
Scheme 39
Hoveyda and co-workers have developed chiral catalysts for asymmetric alkene metathesis. They have demonstrated that with their chiral molybdenum catalyst asymmetric syntheses of dihydrofurans through catalytic kinetic resolution by RCM and enantioselective desymmetrization by RCM are feasible processes (Scheme 40) <1998JA9720>. The use of Schrock’s molybdenum catalysts for asymmetric alkene metathesis has been reviewed <2001CEJ945>.
Scheme 40
Furans and their Benzo Derivatives: Synthesis
A triple RCM reaction cascade has been reported that allows for the construction of dihydrofurans with two adjacent dihydropyran or dihydrofuran rings from a common enantiomerically enriched acyclic precursor (Equation 55) <2001OL1989>. Ring-size-selective metathesis reactions and the synthetic utility of enantiomerically pure 1,5-hexadiene-3,4-diol, derived from D-mannitol, have been discussed in detail <2007ASC215>.
ð55Þ
Blechert and co-workers have demonstrated that the Grubbs’ catalyst can initiate metathesis reactions of cycloalkenes with O- and N-propargyl side chains resulting in a ring rearrangement to form heterocycles such as dihydrofurans (Equation 56) <2001TL5245>. The reaction sequence comprises an enyne metathesis step, RCM–ring-opening metathesis (ROM), and cross metathesis (CM). Alkenes employed in the final CM step can be ethylene and various monosubstituted alkenes.
ð56Þ
Enyne metathesis reactions in the context of natural product synthesis have been reviewed recently by Mori <2007ASC121>. Using the same ruthenium catalyst, a novel tandem diyne cycloisomerization–CM process has been devised to furnish 3,4-divinyl-2,5-dihydrofurans (Equation 57) <1999CC237>.
ð57Þ
Aryl and vinyl zinc halides undergo clean reaction with 3-exomethylene tetrahydrofurans of type 38 in the presence of Pd(PPh3)4 to furnish 2,3-dihydrofurans under desulfonylation (Scheme 41) <2000EJO1711>. The starting materials are easily prepared from propargyl alcohol and a sulfonyl cinnamate.
Scheme 41
521
522
Furans and their Benzo Derivatives: Synthesis
3.07.3.2 Synthesis by Ditopic Cyclization 3.07.3.2.1
[3þ2] Cyclizations
The [4þ3] cycloaddition of furans and allylic cations is a very versatile method for the preparation of 2,5-dihydrofurans. The use of these reactions in an intramolecular mode for the synthesis of carbocyclic frameworks containing cycloheptane rings has been reviewed <2001ACR595>. [3þ2] Addition of carbonyl ylides and alkynes also offers an efficient entry to 2,5-dihydrofuran structures. The Rh-catalyzed formation of cyclic carbonyl ylides and in situ trapping of these reactive species in a 1,3-dipolar cycloaddition is an important method for the synthesis of bridged dihydrofurans and tetrahydrofurans. This reaction cascade can be used to construct polycyclic frameworks of natural products, as has been demonstrated by Graening and Schmalz in the total synthesis of (–)-colchicine (Scheme 42) <2002AGE1524, 2005OL4317>.
Scheme 42
Langer et al. developed a number of reactions that lead to dihydrofuran-containing compounds by reaction of 1,3-C,Odinucleophiles or their masked analogs with 1,2-dielectrophiles. Several tetronic acid and butenolide structures are made available with oxalyl chloride as an electrophile (Scheme 43) <2006SL3369>. The C,O-cyclodialkylation reaction of dilithiated 1,3-dicarbonyl compounds with 1,4-dibromo-2-butene results in regio- and diastereoselective formation of 2-alkylidene-5-vinyltetrahydrofurans. The cyclization of 1,3-dicarbonyl dianions with 1-bromo-2-chloroethane under thermodynamic reaction control affords 2-alkylidenetetrahydrofurans regio- and diastereoselectively <2001JOC6057>.
Scheme 43
A highly diastereoselective method for the synthesis of tetronic acids has been developed based upon a tandem Claisen condensation/transesterification between arylacetate enolates and arylmethylene-substituted 2,2-dimethyl1,3-dioxolan-4-ones. The versatility of this method has been demonstrated in an improved synthesis of (Z)-configured pulvinones (Equation 58) <2007S118>.
ð58Þ
Furans and their Benzo Derivatives: Synthesis
In a Mn(OAc)3-mediated oxidative radical reaction of allenes with dimethyl malonate or ethyl cyanoacetate, an efficient synthesis of 3-butenolides is realized (Equation 59) <2007S45>.
ð59Þ
Treatment of cyclic or acyclic -haloenones with various carbon nucleophiles that possess a double activated methylene group under basic phase-transfer conditions affords 2,3-dihydrofurans in a stereoselective manner with good to high yields. This reaction system provides a general method for the construction of [b]-fused dihydrofuran rings (Equation 60) <1998TL9739>.
ð60Þ
Nucleophilic attack on the highly reactive 1:1 adducts produced in the reaction between triphenylphosphine and dialkyl acetylenedicarboxylates by 2-hydroxyketones leads to vinyltriphenylphosphonium salts, which undergo an intramolecular Wittig reaction to produce functionalized dialkyl 2,5-dihydrofuran-2,3-dicarboxylates in fairly high yields (Equation 61) <1998T9169>.
ð61Þ
A convenient approach to the synthesis of fused furofuran derivatives is provided by the tetrabutylammonium peroxydisulfate-mediated oxidative cycloaddition of 1,3-dicarbonyl compounds to cyclic enol ethers. In the presence of a base such as potassium acetate in acetonitrile, several fused acetal derivatives of type 39 have been prepared in 82–90% yield (Equation 62) <2000S1091>.
ð62Þ
Manganese(III)-mediated oxidative annulation of methylenecyclopropanes with 1,3-dicarbonyl compounds produces spirocyclopropane 2,3-dihydrofuran derivatives in moderate to good yields under mild conditions (Equation 63) <2005JOC3859>.
ð63Þ
A palladium-catalyzed approach to substituted [b]-annulated furans is based on the use of a cyclic allylic dielectrophile of type 40 and a -ketoester which acts as a 1,3-C,O-dinucleophile (Equation 64) <2007S39>. The reaction appears to be generally applicable for furan-annulation reactions.
523
524
Furans and their Benzo Derivatives: Synthesis
ð64Þ
The palladium-catalyzed allylic substitution of the carbonate derivatives of -hydroxy-,-unsaturated sulfones with soft carbon nucleophiles such as -keto esters, 1,3-diketones, and -sulfonyl ketones takes place cleanly and with full regiocontrol to afford -substitution products. These intermediates react further in an intramolecular conjugate addition of the enol moiety to the ,-unsaturated sulfone, to give 2,3,4,5-tetrasubstituted dihydrofurans in moderate to good yields (Scheme 44). The cyclization step is highly stereoselective, giving predominantly or exclusively the 2,3-dihydrofuran in trans-configuration. Thus, from enantiopure -hydroxy-,-unsaturated sulfones, enantiomerically pure tetrasubstituted 2,3-dihydrofurans are available in two steps <1998JOC9406>.
Scheme 44
3.07.3.2.2
[4þ1] Cyclizations
Oxazirconatocyclopentenes, which are prepared from Cp2ZrEt2, alkynes, and ketones, react with propiolates in the presence of CuCl to form 2,5-dihydrofurans in high yield (Scheme 45) <1999TL2375>.
Scheme 45
Silylated propargylmolybdenum species, which are obtained from addition of an alkynyllithium to a silyl-substituted carbene complex, exhibit a unique chemical behavior in their reaction with carbon dioxide to afford -silylsubstituted 3-butenolides after mild acidic workup, in decent isolated yields (Scheme 46) <2006AGE6874>.
Scheme 46
Furans and their Benzo Derivatives: Synthesis
The reaction of 1,4-diazabicyclo[2.2.2]octane (DABCO)-derived quaternary ammonium salts with electrophilic alkenes in the presence of a base opens a stereoselective route to highly substituted 2,3-dihydrofurans <2005S2188>. An ammonium ylide is initially formed that attacks the Michael acceptor. The resulting enolate finally expels DABCO in an O-alkylation reaction, affording trans-2,3-disubstituted dihydrofurans as the major products (Equation 65) <2005S2188>.
ð65Þ
3.07.3.3 Synthesis by Rearrangement The reaction of -diazoketones with ethyl vinyl ether using Rh(II), Pd(II), or Cu(I) catalysts furnishes dihydrofurans by spontaneous rearrangement of a donor–acceptor-substituted cyclopropane intermediate <1996CJC2401>. An asymmetric synthesis of 2,3-dihydrofurans via Rh(II)-catalyzed cyclopropanation–rearrangement of enol ethers with 1-(silanyloxy)vinyl diazoacetates has been achieved with high chemical yields and high ee using the dirhodium tetrakis[N-phthaloyl-(S)-tert-leucinate] [Rh2(PTTL)4] catalyst (Scheme 47) <2005SL1397>. With ethyl diazopyruvate and an Ru(II)–PyBox catalyst, similar asymmetric tranformations have been reported to occur in high ee <2004SL2573>.
Scheme 47
Silicon-assisted ring opening of donor–acceptor-substituted cyclopropanes provides an expedient entry to substituted dihydrofurans. (tert-Butyldiphenylsilyl)methylcyclopropanes undergo ring opening to furnish substituted dihydrofurans in good to excellent yields upon treatment with TiCl4 in dichloromethane. The silyl group which serves to assist the regioselective ring opening can be retained in the product and allows further transformation (Scheme 48) <2001OL2717>. 2-Sila-4,5-dihydrofurans, which are obtained from TMSOTf-mediated ring enlargement of cyclopropyl silyl ketones, can for example be used in subsequent Heck coupling reactions <2005TL7345>.
Scheme 48
gem-Difluorocyclopropenyl ketones have been reported to transform into gem-difluorinated dihydrofurans under mild reaction conditions in good to excellent yields (Scheme 49) <2006SL478>. A diversion of the general pathway in the photochemical di-p-methane rearrangement has been found to lead to dihydrofurans. When one of the alkene moieties carries one or two carbonyl groups, this reaction pathway becomes dominant (Equation 66) <2002OL1155>.
525
526
Furans and their Benzo Derivatives: Synthesis
Scheme 49
ð66Þ
3.07.3.4 Multicomponent Reactions Tetrasubstituted 2,3-dihydrofurans have been prepared in good yields and very high diastereoselectivity (d.r. > 95:5) in a one-step cyclization of aldehydes with activated -ketosulfides of benzothiazole. The reactions were carried out in an ionic liquid medium <2003JOC4406>. -Keto polyfluoroalkanesulfones have been found to react in the same way. Instead of forming a Knoevenagel condensation product with an aldehyde in the presence of piperidine, these compounds give trans-2,3-dihydrofurans in high yield (Equation 67) <2004JOC6486>.
ð67Þ
A regioselective synthesis of 3-substituted 3-butenolides by palladium-catalyzed reductive carbonylation can be carried out with a simple terminal alkyne as starting material (Equation 68) <1999TL989>.
ð68Þ
Alkyl isocyanides, dialkyl acetylenedicarboxylates, and benzoyl cyanides undergo a three-component reaction to give highly functionalized iminolactones (Equation 69) <2006T1845>.
ð69Þ
A multicomponent reaction of a species generated from addition of dimethoxycarbene onto the triple bond in DMAD in the presence of aldehydes or quinones has been described, affording a facile synthesis of dihydrofuran derivatives (Equation 70) <2001TL2043>.
ð70Þ
Furans and their Benzo Derivatives: Synthesis
3.07.4 Tetrahydrofurans The interest in stereoselective synthesis of tetrahydrofurans stems from their common appearance in natural products. Acetogenins <1995S115, 1999JNP504>, polyether ionophore antibiotics <2000CRV2407>, and furofuran lignans <2004S811> are important compound classes due to their biological activities, and a number of reviews regarding their synthesis have been published. Newer methods for the sythesis of tetrahydrofurans with a focus on stereoselective processes have been reviewed <2007T261>. Tetrahydrofurans are accessible through hydrogenation of the furan nucleus. Substituent effects in the catalytic hydrogenation of dimethyl-2-arylfuran-3,4-dicarboxylates have been investigated (Scheme 50) <2000S2069>. A mild method for hydrogenation of aromatic heterocycles in aqueous media has been reported <2006SL1440>.
Scheme 50
3.07.4.1 Synthesis by Monotopic Cyclization 3.07.4.1.1
Formation of a C–O bond
A variety of oxygen-based leaving groups can serve as electrophiles in intramolecular etherification reactions leading to tetrahydrofurans. Simple Williamson etherification is often a viable option in the synthesis of even complex tetrahydrofurancontaining natural products. Usually such a cyclization requires the addition of an activating group, the liberation of the O-nucleophile, and the final cyclization under strongly basic conditions to be carried out in separate steps. Such a three-step sequence has been applied to the synthesis of ionomycin (Scheme 51) <2002OL1879> and mucocin <2002TL8661>.
Scheme 51
In the total syntheses of squamocin A and squamocin D, acetogenins from Annonaceae, a double cyclization has been demonstrated to be feasible for the assembly of bis-tetrahydrofuran motifs (Equation 71) <2000EJO1889>. Intramolecular dehydration to afford tetrahydrofurans can efficiently be carried out by the Mitsunobu reaction <2003JOC4422> and a cationic platinum-catalyzed dehydration <2005SL152>.
ð71Þ
It is well known that enolates act as O-nucleophiles in SN9-type cyclizations to furnish alkylidene tetrahydrofurans (Equation 72) <2004JOC6715>. A double intramolecular SN9 reaction with O-nucleophiles to yield bis-tetrahydrofuran cores of acetogenins has been achieved <1999JOC2259>.
527
528
Furans and their Benzo Derivatives: Synthesis
ð72Þ
Allylic alcohols can serve as p-allyl cation precursors to act as electrophiles in SN9 reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji–Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji–Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <2001OL1953>.
ð73Þ
In an enantioselective route to the F-ring of halichondrin B, the diastereoselection with a C2-symmetric diol in intramolecular asymmetric allylic alkylation (AAA) reactions has been investigated (Equation 74) <2002OL3411>.
ð74Þ
Sulfonyl-substituted homoallylic alcohols undergo 5-endo-trig-cyclization reactions on treatment with base to give both syn- and anti-phenylsulfonyltetrahydrofuran products, depending on the geometry of the double bond in the starting material (Equation 75) <1999T13471>. Homoallylic alcohols containing other types of Michael acceptors, such as unsaturated esters <2003T1613> or ketones <2006S3621>, undergo similar cyclization reactions.
ð75Þ
Bishomoepoxy alcohols are very valuable intermediates for the regioselective synthesis of tetrahydrofurans and tetrahydropyrans. In general, 5-exo-tet-cyclizations are preferred to the 6-endo-tet-mode because of a dominant stereoelectronic effect. However, the mode of cyclization depends on the substrates employed, and with certain substrates the 6-endo-tet-cyclization is favored. It has been demonstrated that with judicious choice of reagents and solvent polarity, a switching of the epoxide opening mode can be achieved. A bulky silyl reagent in nitroethane as the solvent leads to preferential tetrahydropyran formation, whereas camphorsulfonic acid in dichloromethane leads to the opposite reaction outcome, that is, tetrahydrofuran formation (Scheme 52) <2006AGE810>. Enzymatic kinetic
Scheme 52
Furans and their Benzo Derivatives: Synthesis
resolution of racemic epoxyalcohols provides enantiomerically pure starting materials for intramolecular etherification reactions <2001CSR332>. Aziridines can also be employed as electrophiles in such intramolecular nucleophilic substitutions <2003T1483>. The acid-mediated transformation of cis,cis- and cis,trans-bis-epoxides that are separated by one methylene group into tetrahydrofurans occurs with high stereoselectivity and in high yield <1998JOC75>. Stereospecific reductive ring opening of bis-epoxides separated by two methylene groups to 2-alkylidene tetrahydrofurans has been brought about by elimination–cyclization of 1-iodomethyl-1,5-bis-epoxides with zinc dust (Equation 76) <2003OL1931>.
ð76Þ
Another important route to tetrahydrofuran derivatives is the electrophile-promoted cyclization of 4-pentenol derivatives. The electrophile can typically be halogenating agents <2003SL51> or mercuric salts <1996JOC2109> <2006SL642>, whereas arylselenium reagents are reported to give a mixture of tetrahydrofurans and oxetanes in certain cases <2003T7365, 2001T1819>. The effects of mercuric salts on the cyclization of 4-hexen-1-ols to tetrahydrofurans have been studied <2001H(54)629>. Both the regio- and stereochemical outcomes of the reaction depend strongly on the reaction conditions and reagents used. The situation is complicated further by the marked influence of substituents in the -position of the alkoxyalkene (Scheme 53). Electron-withdrawing groups as substituents in the vinylic position of the bishomoallylic alcohol have been shown to improve the regioselectivity of the cyclization. Metalated 2-alkenyl sulfoximines for instance allow for the regio- and stereoselective synthesis of highly substituted tetrahydrofurans <1997LA1881>.
Scheme 53
In the synthesis of ()-homononactic acid, a cis-selective iodoetherification was achieved with complete control of diastereoselectivity (Equation 77) <1996SL777>.
ð77Þ
A double iodoetherification of C2-symmetric acetals has been used for the desymmetrization of 1,6-dienes in an asymmetric total synthesis of rubrenolide (Equation 78) <2005AGE734>. Remarkably, four stereogenic centers have been installed in one reaction step. Stereoelectronic effects in the diastereoselective synthesis of 2,3,5-trisubstituted tetrahydrofurans via iodoetherification have been studied in detail, and I(2,4,6-collidine)2ClO4 proved to be an efficient reagent for highly stereoselective iodoetherifications <2001OL429>.
ð78Þ
Iodoetherifications are particularly valuable reactions for tetrahydrofuran syntheses, since they not only occur with high stereoselectivities but under incorporation of a useful iodide functionality. Substrate-controlled reactions that
529
530
Furans and their Benzo Derivatives: Synthesis
use chiral auxiliaries or chiral alkenes have been studied in depth. Catalytic enantioselective iodoetherification of -hydroxy-cis-alkenes has been achieved using a chiral Co-semicorrin complex 41 with a combination of N-chlorosuccinimide and iodine to produce 2-monosubstituted tetrahydrofurans with up to 90% ee <2003JA15748>.
For selenoetherifications, a number of chiral selenium reagents have been developed <1999T1> based on a chiral ferrocene backbone <1999J(P1)1511>, C2-symmetric aryl groups <1995JOC4660>, and chiral benzyl ethers <2002CEJ1125> or thioethers <2001TA1493>. An organoselenium-mediated asymmetric cyclization of 1-hydroxyoct7-en-4-one 42 with camphorselenenyl tetrafluoroborate 43, generated from camphor diselenide and silver tetrafluoroborate, has been described. A mixture of diastereoisomers was initially formed that could be separated by chromatography. The products were then deselenylated with triphenyltin hydride and AIBN to give enantiomerically pure 2-methyl-1,6-dioxaspiro[4.4]nonanes (Scheme 54) <2006TA2768>. The camphorseleno group was also substituted by an allyl function using allyltributyltin in the presence of AIBN. Enantiomerically pure perhydrofuro[2,3-b]furans can be obtained similarly from 2,2-bisallylketones <2005TA2429>.
Scheme 54
Homopropargylic alcohols are readily available substrates that can be used for the synthesis of -lactones. CuIcatalyzed selenation with PhSeBr at the alkyne terminus affords alkynyl aryl selenides. These react with an excess of p-toluenesulfonic acid monohydrate, in dichloromethane at 60 C, to form a selenium-stabilized vinyl cation intermediate. The cation is then intramolecularly trapped by the tethered hydroxyl group to afford a cyclic selenoketene acetal, which readily adds a molecule of water to give the -lactone products (Scheme 55) <2006SL587>.
Scheme 55
A Pd(II) catalyst system with an oxazoline ligand 44 has been described that allows the desymmetrization of meso-2alkyl-2-propargylcyclohexane-1,3-diols in an asymmetric cyclization–carbonylation reaction. The products which contain a chiral quaternary carbon were obtained in excellent yields with high ee’s (Scheme 56) <2006T9988>. -Hydroxy terminal <2005JOC3099> and internal <2006TL2793> alkenes can be converted to tetrahydrofurans by Pd(0)-catalyzed carboetherification reactions combined with a coupling of aryl or vinyl halides.
Furans and their Benzo Derivatives: Synthesis
Scheme 56
Widenhoefer and co-workers have shown that gold(I) complexes with electron-rich phosphine ligands are highly active catalysts for the intramolecular hydrofunctionalization of allenes with carbon, nitrogen, and oxygen nucleophiles <2006JA9066>. A variety of chiral bisphosphine ligands have been tested in the gold(I)-catalyzed intramolecular hydroalkoxylation of allenes with AgOTs as a cocatalyst; and it has been found that an atropisomeric biaryl bisphosphine ligand 45 delivers superior results in terms of the ee’s achieved (Equation 79) <2007AGE283>.
ð79Þ
Permanganate oxidation of 1,5-dienes to prepare cis-2,5-disubstituted tetrahydrofurans is a well-known procedure (Equation 80). The introduction of asymmetric oxidation methodology has revived interest in this area. Sharpless– Katsuki epoxidation has found widespread application in the catalytic enantioselective synthesis of optically active tetrahydrofurans and the desymmetrization of meso-tetrahydrofurans <2001COR663>. A general stereoselective route for the synthesis of cis-tetrahydrofurans from 1,5-dienes has been developed which uses catalytic amounts of osmium tetroxide and trimethyl amine oxide as a stoichiometric oxidant in the presence of camphorsulfonic acid <2003AGE948>.
ð80Þ
Oxidative polycyclizations with, for example, RuO4 catalysts can be carried out with polyene substrates as complex as farnesyl acetate, geranylgeranyl acetate, and squalene. The cis,cis,trans,trans,trans-configuration of the pentatetrahydrofuranyl diol product resulting from the oxidation of squalene (Scheme 57) has been determined by nuclear magnetic resonance (NMR) spectroscopy <2005T927>.
Scheme 57
An asymmetric permanganate-promoted oxidative cyclization of 1,5-dienes using a chiral phase-transfer catalyst was recorded <2001AGE4496>, and a diastereoselective permanganate-mediated oxidative cyclization with an Oppolzer sultam has been employed in the total synthesis of cis-solamin <2002OL3715>. In a metal–oxo-mediated approach to the synthesis of 21,22-di-epi-membrarollin based on the use of a camphor-derived Oppolzer sultam as
531
532
Furans and their Benzo Derivatives: Synthesis
chiral auxiliary, it has been demonstrated that strong oxidizing agents such as potassium permanganate can be used in chemoselective transformations (Equation 81). The adjacent alkynyl group of the substrate was unaffected and it could be transformed into a second tetrahydrofuran unit in subsequent steps <2005CC5636>.
ð81Þ
Transition metal-catalyzed oxidative cyclization of bishomoallylic alcohols has been successfully applied to the formation of substituted tetrahydrofurans, and both trans- and cis-substituted rings have become accessible depending on the alkene substitution and the metal used. The reagent combination of catalytic vanadyl acetylacetonate and tert-butylhydroperoxide as the primary oxidant has proven to be most successful in this transformation. Epoxidation of bishomoallylic alcohols with these reagents followed by epoxide ring opening affords tetrahydrofurans with high stereoselectivities <2002JOM(661)67>. A vanadium catalyst has been developed that is capable of transforming racemic unsaturated -hydroxyesters to enantiomerically enriched tetrahydrofurans through a resolution/oxidative cyclization reaction (Equation 82) <2006AGE2096>. While the cis-configuration is obtained in the tetrahydrofuran products, with homologous starting materials trans-configured tetrahydropyran products are formed.
ð82Þ
Intramolecular oxidation of phenols and anisoles with in situ-generated dioxiranes affords spiro-2-hydroxydienones in moderate yields when a tethered carbonyl group is present in the substrate (Scheme 58) <2000JOC4179>.
Scheme 58
Ba¨ckvall and co-workers have demonstrated that cis-annulated furans are obtained in excellent yields from -hydroxy alkenes by Pd(II)-catalyzed oxidative heteroatom cyclization (Equation 83) <1995TL7749>. The scope of the Pd(II) catalyst system with O2 in DMSO as reoxidant has been demonstrated with ring sizes five to seven (n ¼ 1–3).
ð83Þ
Furans and their Benzo Derivatives: Synthesis
A versatile stereoselective synthesis of tetrahydrofurans based on this Pd-catalyzed heteteroatom cyclization of -hydroxy alkenes in combination with the coupling of an aryl or vinyl bromide has been developed by Wolfe and Rossi (Equation 84) <2004JA1620>. trans-2,5-Disubstituted and trans-2,3-disubstituted tetrahydrofurans can be obtained with good yields and high diasteroselectivities. With cycloalkanols as substrates, annulated tetrahydrofurans can rapidly be accessed in a highly stereoselective fashion, whereas the cis-2,4 disubstituted tetrahydrofurans can only be prepared with moderate diastereoselectivities according to this procedure (Scheme 59) <2005JOC3099>. The stereochemical outcome of these reactions is explained by a mechanism via alkene insertion into a Pd–O bond followed by C–C bond formation in a reductive elimination step and stereochemical scrambling via -hydride elimination. Deuterium-labeling studies that support this mechanism have been undertaken <2005JA16468>.
ð84Þ
Scheme 59
Metal-catalyzed cycloisomerization reactions of !-alkynols (4-pentyn-1-ol derivatives) provide a rapid and efficient access to tetrahydrofurans. In general, these reactions may proceed through two different reaction pathways, formally leading to endo- or exo-cycloisomerization products. The formation of the exo-tetrahydrofuran product can be achieved with catalytic amounts of tungsten pentacarbonyl (Equation 85) <2005CEJ5735>.
ð85Þ
-Silyl-substituted cyclopropyl compounds of type 46 transform into tetrahydrofurans upon treatment with p-toluenesulfonic acid. The observation that the diastereomeric purity of the products 47 was significantly enhanced during the course of the reaction implies that a SN1-type mechanism is operating (Equation 86) <1994TL6453>.
ð86Þ
A stereocontrolled synthesis of the trans-tetrahydrofuran units in Annonaceae acetogenins that relies on the Sharpless asymmetric dihydroxylation protocol is outlined in Scheme 60 <1999TA2551>. In the first step, the disubstituted double bond of the starting material is dihydroxylated followed by monoprotection as a methoxymethyl ether. Finally, a cobalt-catalyzed oxidation using molecular oxygen as oxidant furnishes the trans-tetrahydrofuran. The stereocontrol during asymmetric dihydroxylation reactions of ,-unsaturated carboxylic esters with trisubstituted double bonds for the syntheses of -butyrolactones has been investigated in detail by Kapferer and Bru¨ckner (Equation 87) <2006EJO2119>.
533
534
Furans and their Benzo Derivatives: Synthesis
Scheme 60
ð87Þ
An electrochemical oxidation route to tetrahydrofuran and tetrahydropyran rings has been described, in which a silyl-substituted enol ether reacts with a regioselectivity that is reversed from the normal polarity of enol ethers (Scheme 61) <2000JA5636>. Aldol reactions of -diazo--ketoesters with aldehydes produce adducts which undergo Rh(II)-catalyzed O–H insertion reactions to yield highly substituted tetrahydrofurans <1997TL3837>.
Scheme 61
In a cobaloxime p-cation-mediated cyclization of an (!-hydroxy--hydroxyalkyl)cobaloxime, complete retention of configuration has been observed (Scheme 62) <1997JOC242>.
Scheme 62
3.07.4.1.2
Formation of a C–C bond
Lewis acid-mediated condensation of an oxasilepin bearing the chiral auxiliary 48 with 3-phenylpropanal gives a 2,3,4,5-tetrasubstituted tetrahydrofuran as a single diastereoisomer in 91% yield (Equation 88). The stereochemical outcome of this reaction was rationalized by assuming an intramolecular Sakurai reaction with a chair-like transition state involving an (E)-configured oxocarbenium ion <2005TL7235>.
Furans and their Benzo Derivatives: Synthesis
ð88Þ
Overman and Pennington have developed a versatile methodology for stereoselective tetrahydrofuran synthesis based on pinacol terminated Prins cyclizations. The general reaction is outlined in Scheme 63. A review on the strategic use of these cascade reactions in natural product synthesis has been published <2003JOC7143>.
Scheme 63
Allylsilanes are commonly employed as nucleophiles in the synthesis of tetrahydrofurans, as exemplified by Scheme 64. Oxidative formation of an oxonium intermediate 49 is followed by a highly stereoselective spontaneous cyclization with the tethered allylsilane moiety <2000JOC3252>.
Scheme 64
Ring-closing alkene metathesis has become a standard method for the synthesis of dihydrofurans, which in turn are easily hydrogenated to tetrahydrofurans. Grubbs N-heterocyclic carbene catalyst can also be used in a one-pot RCM– hydrogenation protocol <2001JA11312>. In the example in Scheme 65, this is followed by in situ desilylation to furnish the tetrahydrofuran 50 as an advanced precursor for an enantioselective total synthesis of gaur acid <2004AGE4788>.
Scheme 65
535
536
Furans and their Benzo Derivatives: Synthesis
The metal-catalyzed ene-type cyclization of allyl propargyl ethers which proceed with d8 metal complexes as catalysts, such as those based on Pd(II) and Rh(I), as well as d6 Ru(II) complexes offers an efficient enantioselective entry to 3,4-disubstituted vinylidene tetrahydrofurans (Equation 89) <1994JA10948, 2004CRV1317>. Mikami and co-workers, Cao, and Zhang have developed several catalyst systems employing chiral bidentate ligands to achieve enantioselectivities of up to 99% ee and it has been found that the electronic nature of the substituent R1 – best being an electron-withdrawing group – can have a pronounced effect on the selectivities observed <2003EJO2552, 2000AGE4104, 2005OL5777>. Echavarren and co-workers have shown, however, that with d10 Au(I) phosphine complexes as catalysts in the presence of alcohols, an alkoxycyclization with the external O-nucleophile takes place and no Alder-ene-type cycloisomerization is observed <2005OM1293>. Kirsche and coworkers have reported a reductive variant of asymmetric enyne cyclizations which also gives high ee’s <2005JA6174>.
ð89Þ
When propargyl allyl ethers are subjected to transition metal-catalyzed enyne cyclization reactions, 3-alkylidenesubstituted tetrahydrofurans are usually formed. A useful variation of this scheme is the Pd(0)-catalyzed tandem enyne cyclization/Suzuki coupling reaction with various arylboronic acids (Equation 90) <2005JOC1712>. The stereoselectivity of this reaction is explained by invoking a chairlike transition state.
ð90Þ
Metal-catalyzed [4þ2] and [5þ2] cycloadditions devoped by Wender and Trost are powerful transformations for the construction of polycyclic ring skeletons. Their intramolecular versions incorporating an ether group in the tether lead to oxygen heterocycles in good yields. A rhodium N-heterocyclic carbene catalyst has been shown to be particularly effective in such [4þ2] and [5þ2] cycloaddition reactions to form [c]-annulated tetrahydrofurans (Scheme 66). In all cases reported, excellent yields have been obtained in less than 10 min reaction time at 15–20 C <2006JOC91>.
Scheme 66
Similarly, intramolecular Pauson–Khand reactions can be utilized for tetrahydrofuran synthesis, when the tethers are oxa substituted. Ligand effects on stereoselectivity in Rh(I)-catalyzed asymmetric Pauson–Khand-type reactions have been investigated and ee’s of up to 92% have been achieved with the 2,2-bis(diphenyl-phosphanyl)-1,1binaphthyl (BINAP) ligand and a Rh(I) precatalyst (Equation 91). However, it has to be noted that the ee is highly substrate dependent, and considerably lower in most other cases <2006S4053>.
Furans and their Benzo Derivatives: Synthesis
ð91Þ
Acylzirconocene chloride complexes behave as an acyl group donor toward unsaturated ,-enones and -ynones under Pd–Me2Zn(Me2AlCl)-catalyzed conditions to give stereoselectively bicyclo[3.3.0] compounds (Equation 92) <2002OL4061>. A mechanistic rationale for the reaction sequence has been given.
ð92Þ
Tsuji–Trost allylation reactions offer multiple pathways to tetrahydrofuran synthesis including C–C bondformation steps. A palladium-catalyzed sequence of allylic alkylation and Hiyama cross-coupling provides a convenient synthesis of 4-(styryl)-lactones (Scheme 67) <2006SL2231>.
Scheme 67
The addition of 2-methyl-2-vinyloxirane to -keto esters in the presence of a palladium catalyst and a chiral phosphine ligand proceeds regio- and stereoselectively to give 2-hydroxytetrahydrofuran-3-carboxylates (Equation 93) <2001JA12907>.
ð93Þ
Stereoselective syntheses of the tetrahydrofuran nucleus by alkoxyl radical cyclizations have been reviewed by Hartung <2001EJO619>. Cyclizations of C-centered radicals are also freqently employed in the synthesis of tetrahydrofurans. In tandem radical cyclizations, high diastereoselectivities can be obtained. Hoffmann has shown that an -silyl effect can be exploited to obtain enhanced diastereoselectivities in such reactions (Equation 94) <1997T8401>. A trans-selective synthesis of 2,3-disubstituted tetrahydrofurans also makes use of a vinylsilane group <1994TL5837>.
ð94Þ
Treatment of iodoalkynes with indium and iodine in methanol promotes a reductive 5-exo-cyclization to furnish bicyclic vinylidene tetrahydrofurans in good yields (Equation 95) <2002TL4585>.
537
538
Furans and their Benzo Derivatives: Synthesis
ð95Þ
Cyclizations of alkyl radicals onto electrophilic alkenes give tetrahydrofurans in high yields as well. This strategy has been employed in the synthesis of ent-nocardione A 51 (Scheme 68) <2004JOC3282>.
Scheme 68
Titanocene-based complexes are efficient electron-transfer reagents toward epoxides <2002T7017>. In the reductive opening of epoxides followed by intramolecular radical cyclization with alkenes, they have proven to be superior radical sources, as has been demonstrated by Gansa¨uer and Rinker. Such reactions have been employed in the stereoselective synthesis of polysubstituted tetrahydrofurans such as ()-methylenolactocin and ()-protolichesterinic acid <1998JOC2829>. Radical cyclizations of epoxides form the basis of the enantioselective syntheses of the furan lignans ()-dihydrosesamin and ()-acuminatin and the furofuran lignans ()-sesamin and ()-methyl piperitol (Scheme 69) <2005S2913>. Furthermore, epoxy esters undergo radical cyclization with titanocene dichloride to yield 2-hydroxy tetrahdrofurans <2006TL7755>.
Scheme 69
Cahiez, Knochel, and co-workers have developed a mixed catalytic system consisting of MnBr2/CuCl and diethylzinc in N,N9-dimethylpropyleneurea (DMPU), which can be used for the stereocontrolled formation of tetrahydrofuran organozinc compounds from readily available unsaturated bromoacetals. The organozinc compounds are readily transmetalated with CuCN?2LiCl, and upon treatment with ethyl (-bromomethyl)acrylate or ethyl propiolate homoallyl- and allyl-substituted bicyclic tetrahydrofurans are obtained in 71% and 63% yield (Scheme 70).
Scheme 70
Furans and their Benzo Derivatives: Synthesis
Reaction of the zinc-organyl with p-chloroiodobenzene in the presence of 5 mol% PdCl2(DPPF) gives a bicyclic benzyl-substituted tetrahydrofuran in 61% yield (DPPF ¼ 1,19-bis(diphenylphosphino)ferrocene). Functional groups such as esters are tolerated in these reactions <1996TL5865>. In the presence of substoichiometric amounts, 1-hexynyllithium 1,!-diiodo-1-alkynes of type 52 undergo a cyclization reaction to afford (diiodomethylene)tetrahydrofurans, retaining both iodine atoms of the starting material (Scheme 71) <2006CC638>.
Scheme 71
A metal-catalyzed tandem 1,4-addition/cyclization of propargyl alcohols with Michael acceptors such as alkylidenemalonates has been developed. In the presence of catalytic amounts of zinc triflate and triethylamine, various 2-alkylidene-1,3-dicarbonyl compounds react with propargyl alcohols to give 3- or 4-methylenetetrahydrofurans in excellent yields (Equation 96) <2004OL2015>.
ð96Þ
Allyl propargyl ethers are easily cyclized to tetrahydrofuran derivatives by titanocene- and zirconocene-mediated reactions. Thus, these compounds are convenient starting materials for the stereoselective synthesis of highly substituted 3-alkylidenetetrahydrofurans (Scheme 72) <1996TL9059>. It is noteworthy that the titanocene- and zirconocene-mediated reactions show opposite (Z)/(E)-selectivities.
Scheme 72
Styrenes and styrene oxides can be combined in a highly chemo- and regioselective fashion to yield 2,4-bis-arylsubstituted tetrahydrofurans using an iron catalyst <2005CC1996>. This tetrahydrofuran synthesis developed by Hilt et al. opens an unprecedented way for the one-step synthesis of racemic calyxolane A and calyxolane B with moderate diastereoselectivities. The iron-catalyzed ring-expansion reaction of epoxyalkenes was considerably
539
540
Furans and their Benzo Derivatives: Synthesis
improved when the original phosphine ligand system [FeCl2(DPPE)] was altered to include nitrogen-containing ligand systems (DPPE ¼ bis(diphenylphosphino)ethane). N,N-Bis(salicylaldehydo)ethylenediamine (salen) ligands gave the best results in inter- and intramolecular ring-expansion reactions (Equation 97) <2006ASC1241>.
ð97Þ
Lo and Fu have developed a Cu(II) catalyst based on chiral bidentate N,N-ligands that effects an enantioselective ring expansion of oxonium ylides derived from oxetanes and -diazoesters of type 53 (Equation 98) <2001T2621>.
ð98Þ
A review about the rearrangement and cycloaddition of carbonyl ylides generated from -diazo compounds is available <2001CSR50>. Enantioselective intramolecular cyclopropanations of allyl 2-diazo-3-silanyloxybut-3-enoates to yield cyclopropyl -butyrolactones have been investigated with a variety of chiral rhodium catalysts. The best results were obtained with Rh2(PTTL)4, where enantioselectivity culminated at 89% ee (Equation 99) <2005TA2007>.
ð99Þ
3.07.4.2 Synthesis by Ditopic Cyclization 1,3-Dipolar cycloaddition of alkenes with in situ-generated carbonyl ylides is a very versatile method for tetrahydrofuran synthesis. The synthetic potential of such transformations has been reviewed by Padwa <2005JOM(690)5533> and has been treated in depth in a monograph . An extension of this methodology utilizes two different catalytic metallocarbene-transfer reactions. The chemoselective CM of unsaturated -diazo--keto esters with Grubbs’ second-generation catalyst followed by Rh2(OAc)4-catalyzed tandem carbonyl ylide formation–intramolecular cycloaddition is realized in a one-pot procedure with impressive yields of 63–86% (Scheme 73) <2006ASC2509>.
Scheme 73
Furans and their Benzo Derivatives: Synthesis
1,3,4-Oxadiazoles are versatile intermediates that undergo domino [4þ2]/[3þ2] cycloadditions with two alkene moieties to afford bridged tetrahydrofuran derivatives. Boger and his coworkers has demonstrated the capacity of this strategy in a double intramolecular cycloaddition cascade to the complex carbocyclic framework of pentacyclic aspidosperma alkaloids (Scheme 74) <2006AGE620>. This transformation results in the formation of three rings and installs all six stereocenters about the central six-membered ring of the natural product in a single operation.
Scheme 74
Stereoselective [3þ2] annulation of optically active allyl silanes which has been pioneered by Panek has become a reliable protocol for tetrahydrofuran synthesis <1995CRV1293>. The versatility of this approach has been demonstrated by Roush and co-workers in several total syntheses <2005JOC8035>, for example, in the synthesis of asimicin <2005JA10818> and amphidinolide E <2006JA15960>. In the synthesis of citreoviral, such a [3þ2] annulation came in use to afford the tetrahydrofuran product 55 as a single stereoisomer (Scheme 75) <2002OL2945>. The reaction involves electrophilic attack of the carbonyl group which is activated by a Lewis acid (SnCl4) on the allylsilane followed by ring closure with the newly formed hydroxy group. An intermediate siliranium ion 54 is held responsible for the stereospecific course of the reaction.
Scheme 75
Lanthanide salts serve as efficient Lewis acid catalysts in the [3þ2] cycloaddition of methylenecyclopropanes with activated aldehydes or ketones (Equation 100) <2003TL3839>.
ð100Þ
541
542
Furans and their Benzo Derivatives: Synthesis
Simple allylic alcohols and vinyl ethers can be coupled to give 2-alkoxytetrahydrofurans employing a Pd(II)/Cu(II) catalyst system under an oxygen atomosphere (Equation 101) <2006SL3110>. The reaction is stereospecific in that the (Z)-cinnamyl alcohol leads to the double-bond geometrical isomer of the product depicted in Equation (101) in 82% yield.
ð101Þ
Dianion aldol condensation reactions with Evans oxazolidinones or Oppolzer sultams as chiral auxiliaries have been demonstrated to be a useful method to generate the core skeleton of furofurans with diastereoselectivities of 5:1–20:1. Stereoselective total syntheses of the furofuran lignans (þ)-eudesmin, (þ)-yangambin, ()-eudesmin, and ()-yangambin according to this procedure have been reported (Equation 102) <2006TL6433>.
ð102Þ
Crotonates bearing an atropisomeric 1-naphthamide moiety can be reacted in a SmI2-mediated reductive coupling with a variety of aldehydes to yield enantiomerically enriched -butyrolactones. The crotonate derived from 2-hydroxy-8-methoxy-1-naphthamide reacted with pentanal to afford the highest ee of >99% in a combined yield of 90% with a cis/trans-ratio of 90:10. The chiral crotonate can also be linked to a Rink amide resin with the C-8 oxygen, and in the solid-phase reaction the same level of axial-to-central chirality transfer was obtained (Equation 103) <2006JOC2445>.
ð103Þ
Oxazirconacycloheptenes, generated in situ by the reaction of a zirconacyclopentene with an aldehyde, can be reacted with a second aldehyde in the presence of CuCl. After hydrolysis, a tetrahydrofuran derived from four different components, an alkyne, ethylene, and two different aldehydes, is obtained in good isolated yield (Scheme 76) <2004T1417>.
Scheme 76
Tandem radical addition–aldol-type reaction of ,-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed trans,trans-stereoselectivity was explained by invoking a cyclic six-membered ring transition state.
Furans and their Benzo Derivatives: Synthesis
Scheme 77
The treatment of 4-chlorobutyronitrile, 3-chloropropyl phenyl sulfone, and other related compounds with a base affords -halocarbanions which are usually prone to undergo intramolecular substitution to produce substituted cyclopropanes. However, these carbanionic intermediates can be trapped with external electrophilic partners, such as aldehydes, to give alcoholate anions, which then cyclize to produce 2,3-disubstituted tetrahydrofurans in excellent yields (Scheme 78) <2002CEJ4234>.
Scheme 78
A frequently applied strategy for the synthesis of tetrahydrofurans, the ring-opening CM reaction of strained oxanorbornenes has been pioneered by Blechert and co-workers <1996AGE411, 2003AGE1900>. Regioselective ring opening and CM of 2-substituted 7-oxanorbornenes provides a stereoselective entry to trisubstituted tetrahydrofurans (Equation 104) <1999JOC9739>.
ð104Þ
The photo-rearrangement of cyclopentanones to tetrahydrofurans has been applied in the synthesis of the cladiellin skeleton (Equation 105) <2006JOC1172>.
ð105Þ
In several natural product syntheses, it has been demonstrated that a tandem ylide formation/rearrangement sequence provides a convenient method to construct synthetic key intermediates containing a oxabicyclo[5.3.1]undecane ring system (e.g., neoliacinic acid and labiatin). This transformation also served to prepare the oxabicyclo[6.2.1]undecane system of ()vigulariol (Scheme 79) <2007AGE437>.
Scheme 79
543
544
Furans and their Benzo Derivatives: Synthesis
A one-pot synthesis of 2,3,5-trisubstituted tetrahydrofurans by a double Hosomi–Sakurai reaction has been described. The product was obtained without the contamination of any regio- or stereoisomers. This remarkable selectivity has been explained by the difference in reactivity between the allylic starting material and the allylic silane formed in situ and between that of the two aldehydes employed (Scheme 80) <2004AGE1417>.
Scheme 80
Molybdenum and rhenium complexes are effective catalysts for the isomerization of a variety of cyclopropanemethanols into tetrahydrofurans. The reaction can proceed via a [3,3]-sigmatropic rearrangement involving an oxo metal cyclopropanemethanolate accompanied by C–C bond cleavage or via a metal-catalyzed intramolecular hydroalkoxylation of an initially generated homoallylic alcohol. The presence of 2,6-di-tert-butyl-p-cresol (BHT) as a polymerization inhibitor proved essential for obtaining high yields in the reactions catalyzed by MoO2(acac)2 (acac ¼ acetylacetonate; Equation (106) <2005CL790>. SnCl4-mediated [3þ2] cycloaddition reactions of cyclopropylmethylsilanes and -keto aldehydes lead to the formation of 2-silylmethyltetrahydrofurans in both a trans- and a cis-selective manner <2005CL538>.
ð106Þ
1-(2-Alkylcycloalk-1-enyl)methyl carbamates of type 56 are useful 1,2-dianion synthons that can be combined with two aldehydes in adjacent positions to provide a versatile synthesis of [c]annulated tetrahydrofurans (Scheme 81). At first, a carbanion of carbamate 56, which exhibits considerable configurational stability, is generated by ()-sparteine-mediated deprotonation; this is then converted to an optically active homoaldol product 57 with up to 96% ee. An (E)-oxonium ion, which is subsequently formed under the influence of BF3, undergoes an intramolecular Mukaiyama-type addition of the enolic moiety onto the carbonyl group of a second aldehyde in the least-hindered conformation. Finally, the carbamoyl group is extruded, and after aqueous workup, diastereomerically pure tetrahydrofurans can be isolated <2005ASC1621>.
Scheme 81
3.07.5 Benzo[b]furans Synthetic methods for the preparation of benzo[b]furans are reviewed in Progress in Heterocyclic Chemistry, annually, and in other specialized reviews <2001SOS(10)11, 1997CHE1245>.
3.07.5.1 Synthesis by Monotopic Cyclization 3.07.5.1.1
Formation of a C–O bond
The cyclization of o-alkynyl phenol derivatives under the influence of a base or copper or palladium catalysts is a simple and reliable route to benzo[b]furans (Equation 107) <1996H(43)101>, given that the substrates are easily
Furans and their Benzo Derivatives: Synthesis
available by alkynyl aryl cross-coupling reactions. It is also known that this cross-coupling of o-halophenols and alkynes can be carried out in situ using bis(triphenylphosphine)palladium diacetate as a catalyst <1986S749>.
ð107Þ
A one-pot method for the preparation of substituted benzofurans via a Pd-catalyzed phenol formation/cyclization protocol starting from 2-chloroaryl alkynes has been developed by Buchwald and co-workers (Scheme 82) <2006JA10694>.
Scheme 82
Using a Pd(PPh3)2(OAc)2/CuI catalyst system, the cyclization can be combined with a cross-coupling step to give rise to 2,3-disubstituted benzofurans <1996JOC9280>. A wide variety of unsaturated halides or triflates can be used. PdI2–thiourea and CBr4 is a highly effective cocatalyst system for such reactions under carbonylative conditions which opens access to benzo[b]furan-3-carboxylates <2000OL297>. For this type of reaction, a one-pot, multicomponent coupling procedure has become available (Equation 108) that involves initial deprotonation of a mixture of o-iodophenol and a terminal alkyne with MeMgCl to give a magnesium phenolate and magnesium acetylide, respectively. Addition of catalytic amounts of Pd(PPh3)2Cl2 and heating leads to a coupling to give an O-alkynylphenoxy magnesium chloride. Addition of a suitable third coupling partner then gives the cyclized final coupling product <2001CC1594>.
ð108Þ
The o-alkynyl phenol cyclization can also be induced by halogen or selenium electrophiles, to introduce functionalization at the 3-position <1999SL1432>. It has been found that the phenol group may be protected as benzyl ether and even methyl ethers can be employed (Equation 109) <2005EJO3334, 2005JOC10292>. When the cyclization is induced with diethylzinc or BuLi/ZnCl2, 3-zinciobenzofurans, which can be subjected to Pd(0)catalyzed cross-coupling reactions, are obtained in high yields <2006AGE944>.
ð109Þ
o-Alkynyl phenols with a leaving group in the propargyl position can be reacted with Pd(0) catalysts under uptake of a carbon nucleophile (Equation 110) <2005T4381>.
545
546
Furans and their Benzo Derivatives: Synthesis
ð110Þ
A tandem homo-bimetallic reaction protocol employing a Pd(0) and a Pd(II) catalyst has been used to prepare 2,3disubstituted benzofurans. The Pd(0) catalyst serves to liberate the phenoxy group, and the product of this reaction can engage in a Pd(II)-catalyzed carbonylative cyclization (Equation 111) <2006ASC1101>.
ð111Þ
A convenient method for the synthesis of benzofurans proceeds via Pd(II)-catalyzed oxidative cyclization of o-allylphenols (Equation 112) <1998JOM(560)163>. Dimethylformamide (DMF) accelerates the reaction to completion within minutes and the addition of LiCl allows the reaction be run at room temperature.
ð112Þ
Intramolecular O-arylation with enolates using palladium <2006T11513> or copper <2005JOC6964> catalysts gives benzofurans in good to excellent yields (Scheme 83).
Scheme 83
3.07.5.1.2
Formation of a C–C bond
Highly substituted benzofurans have been synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using a ruthenium-mediated C- and O-allyl isomerization followed by RCM (Scheme 84) <2005T7746>.
Scheme 84
A simple synthetic route to 3-arylbenzofurans relies on a halogen–metal exchange with methyllithium to induce cyclization with a tethered benzoyl group (Equation 113) <2005SL2504>.
ð113Þ
Furans and their Benzo Derivatives: Synthesis
Cyclization of 2-aryloxy-3-dimethylaminopropenoates catalyzed by Lewis acids leads to a short synthesis of benzofuran-2-carboxylates (Equation 114) <2005T10061>.
ð114Þ
The reaction of dibenzoylacetylene and enol systems, such as acetylacetone, 5,5-dimethylcyclohexane-1,3-dione, 1-naphthol, 2-naphthol, 2,7-dihydroxynaphthalene, or 8-hydroxyquinoline in the presence of triphenylphosphine, leads to tetrasubstituted furans in 65–83% yield (Equation 115) <2002TL4503>. DABCO-catalyzed reaction of -bromocarbonyl compounds with DMAD also yields highly substituted furans <2005JOC8204>.
ð115Þ
A palladium-catalyzed annulation of internal alkynes to o-iodophenol derivatives to afford 3-fluoromethyl benzofurans has also been described (Equation 116) <2004T11695>.
ð116Þ
3-Vinylbenzofurans, 3-vinylfuropyridines, and 3-vinylindoles can be prepared from readily accessible acetylenic precursors by halogen–lithium exchange, which triggers an addition on the triple bond followed by ethoxide elimination. Isomerization of an intermediate exocyclic allene provides a 1,3-diene system that can react in a [4þ2] cycloaddition with electron-poor dienophiles (Equation 117) <2002OL2791>.
ð117Þ
A highly efficient two-step synthesis of benzofurans uses o-acylphenols as readily available starting materials. Addition to ethyl propiolate and subsequent radical cylization/dehydration both proceed in excellent yields (Scheme 85) <2005S387>.
Scheme 85
Katritzky demonstrated the utility of a benzotriazolyl group (Bt) for a synthesis of 3-substituted benzofurans. o-Hydroxyphenyl ketones are reacted in a nucleophilic substitution with 1-benzotriazol-1-ylalkyl chlorides and the intermediates obtained are treated with base and then low-valent titanium to give the benzofuran products (Scheme 86). The sequence was found to work well for 3-aryl- and 3-tert-butylbenzofurans but could not be extended to other 3-alkyl analogs <2001JOC5613>.
547
548
Furans and their Benzo Derivatives: Synthesis
Scheme 86
3.07.5.2 Synthesis by Ditopic Cyclization 3.07.5.2.1
Furoannulation
Zhao and Larock have introduced a convenient method for the preparation of substituted dibenzofurans as well as carbazoles and indoles by palladium-catalyzed cross-coupling of alkynes and appropriately substituted aryl iodides. These reactions proceed by carbopalladation of the alkyne, heteroatom-directed migration of palladium from a vinyl to the adjacent aryl position, and ring closure via intramolecular arylation (Scheme 87) <2006JOC5340>.
Scheme 87
A simple procedure for the synthesis of 3-ethoxycarbonylbenzofurans from salicylaldehydes and ethyl diazoacetate has been developed. The reaction is believed to occur via a semipinacol rearrangement and tautomerization to a -hydroxy acrylate which is trapped by the adjacent phenoxy group (Equation 118) <2006S1711>.
ð118Þ
It has been shown that microwave irradiation gives improved yields in the Rap–Stoermer reaction of salicylaldehydes with diverse phenacyl bromides and iodides (Equation 119) <2007TL431>.
ð119Þ
Furans and their Benzo Derivatives: Synthesis
The condensation of 3-substituted catechols with dimedone under electrochemical oxidation in aqueous medium leads to benzofurans (Equation 120) <2004JOC2637>.
ð120Þ
An indium trichloride-catalyzed three-component reaction of substituted phenols, an arylglyoxal monohydrate, and p-toluenesulfonamide has been shown to furnish 2-aryl-3-aminobenzofurans (Equation 121) <2005SL2047>.
ð121Þ
3.07.5.2.2
Benzannulation
The reaction of Fischer carbene complexes with conjugated dienylacetylenes followed by treatment with iodine leads to benzofurans in good yields <2000TL8687>. By forming three carbon–carbon bonds and a carbon–oxygen bond in this single transformation, both the arene and the furan ring are assembled. The versatility of this reaction has been demonstrated in the total synthesis of egonol (Equation 122) <2003T5609>.
ð122Þ
Another method of benzannulation to a furan ring uses precursors of type 59, which are available by cross-coupling reaction with the corresponding 3-bromofuran. Upon treatment with ethyl chloroformate and triethylamine, a pyrocarbonate is formed which acylates the furan nucleus in an intramolecular reaction. With an excess base the 7-hydroxybenzofurans are obtained (Equation 123) <1998TL5609>.
ð123Þ
3.07.5.3 Synthesis by Rearrangement Zinc triflate-catalyzed condensation of propargyl alcohols and various phenols furnishes 2-methylbenzofurans with an alkyl or aryl group attached at the 3-position in excellent yields (Scheme 88) <2006JOC4951>. Propargyl naphthyl ethers can be rearranged to to naphthofurans in shorter reaction times when exposed to microwave irradiation (Scheme 89) <1996JCM338>. These alkynes first undergo Claisen rearrangement to form an allene intermediate which in turn spontaneously cycloisomerizes to the benzofuran product.
549
550
Furans and their Benzo Derivatives: Synthesis
Oxime ethers prepared from O-phenylhydroxylamine and various acetophenone derivatives were treated with trifluoroacetyltriflate, which is a powerful acylating agent. In the presence of dimethylaminopyridine, benzofurans were formed in a [3,3]-sigmatropic rearrangement, which closely resembles the Fischer indole synthesis, and could be isolated in high yields (Equation 124) <2004OL1761>. A [3,3]-rearrangement of O-arylsulfoxonium intermediates has also been recorded to give benzofurans, albeit in modest yields <2000OL2729>.
Scheme 88
Scheme 89
ð124Þ
A general synthesis of benzofuran-2-thiolates utilizes 1,2,3-thiadiazoles as cyclization precursors. Upon treatment with base, the heterocycle is deprotonated and extrudes nitrogen to generate an alkynethiolate which can be spectroscopically monitored. This species can take up a proton to form a thioketene that undergoes cyclization to a benzofuranthiolate which is finally alkylated with an alkyl halide (Equation 125) <1997CC1753>.
ð125Þ
A novel cyclofragmentation to form 3-arylbenzofurans with concomitant release from a solid-phase support has been developed <2000AGE1093>. Base-induced epoxide opening leads to an alkoxide intermediate that suffers a Grob fragmentation with extrusion of the sulfinate leaving group and formaldehyde (Scheme 90).
Scheme 90
Furans and their Benzo Derivatives: Synthesis
3.07.6 Benzo[c]furans Benzo[c]furans (isobenzofurans) are reactive intermediates that can be regarded as o-quinodimethane equivalents. They readily undergo Diels–Alder reactions with alkyne or alkene dienophiles to form endoxide adducts with restored aromaticity. This transformation is often used to prepare functionalized tetralins. The recent advances in the chemistry of benzo[c]furans and related compounds have been reviewed by Friedrichsen <1999AHC(73)1>. The role of [c]-annulated furans as building blocks in organic synthesis is also discussed . Synthetic aspects of benzo[c]furans have been reviewed in Science of Synthesis <2001SOS(10)87>. Stable crystalline benzo[c]furans that are shielded by an alicyclophan moiety have been prepared by Warrener et al. <2001CC1550>. A broadly applicable synthesis of benzo[c]furans by Warrener relies on Diels–Alder/retro-Diels–Alder reactions with s-tetrazines. Using this method with 3,6-di(pyridin-29-yl)-s-tetrazine, the generation of an isolable 5,6-(bistrimethylsilyl)benzo[c]furan has been achieved (Scheme 91) <2000TL5957, 2002T9413>. The synthesis of relatively stable azuleno[c]furans <2003OBC2383> and naphtho[1,2-c:5,6-c]difuran as a cylcophane precursor has been reported <2003JOC8373>.
Scheme 91
Transition metal-catalyzed decomposition of -diazoesters of type 60 result in the formation of a benzo[c]furan, which was trapped in an intramolecular Diels–Alder reaction with a tethered vinyl group followed by spontaneous N-assisted opening of the endoxide bridge to yield 11-azasteroid analogs (Scheme 92) <1999J(P1)59>.
Scheme 92
Benzo[c]furans can be generated by -elimination of phthalan acetals with a strong base (Equation 126) <2000OL923>. A method for the generation of benzo[c]furans under neutral conditions uses the same type of substrate with Pd2(DBA)3?CHCl3 as a catalyst <2002OL3355>. Similarly, silyl lactols lead to benzo[c]furans or silylsubstituted benzo[c]furans upon treatment with metal fluorides <2002SL1868>.
551
552
Furans and their Benzo Derivatives: Synthesis
ð126Þ
A simple single-step synthesis of symmetrical 1,3-diarylbenzo[c]furans is achieved by the addition of 2 equiv of an aryl Grignard reagent to 3-methoxyphthalide (Scheme 93) <2006SL2035>.
Scheme 93
The formation of dialkyl benzo[c]furan-1-yl phosphonates by Lewis acid-promoted reaction of o-phthalaldehyde with trialkyl phosphites has been described (Equation 127) <2006S4124>.
ð127Þ
1-Vinyl-substituted benzo[c]furans can be prepared by reaction of o-alkynylbenzaldehydes with chromium Fischer carbene complexes. Initially a benzo[c]furan chromiumtricarbonyl complex is believed to be formed which is converted into an alkylidenephthalan derivative or can be trapped with electron-deficient dienophiles with excellent exo-selectivity (Equation 128) <2000OL1267>. More elaborate vinylidene Fischer carbene complexes yield dienyl benzo[c]furans that undergo [8þ2] cycloaddition with DMAD to furnish furanophane derivatives <2003JA12720>. An equilibrium between 2-(o-ethynylbenzoyl)rhenium complexes and rhenium benzo[c]furyl carbene complexes has been observed. These species behave like other benzo[c]furans in the reaction with DMAD <2004OM4121>.
ð128Þ
Anthra[2,3-c]furan, which was predicted to be a highly reactive polyene lacking any significant aromatic character despite being a 14 p-electron system, was prepared by aromatic ring homologation of naphtho[2,3-c]furan with hydroxybutenolide (Equation 129). The reaction product was trapped as a Diels–Alder adduct <1996S77>.
ð129Þ
Furans and their Benzo Derivatives: Synthesis
3.07.7 Dihydrobenzofurans 3.07.7.1 Synthesis by Monotopic Cyclization 3.07.7.1.1
Formation of a C–O bond
Intramolecular nucleophilic substitution/addition reactions of phenoxy nucleophiles are frequently used in syntheses of natural products containing the common dihydrobenzo[b]furan motif. Cleavage of a phenyl methyl ether with BBr3 and reacting the phenoxy nucleophile in an intramolecular SN9 reaction was used to construct the morphine ring skeleton <2002JA12416>. Pd(0) catalysts can be used to liberate phenol groups from allyl ethers which then are suitable nucleophiles for stereoselective intramolecular Michael reactions. By this method, a dihydrobenzofuran key intermediate in the synthesis of the macrocyclic alkaloid lunaridine has been generated (Equation 130) <2002J(P1)1115>. Similarly, a phenol which is methoxymethyl (MOM) protected can be liberated by acid treatment and can then be reacted with a Michael acceptor, constituting a formal total synthesis of lycoramine <1996TL6283>.
ð130Þ
A synthetic approach to enantiomerically enriched dihydrobenzofurans by intramolecular epoxide ring opening in combination with hydrolytic kinetic resolution using Jacobsen’s cobalt–salen catalyst has been reported. By this protocol, dihydrobenzofurans are made available in high ee’s from racemic 1-benzyloxy-2-(oxiranylmethyl)benzenes (Equation 131) <2005TL5239>. The same underlying strategy of intramolecular phenoxyl epoxide opening was applied in the construction of a cyclopenta[b]benzofuran ring in the synthesis of rocaglaol analogs <2004OL4595>. Starting from o-allylphenols, a VO(acac)2/t-butyl hydroperoxide (TBHP) alkene epoxidation can trigger the same transformation in the presence of trifluoroacetic acid with higher efficiency than in the previously used method based on the reagent m-chloroperbenzoic acid (MCPBA) <2002SL942>. The intermolecular condensation of readily available optically pure epoxyaldehydes with electron-deficient resorcinols has been used in the assembly of the dihydrobenzofuran core of several natural products <2005JOC1761>.
ð131Þ
DBU-catalyzed lactonization of o-alkynyl benzoic acids proceeds with high regioselectivities (>95:5) to produce alkylidene phthalides in good to excellent yields (Scheme 94) <2007TL933>.
Scheme 94
A highly efficient synthesis of 1-alkylidene-1,3-dihydrobenzo[c]furans from o-hydroxymethyl iodoarenes and propargyl alcohols uses a bimetallic Pd/Cu-catalyzed Sonogashira coupling/cyclization reaction (Equation 132) <1999SL456>. Pd/1,4-bis(diphenylphosphino)butane (DPPB)-catalyzed reaction of o-allylphenols under a CO atmosphere leads to carbonylative cyclization to form benzannulated lactones <2006ASC1855>. A similar carbonylative cyclization leads to the stereoselective formation of 3-alkenyl phthalides <2006T4563>.
553
554
Furans and their Benzo Derivatives: Synthesis
ð132Þ
An asymmetric synthesis of the dihydrobenzo[b]furan segment of epheradine C has been achieved by an iodotrimethylsilane-mediated debenzylation–benzylic etherification (Equation 133) <2000J(P1)893>.
ð133Þ
Nucleophilic aromatic ipso-substitution with alkoxides to prepare dihydrobenzofurans is also a commonly applied strategy. The morphinan ring system has been generated by such a reaction on a nitro-activated aryl fluoride <2004JOC5322>. A surprisingly simple one-pot synthesis of 2-aryl-5-substituted-2,3-dihydrobenzofurans from readily available o-nitrotoluenes and benzaldehydes or benzoyl compounds has been described based on a procedure from Bartoli (Equation 134) <2005JOC3727>. o-Trimethylsilylmethyl-substituted aryl bromides undergo the same type of reaction with aromatic aldehydes and ketones upon treatment with TBAF <2005SL1922>.
ð134Þ
Pd-catalyzed aryl etherifications to yield dihydrobenzofurans have been achieved by Hartwig and co-workers using bulky ferrocenylphosphine ligands (Equation 135) <2000JA10718> and by Buchwald and co-workers using bulky electron-rich o-biarylphosphine ligands <2000JA12907>.
ð135Þ
An iridium(III)-catalyzed tandem Claisen rearrangement–intramolecular hydroaryloxylation protocol has been described that allows the transformation of allyl aryl ethers to dihydrobenzofurans under mild conditions (Scheme 95) <2005TL1237>. An in situ-generated PPh3AuOTf complex also proved to be an efficient catalyst for this transformation <2006SL1278>.
Scheme 95
Furans and their Benzo Derivatives: Synthesis
A Pd-catalyzed oxidative cyclization of phenols with oxygen as stoichiometric oxidant in the noncoordinating solvent toluene has been developed for the synthesis of dihydrobenzo[b]furans (Equation 136). Asymmetric variants of this Wacker-type cyclization have been reported by Hayashi and co-workers employing cationic palladium/2,29bis(oxazolin-2-yl)-1,19-binaphthyl (boxax) complexes <1998JOC5071>. Stoltz and co-workers have reported ee’s of up to 90% when ()-sparteine is used as a chiral base instead of pyridine <2003AGE2892, 2005JA17778>. Attempts to effect such a heteroatom cyclization with primary alcohols as substrates, on the other hand, led to product mixtures contaminated with aldehydes and alkene isomers, which is in contrast to the reactions with the Pd(II)/O2 system in DMSO <1995TL7749>.
ð136Þ
3.07.7.1.2
Formation of a C–C bond
Intramolecular radical cyclizations of allyl 2-haloaryl ethers proceed well in the annulation of dihydrofuran rings onto arenes as exemplified in the synthesis of a spiropiperidine dihydrobenzofuran (Equation 137) <1996T10935>. Optically active starting materials for this reaction can be prepared by a regioselective and enantiospecific rhodiumcatalyzed allylic etherification developed by Evans and Leahy <2000JA5012>. SmI2 can also be used as promoter for radical cyclizations with aryl bromides. Naphtho[b]dihydrofurans have been prepared in good yields according to this protocol <2005T1863>.
ð137Þ
Intramolecular Heck reactions for building up complex oxacyclic skeletons are a common theme in the synthesis of natural products. These reactions are exceptionally valuable for the installation of quaternary carbon stereocenters. In the morphine total syntheses by Overman <1994PAC1423> and Trost et al., intramolecular Heck reactions to form dihydrobenzofurans served as strategic key steps (Equation 138) <2005JA14785>. Asymmetric variants of intramolecular Heck reactions based on BINAP ligands to yield dihydrobenzofurans have also been investigated <1998T4579>.
ð138Þ
When the Heck cyclization is carried out under oxidative conditions (intramolecular Fujiwara–Moritani arylation), spirocyclic dihydrobenzofurans are formed in good yields directly from aryl ethers (Equation 139) <2004AGE6144>.
555
556
Furans and their Benzo Derivatives: Synthesis
ð139Þ
A three-component domino reaction catalyzed by palladium that produces 4,5-disubstituted dihydrobenzo[b]furans from readily available starting materials has been developed by Pache and Lautens. The reactions of iodobenzenes of type 61 with BuI and tert-butyl acrylate, as shown, give good yields of cyclization products (Scheme 96) <2003OL4827>. A reaction mechanism which involves sequential alkylation–alkenylation has been proposed.
Scheme 96
An enantioselective method for the synthesis of 3-functionalized 2,3-dihydrobenzofuran derivatives via an intramolecular carbolithiation reaction of allyl 2-lithioaryl ethers uses ()-sparteine as a chiral inductor. A variety of electrophiles can be reacted with the cyclized organolithium intermediate. With certain substrates, however, -elimination occurs instead (Equation 140) <2005CEJ5397>.
ð140Þ
It has been shown that vinyl radicals offer a facile access to 2,3-disubstituted dihydrobenzofurans. In these reactions, the vinyl radicals engage in a remarkable 1,6-H-atom transfer (Equation 141) <2005SL2603>.
ð141Þ
Furans and their Benzo Derivatives: Synthesis
The C–H insertion reaction of aryldiazoacetates to furnish dihydrobenzofurans is best carried out with dimeric rhodium(II) catalysts. Rh2(PTTL)4 has proven to be the catalyst of choice for the asymmetric version of this process, providing exclusively cis-2-aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans with an ee of up to 94% (Equation 142) <2002OL3887>.
ð142Þ
Aromatic C–H bond activation opens an attractive pathway to achieve cyclizations with tethered alkenes for the synthesis of dihydrobenzofurans <2001JA9692> <2003OL1301>. An auxiliary-directed asymmetric alkylation via C–H bond activation to yield a virtually enantiomerically pure 2,3-cis-disubstituted dihydrobenzofuran for an enantioselective synthesis of (þ)-lithospermic acid has been reported by Bergman, Ellman, and co-workers (Scheme 97) <2005JA13496>.
Scheme 97
3.07.7.2 Synthesis by Ditopic Cyclization Reactions of salicylic aldehydes with the chloromethyl tolyl sulfone anion afford 2-hydroxydihydrobenzofurans in moderate to good yields (Scheme 98) <1998T6811>. Formation of an epoxide intermediate that rearranges to the corresponding homologated alcohol is believed to be involved. Decarboxylation of the reaction product is prevented by lactol formation <1998T6811>.
Scheme 98
Enders et al. have achieved an organocatalytic asymmetric synthesis of cis-substituted dihydrobenzofuranols by intramolecular aldol reaction of compounds of type 62 with proline as catalyst (Equation 143) <2006SL3399>.
ð143Þ
557
558
Furans and their Benzo Derivatives: Synthesis
A nucleophilic allylation–heterocyclization via bis-p-allylpalladium complexes with allyltributylstannane and an o-chloroallyl benzaldehyde generates allyl-vinyl-substituted phthalans in good yields (Equation 144) <2002CL158>. No Stille coupling products have been observed in these reactions.
ð144Þ
Benzo[ f ][1,2]oxasilepines, which are available by RCM, have been employed in the synthesis of cis- and transdihydrobenzo[b]furan neolignans (Equation 145) <2005SL3011>. A mechanistic proposal for the stereochemical outcome of this variant of the Hosomi–Sakurai reaction has been given <2007CEJ557>.
ð145Þ
[3þ2] Addition of allyl silanes to o-benzoquinones in the presence of zinc salts furnishes a direct access to 7-hydroxydihydrobenzo[b]furans (Equation 146) <2002TL5349>.
ð146Þ
A general approach to 2-aryl-7-alkoxy-benzofuranoid neolignans is based on a Lewis acid-promoted reaction of styrenes with N-phenylsulfonyl-1,4-benzoquinone monoimines. Regioselective formation of the 2-arylbenzofuranoid ring system is followed by conversion of the aromatic N-phenylsulfonyl moiety into a propenyl substituent (Equation 147) <1996TL6969>.
ð147Þ
A radical cyclization onto cross-conjugated quinone monoacetals provides a general approach to 5-hydroxydihydrobenzo[b]furans upon aromatization with p-toluenesulfonic acid (Scheme 99) <2003CC526>. A biomimetic route to dihydrobenzofurans employs a dihydroquinone-mediated reductive cyclization of 2-hydroxyethyl-substituted quinone precursors <2001JOC4965>.
Scheme 99
Furans and their Benzo Derivatives: Synthesis
Stereoselective oxidative dimerization of cinnamyl derivatives bearing an Oppolzer sultam as chiral auxiliary has been performed both enzymatically (HRP/H2O2) and by chemical means with Ag2O. This method provides an enantioselective access to dehydrodiconiferyl ferulate (Equation 148) <2001T371>.
ð148Þ
Instead of performing a furoannulation onto an aromatic nucleus, dihydrobenzofurans can also be accessed by [2þ2þ2] cycloaddition reactions. Nickel <2002JOC7724> and cobalt complexes <2000JOC2003> efficiently catalyze such cyclotrimerization reactions to benzofuran moieties. Monosubstituted allenes react with good regioselectivity with nonsymmetric dipropargyl ethers under cobalt(II) catalysis (Equation 149) <2003CC718>. A monophos-based chiral iridium complex was shown to furnish axially chiral furoannulated tetraaryl compounds <2004JA8382>.
ð149Þ
5-Substituted phthalides can be prepared in a [2þ2þ2] cycloaddition of two molecules of methyl propiolate with propargyl alcohol. This cyclotrimerization, which is catalyzed by a cobalt(II)–DPPE complex in the presence of catalytic amounts of zinc, affords the reaction products in acceptable to good yields (Equation 150) <2005CC4955>.
ð150Þ
3.07.7.3 Synthesis by Rearrangement In the rhodium-catalyzed formation of oxonium ylides of type 63, an asymmetric [2,3]-rearrangement has been achieved. When N-phthaloyl-(S)-tert-leucine was used as ligand, an ee of up to 60% was obtained (Scheme 100) <1997TL4705>.
Scheme 100
Dihydrobenzofurans can be obtained via dienone–phenol rearrangement of spirooxetanes prepared by photoaddition of quinones with electron-donating alkenes (Scheme 101) <1996H(43)619>.
559
560
Furans and their Benzo Derivatives: Synthesis
Scheme 101
Either benzo- or dihydrobenzofurans can be obtained in the [3,3]-sigmatropic rearrangement of N-trifluoroacetylenehydroxylamines, depending upon the choice of the reagent (Scheme 102) <2006SL3415>.
Scheme 102
Flavones have been shown to suffer from a stereospecific ring contraction to give trans-2-aryl-2,3-dihydrobenzo[b]furan-3-carboxylates upon treatment with phenyliodonium acetate, trimethyl orthoformate, and sulfuric acid (Equation 151) <2002T4261>.
ð151Þ
3.07.8 Further Developments Asymmetric catalytic hydrogenations of furan derivatives have been achieved with homogeneous catalyst systems using either an Ir-catalyst with bicyclic pyridine-phosphinite ligands <2006AGE5194> or cationic Rh-complexes with diphospholane ligands <2006OL4133>. The asymmetric hydrogenation of furans and other heteroaromatic compounds has been reviewed <2007ACR-ASAP>. The cycloisomerization of alk-3-yn-1-ones to furans, which is known to be catalyzed by Au, Pd, Cu, and Hg, can also be effected using ZnCl2 as a catalyst affording 2,5-di- and 2,3,5-trisubstituted furans in high yields <2007OL1175>. The scope of the cycloisomerizations of allenyl ketones to yield substituted furans has been extended with substrates that bear two alkyl or aryl substituents at the 4-position <2007AGE5195>. These reactions involve a [1,2]-migration of an alkyl or aryl group. Mechanistic details of Cu-, Ag-, and Au-catalyzed reactions involving [1,2]-migrations of heteroatom-bound groups have been reported <2007JA9868>. A cyclization reaction between 2,3-bis(trimethylsilyl)buta-1,3-diene and acyl chlorides has been described to furnish 2,5-disubstituted furans in good yields <2007CC3756>. The known cyclization of ,-unsaturated--alkynyl ketones to furans has been applied in an efficient one-pot synthesis of substituted furocoumarins <2007CC3285>. Ring-closing metathesis of enol ethers has been described to yield 2,3-dihydrofurans. These can be aromatized to furans if they possess a leaving group <2007OL953>. A synthetic method for the preparation of multisubstituted furans employing ynolates has been described <2007OL1963>, which can also be used for the preparation of pyrroles and thiophenes. A highly efficient cascade reaction of propargyl 2-bromoallyl ethers with a tethered 3-oxoalkyne has been described to give efficient access to tricyclic [c]-annulated furans <2007JOC1395>. [c]-Annulated furans have also been made
Furans and their Benzo Derivatives: Synthesis
available by a Pd-catalyzed reductive cyclization of conjugated enynals bearing an additional alkyne moiety <2007OL1191>. Barluenga and co-workers have described cycloaddition reactions of Fischer carbene complexes with ,-unsaturated ketones and aldehydes. The initially formed 2,3-dihydrofuran products can be transformed to furans with variable substitution patterns <2007AGE4136>. Krause and co-workers described optimized procedures for chirality transfer in the Au-catalyzed cycloisomerization of -hydroxyallenes to 2,5-dihydrofurans <2007SL1790>. A three-step access to pulvinones involving the cyclization of 3-aryl-2-(arylacetoxy)acrylates has been developed <2007S2240>. 3(2H)-Furanones bearing vicinal stereocenters in the 2-position and the adjacent side chain have been made available by an asymmetric protocol which involves asymmetric dihydroxylation of enynones followed by Hg(II)-catalyzed cyclization <2007CC2494>. The synthesis of 3-alkoxy-2,5-dihydrofurans using a Au(I)-catalyzed cyclization of alkoxyallene-derived -allenyl alcohols and their allylic oxidation to -alkoxybutenolides has been described <2007SL1294>. Oxidative cyclizations of dienes and polyenes mediated by transition-metal-oxo species to yield tetrahydrofurans and tetrahydropyrans have been reviewed by Piccially <2007S2585>. A multigram synthesis of diastereomerically pure tetrahydrofuran diols that applies the oxidation of 1,5-dienes has been published <2007S2751>. In the total syntheses of 2,5-diaryl-3,4-dimethyltetrahydrofuran lignans (þ)-fragrasin A2, (þ)-galbelgin, (þ)-talaumidin, ()-saucernetin, and ()-verrucosin, a novel ring closure to tetrasubstituted tetrahydrofurans by intramolecular attack on a quinoid intermediate has been described <2007SL475>. A novel Pd(II)/Pd(IV)-catalyzed aminooxygenation of alkenes has been developed that furnishes 3-amino-4-aryltetrahydrofurans in good yields with selectivities in favor of the trans diastereoisomer <2007AGE5737>. Reactions of an optically active double allylation reagent with aldehydes have been reported to give 1,1,2,4-tetrasubstituted tetrahydrofurans in good yields and excellent stereoselectivities <2007JA3070>. Full details for the synthesis of hexahydrocyclopenta[c]furans by intramolecular Fe-catalyzed epoxide opening with alkenes are given and the application of these reactions has been demonstrated in the synthesis of lignan isomers <2007ASC2018>. A Ni-catalyzed cyclization cross-coupling reaction of iodoalkenes with alkyl zinc halides has been employed for the synthesis of various tetrahydrofuran derivatives <2007AGE-ASAP>. The TiCl4-catalyzed anti-Markovnikov hydration of alkynes has been applied to the synthesis of various benzo[b]furans <2007JOC6149>. Fu¨rstner and co-workers have demonstrated the utility of the PtCl2-catalyzed carboalkoxylation of protected o-alkynyl phenols in the synthesis of the pterocarpene nucleus of erypoegin H <2007AGE4760>. Naphthalene fused 2,3-dihydrofurans have been shown to be available through a Pt- and Ru-catalyzed aromatization of enediynes with concomitant intramolecular nucleophilic additions <2007S2050>.
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Furans and their Benzo Derivatives: Synthesis
Biographical Sketch
Timm Graening, born in Flensburg, Germany, studied chemistry at Christian-AlbrechtsUniversita¨t Kiel. He received his doctorate from University of Cologne for work on the total synthesis of the alkaloid colchicine under the guidance of H.-G. Schmalz. After a postdoctoral stay in the laboratory of John Hartwig at Yale University working on Ir-catalyzed asymmetric ketone enolate allylation, he moved to Technische Universita¨t Berlin, where he is leading a junior research group since 2006. His research interests are transition metal-mediated C–H functionalization reactions, the design of asymmetric rhodium catalysts for C–H activation, and natural product synthesis.
Frauke Thrun, born in Hoyerswerda, Germany, has been studying chemistry at Technische Universita¨t Berlin since 2002; she joined the group of Timm Graening in 2007. She is currently working on the rhodium-catalyzed functionalization of C–H bonds for her diploma thesis. As a trainee she joined the group of Anatoli A. Popov at the Russian Academy of Sciences of Moscow in 2006, where she investigated the thermodynamical behavior of polypropylene blends. She received a scholarship of the Klaus Koch Stiftung in 2004 and 2005.
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3.08 Furans and their Benzo Derivatives: Applications B. A. Keay and J. M. Hopkins University of Calgary, Calgary, AB, Canada P. W. Dibble University of Lethbridge, Lethbridge, AB, Canada ª 2008 Elsevier Ltd. All rights reserved. 3.08.1
Introduction
571
3.08.2
Furan Derivatives
572
3.08.2.1
Pharmaceuticals
572
3.08.2.2
Textiles and Fibers
574
3.08.2.3
Fossil Fuels, Derivatives, and Related Products
574
3.08.2.4
Dyes and Photosensitizers
575
3.08.2.5
Surface Active Agents and Detergents
579
3.08.2.6
Cellulose, Lignin, Paper, and Other Wood Products
580
3.08.2.7
Industrial Organic Chemicals, Leather, Fats, and Waxes
582
3.08.2.8
Essential Oils and Cosmetics
582
3.08.2.9 3.08.3
Agrochemical Bioregulators
585
Benzofuran Derivatives
587
3.08.3.1
Pharmaceuticals and Bioactive Compounds
587
3.08.3.2
Cosmetics, Perfumes, and Essential Oils
597
3.08.3.3
Pesticides
600
3.08.3.4
Dyes, Fluorescers, and Electroluminescent Compounds
602
3.08.3.5
Polymers and Polymer Additives
604
3.08.3.6
Miscellaneous Applications
612
3.08.4 3.08.4.1
Further Developments
3.08.4.1.1 3.08.4.1.2 3.08.4.1.3 3.08.4.1.4 3.08.4.1.5
3.08.4.2
614
Furans
614
Pharmaceuticals Fossil fuels, derivatives, and related products Surface active agents and detergents Essential oils and cosmetics Agrochemical bioregulators
Benzofurans
3.08.4.2.1
614 614 614 615 615
615
Pharmaceuticals
615
References
616
3.08.1 Introduction This chapter describes various applications of furan and benzofuran derivatives since 1996. The subject matter concentrates on the actual use of molecules that contain one or more of the following ring systems: a furan ring, dihydro- and tetrahydrofuran (THF) ring, 2(5H)- and 3(2H)-furanones, five-membered anhydrides, benzofurans, isobenzofurans, dibenzofurans, benzofuranones, benzoanhydrides, polyarylfurans (and derivatives therefrom), and their hydro derivatives. This chapter is not an exhaustive review of the literature since 1996 due to the large number of references found on this topic and the page limitation. Thus, what appears is a selection. There were too many references to simple compounds, like THF, maleic anhydride, succinic anhydride, and phthalic anhydride, and so for
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the most part they are not discussed in detail. The reader is referred to Chemical Abstracts for references related to these compounds. It was very difficult to distinguish whether compounds described in patents had an actual application or were being listed as the subject of a claim. Therefore, molecules whose claim in applications would be of general interest have been included. Again, due to space restrictions, biologically active molecules isolated from natural sources have not been included.
3.08.2 Furan Derivatives 3.08.2.1 Pharmaceuticals A wide variety of pharmaceuticals which incorporate a five-membered ring containing one oxygen atom have been prepared. A number of compounds have been reported which contain a furan ring. Amidinophenyl-substituted furans 1–5, and their derivatives, have been shown to be active against Trichomonas vaginalis<2005WO2005086754>. The described compounds exhibit in vitro activity against metronidazole-sensitive and -resistant T. vaginalis isolates. IC50 concentrations were measured that were not elevated in the metronidazole resistant isolate, which suggests that their activity is not affected by parasite mechanisms that confer resistance to 5-nitroimidizoles. Furan 2 has also been shown to be an active antimicrobial agent against African trypanosomiasis and Pneumocystis<2004JMP351>. The unsubstituted 1, while active, suffered from poor oral activity in rodent models for both infections. Incorporation of the oxime units in 2 led to excellent oral activity. Furan containing aminoalcohol 6 belongs to a class of pharmaceutical compounds for use as immunosuppressants for the treatment and/or prevention of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, multiple sclerosis, psoriasis vulgaris, atopis cermatities, insulin-dependent diabetes, glomerulonephritis, and graft rejection. The compound was studied for its effect on adjuvant arthritis in rats <2005JPP2005041867>.
A compound containing the furan labdane diterpene rotundifuran 7 was extracted from the fruit of Vitex rotundifolia <2004MIP308-01>. Because rotundifuran specifically inhibits cholesterol acyltransferase, the isolated compound is effective in lowering blood cholesterol and can be used in the prevention of cardiovascular disease caused by hypercholesterolemia. The inclusion complex of bromofuran 8 not only increased the aqueous solubility of the furan compound, but also the dissolution rate <2004JPS197>. A suckling murine model was used to study the anticryptosporidial efficacies of both the drug and the inclusion complex with -cyclodextrin (-CD). While oral administration of furan 8 considerably decreased the intensity of the infection, -CD showed similar anticryptosporidial activity to that of the inclusion complex and higher activity than furan 8 alone. Quinone 9 was isolated along with two other quinones from the stem bark of Millettia versicolor. Pharmacological data showed that quinone 9 possessed anti-inflammatory properties, whereas the other two isolated compounds did not <2004CNP1535972>. Furan containing androstadiene derivative 10 has been shown to be useful for the therapeutic treatment of inflammatory disorders of the respiratory tract <2002USP2002177581>. Successful results were obtained when compound 10 was combined with a long acting 2-adrenoreceptor agonist and the combination was administered by inhalation.
Furans and their Benzo Derivatives: Applications
A combination therapy for the inhibition of PBPase has been described using furan 11 and THF 12 <2003WO0203978>. Along with one other antidiabetic agent, the furan compounds are converted in vivo or in vitro to MPO32, which inhibits FBPase. Biological examples show FBPase inhibition in human, rat, and mouse livers, inhibition of gluconeogenesis in rat hepatocytes, along with inhibition of glucose production. The vine Tinospora smilacina (known as snakevine) has been used in traditional medicine for countering snake venom. The major component isolated from the vine is the clerodane-type compound columbin 13 along with a minor component 14 containing a heavily oxygenated THF ring in place of the furan in columbin <2003MI308-02>.
Tanshinol A 15 was isolated from the cytotoxicity-guided fractionation of the roots of Salvia miltiorrhiza <1997MI339>. This compound was one of the 18 responsible for the cytotoxicity against five cultured human tumor cell lines, that is, A549 (non-small cell lung), SK-OV-3 (ovary), SK-MEL-2 (melanoma), XF498 (central nerve system), and HCT-15 (colon). The proliferation of each tumor cell line was significantly inhibited (IC50 values from 0.2 to 1.8 mg ml1) during the continuous exposure of the tumor cells to the tanshinone compounds for 48 h.
THF derivatives have also been found to be components of many pharmaceutical compounds. The elaborate THF-containing compound 16 is the active component of a new medicine which has been shown to possess action resisting cancer as well as the AIDS virus <2004CNP1535972>. The polymorphism that is displayed by compound 17 has been used as an advantage, as one specific polymorph has been isolated, and pharmaceuticals containing such compounds have been used to treat fungal infections in mammalian subjects <1999WO9918097>.
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3.08.2.2 Textiles and Fibers Furan-containing compounds have been incorporated into fabrics to enhance specific properties. Furan derivative 18 has been described in a process for counteracting human sweat malodor <2000EPP1113105>. This compound was used as an additive to a base perfume compound to counteract the undesirable odor. Functional fiber products incorporating furan compounds have been produced which have relaxing effects on the skin and help suppress skin blemishes <2005JPP2005113297>. The fiber products possess melanin inhibitors containing furanones 19 deposited on the fiber surface. These compounds are adhered to the fiber surface using pads or sprays and are often deposited as inclusion compounds with cyclodextrins. A fabric containing these treated fibers showed good retention of a dispersion comprising a silicone binder and microcapsules containing 3-tetradecen-4-olide and perfumes, even after washing 310 times.
Various furan compounds have been incorporated into a polyester fiber to provide electrostatic resistance toward antistatic fabrics <1999KRP160475>. Up to 1 wt.% of the furan compound was combined together with a polyoxyalkylene glycol compound and a nonreactive lithium alkylsulfonate to copolymerize the polyester. Upon drying, melt spinning, and stretching, the formed polyester fibers showed excellent electrostatic resistance.
3.08.2.3 Fossil Fuels, Derivatives, and Related Products Furan-containing compounds have found widespread application in the fossil fuel industry, either as single compounds or as part of polymeric compositions. Ethyl furanoate 20 has been used as an antiknock additive in gasoline fuels <2005USP2005229479>. The octane quality of fuel for an internal combustion engine improved with the antiknock additives, including this furan compound. Another report of gasoline antiknock compounds described a three-component system consisting of (1) a primary additive, consisting of an iron, lead, manganese, or rare earth metal compound; (2) a secondary additive, selected from ethers or nitro compounds; and (3) a sulfur passivating agent and an antiwear additive for prevention of inhibition of valve seat recession in the engine. The secondary antiknock additive contains furans as the ether component to aid in the antiknock activity of this particular system. <2005WO2005087901>. Three furan-containing compounds were used to investigate the ignition quality of compounds derivable from renewable sources, their effects on regulated emissions from conventional spark ignition engines, and their effects on gasoline properties <1998EF918>. The results showed that furfuryl alcohol 21, furfurylamine 22, and 2-methylfuran 23 enhance engine ignition quality, expressed by their capability to suppress engine knock. The furans performed better than methyl t-butyl ether (MTBE), an industry standard for an oxygenated additive. These effective antiknock compounds allow for a reduced aromatic content in gasoline without any further negative effects on the gasoline properties. Furthermore, 2-methylfuran and furfurylamine reduced hydrocarbon and CO emissions relative to the base fuel even at the same air–fuel ratio level.
Furans and their Benzo Derivatives: Applications
An earlier invention provides a fuel composition which comprises a major amount of a fuel boiling in the gasoline boiling range and a minor amount of an additive comprising of a furan derivative <1997EPP795596>. The additive concentrations of furans 24–26 for addition to such fuel and a method of operating an internal combustion engine using such a fuel composition was also described. The resulting fuels containing the furan additives gave rise to octane requirement increase control and/or octane requirement reduction effects. The adverse effects of asphaltenes in liquid hydrocarbons have been shown to be reduced by incorporating into the liquid hydrocarbon a sufficient concentration of a dispersant to disassemble agglomerates of the asphaltenes. Furan represents a molecule of suitable polarity to aid in the breaking up of these deleterious aggregates <1999USP6187172>. Poly-THF derivatives have been shown to be active combustion improvement agents for diesel fuel <2001EPP1188812>. Such compounds can be present as either an additive, at 0.01–1 wt.%, or can be present as a base fuel, at 40 wt.% (preferably 10–15 wt.%).
There are many reports on the use of furan and furyl alcohol containing polymeric resins in the petroleum reservoir field. Curable permeable polymeric resins are injected and hardened into solid masses within petroleum reservoirs to enhance the reservoir permeability and consist of a polymerizable resin, a hardening agent, an aromatic hydrocarbon diluent, a silane coupling agent, a foaming agent, a compressible gas, and a degradable material. Upon hardening of the material in the reservoir, the degradable component is allowed to degrade to form the curable permeable mass. A furan-furfuryl alcohol resin has been found to be a suitable resin for these purposes and in the right composition is suitable for consolidating and strengthening sensitive petroleum reservoirs while retaining or enhancing the desired permeability <2005USP2005197258>. A furan-containing polymer consisting of furfuryl alcohol has been used in sealing materials for petroleum recovery pipes or for forming a barrier in a petroleum wellbore. Along with the furyl polymer, the sealing material also consists of an organosilane coupling agent, a cationic surfactant, hollow microspheres, and, optionally, a dispersing agent and a lightweight filter <2004USP2004262003>.
3.08.2.4 Dyes and Photosensitizers The use of furans in photomaterials has continued to evolve since 1996. Aryl-substituted furans 27 and 28 have been synthesized as difunctional fluorophore molecules <2005TL277>. 2,29-Bis(2-furyl)-4,49-(N,N,N9,N9-tetraphenyl)diaminobiphenyl 27 and 5,59-bis(4-N,N9-diphenylaminophenyl)-2,29-bifuryl 28 both contain the hole-transporting triphenylamine units and are also light emitting. These new difunctional compounds emit blue photoluminescence and have high highest occupied molecular orbital (HOMO) energies as well as high glass transition temperatures. Furan itself has been used as part of a series of heteroaromatic bases quadrapolar chromophores <2003MI385>. The newly described systems present a A-p-D-p-A and a D-p-A-p-D general framework, where A represents a p-deficient heteroaromatic ring and D represents a p-excessive five-membered heterocycle, such as furan. These systems have been shown to have large two-photon absorption activities in the femtosecond regime, with a two-photon absorption cross section as high as 150 GM with 150 fs laser pulses.
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A furylmethyl group has been incorporated into a dye developer–coupler combination which has been shown to be useful for the oxidative dyeing of keratin fibers, especially human hair <2002WO2072568>. The regioisomeric furans 29 and 30 belong to this class of compounds and are easily synthesized from the corresponding aldehydes and a previously generated aminophenyl carbamate.
The lightfastness of azo dyes containing benzene, thiophene, and furan groups 31 and 32 has been studied for both the individual dyes and their binary mixtures in a cellulose acetate butyrate on an installation for accelerated photochemical aging <2002RJAC254>. The results showed that the lightfastness of the azo dyes containing benzene groups was higher than that of the heterocyclic groups, with the thiophene-containing groups being more stable under irradiation than the furan-containing compounds. The furan molecules did increase the lightfastness of the benzene containing azo dyes upon combination. This increase comes from the fact that the heterocyclic dye shields the benzene dye from irradiation, thus increasing the lightfastness.
Furan containing fulgides 33 and 38 were synthesized and subsequently derivatized and cyclized under photochemical conditions to provide materials with photochromic properties (Scheme 1) <2000CC1397>. (E)-Fulgides 33 reacted with malononitrile and diethylamine in THF to provide the dicyanomethylene derivative 35, which underwent photochemical cyclization in toluene at 366 nm to provide photochromes 36. These thermally stable blue photochromes underwent the reverse reaction upon exposure to white light. The (Z)-fulgides 38 gave the corresponding dicyanomethylene compounds 39 under similar reaction conditions. In toluene, compound 39 first isomerized to (E)-40 before undergoing cyclization at 366 nm to afford the tricyclic derivative 41. As was observed previously, the thermally stable blue photochromes underwent the reverse reaction upon exposure to white light. Dicyanomethylene 35 could he deprotonated at the methyl group syn to the dicyanomethylene group by boiling with diisopropylamine in THF. The generated anion 37 reacted with the adjacent cyano group to afford imine 42, which isomerized to the amine 43. As was expected, a toluene solution of amines 43 photochemically cyclized at 366 nm to yield thermally stable blue-green photochromes 44, which would also undergo the reverse reaction on exposure to white light. Photochromes 34, 36, and 41 all showed bathochromic shifts when the push–pull effect was enhanced, which has been reported for infrared active dyes. Photochromes 44 had increased charge-transfer character, due to the ability to retain the benzene ring, which can be seen in the resonance structure 45. This resonance ability results in the broad absorption band in the region between 750 and 800 nm. Compounds based on amines 43 are proposed to be well suited for optical memory devices and security printing due to the spectra of colored forms, their thermal stability, fatigue resistance, and high efficiency for coloring and bleaching.
Furans and their Benzo Derivatives: Applications
Scheme 1
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A series of furyl-substituted oxazoles have been synthesized and their spectral and luminescent properties compared to the analogous phenyl and thiophenyl compounds <1999CHE275>. The furan-containing analogues were found to both absorb and emit light at longer wavelengths than the corresponding 2,3-diphenyloxazoles, but at shorter wavelengths than their thiophene analogues. The observed trend is most likely due to the greater polarizability of the thiophene ring over that of furan and phenyl. The incorporation of carbonyl groups into the furan ring led to approximately the same shift to long wavelengths in the absorption spectra as for the 2,3-diphenyloxazole and the thiophene analogue. Given the 20–40 nm bathochromic shift, it is due not only to the extended conjugation offered by the carbonyl but also to the electron-accepting nature of the group. Differing absorption spectra in toluene and ethanol indicate that the molecules are weakly polar in the ground state and are better solvated by toluene, but upon excitation the electron density is shifted into the carbonyl group further polarizing the species and allowing the excited state to be better solvated in the polar solvent ethanol.
The use of organic chromophores as nonlinear optical (NLO) materials has generated much interest due to their potential use in optical modulation, molecular switching, optical memory, and frequency doubling applications. For heterocyclic moieties it has been shown that the products of dipole moment and molecular hyperpolarizability (m) are higher than those of benzene analogues. For a series of sulfone-substituted furan chromophores, the synthesis, ultraviolet–visible (UV–Vis) absorption spectra, and second-order NLO properties have been reported <1997TL6407>. The UV–Vis absorptions for compounds 52–57 all show max values in dioxane below 440 nm, with no absorptions above 500 nm detected. The phenyl sulfones had higher max values and lower charge-transfer energies than the corresponding methyl sulfones. The greater transparency of furans 52–57 should allow their use in blue-green laser lights by the frequency-doubling technique. To probe the NLO properties of these chromophores, the molecular hyperpolarizabilities were estimated by solvatochromism. The mg and mgo values for 52–57 were 1.8–8.7 times and 1.0–5.9 times larger than that for para-nitroaniline (PNA), respectively. The substituent on the sulfone group was found to have an effect, with the phenyl sulfone group showing increased second-order nonlinearities when compared to the methyl sulfone group.
A recent report detailed the synthesis and applications of a series of dicyanomethylene-substituted dihydrofurans 58 <2005USP2005009109>. All the fluorophoric compounds contained a 2-dicyanomethylen-3-cyano-2,3-dihydrofuran moiety and at least one donor group conjugated to the dihydrofuran ring. The donor group most often contained an aryl spacer with a substituted donor atom, such as N, O, S, or P, in the para-position of the aryl substituent. These
Furans and their Benzo Derivatives: Applications
fluorophores can be used in methods to label, detect, and quantify biomolecules and various biological structures. The interaction with the biomolecules occurs in a variety of manners, such as covalent bonding, ionic bonding, p–p interactions, by forming a hydrophobic interaction, or by van der Waals interactions. The same dihydrofuran scaffold has also found applications in optical devices <2002USP6393190>. Compounds derived from chromophore 59 were a component of a derived polymer for the construction of optical waveguides. Optical devices, including laser frequency converters, optical interferometric waveguide gates, wideband electrooptical guided wave analog-to-digital converters, and optical parametric devices, incorporating the above mentioned waveguides were also described. Polymeric thin films containing the novel chromophore 59 have also been used in optical waveguides and devices <2001WO01098310>. Compounds of this type were copolymerized with a chlorinated norbornenedicarboxylic acid derivative and a chlorinated xylylenediol to provide an electrooptical polyester.
The azulenyl furanone 60 was a key intermediate in the synthesis of the monofunctional azulenyl squaraine dye NIRQ700 61 (NIRQ ¼ near-infrared quencher) <2003TL3975>. The resulting nonfluorescent squaraine dye absorbed in the 600–700 nm range and can potentially be used to quench a number of available NIR fluorochromes in order to extend the spectrum of biological quenching assays.
The furanone component has been incorporated into highly photostable organic fluorescent pigments <1996LA679>. N-Arylpyrrolopyrrolediones (DPP) were prepared by the condensation of the corresponding lactones with arylamines. The result was bright red pigments that displayed an intense red to orange solid-state fluorescence.
3.08.2.5 Surface Active Agents and Detergents The dry cleaning process typically relies on nonaqueous, lipophilic fluids as either the solvent or the cleaning solution. Cleaning with lipophilic fluids minimizes fabric damage, but these fluids have poor hydrophilic and/or combination soil removal capabilities. Additives may be used to aid in soil removal, but such additives are often insoluble in lipophilic fluids or ineffective in these fluids. This brings about a need for combinations that can provide lipophilic fluids with bleaching capabilities, lipophilic fluid cleaning compositions having bleaching capabilities, and processes to make these fluids. 2,5-Dimethylfuran 62 has been used as a photosensitizer comprising part of a fluid composition that was able to provide a lipophilic fluid with bleaching capability, and lipophilic fluid cleaning compositions also possessing bleaching capabilities <2004USP2004266648>. A dihydrofuran skeleton based on furan-maleimide Diels–Alder adducts 63 has been incorporated into two new surfactant molecules <2005L3259>. The thermally labile Diels–Alder adduct connects the hydrophilic and hydrophobic sections of each molecule. Each surfactant molecule contains the same hydrophobic dodecyl tail segment but varies in the hydrophilic portion of the molecule, with one having a phenol-derived head group and the other a carboxylic acid head group. Upon
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deprotonation of the head groups, water-soluble surfactants result. It was revealed that room temperature aqueous solutions of both surfactants exhibited classical surface-active agent behavior similar to analogous alkyl aryl surfactant molecules. Dynamic surface tension and dye solubilization techniques were used to determine the critical micelle concentrations for each surfactant. Spherical micelles were detected for these surfactants by the use of small-angle neutron scattering measurements of the aqueous surfactant solutions. Spherical micelles with radii of 18.8 and 16.5 A˚ were detected for the phenolate and carboxylate system, respectively.
The amide surfactant 66 was prepared by the reaction of equimolar amounts of 3-dimethylaminopropylamine 64 and dihydro-3-(2-hexadecenyl)furan-2,5-dione 65 (Equation 1) <1997GBP2314339>. These surfactants have shown the advantages of being compatible with anionic surfactants, perfumes, and enzymes, are formulatable over a pH range of 5–12, have good handling properties, reduce redeposition of soils on fabric in the wash, are low in toxicity, and they enhance the cleaning of clay soiled articles. Surfactant 66 is present in detergents in 0.1%.
ð1Þ
3.08.2.6 Cellulose, Lignin, Paper, and Other Wood Products Two furan-containing cellulose esters, 67 and 68, with complex structures were synthesized in a one-pot reaction and shown to be sensitive against hydrolysis and light <2005MI333>. Due to the mild reaction conditions and efficiency of the process, very pure and highly functionalized cellulose derivatives were obtained up to a degree of substitution of 2.5 and they possessed a degree of polymerization in the range of the starting cellulose. These new compounds were characterized using both one-dimensional (1-D) and 2-D NMR techniques, which further validated the purity of the structures, and showed the pronounced regioselectivity for functionalization of the primary OH. The high purity, structural features, solubility properties, and the film-forming properties make these new materials desired products for the preparation of membranes with tailored separation characteristics.
A furfuryl alcohol 21 containing polymer was impregnated into wood samples providing wood that is uniform in color and density throughout the treated zone <2004WO2004011216>. This process is accomplished by treating a wood sample with a solution of a polymerizable furan monomer mixture containing the furfuryl alcohol, water, a stabilizing co-solvent, and at least one initiator. It was anticipated that the furan polymer impregnated wood would
Furans and their Benzo Derivatives: Applications
have improved properties such as dimensional stability, and decay and weather resistance. The preferred used of these treated woods are in applications as building parts, boat parts, marine items, outdoor items, bridge parts, railway sleepers, cooling tower slats, utility poles, heavy timbers, fenceposts, stakes, highway items, flooring, and containers. Furfuryl alcohol concentrations varied between 22.5 and 47.5 wt.% of the impregnating solution applied to the wood. The effects of the impregnated polymer were evidenced in the anti-swelling efficiency, which was remarkably high, even at lower concentrations of furfuryl alcohol, although the moisture exclusion efficiency was lower for higher concentrations of the alcohol. These results, along with further leaching experiments, confirmed the fact that the wood was filled with the polymer, and not with any other components of the impregnating solution. Increases in the hardness, bending strength, and modulus of elasticity were observed for the treated wood samples, whereas the impact strength was observed to decrease. The same simple furan compound 21 was applied as a resin to both soft and hard woods, and the carbonization behavior and the density dependence of the bending strength were observed from the untreated woods and the treated woods through heat treatment <1999MI133>. At lower heat treatment temperatures of approximately 400 C, the bending strength of woods were the lowest; the same tendency was observed for the woods treated with the furfuryl alcohol resin. The impregnation of this resin did not make the bending strength increase, but it did result in the decrease in volume shrinkage. Urea-formaldehyde resins modified with furfuryl alcohol 21 were synthesized using different ratios of furfuryl alcohol, and the resulting resins were evaluated as wood adhesives <1996MI17>. An aqueous solution of p-toluenesulfonic acid was used as the hardening catalyst. The effects of varying the amounts of the furfuryl alcohol composition as well as the amount of the sulfonic acid on the shear strength of the synthesized adhesive were studied. Optimal results were obtained for 30%, 45%, and 60% of the furfuryl alcohol-modified urea-formaldehyde as the most suitable resin for wood adhesives, using 10 times less sulfonic acid. Increasing the amount of furfuryl alcohol was not suitable for wood adhesive application, as it affected the stability of the resin and weakened the adhesive bond. It was concluded that the shear stress of the modified resin was twice that of the unmodified resin. The degradation of wood-based paper, cotton-based paper, and pure cotton liners provide the furan products furfuryl alcohol 21, furfural 69, 2-acetylfuran 70, and 5-methylfuran 71 in accelerated laboratory experiments <2000MI110>. These types of paper are used as insulators in power transformers, and the analysis of the furancontaining products in the transformer oil provides an excellent method for monitoring transformer condition. The concentration of furfural was found to be the highest of all the furan-containing products, indicating that furfural analysis could provide a sensitive troubleshooting tool for rapid aging. In similar work, the analysis of furan-containing compounds has been used to aid in the determination of aging of solid insulation in electrical transformers <2003MI921>. This solid insulation is comprised mainly of Kraft paper, in which the cellulose polymer chain breaks down as the paper ages, and this is accompanied by an increase in the content of various furanic compounds in the dielectric liquid. Analyzing for the presence of furan-containing compounds allows there to be a determination as to whether the breakdown of the paper is in an active condition, and a determination as to the relative degree of paper breakdown that has occurred.
Furfural 69, which can be manufactured from hardwood waste, is used for the manufacturing of a furfural-acetone monomer <2000MI15>. This monomer is then used to obtain furfural resins which are suitable as binders for the production of particleboards. In a further application, these furan resins of low toxicity have been used as adhesives in the manufacture of plywood <1999MI24>. The use of such resins is recommended as it leads to products with advantageous economic and ecological indicators. The result is plywood with good physiomechanical properties when the Monomer furfuryl alcohol (FA) was used as the adhesive. Similar to the use of furan-containing compounds in the determination of aging of electrical transformer insulation, the UV properties of furan derivatives were used to aid in the detection of the selective hydrolysis of 4-deoxy-4-hexenuronic acid groups, which are the products of conversion for a major part of the 4-O-methylglucuronic acid groups during kraft pulping <1996MI43>. Due to the alkene functionality of the hexenuronic acid, reaction with several bleaching chemicals, such as Cl, ClO2, O3, and peracids, is possible. Permanganate will also react with this double bond, which contributes to the kappa number of the pulps. This selective hydrolysis method has potential to be part of elemental-chlorine-free and totalchlorine-free bleaching sequences. The amount of the furan derivatives detected correlated linearly with the decrease in the kappa number of both unbleached and O-bleached hard- and softwood pulps. Depending on the type of pulp used, the
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hydrolysis removed 20–60 meq per kilogram of pulp and decreased the kappa number by 2–7 units. This selective hydrolysis method was found to have no profound effect on the paper technical properties for the fully bleached pulps, but did significantly improve the brightness stability of the O- and peroxide-bleached pulps.
3.08.2.7 Industrial Organic Chemicals, Leather, Fats, and Waxes Furan itself can be used as the starting material for the synthesis of 1-methylpyrrole <2002MI179>. -Al2O3 was found to be an effective catalyst for the dehydration reaction between furan and methylamine to afford 1-methylpyrrole. A yield of 57.6% was achieved under the experimental conditions of a reaction temperature of 400 C, a methylamine/ furan molar ratio of 1.5, and the molar flow rate of furan approximately 3–3.5 mmol/h. Furan was adsorbed onto Brønsted acid sites on the catalyst, while the methylamine was adsorbed onto Lewis acid sites. With this heterogeneous catalyst, the rate determining step of the mechanism was suggested to be the adsorption of furan on the Brønsted acid sites to form a ring-opened species, which is followed by the insertion of the adsorbed methylamine to form secondary amine intermediates. Further dehydration at the Lewis acid sites would yield 1-methylpyrrole. Furan was also the starting material in the indirect electrochemical preparation of 2,5-dimethoxyfuran in a packed bed electrochemical reactor <2001MI185>. This process had a current efficiency of >9000 %, a product yield >90 %, and the electrical energy consumption was <3 kW h kg1 of product under the optimized operating conditions. These conditions required a reaction temperature between 0 and 5 C, 4.0–4.6 V of electrolysis voltage, and >2000 A m2 operating current density (c.d.). The donor ability of the furan ring was exploited in the formation of rhodium complexes of [Rh(CO)2Cl]2 <2000CHJ18>. As a ligand on rhodium, these new complexes were evaluated as catalysts in the carbonylation of methanol to acetic acid. It was observed that the free donor groups enhanced the stability of the metal complexes and improved the catalyst activity. In another transition metal application, the modifying effects of furan on CO adsorption on a Cu/Al2O3 catalyst have been studied by Fourier transform infrared (FTIR) spectroscopy in the hydrogenation of crotonaldehyde <2000PCP283>. The co-adsorption of furan weakened the four bands at 2136 and 2120 cm1 due to CO on Cu(I) sites and at 2089 and 2060 cm1 due to CO on Cu(0) sites. These sites could be regenerated when furan desorbed at 298 K. When compared to other catalyst poisons, furan has less of an effect than pyrrole and cyclopentadiene, and was shown to have little effect on catalyst selectivity between alkene and carbonyl reduction. Furfural 69 has been used as a chemical feedstock for the production of furan via two production methods involving the decarbonylation of furfural <2005MI7>. Processes in both the liquid and gas phases were described for the preparation of furan through the decarbonylation of furfural using noble metal and metal oxide catalysts. The results of the study led the authors to state that the research trends for preparing furan based on the decarbonylation of furfural should mainly be concentrated on more effective catalysts and environmentally friendly processes. The reaction of 3,4-tetrahydrofurandiol 72 with at least one metal catalyst has been used as a process for the production of THF or a mixture of THF and its precursors <2003WO03042201>. The parent diol is hydrogenated in the presence of either Rh, Re, Pd, Ru, or Ni catalysts. Hydrogenation of diol 72 in dioxane at 500 psi and 200 C for 2 h in the presence of a carbon-supported catalyst containing Re (10%) and Ni (1%) afforded THF with 53.5% selectivity, as well as the THF precursors 2,5-dihydrofuran and -butyrolactone.
The susceptibility of leathers to moisture makes waterproofing of this material an important process. It was demonstrated that effective hydrophobization compounds for leather consisted of a liquid polysiloxane and a fluorine-containing organic compound containing a furan ring <1999MI32>. A treatment solution comprising 47.5% polyethylhydrosiloxane, 47.5% polydimethylsiloxane, and 5% of the fluorine-containing furan compound increased the water resistance of suede leather by a factor of 3–6 when compared to a treatment solution absent in the furan.
3.08.2.8 Essential Oils and Cosmetics Alkylfurans have been used in the cosmetic treatment of cellulitis <2005FRP2870740>. Specifically, the effects in the metabolism of guinea pig adipocytes of cis,cis-8,11-heptadecadienyl-2-furan 73 have been studied. In another
Furans and their Benzo Derivatives: Applications
skincare-related application, an anti-inflammatory effective amount of 3-furan carboxylic acid 74 has been used in a cosmetic or pharmaceutical formulation as a topical application <2002USP6387947>. The desired formulation optionally comprises an anti-irritant effective amount of ferulic acid, in combination with an irritating active component, for example, balsam of Peru, and the antimicrobial effective 2-furan carboxylic acid 75. The anti-irritant effects of compositions containing 0.1% ferulic acid, 2-furan carboxylic acid 75, and 3-furan carboxylic acid 74 in aqueous ethanol (1:1) were tested in subjects with a history of skin sensitivity to balsam of Peru. Upon application of the test compositions to the ventral forearms of the subjects, 20 min was allowed for complete absorption before the irritant (balsam of Peru) was applied to the test sites. The skin irritation was measured in terms of increase in skin redness and compared with the controls. It was observed that both 2- and 3-furan carboxylic acids showed some reduction in the onset of skin irritation, by 49% and 48%, respectively.
The hair-care industry has made use of structurally simple furan derivatives. 2-Aminofuran 76 has been used as the active ingredient in a hair dyeing composition that is comprised of the dyeing medium 76 or its acid or base addition salt and at least one oxidation base <2005EPP1498109>. This report describes the use of amine 76 for the oxidative dyeing of keratin fibers by applying the composition containing the furan compound to the fibers along with an oxidizing agent. Keratin-reducing furan derivatives 77 are useful agents for permanent hair waving <2000DEP19840899>. Such derivatives, or salts thereof, have a gentle, uniform waving action and cause no allergic or sensitizing reactions. The composition preferably consists essentially or exclusively of natural components of fresh roasted fruits of the coffee bush, selected from furfurylmercaptan, cysteine, cysteamine, ascorbic acid, arginine, coffee oil, methanethiol, coffee extract of coffee powder.
The fragrance industry has made use of small molecule epoxy furans. The rose flavone epoxide 78 and rose isoflavone epoxide 79 are components of a perfume that is mild and gives refreshing feels <1996JPP8092588>. Perfumes containing these components can be used in the manufacture of cosmetics, air fresheners, and other products.
In a disclosure regarding the use of alicyclic carboxylic acid oxycarbonylmethyl esters and their use as odorants and perfumes, a composition was described in which two furan compounds were components <2005WO2005108534>. 4,5-Dimethyl-3-hydroxy-2(5H)-furanone 80 and 3a,6,6,9a-tetramethyldodecahydronaphtho[2,1-b]-furan 18 were present in 2% in the described perfume. In another fragrance-related application, compound 18 was a component of a perfume composition which was added to a shampoo formulation designed to enhance permeation as well as provide desired fragrant effects <2002JPP2002241238>. The fused tricyclic furan 18 was incorporated as 20% of the perfume mixture of which that was a component of the shampoo in 0.7%.
583
584
Furans and their Benzo Derivatives: Applications
Another saturated tetrahydrofuryl core has found application as a component of liquid crystals. Cholesteric liquid crystal polymers are useful as photostable UV filters in cosmetic and pharmaceutical preparations for the protection of human epidermis and hair against UV radiation, especially in the range 280–450 nm <2000DEP19848130>. Fused bifuran 81 is a suitable monomer for the preparation of these desired polymers as it contains the requisite characteristics of having more than one chiral, bifunctional subunit type which is capable of forming a cholesteric liquid crystal phase with a pitch of <450 nm. It also contains an achiral aromatic or cycloaliphatic hydroxyl or amino carboxylic acid subunit, achiral aromatic or cycloaliphatic dicarboxylic acids, and/or achiral aromatic or cycloaliphatic diols or diamines. Polymers prepared from suitable monomers, such as diol 81, can also be used as UV reflectors, UV stabilizers, and multilayer pigments.
The essential oil and cosmetic industry has found wide use for saturated and unsaturated furanones. In a study on the use of monoterpenes, sesquiterpenes, and/or diterpenes, and their derivatives for reducing the adhesion of keratinophilic fungi on surfaces, the THF derivative 82 was a constituent of a cream used to treat this problem <2004USP2004219190>. This composition relates to washing and/or cleaning, textile treatment agents, body-care products, cosmetics or pharmaceuticals containing the aforementioned substances. The cream developed contained (wt./wt.%): dehymuls (4.5), myritol 331 (5.0), cetiol OE (5.0), 82 (1.0), zinc stearate (1.0), glycerin (5.0), magnesium sulfate heptahydrate (0.5), farnesol (0.001), and water (to 100). Low molecular weight butyrolactones (220) possessing more than one O-containing functional group have been applied as oral biofilm inhibitors <2004JPP2004155681>. Dentrifices were prepared that contained these inhibitors and were shown to prevent dental caries, periodontal diseases, halitosis, etc. Results using hydroxymethylbutyrolactone 83 showed reduced pathogenicity (protease activity/bacterial count) against Porphyromonas gingivalis.
Furanone 84 was exploited for its fragrant properties in the hair-care industry <2002JPP2002284660>. Perfume compositions for hair preparations which emit strong fragrance while drying or styling with warm air from hair dryers are desired. 5-Hexyldihydro-5-methyl-2(3H)-furanone 84 was one of a number of small molecule compounds used for this purpose. Furanone 85 was prepared from its unsubstituted hydroxyl parent compound for fragrance applications <1997DEP19532314>. Tonka bean-like, lovage-like, fruity, or other fragrant features are characteristic of substituted 5-hydroxyfuranones and their derivatives. These features blend well with other fragrances and are useful for perfuming cosmetics, household products, textiles, etc.
Furan derivatives have been used to inhibit the formation of melanin when combined with other agents <2000JPP2000302642>. For the group consisting of 5-methyl-2(3H)-furanone 86, 2,5-dimethyl-4-hydroxy-3(2H)thiophenone, 2-buten-4-olide, and 2-hydroxymethylfuran 21, the in vitro formation of tyrosinase was inhibited by
Furans and their Benzo Derivatives: Applications
90%. Bioinspired furan compounds have been effective agents for the treatment of skin disorders. Vegetable oil furan lipids belong to a group of substances that are able to act as agents for increasing skin lipid synthesis, in particular lipids of the epidermal skin barrier <2001WO021150>. These compounds allow for the development of a composition containing a pharmaceutically or dermatologically acceptable medium. The use of such compounds allows for the prevention and/or treatment of the deterioration of the skin barrier (dry skin, skin subjected to actinic radiation, ichthyosis, acne, xerosis, atopic dermatitis, sensitive skin, chafing and reactive skin, itching).
3.08.2.9 Agrochemical Bioregulators The citrus-derived limonoids limonin 87, nomilin 88, and obacunone 89 along with their semisynthetic derivatives were evaluated for their antifeedant activity and the results were compared against Spodoptera frugiperda <2002JFA6766>. To these natural limonoids, which were obtained from the seeds of the citrus lemon, simple chemical transformations were carried out on functional groups that were considered to be important for the biological activity. These groups included the C-7 carbonyl, which was reduced to the corresponding alcohol, from which the related acetates, oximes, and methoximes were prepared, and the furan ring, which was hydrogenated in the cases of limonin and obacunone. The antifeedant activity of the natural limonoids and the semisynthetic derivatives was confirmed by comparison with previously reported data which shows that insect species vary in their behavioral responses to the structural modifications. For two of the natural limonoids and three semisynthetic derivatives, highly significant antifeedant activity (p < 0.01) was observed against S. frugiperda.
In a structure–antifeedant activity relationship study of the structurally related clerodane diterpenoids, furancontaining compounds 90 and 91 were found to exhibit remarkable feedant-deterrent activity against Tenebrio molitor <2000JFA1384>. These studies indicated that stereoelectronic factors are more important than the hydrophobic properties as determinants of antifeedant activity, and that a furan ring in the side chain and an ,-unsaturated carbonyl or spiro-epoxide group appear to be a necessity for the desired biological response. Studying the conformation of these molecules illustrated that the optimum interaction distance between these moieties is between 9.5 and ˚ 10.5 A.
585
586
Furans and their Benzo Derivatives: Applications
Avocadofurans are isolated from specialized idioblast cells of the avocado or can be synthetically prepared and have demonstrated novel insecticidal activity <2000USP6133313>. Insecticidal formulations containing the saturated avocadofurans 92 as well as the (E)- and (Z)-isomers of the unsaturated derivatives 93 inhibit larval growth and are suitable for control of Spodoptera exigua. The importance of the unsaturation of the furan ring on the insecticidal activity of avocadofurans has been examined by comparison of the activity of two naturally occurring avocadofurans, 2-(pentadecyl)furan (92: n ¼ 14) and 2-(heptadecyl)furan (92: n ¼ 16), with the toxicity of five THFs 94 with alkyl chains at the 2-position and with side chains varying in length from 14 to 18 carbon atoms <2000JFA3642>. Upon removal of the double bonds of the furan ring, the detrimental effects on the mortality and growth of the generalist insect herbivore S. exigua was significantly reduced. When subjected to 7 day bioassays, the S. exigua larvae were considerably more affected when fed a diet containing the natural avocadofurans as compared to larvae fed a diet of the THF analogues. When compared to control experiments, reduced larval growth was observed for the THF compounds, but larval mortality did not significantly increase. These results illustrate the importance that the double bonds of the furan ring in the natural avocadofurans play with respect to their insecticidal effects.
The marine diterpene, crenulacetal C, isolated from the brown alga Dictyota dichotoma, is an inhibitory compound against Polydora websterii, a harmful lugworm that had adverse effects on pearl oyster cultivation <1998CPB462>. Structure–activity relationship studies were performed which led to the synthesis of several synthetic compounds having an aromatic moiety with a hydroxyalkyl side chain. A bioassay was performed using P. websterii larvae as well as pearl oysters which suggested that 1-(2-furyl)-1-nonanol 95 was the most promising inhibitor. Furan-containing diaroylurea compounds 96 have been designed and prepared and their application toward insecticidal activity probed <1998MI282>. A series of N-aroyl-N9-(5-aryl-2-furoyl)ureas were synthesized and a bioassay showed that some of the novel compounds exhibited activity against second-instar larvae of the yellow fever mosquito (Aedes aegypti L.). The sesquiterpene furan epingaione 97 was isolated from the ethanol extract of Bonita daphnoides leaves and stems and showed growth regulatory activity on gravid adult female Boophilus microplus (southern cattle tick) <1997MI231>. To inhibit the hatching of the B. microplus eggs by 50% (Fid50), the dose of epingaione required was 0.4 0.06 mg g1 of the tick body weight. A dose of this strength inhibited the sequestration of protein into eggs oviposited by 80% and left these eggs nonagglutinated and wrinkled. Further examination of the ovarian sections from the treated ticks revealed significant degeneration of funicle cells and reduction in yolk content.
Furan compounds of the basic structure 98 have been prepared and are directly sprayed or applied to a water surface and show good fungicidal activity, especially against rice blast <1998JPP10114765>. An aqueous suspension of the acid 98 was applied to the water of a rice seedling culture pot, and greatly suppressed the development of blast due to Pyricularia oryzae. The fungicidal properties of some triphenyltin carboxylates were screened in vitro against Ceratocystis ulmi, the causative agent of Dutch elm disease, using a shake culture method <1998AOM25>. Spectral data indicated that the solid-state structures of the carboxylates were monomeric, except in the case of the 2-furan carboxylic acid derivative 99, which was found to be polymeric. The results of the screening showed that the organotin compounds were effective inhibitors of C. ulmi, but the furan carboxylate showed markedly decreased activity compared to other carboxylate anions. This decreased activity is attributed to the polymeric structure adopted by this particular adduct.
Furans and their Benzo Derivatives: Applications
3.08.3 Benzofuran Derivatives 3.08.3.1 Pharmaceuticals and Bioactive Compounds Benzofurans are found in many compounds that are of current interest due to a broad range of biological activity. Examples are found in natural products, existing pharmacological formulations, and promising lead compounds. Amiodarone 100 is an antiarrhythmic drug developed in Belgium in the early 1960s. It is marketed as pacerone by Upsher-Smith Laboratories and as Cordarone by Wyeth-Ayerst. It is classified as a type III antiarrhythmic agent and operates by slowing nerve impulses in the third phase of the cardiac action potential <1999USP5981514>. Continuing studies into the activity of this compound have discovered varied forms of activity. The discovery that amiodarone also has antiadrenergic action in the heart prompted an investigation in Chinese hamster ovary cells. Amiodarone was found to suppress vesicular monoamine transport by inhibiting the uptake of [3H]norepinephrine <1999MI834>. Other amiodarone analogues 101–104 have appeared in the patent literature. Ester 101 inhibited G proteincoupled and ATP-sensitive potassium currents <2004MI134>. Analogue 102, in which the n-butyl group of amiodarone is replaced by a branched ester, is converted into a less lipophilic metabolite resulting in a better safety profile. It is reported to be effective in the treatment of ventricular tachyarrhythmias in patients with congestive heart failure <2003WO03050102>. Hydrochloride 103 has been patented for different activity. It is purported to be a triiodothyronine receptor ligand for the treatment of disorders involving the expression of T-3 regulated genes <1996USP5585404>. Amiodarone analogue 104 is an inhibitor of transmembrane potassium currents and is also a potential cardiac drug <2003WO03009839>. I
I O
O
CO2CH3
CH2CH2 NBu2 H3CSO2HN
I
I
Bu O
CH3
Amiodarone
O
100
101
I I OCH 2CH2 NEt 2
O
OCH2CH2NEt2•HCl
O
OH
O
I I O H3CO
O
O
102
O
103
104
O
O
CH2CH2CH2NBu 2 H3CSO2HN
H3CSO2HN Bu
Bu
O
O Dronedarone
105
106
587
588
Furans and their Benzo Derivatives: Applications
Dronedarone 105, an antiarrhythmic drug related to amiodarone, is under development by Sanofi-Aventis. It is offered as a noniodinated alternative to amiodarone in order to avoid some of amiodarone’s iodine-related side effects. A comparison of the two compounds has recently been published <2005MI217>. An evaluation of the electrophysiological effects of dronedarone on the human biochemical counterparts to the cardiac delayed rectifier Kþ current in Xenopus oocytes has been reported <2003BJP996>. The ability of dronedarone to inhibit D-amyloid aggregation has also been evaluated <2001BML255>. Underlining the importance of drondarone development, a process for the synthesis of synthetic intermediate 106 used for the preparation of dronedarone has been patented <2004 USP6828448>. A very promising candidate compound for the treatment of various central nervous system (CNS) disorders has emerged from Abbot Laboratories <2004USP6822101>. ABT-239, 107, is an H3 histamine receptor antagonist. The synthesis of ABT-239, several analogues, and an evaluation of their pharmacokinetic properties has been described. The compounds were evaluated for H3 binding in human and rat cells and in two behavioral models in rats. The compound has potential in the treatment of cognitive disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease <2005JME38>. ABT-239 has been evaluated in in vitro pharmacological and in vivo pharmacokinetic profiles against other H3 receptor antagonists in a wide variety of tests <2005MI165>. A series of analogues in which the cyanophenyl substituent of compound 107 is replaced by 17 different aryl and heteroaryl groups has been prepared. Two derivatives 108 and 109 have shown high in vivo potency <2005MI25>. CN N O ABT-239
107
N
N N
N
N
CN O
O
108
109
Galanthamine 110, structurally related to the morphine family 111, is a naturally occurring dibenzofuran isolated many years ago from several plant sources. It was later discovered to possess very useful biological activity. It is a highly specific reversible inhibitor of acetylcholinesterase. The FDA granted approval to Janssen Pharmaceutica to sell this drug in 2001. It is marketed under the name reminyl for the treatment of Alzheimer’s disease <2006MI268>. A recent review examines this drug and other anticholinesterase compounds used to treat Alzheimer’s disease <2004MI3121>. A series of open D-ring analogues 112 and the novel cyclic example 113 have been prepared and evaluated. They were found to have less activity than galanthamine <2003BML2389>. Another analogue, ()-9dehydrogalanthaminium bromide 114, was found to enhance place and object recognition in an animal model <2003MI113>. CH 3 N
Me N
H HO O (–)-Galanthamine
110
OMe
HO
O
OR
111 R = Me; codiene R = OH; morphine R = OCOCH3; heroin
Furans and their Benzo Derivatives: Applications
Me
Br –
Me
R
EtO 2 C N
N
O
Me N
HO O
HO
HO
OMe
112
O
R = CH2OH, CH2Cl, CHO
O
OMe
113
OMe
114
Other compounds are also potential CNS agents associated with cholinesterase activity. Amide 115, and a host of analogues with varied types of benzo rings, is a nicotinic acetylcholine receptor agonist claimed to improve perception, concentration, and memory <2003WO03055878>. Example 116, which shares the azabicyclo substituent, binds to nicotinic acetylcholine receptors for disorders involving reduced cholinergic function, such as Alzheimer’s disease, ADHD, anxiety, etc. <2003WO03087102>. Phenol 117 and its carbamate derivatives have been patented for the treatment of memory dysfunction <1998USP5708007>. Pyridyl amide 118 is an anticholinergic compound that inhibits nerve impulses for the reduction of smooth muscle spasm <2005WO2005102344>. O O
HN
115
N
CN
O N
N
N
N
116
OH
Ar
Cl
Cl
O
HN
O
117
O O OMe
N N
118
Me
Several benzofuran derivatives with similar topologies find application in the treatment of sleep disorders. One compound developed by the Takeda Corporation is ramelteon 119. It has recently been approved in the US for the treatment of insomnia. Ramelteon is a highly selective agonist for MT1/MT2 (melatonin) receptors. One of ramelteon’s advantages is that it does not interact with opiate, benzodiazepine, or serotonin receptors, thereby avoiding dependency problems <2005MI1057>. Tricyclic amide 120 has also been patented for application to disorders of the melatoninergic system <1999USP5998461>. Two closely related cyclopropyl derivatives, 121 and 122, and their 2,3-dihydro analogues have also been developed for similar applications <2003USP6569894, 1999USP5856529>. O
O
H3COCHN H3C
NHCOCH3 O
H3C N H (CH2)n Ar
O O
O
Ramelteon
119
N H
120
121
n = 1–9
O
122
The furocoumarins constitute an important class of bioactive natural products which have led to many other compounds of potential value. Examples are the psoralens, the angelicins, allopsoralens, and the furo[3,2-c]coumarins 123–126 and their 2,3-dihydro derivatives. They exhibit a wide range of activity and applications include the treatment of skin disease, phototoxicity to neoplasms and bacteria, analgesic and anti-inflammatory activity. A recent review summarizes synthetic approaches to a wide range of these compounds, recent naturally occurring examples, and examines the range of their biological activity <2004CME3239>. The preparation of a specific psoralen derivative, 127, has been patented. This compound is purported to have a broader antibacterial spectrum than other agents <2006WO2006028024>.
589
590
Furans and their Benzo Derivatives: Applications
O
OH
O O
O
O O
O
O
O
O
Psoralen
O Allopsoralen
Angelicin
123
O
Furocoumarin
125
124
O
O
O
127
126
Many scientists are looking to folk remedies for compounds with useful biological activity. Gancaonin 128 isolated from Glycyrrhiza uralensis (Chinese licorice) was found to exhibit antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) <2004CME3239>. Six other benzofuran natural products 129–134 were isolated from the mulberry tree. All of these compounds showed considerable activity against MRSA and several vancomycinresistant enterococci <2002MI536>.
MeO
O
OH
OH
HO
O
HO
OMe
OH
128
129
OH
OH HO
R
O HO
OH O
MeO
H
OH O
H
130 O
OH
131: R = CH2CHC(CH3)2 132: R = H
HO OH
OH
R HO
R
OH O
HO
OH
OH O
OH O O
OH
O
OH
HO
133
HO
134 Three new oligomeric benzofurans 135–137 were isolated from Ligularia stenocephala, an aster of Chinese origin. This plant has been used as a folk remedy in the treatment of edema and scrofula (a tubercular infection of the skin of the neck). Compounds 136 and 137 lacked cytotoxic activity but exhibited mild antibacterial activity <2005PHA155>.
Furans and their Benzo Derivatives: Applications
OMe
MeO
O O
MeO
OMe
135 MeO
OMe
O O
O
O
O
MeO O
O
MeO
OMe
OMe OMe
MeO OMe
MeO
MeO MeO
OMe
OMe
136
137 During a screening for antimalarial compounds based on Mexican folk remedies, three novel arylbenzofuran aldehydes were isolated from the tree Andira inermis. Example 138, andinermal B, is thought to be responsible for the antiplasmodial activity of this extract <2001P769>. Pyrimidine-substituted benzofuran 139 is active against a collection of pathogenic bacteria such as S. aureus, Enterococcus, and Streptococcus pneumoniae. It is particularly effective against respiratory tract bacteria <2006ESP2250474T>. Examples of dihydroxybenzofurans 140 inhibit chorismate synthase in bacteria, which is part of the shikimate pathway <2003GBP2386891>. Ester 141 has been patented for use in pharmaceutical compositions for a rather wide range of disorders <2000USP6057341>. Dibenzofuran 142 has antimicrobial activity against Bacillus subtilis. The compound is isolated from the culture of a slime mold <1999JPP11080146>. N
H 2N OH
CHO
N
O OMe MeO
OH
140 Ar = 3-carboxyphenyl, 2-hydroxy-4-methoxyphenyl, 4-diethylamino-2-hydroxy
OMe
139 Cl
CO2 R
O
Ar
OH O
MeO
138
O
HO
H 2N
O
O
OMe
O
Cl
MeO
OMe
O Cl
O
141
OH HO
142
C5H11 O
Propafenone 143, a drug in clinical use as an antiarrhythmic, has activity in the modulation of cancer multidrug resistance. A series of benzofuran analogues of propafenone, such as compound 144, have been synthesized and evaluated in a daunomycin cytotoxicity assay <1996JME4767>. The results of this work were later the subject of a comparative molecular field analysis (3-D quantitative structure–activity relationship (QSAR)) <1998QSA301>. Ph
Ph
H3CO
OH O H N
O HO
Propafenone
143
O
N
144
N
591
592
Furans and their Benzo Derivatives: Applications
Tetraazol 145 is an inhibitor of phosphoinositide-3-kinase (PI3K), a signaler in the development of breast cancer <2004WO2004108709>. Aryl ketones based on the structures 146–148 have been patented for use in the treatment of neoplastic and autoimmune diseases <2005WO2005061476>. Compounds such as amine 149 were part of a series of compounds developed for the treatment of multidrug resistant neoplasm <2000USP6124211>. Ketone 150 was the most active of 18 analogues with varied substitution in the phenyl ring. It had the same cytotoxicity as the lead compound on which it was based, but was longer-lived <2004BML455>. R
N
O
O MeO
O O
HN
N
145
O
N
N NH
Ar
O
N
146
N
O N
Ar
147
O
Ar
148
Ar = Ph, pyridyl, pyradinyl
R = cycloalkyl
O
R2N
O
N
OH
Me O OMe
O
O
Ph
150 OMe
O
149 Three benzofurans have antitumour activity by virtue of their action in the inhibition of tubulin polymerization. Compound 151 is thought to bind to tubulin via p-stacking interactions <2004USP0044059>. A series of dihydrobenzofuran and benzofuran lignans were synthesized and evaluated for their antitumor properties. Examples varied in the substituents of the aryl group and the presence or absence of the cinnamate double bond. Example 152 was the most active example screened against 60 human tumor lines. These compounds represent a new class of antimitotic agents that act via inhibition of tubulin polymerization <1999JME5475>. In a screen for other tubulin polymerization inhibitors, benzofuran 153 was one of a series of analogues of the marine natural product curacin A prepared in a mixture library separated by fluorous technology. This compound had considerable potency in protein and cell-based growth inhibition screens <2000JA9391>. OMe
HO
O
O HO
OMe
OH
MeO
OH MeO
O
OMe
153
OH
OH
O
MeO
O
O
152
OMe
OMe
151 There are over 50 naturally occurring derivatives of rocaglamide 154, a lignan extracted from plants of the Aglaia species. As an Asian folk remedy, these extracts have been used as anti-inflammatories. A study of 15 derivatives found several that are potent and specific inhibitors of nuclear factor B (NF-B) activation, a process involved in the mediation of inflammatory response. They also have cytostatic activity in human cancer cell lines <2002JBC44791, 2005MI7075>. Of 13 examples, rocaglamide and ester 155 were found to have the greatest antiproliferative effect on a human monocytic leukemia cell line <1999ZN1075>. The analogue of rocaglamide, 156, is an inhibitor of interleukin-8 and has been patented for its potential pharmaceutical application to systemic inflammatory processes or hyperproliferation <2005WO2005113529>.
Furans and their Benzo Derivatives: Applications
HO MeO
O
MeO
O
R2
R
HO
CONH 2 F
O
R1
Rocaglamide OMe
154: R = CONH2 155: R = CO2Me
156 R2, R2 = alkoxy or alkylamine
Several synthetic benzofurans have been patented for their anti-inflammatory properties. Sulfonamide 157 (and 2,3-substituted variations) <1998USP5773467> and aminobenzofuran 158 are phosphodiesterase inhibitors for the treatment of asthma and other lung diseases <2004WO2004009557>. Oxalylamino benzofurans 159 are proposed to prevent and treat inflammatory processes of the airways <1996USP5565488>. Two similar classes of compounds represented by urea 160 and ketone 161 also have anti-inflammatory properties <1997WO9728143, 1997WO9728144>. Benzofluorene 162 is an N-methyl-D-asparate (NMDA) antagonist for the treatment of pain relief <2003WO03014124>. SO2 NMe 2
NH2 O
O O OH
R1
O
157
HO
H N
R O
O
XR
O
159
158 X = O, S R, R1 = alkyl O
H N
H 3CHN
Ar O
NH
O
160
Bu
O
CO2 H
O
t
But
162
161 Ar = heteroaryl
Beraprost 163 is a prostacyclin analogue developed by United Therapeutics. It inhibits platelet aggregation induced by adenosine diphosphate (ADP) and collagen but is more stable than PGI2. It has proved to be effective in the treatment of peripheral vascular disease and pulmonary hypertension <1998MI645>. A more recent review examines the activity of a range of prostacyclin analogues including beraprost <2004MI139>. Benzofuran 164 was developed for the treatment of chronic obstructive pulmonary disease, emphysema, bronchitis, and other lung diseases <2005WO2005056009>.
Cl
Cl
N
O
NH
CO2Na O
O
CH3
HO HO
Beraprost 163
O
CH3 OMe
164
N N CH3
593
594
Furans and their Benzo Derivatives: Applications
Compound 165 and its derivatives inhibit serine protease enzymes such as TF/factor VIIa and Xa (tissue factor) <2004USP0235852>. Benzofurans 166 and 167, which have transposed functional groups, are both TF/factor X inhibitors. Tissue factors are involved in the release of thrombin, so these compounds are applied to the treatment of clotting disorders <2003WO03082847, 2005JPP2005120080>. Diarylbenzofuran 168 is used to inhibit bone loss <1996USP5489587>. NH 2
HN NH O NH
O 2S
O
OH
OMe O
165
H2N N
NMe 2
O
O
R O
HN
X
NH O
O
Y
O
166
O
HO Ar
168
167
Y = amino, cycloalkyl, or heterocyclyl
X = H, halogen
R = amino, aminoalkyl Ar = Ph, Pyridyl
In the treatment of diabetes and related blood sugar diseases, many benzofuran compounds find application. Sulfone 169 is a new and very potent inhibitor of aldose reductase, discovered during a Pfizer library screen. Inhibition of aldose reductase prevents the buildup of sorbitol from glucose which can lead to retinal and nerve disease, common complications associated with diabetes <2005JME6326>. Amide 170 has been patented for the treatment of medical conditions mediated by glucokinase. Overactivity of glucokinase leads to dangerously low blood sugar levels <2004WO2004046139>. Benzofuran glucopyranoside 171 was isolated from the heartwood of Pterocarpus marsupium, the Indian kino tree. A herbal remedy uses extracts of this for the treatment of diabetes <2003WO03087093>. Carboxylic acids 172 and 173 have both been patented for use as antidiabetic agents. The latter is also purported to have application in the treatment of obesity, hyperlipidemia, and cardiovascular diseases <2005FRP2862646, 2004WO2004011446>. Bibenzofuran 174 and other biaryl compounds are treatments for insulin resistance and hyperglycemia <2002USP6444670, 1996IJB1304>. HO
R H Cl
O S O
H N
N N O N
O
169
O O
O
170 R = alkyl, alkoxy, heterocyclyl
171
OH
O HO
OH
OH CO2 H
CO2 H CO2 R O
O
N
172 R = H, alkyl, aryl
O
O
O
173
Ar O OH
174
OH
Furans and their Benzo Derivatives: Applications
The potentially beneficial properties of antioxidants have been a common subject in the popular press. Such compounds have the ability to eliminate toxic free radical species in living systems. Antioxidants are claimed to have cytoprotective properties in the inhibition of cancer, heart disease, and various skin disorders, and are often simply labeled as antiaging. There is a host of benzofuran examples in the recent literature that find application in all of these areas as potential pharmaceuticals, cosmetics, and polymer stabilizers. Ketone 175 is an example of a naturally occurring antioxidant isolated from Pandanus odoratissimus, the screw pine of Southeast Asia <1998P2145>. Phenolic benzofuran 176, isolated from various yeasts, has also demonstrated antioxidant activity. A report has appeared in which benzofuran 176, and several acyclic analogues 177, are synthesized by Pd-coupling reactions. Antioxidant activity was evaluated using guinea pig liver microsomes <1999BML1029>. Hydroxybenzofurans 178 <2003WO03066618> and 179 <2003WO03066618, 2003USP6653346> and substituted variants are examples of compounds that have been patented as cytoprotective agents for the treatment of skin disorders, ischemia, inflammation and cardiac diseases. Compounds with the general structure 180 inhibit glycation, a process associated with the development of atherosclerotic plaque. These examples are patented for use in cosmetics that alleviate the signs of aging in skin and hair <2001FRP2833165>. Compound 181 is an analogue of the ubiquitous antioxidant butylated hydroxyanisole (BHA). Like the many examples above, it has also been patented for therapeutic use in the treatment of ischemic diseases such as arteriosclerosis and myocardial infarction <1996USP5574178>. MeO
MeO
O
OH
R
Ar
O
O
O O
177
176
Ar = Ph, 4-subst. Ph, 2-furyl, 2-thiophenyl
R = H, Me, OMe
HO
HO O
178
O
HO
O
HO
175
HO
HO
O
H3C
But
OR O
CH 3
O
But
180
179
181
R = H, alkyl, COR
The following represents a miscellanea of biological activity associated with particular benzofuran derivatives. Benzofuran 182 modulates vitamin D receptor (VDR) for the treatment of bone disease and psoriasis <2005WO2005051938>. The N-hydroxy amides 183 have been developed for the treatment of multiple sclerosis <2002DEP10103506>. Carbamates such as derivatives 184, with a wide variety of R groups, are cannabinoid receptor modulators for the treatment of various CNS disorders <2005WO2005000829>. Pyridazine-subsituted benzofuran 185 inhibits tumor necrosis factor alpha (TNF-). Such compounds are frequently used as antiinflammatories in the treatment of arthritis <2004WO2004078751>. Compound 186 is an inhibitor of STAT6 (signal transducer and activator of transcription protein 6) applied to the treatment of allergic diseases <2004USP6797711>. Benzofuran and 2,3-dihydrobenzofuran derivatives 187 are 3-adrenoreceptor agonists which are useful in the treatment of obesity <2004USP6780859>. O R R1
HO
N
NH 2 R
O O
182 R, R1 = alkyl or fluoroalkyl
H N
(CH2)n
183 R = alkyl or N-alkyl n = 1–4
O
OR O
184
O R
N
N
185 R = alkyl, alkenyl
O
595
596
Furans and their Benzo Derivatives: Applications
R Ph
OH
H N
N N
Ph O
Ar
O
O
187
186
R = alkyl
The diarylbenzofurans 188 are associated with the inhibition of steroid 17-hydroxylase and steroid C17/20 lyase. These processes are part of the biosynthesis of androgen, and blocking this process may help patients with hormonedependent breast and prostate cancers <2004USP6689798>. Benzofurylpyrone derivatives, such as 189, have been developed for the treatment of hypertriglyceridemia and artereosclerosis <2003USP6589984>. Azide 190 is a Ca2þ chelator that has been incorporated into rat fibroblasts. Photolysis of the azide functional group greatly reduces the binding affinity for the calcium ion leading to a rapid increase in the intracellular Ca2þ concentration. This process is used to mimic related cellular responses associated with nerve and muscle cells <1996USP5552555>. Hydroxybenzofurans 191 are estrogenic agents with possible contraceptive use <2003WO03051860>. Compounds 192 are examples that inhibits smooth muscle cell proliferation for use in the treatment of endometriosis and uterine fibroid disease <1996USP5523309>. Benzofurans 193, in which the 2,3-dihydrobenzofuran ring is tethered to a guanidine, have vasoconstrictor activity <1997USP5703115>. A series of compounds based on hydroxybenzofurans 194 have been patented for the prevention or treatment of respiratory diseases <2004WO03082264>. Pyrollidine alcohol examples 195 and 196 activate the contraction of smooth muscle tissue <2000FRP2781799, 2000FRP2781800>. Py
OH
Ar O
O
188
O O
189
Py = 2-, 3-, or 4-pyridyl
N3 O
O
HO N
OH O
NR 2
O
R2N
O
190
CO 2 Et
R
R = CH2CO2Et O
R
191
R = alkoxy or cyanoalkyl R2N
NMe 2
H N
193
192
R = H, C1–C6 alkyl
R = OH, alkyl, aryl
O
HO
NR
N H
O
R
R
RO R1
R
O
R
O
O
194 R = H, acyl R1 = H, CO2H
N
HOH2 C
195 R = alkyl
N
OH
196 R = alkyl
Compounds such as 197 and 198 are serotonin agonists <2001WO0109122>. Two unusual natural products were isolated from an Australian sponge (Ianthella). Iantheran A 199 and a (Z,E)-stereoisomer showed nonspecific activity as Na,K-ATPase inhibitors <2001BMC179>. Bisamidino bis(benzofuran) 200 inhibits NHE-3, which is involved in sodium/proton exchange <2001WO0172742>. Compound 201 is a metalloprotease inhibitor <2002EPP1217002>.
Furans and their Benzo Derivatives: Applications
H N
OH
Br
H N
O
Br SO3Na
N Br
NaO3S O
O
197 NH2
HOHN
O
O N
NH
O
200
Br
199
198
HN
O
HO
O2 S N O
H2N
201
O
Spiro compounds 202 and 203 are antagonists of the mineralocorticoid receptor. This limits the production of excess aldosterone, which, in turn, leads to increased sodium uptake and potassium loss. This condition, known as Conn’s syndrome, is associated with hypertension <2005WO2005110992>. Amine 204 is a seratonergic 5-HY5-HT2 agonist for the treatment of glaucoma <2003WO03051352>. R1 R2
CF3
O
Cy
O
R1 R2
N O
HO
N
Cy
O O
202
203 NH 2
Cy = cycloalkyl
204 Prucalopride 205 is a new drug developed by Janssen for the treatment of irritable bowl syndrome and constipation (an issue euphemistically referred to as ‘colonic transit’) <2004AUP770580B>. It is a very specific serotonin (5-HT4) receptor agonist and its effectiveness has been demonstrated in animal <2003MI2065> and human systems <2002MI1347>. NH2 Cl O O
N
H
N CH2CH 2 CH2 OCH3 Prucalopride
205
3.08.3.2 Cosmetics, Perfumes, and Essential Oils In the area of cosmetics, benzofurans figure in three principal areas. Hydroxybenzofurans are common components in cosmetics due to their antioxidant and cytoprotective properties (discussed in Section 3.08.3.1). There are many
597
598
Furans and their Benzo Derivatives: Applications
allusions in the patent literature as to the antiaging properties of these formulations. Two other areas of application are in formulations for skin depigmentation and in UV absorbers for suncreens. Several benzofurans such as 206 <2003FRP2830443> and compounds based on the structure 207 are used for skin depigmentation <1998USP5730962>. One patent covers derivatives of moracin M for this application <2003FRP2833259>. Moracin M, 208, is a natural product isolated from mulberry trees <1992MI308-47>. Moracin M and related compounds also have antifungal and cyclooxygenase inhibitory activity <2002JNP163>.
OH R HO OH
HO
R
O
206
O
HO
O
OH
208
207
Moracin M
R = H, alkyl
Benzofuran 209 is another example of a bleaching agent <2005JPP2005306792>. Cosmetic compositions containing lactone 210 and anhydrides 211 and 212 have been patented as inhibitors of melanin production for the treatment of dyspigmentation <2004JPP2004238309>.
R
O
Bu OMe
R
O OMe
O
O O
O
O O
R
O
OMe
209
O
210
R
O
212
O
211 R = H, C1–C6 alkyl, alkoxy, or halogen
Benzofuran 213 has been patented for use as a UV absorber in cosmetics and as a UV stabilizer in plastics <1997USP5665334>. A wide range of 3-substituted phthalides, for example, 214, and 3-alkylidene phthalides 215, are used in dermatological formulations to protect dibenzoylmethane compounds in the compositions from UV radiation <2003FRP2827509>.
O
R
O
O O
NH R
1
O
(CH2CH2)n OH
O
O
213 R = H, Me, Et R1 = H, OH, OR n = 1,2
CN
214
N(Bu) 2
215
R
R = NMePh, NNCOPh, Pr, CH=CHPh
Synthetic benzofurans have been developed as perfumery additives and many naturally occurring benzofurans are associated with fragrances and spices. One patent gives the preparations of a series of over 30 very simple acylbenzofurans and their 2,3-dihydroderivatives 216. Also presented are the aromas associated with each compound. Example 217, for instance, has a ‘‘flowery, orange blossom scent’’ while t-butyl ketone 218 has an ‘‘almond, honey’’ smell <1998USP5972878>. Several novel sesquiterpene compounds, such as hexahydroisobenzofurans 219 and 220, have been developed for use as perfume or flavoring components <2004USP0192577>.
Furans and their Benzo Derivatives: Applications
R2 R3
O O
R
O
1
O
216
O
Me
R1 = H, Et, Me, But, alkenyl R2 = H, Me, Et R3 = H, OMe
218
O
219
Bu t
O
217
O
220
Pseudoesters, for example, 221, in which the alcohol portion is a fragrance (such as geraniol), have been developed for the slow release of scent. Alkaline hydrolysis of compound 221 requires time so that the rate at which scent is released is prolonged over that of simple evaporation <2001J(P2)438>. A similar approach involves the preparation of acyclic esters 222 and 223 from phthalide 224 and phthalic anhydride 225, respectively. In this case, the slow release of fragrance is the result of an intramolecular transesterification processes <2003USP20030148901>. O
O
O
O
O
OH
222
224
O
O
O H O
O
O
H
221 225
O
223
O
Phthalides often make up a significant amount of the volatile compounds isolated from a variety of plant sources. There is a significant interest in many such compounds as Western society pays more attention to Asian herbal lore. A very common example is sedanolide 226. It is a major component of celery seed but is also found in many other plants. It has been evaluated for its cytoprotective properties <2001MI233>. Sedanolide is also extracted from the Korean medicinal plant and spice cheongung (Cnidium officinale) along with phthalides 227–230. Butyl phthalide 227 was the major component of this extract <2004MI603>. Another analysis of the same extract found 3-isobutylidene phthalide 230 to be a component. This plant is a traditional remedy for the treatment of genital inflammatory diseases in women <2002MI49>. Butylidene phthalide has also been found in the essential oil of Glaucosciadium cordifolium, a flowering plant found in Turkey <2000MI45>. O
O O
O Bu Sedanolide
O O
Bu
227
O
O
O
O
Pr
228
229
230
226 The enantioselective synthesis of phthalide 227 (the (S)-isomer), and other substituted phthalides, and the determination of their absolute configuration has been reported <2005CH218>. In a different approach to the same compounds, 2-alkylbenzoic acids were fed to microorganisms known to affect asymmetric hydroxylation. Lactonization of the resulting alcohols yielded the phthalides, used as scents in cosmetics and soaps <1997JPP10243794>. There is sufficient interest in these optically pure compounds for a chiral gas chromatography (GC) stationary phase to have been developed to quantify stereoisomeric mixtures. A silylated -CD was employed
599
600
Furans and their Benzo Derivatives: Applications
and the enantiomeric distributions of phthalides in celery, celeriac, celery seed, and fennel extracts were determined <1997JFA4554>. Lactone 231 was one of the 58 components identified in the volatile oil extracted from Dysosma versipellis, a Chinese plant in therapeutic use <2004MI143>. Tetrahydrobenzofuran 232 was isolated from the rhizome of Curcuma zedoaria Rosc., a herb found in East Asia <2004MI9>. The tropical plant Ageratum conyzoides L., Asteraceae, found in Central America, is a widely used medicinal plant which also has insecticidal properties. The benzofuran 233 is one of the components of its essential oil <1998P1385>. O MeO O O
O
MeO
232
231
233
3.08.3.3 Pesticides The rocaglamides 154–156 were discussed previously for their antibacterial properties (Section 3.08.3.1), but these compounds also have insecticidal properties. Four rocaglamides were isolated from Aglaie oligophylla including a new example 234, bearing a pyrrolidine amide <2001JNP415>. Two other rocaglamides (235 and a novel bridged example 236) were similarly isolated and their absolute configurations established <2003JNP80>. The insecticidal properties of these compounds were evaluated against Spodoptera littoralis. Bridged example 236 proved to be the only inactive compound. A survey of the rocaglamides, their structures, and biological activities was published in 2001 <2001COR923>. O HN O
O MeO
MeO N
O
HO
NH 2
HO
O
HO
O
HO
MeO
NH 2
O
O O
O O
O
O
O O
HO OMe
MeO
234
OMe
MeO
OMe
235
236
An extract of Angelica acutiloba was assayed for insecticidal activity against the larvae of Drosophila melanogaster. From the active portions were isolated two phthalides, (Z)-butylidene phthalide 228, (Z)-ligustilide 237, and two psoralens, xanthotoxin 238 and isopimpinellin 239. Phthalide 228 had the greatest activity. Structure–activity relationships suggested that the aromatic ring was critical. Inhibition of acetylcholinesterase was determined to be the mechanism of action <2004JFA4401>. O
OMe
O
O
O O Pr
Pr
O
(Z )-Butylidenephthalide
(Z )-Ligustilide
OMe Xanthotoxin 3
228
237
238
O
O
O
OMe Isopimpinellin 4
239
O
Bishydrazide 240 is an insecticide used to combat Lepidoptera, presumably moths <1996JPP8231528>. A series of amides of benzofuran-2-carboxylic acid were evaluated for activity against the fearsome sweet potato weevil. The
Furans and their Benzo Derivatives: Applications
most potent example, 241, was equivalent in activity to the insecticide dimethoate <1998MI241>. Ketones 242 and 243 inhibited the larval growth of yellow mealworms. The mealworm beetle is a pest that infests stored grain <1998JNP1209>.
H N
Ph O
N N
O N H
O
MeO
O
O
241
240
O
OH
O O
O
242
243
The synthesis of a series of antifungal compounds 244 that have moderate activity against strains of Candida has appeared. Candida is a yeast that is responsible for human infections, such as thrush <2003MI2002>. Nitrile 245 has been patented as a treatment for rice blast (Magnaporthe grisea). Rice blast is a fungus that constantly threatens the Asian food supply <2001JPP13113>. A series of three diacetylbenzofurans, namely the 2,4-isomer 246 and its 2,3and 2,7-isomers, exhibited antibacterial and antifungal activity (referenced against nystatin and amphotericin B). Structure–activity relationships indicated that the 3-acetyl group is important for greatest activity <2005BMC4796>. O O
R
CH3
H
N O O O
NH
O
O
CN
O
H
246
245
R1
244
R = Me or Ph R1 = H, Cl, OCH3
Benzofurans 247 <2002USP6352958> and 248, both of which bear pyrimidinedione groups, are pre- and postemergent herbicides. The second is reported to have application to broad-leaved weeds, cyperaceous weeds, and the protection of rice crops <2000USP6130187>. Phytotoxic compound 249, isolated from the South American plant Trichocline reptans, was effective in inhibiting the growth of Chenopodum album (the weed known as common lambquarters) but less so against Sorghum halepense (Johnson grass) <2000MOL435>. Cl X R O O
O
N
O
F O
N
HO
O O
NH H 3C CF3
247 X = H, halogen, CN, NO2, NH2
N
O CF3
248 R = H, alkyl, haloalkyl, or hydroxyalkyl
249
601
602
Furans and their Benzo Derivatives: Applications
Two promising herbicides, KIH-2031 250 and KIH-6127 251, were developed by Kumiai for the treatment of cotton and rice, respectively. Based on these structures, six new phthalide derivatives (252–254: X ¼ O, S) were prepared as potential herbicides. Of these, compound 252 (X ¼ O) was found to be very effective in combating Echinochloa, the largest weed problem affecting rice paddies. Under the trade name PyriftalidTM, this compound was registered for use in 2001 by Syngenta. It is combined with cinosulfuron and marketed under the name APIRO Ace GR as a broad-spectrum herbicide <2001MI205>.
MeO
OMe
OMe
N
N
N
S
MeO
N
S
CO2 Na
CO2Na
KIH-2031
KIH-6127 Cl
250
OMe
OMe
OMe
N
N MeO
COCH 3
251
N
N
MeO
X
N X
O
O
MeO
N
X
O
O
O
O
OMe H3C Pyriftalid
R
253
252
254 X = O, S
3.08.3.4 Dyes, Fluorescers, and Electroluminescent Compounds Both benzo[b]- and benzo[c]furans have important luminescent and electroluminescent properties. Hexaphenylisobenzofuran 255 has been incorporated into an organic light-emitting diode device, spin-coated into a host polymer. It is able to transport electrons and electron holes but is better in the former application <2002SM247>. A patent has appeared for electroluminescent devices that contain a metal complex of pyridylsubstituted benzofurans based on isomers 256 and 257: the metals employed were Ir, Pt, Rh, and Pd. Different ligands are included in the patent but the benzofuran complexes were more efficient and longer-lived <2005USP2005027123>. Aminoarylbenzofurans such as compounds 258 and 259 are used as dopants in an electroluminescent device. They are blue light emitters <2004USP6828044>. Ph
Ph
Ph O
O
Ph Ph
Ph
N
256
O
N
257
255 H H N Ar N O
O
258
NR2 O
259
Furans and their Benzo Derivatives: Applications
Benzofuran trimers 260 and 261 were prepared to explore their electroluminescent properties. These two examples had different electronic properties by virtue of trimer 260 being through-conjugated and 261 being cross-conjugated. As expected, the through-conjugated trimer 260 had its absorption and emission spectra red-shifted by 50 nm. Solubility, aggregation, and film-forming properties were modulated by n-hexyl or t-butyl substitution. When incorporated into devices, the t-butyl-substituted example exhibited blue emission. While the authors found the electroluminescence results disappointing, this work predicts the impact of connectivity on potential polymeric versions <2004CEJ518>. O O O
O
O
260
O
261 Many benzofuran-2-ones find application as dyes. For example, styryl analogues based on compound 262 were developed as a polymer colorant <2000WO0053597>. Compounds 263 and 264 are among several stereoisomeric compounds that are patented as dyes <2000WO0024736>. Dibenzofuran 265 is a photochromic compound for use as an ink or in plastic films <2001CNP1328109>.
O
O
O
O
O
O NH
N H
O O
262
O O
263
O
O
Ar
264
265 1
Ar
Ar, Ar 1 = Ph, heteroaryl
Phthalides 266 and 267 are color formers and fluorescent brighteners for thermographic papers <1996EPP0709226>, and hydrazone 268 is an electrophotographic photoreceptor <2000JPP2000143654>. Compounds based on benzofurans 269 and 270 are charge-transporting agents used to improve the photosensitivity of a photoreceptor <2001USP6210847>. A series of fluorescers based on naphthalamide 271 (R ¼ Prn, Bun, n-hexyl, (CH2)3OCH3) were prepared by Pd cross-coupling reactions and their emission spectral properties and quantum yields determined. Substituents on the benzofuran could be use to tune the emission spectra <2005DP27>. O
O O CH3
Me 2N
Me
O
O
O
NH Ph
OH
N
266
N N Me
HN O
Me
Me
268
267
O NR
R 2N O
269
N
NR12
Ar2 N O
270
NR 2
O
O
271
Sodium-binding benzofuran isophthalate (SBFI) 272 is a fluorescent indicator developed to measure intracellular Naþ concentrations <1989JBC19449>. Its structure incorporates a diaza crown ether portion for cation binding and
603
604
Furans and their Benzo Derivatives: Applications
two pendant benzofuran moieties. At higher Naþ concentrations the emission efficiency at two excitation wavelengths changes, allowing for quantitation via ratio fluorimetry. The sodium gradient between cellular and extracellular material is involved in nutrient uptake, epithelial transport, and the transmission of electrical impulses. A recent paper describes an in situ calibration technique that corrects for spectral shifts in cytosol not accounted for by in vitro calibration methods <2001MI1623>. O
O –
–
O2 C
N
O
O 2C CO2–
O
N O MeO
CO2–
OMe
272 Potassium-binding benzofuran isophthalate (PBFI) 273 is a comparable fluorescer that incorporates a larger aza crown for complexing potassium ions. The tetraammonium salt of PBFI was used to examine the influence of potassium nutrition on apoplastic Kþ in situ by fluorescence imaging of the leaves of Vicia faba (a broad bean) <1997MI1609>. –
–
O2 C O
O CO2–
O
N OMe
CO2–
O2C O
N O
O
MeO
273 Fluorescence probes for the Zn2þ cation 274 and 275 have recently been developed. Their structures are also based on the benzofuran fluorescer but with a pendant polyamine ligand. The operating principle is the same as for SBFI and PBFI. These examples are reported to have high sensitivity and good membrane permeability. Interference by other commonly bioavailable cations, Ca2þ, Mg2þ, Naþ, and Kþ, was not a problem. The Cd2þ cation was found to interfere and Cu2þ and Co2þ quenched the benzofuran fluorescence, but since these ions are generally found at low concentrations in biological systems this does not limit the potential utility of this analytical tool <2002JA10650, 2002WO02102795>. N MeO N
N Ar
N H
Ar =
O
O
N
CO2H
274
CO2H
275
3.08.3.5 Polymers and Polymer Additives Phthalides and phthalic anhydrides are extremely common components in a huge variety of polymers, and are prepared using many chemical processes. There are over 1300 references to polymers derived from phthalic anhydrides in the Registry File of Chemical Abstracts. Phthalic anhydride itself is used in polyester resins but there are also many examples of polyimides that are derived from related anhydrides. In this section, a few examples representing a range of structure and polymerization process are presented.
Furans and their Benzo Derivatives: Applications
Chlorophthalide 276 polymerized using a Friedel–Crafts reaction gives polymer 277, an example of a poly(arylenephthalide). In this example, a ‘novel rearrangement’ was observed during the polymerization which led to a scrambling of the chloro substituent’s position <1995MM7325>. This actually appears to be a Hayashi rearrangement, discovered in 1927. Cl O
O O
O
HCl
O
Cl *
276
Cl
O
Cl
n
277
m
Fluorinated bis(anhydride) 278 was used to prepare polyimide 279. Polymer 279 was used in a new copolymer formulation in which methyl methacrylate (MMA) containing dissolved polyimide was subjected to free radical polymerization. The resulting polymers were found to have improved solubility and good heat resistance. Also employed as a copolymer was poly(diphenylene phthalide) 280 <2001MI317>. O Br O
CF3
O n
O
O
CF3
O O
278
Br
O
280 O
F3C
O
F3C
CF 3
O
O
CF3
N
N
CF3
N N
CF3
O
O O O
279 Diaryl phthalides, particularly phenolphthalein 281 and several phthalides derived from it, are widely used for the preparation of ‘cardo’ polymers. The term is derived from the latin word for hinge or pivot, which is an apt name given that the aryl substituents are hinged on the C-3 carbon of the phthalide. In one application, compound 281 was used to prepare phthalamide 282 and both bisphenols were copolymerized with terephthaloyl chloride 283 to form polyesters. These formed strong flexible films with improved thermal stability and solubility <1997PSA3227>. O
O CH3
O
N COCl
ClOC
283
OH HO
OH HO
281
282
Usually, phenolphthalein-derived polymers are polymerized through the hydroxyl groups, thus destroying their wellknown indicator properties. There is one example in which phenolphthalein and o-cresolphthalein 284 have been polymerized with formaldehyde to form phenol/formaldehyde type polymers, for example, 285. These polymers retain the indicating properties of the monomers with potential application in pH test strips and optical pH sensors <2005PSA1019>.
605
606
Furans and their Benzo Derivatives: Applications
O
O O
O
CH2O
H2 C n
*
OH
OH HO
HO
285
284
Five poly(arylene phthalide ketones) including 286 and 287 were used to modify electrodes for the voltammetric determination of nitroaromatic mixtures. This has potential applications in the area of explosives detection <2005MI508>.
O
O
O
O O
O
n
O O
286
O O
O
O n
O
287
O O
A series of novel polyimides were prepared from diaminophthalide 288 and four anhydrides 289 for the investigation of water-permeable membranes. Of the polymer products 290, the best permeability was associated with bulky groups (trifluoromethyls) on the polyimide chains <2005JAPS2047>. There are other variants of diaminophthalide 288 used to prepare polyimides and polyamides. A fluorinated variation 291 has been used for polyimide synthesis <2004MI979> as has 292, derived from o-cresolphthalein 284 <1999PSA455>. O O
O X
O O
O
NH2
H2N
O
O
O
289
288
X = O, SO2 , C(CF3 ) 2 , or direct bond
O
O X
O
O
O
N
N
*
* O O O
290
O X = O, SO 2 , C(CF3 ) 2 , or direct bond
n
Furans and their Benzo Derivatives: Applications
O O O O H2 N
H2 N
291
CF3
Me
Me
NH2
O
O
NH2
O
O
F3C
292
Diarylphthalide 288 was incorporated into polyimide copolymers 293 upon polymerization with 1,4,5,8-naphthalene tetracarboxylic dianhydride and seven different diaminoarenes, all of them variants of phenyl ethers. Six-membered ring imides have several advantages over their phthalimide counterparts but suffer from poor solubility properties. Incorporation of the phthalide structure enhanced solubility and the polymers could be cast into films with good mechanical and thermal stablility <2006PSA940>. Diamine 288 has also been used to prepare a poly(ureaimide) by reaction with the bis(isocyanate) 294 and three anhydrides 289 (X ¼ SO2), ketone 295, and pyromellitic dianhydride 296 <1999JAP1719>. O
O *
O
O
N
N Ar
O
O
O
O N
N
O
O
O
293
* n
O
O
O O
NCO
OCN
O
294
O
O
295
O
O
O
O
O
O
O
296
Fluorinated phthalide 297 has been used to prepare polyketones such as 298, by polymerization with bisphenol A 299. This example has a glass transition temperature of 215 C and forms strong transparent films. Remarkably, this is a polymerization based on an aromatic substitution reaction (SN2Ar) <1997MC210>. O
O
CH 3
F
F
HO
OH CH 3
O
299
O
297 O
O
CH3 O
O CH3
O
n
O
298 Blends of poly(ether sulfone) 300 with the poly(hydroxyether) of bisphenol A proved to be quite homogenous and had better thermal stability, though phase separations occurred at higher temperatures <2003PLM867>. As a
607
608
Furans and their Benzo Derivatives: Applications
copolymer with 1,1-dichloro-2,2-bis(4-hydroxyphenyl)ethylene, 300 formed polymers with high impact strength and good thermal properties <2001JMA4479>. O
O2 S
O
n
O O
300 Bisimide 301, derived from compound 288, was used to prepare an alternating (as opposed to block) poly(esterimide) by reaction with bisphenol A. Such polymers have better solubility properties than pure poly(imide)s <2000PSA1090>. O
O
O
O
CO 2 H
N
N HO 2 C O
O
O
O
301 The benzofuro-benzofuran structure 302 is easily prepared by the reaction of glyoxal and phenol. Substituted phenols are readily available and give substituted versions of compound 302. Such difunctional examples are suited to the preparation of many types of polymers and a review of this area has appeared <2002MI1086>. Dialdehyde 303, prepared by the oxidation of the dimethyl precursor, was reacted with diamine 304 to produce the polyimide 305 (Equation 2) <2003MI43>. In an unusual polymerization approach, dialdehyde 303 was polymerized with bis(cyanoacetate) 306 (n ¼ 2 or 4) in a Knoevenagel polycondensation giving polymer 307 (Equation 3) <2001JAPS505>.
O
O
302 OHC
CHO
* H2N
O
N H
N
O
O
O
(CH 2 )n
306
O
O
305
O
O CN
* n
ð2Þ
303
303 + NC
N
NH2
304
O
N H
DMAP/ THF *
O H
H
O(CH2)n O * n
NC
CN
O
ð3Þ
O
307 Bis(anhydride) 308 was employed to prepare eight different polyimides, such as 309, using various diaminoarenes (Equation 4). The preparation of precursor 308 involves permanganate oxidation of four methyl groups. Note that in
Furans and their Benzo Derivatives: Applications
this oxidation a dehydrogenation of the central ring fusion also takes place <2004MI1629>. Polymer 311 is one example of many copoly(ester-amide)s prepared by the reaction of diacids such as 310 with nine different aryl diamines (Equation 5). The interest here was to form a polymer combining the thermal stability and strength of a polyamide with the desirable solubility characteristics of a polyester. Note that the copolymer formed in this approach has regularly alternating amide and ester functional groups <2004MI2783>. O
O
O
O
O
H2N Ar NH2
O
O
*
ð4Þ
O
O
O
O
309
308 O
O
O
HO2C
Ar
N
n
O O
O
N
*
CO2H
O
O
O
311 H2N Ar NH2
ð5Þ
O
O
O
O
*
O O HN Ar NH
* n
O
O
310 An interesting paper describes the preparation of oligomeric phthalocyanine molecules using a Diels–Alder reaction, the long-range goal being the preparation of conducting polymers. Compound 312, containing two 1,4epoxynapthalene units, was prepared by indole cyclization. This intermediate acts as the dienophile component and is also elaborated into the diene component. Reaction of compound 312 with tetraphenylcyclopentadiene followed by thermolysis gives the bis(isobenzofuran) 313, which is trapped in situ by 312 to give the monster trimeric phthalocyanine 314 (Scheme 2). Since each end of trimer 314 retains a 1,4-epoxide, further Diels–Alder polymerization is easily conceivable <2000EJO303>. In a similar fashion, the Ni complex 315 was polymerized with p-benzoquinone to give polymer 316 (Equation 6) <1997SM439>.
OBu O
N OBu
OBu
N Ni N
O
N
O OBu
O
ð6Þ OBu
315 *
O
N
*
OBu
N Ni
O * O
N
* OBu
N
OBu
316
O
n
609
O2N
O2 N
O Ph
Ph
i, OBu O
OBu
N H N
OBu
Ph
ii, heat
O
N H N
OBu
Ph
O
OBu
N
O2N
N OBu
OBu N
H N
NO2
OBu O
OBu
O
O2N
N OBu
OBu
N H N H N
NO2
314 Scheme 2
OBu
313
O2N
N H
O
NO2
312
O
N H N
OBu
NO 2
OBu
OBu
N H
OBu O
OBu
O
N OBu
OBu
N H
O
N H N
NO2
OBu
Furans and their Benzo Derivatives: Applications
Novel polymers have been prepared by the Diels–Alder reaction of two bis(isobenzofuran)s and a series of bis(acetylene) imides. Bis(isobenzofuran) 317 was prepared from phenylphthalide precursors. Two varieties of bis(acetylene)s 318 and 319 were prepared by the reaction of various aromatic anhydrides with amine 320 (Equation 7) or by the reactions of various diamines 321 with 4-phenylethynylphthalic anhydride 322 (Equation 8). One example of the polymers formed is 323 (Equation 9) <2000MI299>. Ph
Ph X
O
O
Ph
Ph
X = direct bond, O
317 O
O
Ph O
NH2
Ar
O
O Ar = O
O
O
O
320 ð7Þ O
Ph O
N
O
Ar
O
Ph O
N O
O
O
318 Ph
Ph
O O
O
N Ar N
H2N Ar NH2
321 322
O
O
Ar =
O
319
Ph
319 317
Ph
O
N Ar N
X O
ð8Þ
O
O
O
Ph
Ph
O
O
O
O
n
ð9Þ
Ph Ph
Ph
323 There are a few examples of polymers based on vinylbenzofurans. Vinyldibenzofuran 324 has been patented for use in copolymer formulations with other vinyl arenes, used to prepare light-emitting devices <2004USP6803124>. Benzofuran 325 was developed as one of four polymerizable monomers that contain a built-in antioxidant. The polymerization process was transition metal catalyzed <2003MM8346>. Benzofuran 326 also contains the styrene substructure, but there are few examples of its polymerization. Poly(2,3-benzofuran) films were synthesized by anodic oxidation on stainless steel in the presence of boron trifluoride etherate. The films had good thermal stability and conductivity of 102 S cm1 <2005MI1654>.
611
612
Furans and their Benzo Derivatives: Applications
HO O
O
O
326
324
325
In the area of polymer additives, Ciba Geigy’s Irganox HP-136 327 is produced as a 9:1 mixture of isomers. Irganox is a widely used nonphenolic phthalide which acts as a radical scavenger that often works in concert with other antioxidants such as IRGAFOS, a phosphorus-based compound <2002MI489>. A report has appeared that describes its physical behavior in polypropylene <2002MI263>. There are many patents that describe antioxidants based on hundreds of the variably substituted lactone that is the core of Irganox HP-136. They are applied to the phenol-free stabilization of polyolefin fibers <2003USP6521681>, polycarbonates <2000USP6310220>, and as stabilizers and antiozonants for elastomers <2000USP6140397>.
t-Bu
t-Bu O
O
O
O
t-Bu
t-Bu
Irganox HP-136
327 In other applications, phthalides 328–330 were added to the polymerization of MMA and styrene in an effort to add thermostability to the favorable properties of the vinyl polymers. The examples with Cl directly attached to the phthalide ring were found to act principally as chain-transfer agents. Nonhalogenated compounds participated in chain-transfer and initiation processes <2001MI37>. Aryl phthalides 331–333 have been employed as stabilizers for the processing of polymers to limit chain cleavage and oxidation <2001WO132762>. O
O
O
O
O
O
Cl Cl
328
O
Cl
329
Ph O
O
O
O
O
331
O
O X
O Ph
330
332
O
O
O
333 X = O, S
3.08.3.6 Miscellaneous Applications Phthalic anhydride 225 has been used in the environmental analysis of alcohol ethoxylates, which are widely found surfactants. Samples are derivatized with phthalic anhydride converting the ethoxylates into phthalate half-esters. Under analysis by electrospray LCMS, the derivatized alcohols gave stronger signals with less background in the negative ion spectra <2005JCH39>.
Furans and their Benzo Derivatives: Applications
O O O
225
In a chemically similar application, phthalic anhydride was reacted with the naturally occurring polymer chitosan, a polyaminosugar. Reaction with the amino groups gave a polymer with half phthalamide residues. This substance shows promise as a matrix for colon-specific, orally administered drugs which must survive the acidic conditions of the stomach <1999MI103>. Due to its high reactivity in Diels–Alder reactions and the crystallinity of its adducts, the commercially available 1,3diphenylisobenzofuran 334 is often the reagent of choice for trapping and characterizing reactive, transient alkenes. There are over 40 adducts of 334 in the Cambridge Crystallographic Database. Two recent examples are cyclopropene 335 <1998ZOB1830> and strained amide 336, which give the adducts 337 and 338, respectively <1999TL443>. Ph Ph O
N
O
O Ph
Ph
335
334
Ph
O
N O
H3 C
Ph
336
H3 C
338
337 Isobenzofuran 327 is also used to quantitatively measure the rate of singlet oxygen generation in biological systems by UV spectroscopy. For example, it was used to investigate the kinetics of singlet oxygen generation by the photosensitizer hypericin when bound to liposomes <1998MI135>. Naphthodifuran 339 <2003JOC8373> was one of several isobenzofurans employed in the preparation of pimolecular switches (Scheme 3). Reaction of naphthodifuran 339 with 2 equiv of dimethyldihydropyryne 340 (both
But
i, But
340 O ii, Fe2 (CO)9
O
341 339
46 °C
But
hν
But But
But But
But 46 °C
343 But Scheme 3
But
342 But
But
613
614
Furans and their Benzo Derivatives: Applications
reactants generated in situ), followed by deoxygenation, gave chrysene 341. The p system of 341 is continuous, end to end. Photolysis of 341 results in the opening of the pyrene ends to metacyclophanediene 342 and the disruption of the ring current circuit. Thermal ring closure back to 341 takes place via intermediate 343. Thus, this molecule is a three-way pi-molecular switch with closed/closed, open/open, and open/closed switch states, two of which can be controlled thermally or photochemically.
3.08.4 Further Developments 3.08.4.1 Furans 3.08.4.1.1
Pharmaceuticals
Furan containing compounds 344–347 were obtained from a bioassay-directed isolation and purification of Amelanchier candensis <2006MIP308-26>. The isolated compounds were shown to inhibit lipid peroxidation by 85% at 100 ppm when compared to 89, 87, and 98% for the common antioxidants butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and tert-butylhydroxyquinone (TBHQ) at 1.67, 2.2, and 1.67 ppm, respectively. While not selective, some of the isolated compounds inhibited cyclooxygenase (COX)-1 and -2 enzymes.
3.08.4.1.2
Fossil fuels, derivatives, and related products
A furan containing resin has been used as an important component in a remedial method for controlling particulates within a petroleum reservoir <2007USP2007007010>. The process consists of placing an aqueous tackifying treatment fluid and a curable or non-curable polymer or resin into the unconsolidated zone of the reservoir, of which the furan resin is a constituent of the mixture.
3.08.4.1.3
Surface active agents and detergents
Diels–Alder adducts 348 and 349, formed upon reaction of a furan and a maleimide, resulted in the formation of surfactant molecules with the thermally labile Diels–Alder adduct connecting the polar and non-polar segments of the molecule <2006USP7022861>. The molecules each possess identical nonpolar dodecyl tail segments with differing polar headgroups. Anionic salt formation results in water solubility, and upon exposure to temperatures >60 C, a retro Diels–Alder reaction occurs, yielding hydrophilic and hydrophobic fragments. The formed aqueous solution subsequently loses all of its surface active behavior.
Furans and their Benzo Derivatives: Applications
3.08.4.1.4
Essential oils and cosmetics
The cosmetic use of furan 350 as an agent for promoting and/or inducing and/or stimulating the pigmentation of keratin materials and/or as an agent for preventing and/or limiting the depigmentation and/or bleaching of keratin materials, particularly of human keratin materials such as hair, has been described <2006WO2006136828>. At a concentration of 50 mM, 106 inhibited the activity of 15-hydroxyprostaglandin dehydrogenase by 80%. A hair lotion containing 350 makes it possible to prevent and/or reduce the canitites of the hair.
3.08.4.1.5
Agrochemical bioregulators
In a study on the feeding deterrent activity of substituted lactones, the furanones 351 and 352 were identified for their strong activity <2006MIP308-27>. Furanone 351 was the strongest antifeedant for L. decemlineata larvae and adults, and for the Colorado potato beetle, 352 was the antifeedant of choice.
3.08.4.2 Benzofurans 3.08.4.2.1
Pharmaceuticals
A review of coumarins, azacoumarins, and furocoumarins has recently appeared. It correlates structure and biological activity for examples investigated over the last decade <2006MIP308-85>. Benzofurotriazoles 353 were prepared and their activity in the inhibition of CYP26A1 evaluated in a MCF-7 cell assay. These compounds are analogues of the advanced pharmaceutical candidate liarozole, 354 <2006MIP308-86>. CYP26A1 catalyzes the metabolism of all-trans retenoic acid (ATRA) and is believed to be principally responsible for controlling the levels of this retenoid. Elevated levels of ATRA are used to treat hormone refractory prostate cancer and psoriasis. It is hoped that inhibition of CYP26A1 will limit the development of resistance to these retinoid treatments.
Sulfonamide 355 has been patented for its activity against the hepatitis C virus <2007USP7217730>. Analogues of oxazole substituted benzofuran 356 show high affinity for GABA A cc5 receptor binding sites <2007WO2007054444>. They have been patented as potential treatments for cognitive disorders.
615
616
Furans and their Benzo Derivatives: Applications
Aminobenzofuran 357 is a receptor agonist for 5-HT4, a potential therapeutic agent for the treatment of CNS, gastrointestinal, and neurological disorders <2007WO2007048643>. A host of analogues of the diarylpropane series, 358, are vitamin D receptor modulators. These compounds have the advantage of reduced hypercalcemic activity and show promise in the treatment of bone desease and psoriasis <2006USP20070106095>.
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Furans and their Benzo Derivatives: Applications
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Furans and their Benzo Derivatives: Applications
Biographical Sketch
Dr. Brian A. Keay was born in Toronto (1955) and received his Honors. B.Sc. Co-op (1979) in chemistry and Ph.D. (1983) in organic chemistry from the University of Waterloo working with Prof. R. Rodrigo. After a Natural Sciences and Engineering Research Council of Canada (NSERC) postdoctoral fellowship with Prof. E. Piers (1983–85, University of British Columbia), he joined the faculty at the University of Windsor as an assistant professor (1985). In 1989, he moved to the University of Calgary where he is now professor and head of the Department of Chemistry (since July 2002). He currently oversees a research group consisting of one PDF and seven graduate students. His research interests include the design and synthesis of asymmetric ligands for use as catalysts or substrate bound chiral auxiliaries with Lewis acids and transition metals, palladium-catalyzed polyene cyclizations, asymmetric intramolecular Diels–Alder reactions, and the synthesis of natural products.
J. Matthew Hopkins was born in Bridgewater, NS (1978), and received his B.Sc. (Honours) in chemistry from Acadia University in 2000. With postgraduate support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Alberta Informatics Core of Research Excellence (ICORE), he completed an M.Sc. (2003) in organic chemistry at the University of Calgary working under the supervision of Dr. Brian A. Keay. He is currently enrolled in the Ph.D. program at the University of Calgary, still under the supervision of Dr. Keay with support from both NSERC and the Alberta Ingenuity Fund (AIF). His doctoral research focuses on the construction of new bis-phosphine ligands and their application to asymmetric catalysis.
Furans and their Benzo Derivatives: Applications
Born and raised in Toronto, Dr. Peter W. Dibble obtained his Ph.D. working with James G. Smith and Russell Rodrigo at the University of Waterloo, Waterloo, Ontario. He did postdoctoral work with Carl Johnson at Wayne State University in Detroit. Dr. Dibble joined the faculty of the University of Lethbridge in 1990 and is now associate professor of chemistry. He has developed methodology for the preparation of a wide variety of isobenzofurans and most recently has been applying bis(isobenzofuran)s to the synthesis of unusual cyclophanes.
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3.09 Thiophenes and their Benzo Derivatives: Structure P. Molina, A. Arques, and I. Cartagena University of Murcia, Murcia, Spain ª 2008 Elsevier Ltd. All rights reserved. 3.09.1
Introduction
625
3.09.2
Theoretical Methods
628
3.09.2.1
General
628
3.09.2.2
The Role of d Orbitals on Sulfur
628
3.09.2.3
Total Energies
634
3.09.2.4
Charge Distribution
635
3.09.2.5
Dipole Moments
637
3.09.2.6
Orbital Energies – Ionization Potentials
639
3.09.2.7
Excitation Energy – UV Spectra
641
3.09.2.8
Vibrational Frequencies
644
3.09.2.9
Bond Lengths and Angles
646
3.09.3
Experimental Structural Methods
649
3.09.3.1
Molecular Structure
649
3.09.3.2
Molecular Spectroscopy
661
3.09.3.2.1 3.09.3.2.2 3.09.3.2.3 3.09.3.2.4 3.09.3.2.5 3.09.3.2.6 3.09.3.2.7
3.09.4
Proton NMR spectroscopy Carbon-13 NMR spectroscopy Sulfur-33 NMR spectroscopy Mass spectrometry Ultraviolet spectroscopy IR spectroscopy Photoelectron spectroscopy
661 667 674 676 679 681 684
Thermodynamics
690
3.09.4.1
Aromaticity
690
3.09.4.2
Conformational Analysis
705
3.09.4.3
Tautomerism
715
3.09.4.3.1 3.09.4.3.2 3.09.4.3.3 3.09.4.3.4
Compounds Compounds Compounds Compounds
with with with with
a hydroxy group more than one hydroxy group a thiol group an amino group
References
715 721 724 725
727
3.09.1 Introduction Thiophene was first discovered in 1882 by Victor Meyer. It is a colorless liquid with a boiling point of 84.4 C (760 Torr) and a melting point of 38.3 C <1983KO965>. Although it is generally thought to have an odor similar to benzene, pure thiophene, when distilled from copper(II) chloride, is practically odorless. It is highly flammable, moderately toxic, immiscible with water, and soluble in organic solvents. Some of the physical properties of thiophene are listed in Table 1.
625
626
Thiophenes and their Benzo Derivatives: Structure
Table 1 Physical properties of thiophene Physical property
Value
Melting point Boiling point Flash point Dipole moment Dielectric constant (16 C) Refractive index Density Heat capacity Surface tension (25 C) (50 C) Thermal conductivity (25 C) (50 C) (100 C) Critical temperature Critical pressure Critical molar volume Diamagnetic susceptibility Enthalpy of fusion (39.4 C) Enthalpy of vaporization (25 C) Vapor pressure (mmHg) 10 40 100 400 760
38.3 C 84.4 C 1.11 C 0.55 D 2.76 1.528920 1.604920/4 g cm3 123.8 J mol1 K1 30.68 mN m1 27.36 mN m1 0.199 W m1 K1 0.195 W m1 K1 0.186 W m1 K1 579.4 K 5.69 mPa 219 cm3 mol1 57.2 (m l06) 1.19 kcal mol1 8.30 kcal mol1 Temperature ( C) 10.9 þ12.5 þ30.5 þ64.7 þ84.4
Thiophene was synthesized by ring closure of succinic acid with phosphorus pentasulfide. Although thiophene is found in deposits of lignite, coal, and crude oils, its extraction from these sources is not feasible. A summary on the investigation of thiophene and thiophene derivatives occurring in petroleum, oil shales, and coals has been covered by Galpern in ‘‘Thiophene and its derivatives’’ <1985HC(44)325>. Laboratory procedures involve heating anhydrous sodium succinate with phosphorus trisulfide under a carbon dioxide stream. Industrial processes involve continuous vapor-phase techniques that use C4 raw materials and sulfur compounds in the presence of metal oxide catalysts. Thiophene is an aromatic compound. Its structure can be assumed to be derived from benzene by replacement of two annular CH groups with sulfur. The sulfur atom in this five-membered ring acts as an electron-donating heteroatom by contributing two electrons to the aromatic sextet and thiophene is thus considered to be an electron-rich heterocycle. The fact that the lone pair on sulfur contributes to the aromaticity is seen in the lower dipole moment of thiophene as compared to its saturated analogue tetrahydrothiophene (0.52 D vs. 1.90 D) <1972JA8854>. In thiophene, the dipole is directed from the ring toward the heteroatom. Although thiophene is aromatic and assumed to be derived from benzene, the bond-length equivalence seen for the C–C and C–H bonds in benzene is not found here. In thiophene, as will be discussed later, the C–S, C(2)–C(3) [C(4)–C(5)], and C(3)–C(4) bonds are all different in length as are the C–H bonds. The numbering in thiophene 1 starts at the sulfur atom and continues around the ring. The C-2 and C-5 carbon atoms are also designated as C-; the C-3 and C-4 carbons as C-. Substituted thiophenes are named similarly to substituted benzenes. Some of the more common radicals (2–5) are shown in Figure 1. There are two dihydro derivatives, 2,3- 4 and 2,5-dihydrothiophene 5 and a single tetrahydrothiophene 6. The benzo derivatives benzo[b]- 7 and benzo[c]thiophene 8 are considered analogues of naphthalene while dibenzothiophene (DBT) 9 is related to phenanthrene. Several books and reviews are available on the chemistry of thiophenes. Much of the work up to 1950 has been documented by Hartough <1952HC(l), B-1954MI1>. Gronowitz has either authored or edited a variety of articles dealing with thiophene. Some of them have appeared in the Advances in Heterocyclic Chemistry series <1963AHC(1)1> and supplemented periodically in Organic Compounds of Sulfur, Selenium, and Tellurium , and also in a five-part series entitled Thiophene and Its
Thiophenes and their Benzo Derivatives: Structure
Derivatives, in the Weissberger series The Chemistry of Heterocyclic Compounds <1985HC(44), 1986HC(44/2), 1986HC(44/3), 1991HC(44), 1994HC(44)>. Much of the work up to 1996 has been documented in CHEC(1984) and CHEC-II(1996) and, consequently, the work here concentrates on the chemistry of thiophene since then.
Figure 1 Thiophene and some derivatives.
Interest in thiophene has also been extended to the study of oligomers of thiophene and their derivatives due to its wide range of photobiological effects <1991T8443, 1993PHB246> and as alternatives to inorganic materials in the synthesis of a class of organic conducting polymers . These electron-rich conjugated oligomers have p-electron systems similar to the linear cis,trans-polyenes. These oligomers display high electrical conductivity in the oxidized form and possess nonlinear optical (NLO) properties . Polythiophene (PT) is attractive in that it is stable in air, and when some of the hydrogens are substituted by alkyl or phenyl groups, it is soluble in most organic solvents <1986SM(15)169>. On the other hand, conjugated thiophene-based polymers offer a myriad of opportunities to couple analyte receptor interactions, as well as nonspecific interactions, into observable (transducible) responses. A key advantage of conjugated polymer-based sensors over devices using small molecule (chemosensor) elements is the potential of the conjugated polymer to exhibit collective properties that are sensitive to very minor perturbations. In particular, the conjugated polymers’ transport properties, electrical conductivity, or rate of energy migration provide amplified sensitivity <1998ACR201>. Polymers are often used in sensory devices as passive supports or structural materials to provide stability. Conjugated polymers generally exhibit semiconductive to insulating levels of conductivity in their pristine state but can be made conductive by doping . The term doping is derived in analogy to semiconductor systems. However, in contrast to semiconductor systems, doping does not refer to the replacement of atoms in the material’s framework. Doping in the case of a conjugated polymer refers to the oxidation or reduction of the p-electronic system, p-doping and n-doping, respectively, and can be effected chemically or electrochemically. To maintain electroneutrality, doping requires the incorporation of a counterion. Conjugated electroactive and/or photoactive PTs can be successfully utilized for the specific detection of a large variety of analytes such as cations, anions, proteins, and nucleic acids <2000CRV2537, 1997AM1087, 1999AM1491, 1998AM93, 1998JA5274, 2000CC1847, 2001TL155, 2002AGE1548, 2003NMA419, 2003JA4412, 2004JA1384>. Using appropriate side-chain ligands, these smart materials can provide new platforms for the optical transduction of molecular binding interactions, including molecules of biological importance. In particular, it has been demonstrated that versatile postfunctionalization or electrostatic approaches can easily lead to a large number of different responsive (chromic) PT derivatives. It is firmly believed that these novel optical chemo- and biosensors should find applications in the areas of diagnostics, therapeutics, and drug screening <2004T11169>. Hybrid materials which combine the electronic conductivity of thiophene-conjugated polymers and the redox and optical properties of metal complexes are being developed to take advantage of synergistic electronic interactions.
627
628
Thiophenes and their Benzo Derivatives: Structure
Many systems show a splitting of the metal redox wave analogous to that in dinuclear complexes with through-ligand metal–metal interactions (super-exchange). The influence of the conjugated backbone on electron transport between metal centers has been the focus of much work, and the existence of a super-exchange pathway has been demonstrated. Several systems have been shown to exhibit catalytic and photocatalytic activities, and a number of applications in sensors have been described. More recently, there has been growing interest in a new type of redox polymer that is a hybrid of materials from PTs and will be referred to as conjugated metallopolymers. The key feature of this class of material is that the metal is coordinated directly to the conjugated backbone of the polymer, or forms a link in the backbone, such that there is an electronic interaction between the electroactive metal centers and the electroactive polymer backbone. This can enhance electron transport in the polymer, enhance its electrocatalytic activity, and lead to novel electronic and electrochemical properties <1999JMC1641>. Conjugated mono(ferrocenylethynyl)oligothiophene and bis(ferrocenylethynyl)oligothiophene complexes have been prepared. The cyclic voltammograms of the complexes all contain a reversible ferrocene oxidation wave and an irreversible oligothiophene-based wave. The potential difference between the two waves (E) varies depending on the length and substitution of the oligothiophene group. Several of the mono(ferrocenylethynyl)oligothiophene complexes couple when oxidized, resulting in the deposition of a redox-active film on the electrode surface. In solution, electrochemical oxidation of the Fe(II) centers yields the corresponding monocations and dications, which exhibit oligothiophene-to-FeIII charge-transfer transitions in the near-infrared (near-IR) region. The band maxima of these low-energy transitions correlate linearly with E, while the oscillator strengths show a linear correlation with negative slope with E. The complexes with similar charge-transfer transition dipole lengths show an increase in the extent of charge delocalization with smaller E. Comparisons between complexes with different-length oligothiophene ligands show that a reduction in E results either in greater delocalization of charge or in charge being delocalized further along the rigid oligothiophene ligand. These results have important implications in understanding charge delocalization in metal-containing polymers <2000JA10121>.
3.09.2 Theoretical Methods 3.09.2.1 General Molecular orbital (MO) calculations have been used to obtain properties of molecules, ions, and radicals, some of which include bond distances, bond angles, heats of formation, ionization energies, and dipole moments. Molecular parameters (bond lengths and bond angle and dipole moments) of thiophene have been predicted by density functional theory with the combined Becke3-LYP gradient exchange-corrected functional (DFT(B3LYP)) and the conventional ab initio MP2(full) approach. The molecular parameters computed by means of the DFT method are in a good agreement with those predicted by the MP2 approach and with the experimental data. Semi-empirical calculations involving the quantum consistent force field/p-electron configuration international singles diffraction (QCFF/PI þ CISD) method and ab initio calculations using the complete active space selfconsistent field (CASSCF) and Hartree–Fock (HF)/6-31G* methods have been used to calculate vibrational frequencies of the in-plane modes for thiophene derivatives <1994JCP(100)2571, 1991JCP(94)957, 1991JCP(94)965, 1991JCP(95)4783>. Ab initio molecular orbital calculations have been carried out on a number of organometallic complexes containing thiophenic moieties in an attempt to understand the usual preference for insertion of metal fragments into the sulfur– carbon(vinyl) bond. An excellent review by Henriksson-Enflo <1985HC(44/1)2l5> has also covered literature up to 1981; the reader is encouraged to consult it for complete details on prior work.
3.09.2.2 The Role of d Orbitals on Sulfur The first attempt to extend the Hu¨ckel MO method to heterocycles was made by Wheland and Pauling <1935JA2086> in a study of the thiophene molecule. Only the 3pp-orbital on sulfur was assumed to contribute to the p-electron wave function. The first suggestion that 3d-orbitals might participate in the sulfur–carbon bond was made by Schomaker and Pauling a few years later <1939JA1769>. A number of authors have later presented results from Hu¨ckel-type calculations on thiophene and related sulfur-containing systems using a 3p–3d hybrid atomic p-orbital on the sulfur atom. Biclefeld and Fitts made a Pariser–Parr–Pople-type (ppp-type) calculation, where the
Thiophenes and their Benzo Derivatives: Structure
basis set was enlarged with 3dp- and 4pp-functions on sulfur <1966JA4804>. Their results showed that 3dp-atomic orbitals (AOs) participate only to a small extent in the ground state. The electronic spectrum was, however, markedly influenced. The 3dp-orbitals also had a noticeable effect on the dipole moment. The first attempt to give a description of the electronic structure of thiophene including all valence electrons was made by Clark <1968T2663>. He used the complete neglect of differential overlap CNDO/2 method of Pople, Santry, and Segal, modified in order to include 3d-, 4s-, and 4p-AOs for sulfur in the basis set. The results showed a rather large participation of the 3d-orbitals in the sulfur–carbon bond. The calculated population was 0.24 and 0.14 for 3d and 3dp. respectively. Calculation of the dipole moment made it clear that the effect of the 3d-orbitals was overestimated by the CNDO/2 method. Clark and Armstrong have published results from an ab initio calculation on thiophene using contracted Gaussian basis functions <1970CC319>. A basis of 127 primitive Gaussians was reduced to 50 contracted functions; four s, two p, and two d functions for sulfur, three s and one p functions for carbon, and three s functions for hydrogen. The energy lowering due to the inclusion of the 3d-functions was found to be 0.12 a.u. with a population of 0.72 electrons in S 3d-orbitals. A large fraction of this population should, however, be attributed to S 3s, since six d-type functions were used instead of five. The result from a population analysis, using the method of Mulliken, is presented in Table 2 <1972TCA171>. The population in the S 3d-orbitals is found to be 0.18. Of this, only 0.04 electrons are attributed to the 3dp-orbitals. The effect of backbonding in thc p-orbital 1a2 is thus found to be small (the 3d-population in this orbital is 0.01). It is interesting to compare these populations with the variation of the gross atomic charge on sulfur. The calculation without S 3d basis functions gives a charge of þ0.49. With these functions, the charge is reduced to þ0.00. This decrease is much larger than the corresponding 3d-population. The effect of the 3d-functions is to increase the populations in the S 3s- and S 3p-orbitals. Thus they act as ‘polarization functions’ rather than as independent valence orbitals.
Table 2 Gross atomic populations and charges for thiophene No pol. S (s-orb.) S (ps-orb.) S (pp-orb.) S (ds-orb.) S (dp-orb.) q (S) C1 (s-orb.) C1 (ps-orb.) C1 (pp -orb.) q (C1) C3 (s-orb.) C3 (ps-orb.) C3 (pp -orb.) q (C3) H1 (s-orb.) H1 (p-orb.) q (H3) H3 (s-orb.) H3 (p-orb.) q (H3)
H 2p
5.790 6.003 3.725
5.787 5.995 3.727
þ0.482 3.324 2.135 1.109 0.568 3.166 1.983 1.028 0.177 0.733
þ0.491 3.263 2.076 1.105 0.444 3.124 1.907 1.025 0.056 0.826 0.027 þ0.147 0.864 0.028 þ0.108
þ0.267 0.764 þ0.236
S 3d
H 2p and S 3d
5.804 6.278 3.723 0.143 0.038 þ0.016 3.184 1.976 1.085 0.245 3.187 2.021 1.035 0.243 0.751
5.806 6.284 3.727 0.143 0.037 þ0.001 3.134 1.894 1.080 0.108 3.146 1.941 1.032 0.119 0.847 0.030 þ0.123 0.869 0.028 þ0.103
þ0.249 0.768 þ0.232
The 3dxz- and 3dyz-AOs on sulfur are included in the linear combination of atomic orbitals in a semi-empirical SCF MO study of thiophene. The extension of the SCF MO method to include more than one atomic orbital per atomic site is accomplished by a point-charge model for the evaluation of two-center repulsion integrals. A comparison of the SCF molecular orbitals with and without the inclusion of these higher atomic orbitals shows that the d orbitals participate in the p-electronic structure of thiophene to only a small extent, but that their participation affects the calculated electronic properties to a great extent <1966JA4804>.
629
630
Thiophenes and their Benzo Derivatives: Structure
The p-electronic densities obtained from an MO calculation which includes the zero differential overlap approximation (Equations 1 and 2) indicate the general disposition of charge in the molecule rather than the exact populations of the AOs. These electronic densities represent the populations of modified AOs which are not well localized. Thus, the relative values of the AO densities, rather than their precise magnitudes, reflect the general electronic behavior of the molecule. ðijjkl Þ ¼ ij kl ðijjkkÞ
ð1Þ
< i jj > ¼ ij
ð2Þ
According to the charge densities given in Table 3, the -carbon atom in all three models is more susceptible to electrophilic attack than is the -carbon atom. This prediction is in agreement with experiment, which finds the -carbon atom highly favored. The effect of adding higher AOs on sulfur is to increase the electronic charges on the sulfur and -carbon atoms at the expense of the -carbon atoms. This effect on the calculated dipole moment is quite pronounced in that it changes the direction (sign) of mtotal and brings mtotal into close agreement with the experimental value.
Table 3 Calculated charge densities and dipole moments
Sulfur a-Carbon b-Carbon mp (D) m (est.)a (D) mtotal (D)
Five-orbital model
Seven-orbital model
Eight-orbital model
Sappenfielda
Wachtersb
Solonyc
Exptl.d
1.793 1.064 1.040 1.67 1.49 0.18
1.843 1.086 0.993 0.81 1.49 0.68
1.848 1.084 0.992 0.77 1.49 0.72
1.809 1.022 1.073 1.99 1.49 0.50
1.860 1.060 1.010 0.93 1.49 0.56
1.906 1.020 1.030 0.87 1.49 0.62
----------0.55 0.04
a
<1963T157>. <1964T2841>. c <1965CJC1569>. d <1953JCS1622>. b
The p ! p* electronic spectrum predicted by the five-orbital model is in reasonable agreement with experiment, but the inclusion of additional AOs on sulfur does improve the agreement by lowering the 1A1 and 1B1 transitions of the second band to fit more closely the experimental value of 6.59 eV. Moreover, the 1A1 and 1B1 transitions of the first band are closer together in the seven- and eight-orbital models. This situation is in keeping with the findings of Gronowitz <1958AK239>, who reported two maxima at 5.28 and 5.37 eV and stated that the first broad band is composed of two or three overlapping transitions of comparable intensities. The singlet–triplet transitions involving these same MOs are fortuitously close in the eight-orbital model to the experimental values 3.90 and 3.96 eV. The occurrence of these two closely spaced spectral transitions answers the query of Padbye and Desai <1931MI204, 1935JA2086> as to whether one or two transitions are being observed. The MO 4 in the eight-orbital model is predominantly the AO 8. An electronic transition from an MO occupied in the ground state (1, 2, or 3) to the MO 4 is in effect a transition from an MO to essentially the localized AO 8. Thus, we may regard such a transition as an intramolecular electron transfer. This procedure of including several AOs on an atom in the linear combination of atomic orbitals (LCAO) scheme and obtaining MOs which are essentially pure AOs may prove useful in future work for studying intramolecular electron-transfer processes and n ! p* transitions. Because it has used hydrogen-like AOs instead of STOs for evaluating the two-electron two-center integrals in the SCF MO scheme, an anomaly arises in the eight-orbital model. The redefinition of 8 as 8 changes the signs of the integrals <2, 8>, b28, (11j18), (18j18), (18j66), and (16j86), but does not change the orthogonality conditions for the AOs. These sign changes affect the final results by changing the signs of c18, c38, c48, c58, and c78 in Table 4. However, the calculated physical properties depend only on the squares of these coefficients and hence are not affected. In these calculations, the sign of 8 is such that the sign of the largest lobe above the molecular plane has the same sign as the only lobe of 2. In conclusion, the 3dxz- and 3dyz-AOs on sulfur participate only slightly in the ground state of thiophene. Nevertheless, this small participation does influence the charge densities and the electronic spectrum markedly.
Thiophenes and their Benzo Derivatives: Structure
Table 4 SCF MOs and eigenvalues for thiophene Model
Energy level (ev)
Five-orbital model 1 ¼ 0.506 11 þ 0.423 1(2 þ 5) þ 0.439 3(3 þ 4) 2 ¼ 0.800 11 0.040 2(2 þ 5) 0.422 2(3 þ 4) 3 ¼ 0.592 6(2 5) þ 0.385 8(3 þ 4) 4 ¼ 0.321 91 0.565 2(2 þ 5) þ 0.358 9(3 þ 4) 5 ¼ 0.385 8(2 5) 0.592 6(3 4)
14.088 7 11.097 2 10.833 6 0.249 1 1.850 3
Seven-orbital model 1 ¼ 0.459 91 þ 0.435 4(2 þ 5) þ 0.445 5(3 þ 4) þ 0.078 8(6 þ 7) 2 ¼ 0.594 3(2 5) þ 0.357 8(3 4) þ 0.137 2(6 7) 3 ¼ 0.812 51 0.007 2(2 þ 5) 0.412 1(3 þ 4) 0.001 1(6 þ 7) 4 ¼ 0.354 11 0.517 4(2 þ 5) þ 0.358 6(3 þ 4) 0.202 5(6 þ 7) 5 ¼ 0.318 5(2 5) 0.602 0(3 4) þ 0.190 3(6 7) 6 ¼ 0.054 11 0.206 7(2 þ 5) þ 0.055 1(3 þ 4) þ 0.672 9(6 þ 7) 7 ¼ 0.213 1(2 5) 0.098 2(3 4) 0.667 1(6 7)
14.316 7 11.322 3 11.050 9 0.989 7 1.250 7 6.860 4 6.901 4
Eight-orbital model 1 ¼ 0.466 31 þ 0.434 7(2 þ 5) þ 0.441 8(3 þ 4) þ 0.078 5(6 þ 7) 0.043 38 2 ¼ 0.594 2(2 5) þ 0.357 9(3 4) þ 0.137 2(6 7) 3 ¼ 0.807 81 0.012 8(2 þ 5) 0.415 4(3 þ 4) 0.002 6(6 þ 7) 0.045 38 4 ¼ 0.205 61 0.212 2(2 þ 5) þ 0.158 0(3 þ 4) 0.076 6(6 þ 7) þ 0.897 88 5 ¼ 0.291 51 0.472 2(2 þ 5) þ 0.322 9(3 þ 4) 0.188 2(6 þ 7) 0.435 78 6 ¼ 0.318 6(2 5) 0.601 8(3 4) þ 0.190 5(6 7) 7 ¼ 0.053 71 0.207 0(2 þ 5) þ 0.055 2(3 þ 4) þ 0.672 7(6 þ 7) 0.014 88 s ¼ 0.2l3 2(2 5) 0.098 3(3 4) 0.667 0(6 7)
14.366 6 11.348 9 11.121 8 1.355 4 0.945 1 1.223 8 6.833 0 6.872 5
In the last few years, the coordination chemistry of thiophenes has developed rapidly <1988ACR387, 1990CCR61, 1991PIC259, 1994JMO287>. Density functional calculations have been carried out to study the pyramidal coordination of the sulfur in the thiophene complex [Cp(CO)2Fe(1 T)]þ (Cp ¼ cyclopentadienyl; T ¼ thiophene). Total energy calculations showed the optimal value of the angle between the Fe–S bond and the thiophene plane to be 120 . An analysis of the changes in the orbitals brought about by the angular variation reveals that the mechanism by which this process take places is the reduction of the antibonding interaction between the occupied Fe dp orbitals and the S p-canonical lone pair in free thiophene. The mechanism found is consistent with the idea of sp2 ! sp3 rehybridization of the sulfur atom in thiophene. Calculations performed with and without inclusion of the S 3dbasis orbitals show a similar mechanism for the pyramidal distortion. The more appropiate axis choice for CpM(CO)2 is one in which the z-axis is along the future Fe–thiophene bond. The mirror plane of this complex lies in the yz plane. The [CpFe(CO)2]þ fragment of Cs point group symmetry has at low energy three occupied metal-based orbitals (see left side of Figure 2): 17a9 (z2, 3%; yz, 18%; x2 y2, 52%), 18a9 (z2, 18%; yz, 58%; x2 y2, 6%), and 12a0 (xz, 65%; xy, 5%). In the 3dyz-based orbital 18a9, the small contribution of the 3dz2-orbital causes a dissymmetry in the nodal p-character as is shown in 10 (Figure 3). At higher energy is the lowest unoccupied molecular orbital (LUMO) low-lying acceptor metal-based orbital 19a9 (4s, 5%; 4y, 8%; 4z, 2%; z2, 54%; yz, 3%; x2 y2, 2%) <1995OM1292>. For the Z1-coordination, the crucial orbitals of thiophene are the high-energy occupied sulfur ‘lone pairs’: the p-lone pair 2bl (S(pp), 45%) and the s-lone pair 6a1 (S(3s), 25%; S(3pz), 58%) separated by 0.801 eV. In free thiophene, these canonical ‘lone pairs’ of sulfur come from different symmetries due to the sp2 hybridization. There are many possible conformations for the complex [CpFe(CO)2(Z1 T)]þ corresponding to different values of the angle in 11. As shown in Figure 2, the coplanar geometry of the complex [CpFe–(CO)2(1–T)]þ has at low energy six occupied orbitals: the highest occupied molecular orbital (HOMO) 26a9 (Fe(yz), 11%; S(y), 40%), 17a0, 16a0 (Fe(4x) 2% ; Fe(xz), 60%; Fe(xy), 7%), 25a9 (Fe(z2), 16%; Fe(yz), 30%; Fe(x2 y2), 14%), 24a9 (Fe(yz), 31%; Fe(x2 y2), 38%), and 23a9 (Fe(z2), 10%; Fe(x2 y2), 3%; S(s), 15%; S(z), 57%). At somewhat higher energy is the unoccupied metal-based dz2 orbital 27a9 (Fe(4s), 1%; Fe(4y), 2%; Fe(z2), 60%; Fe(yz), 4%; Fe(x2 y2), 2%; S(s), 14%; S(z), 8%). Due to a small overlap integral, the orbitals 12a0 in [CpFe(CO)2]þ and la2 in thiophene are mainly nonbonding. The 23a9 and 27a9 orbitals come from the bonding and antibonding interaction of the unoccupied 19a9 metal orbital with the 6a1 s-lone pair in thiophene. The 23a9 orbital represents the s-donation from the thiophene to the LUMO orbital in the metal
631
Thiophenes and their Benzo Derivatives: Structure
fragment. The occupied 25a9 and 26a9 levels are the bonding and antibonding combinations of 18a9 in the metal fragment and the 2bl p-lone pair in thiophene. The ocurrence of this destabilizing interaction in the coplanar conformation provides an important clue for understanding why the sulfur coordination in the Z1-geometry is pyramidal.
–13.0 27a′
–14.0
Fe
19a′
Energy (eV)
632
26a′ 17a′
–15.0
1a2
S 2b1
S
Fe
12a′ 18a′
16a″
Fe –16.0
25a′
6a1
S
17a′ 24a′
S
Fe 23a′
Figure 2 Orbital interaction diagram for [CpFe(CO)2]þ and thiophene in the coplanar orientation.
Figure 3 3dyz-Based orbital 10 and conformations for the complex 11 corresponding to different values of the angle .
The role of the 3d-basis orbitals on S has also been investigated in this process. The energy profile including 3dorbitals is presented in Figure 4 (curve b). This curve shows, with some numerical value variations, the same qualitative features as Figure 4 (curve a). A deeper minimum of 2.291 eV (52.75 kcal moll) is obtained. With a detailed study of the Walsh diagram and population and fragment orbital variations, it arrives at the same conclusions as in the case in which S(3d) orbitals are excluded. Thus the inclusion of S 3d-orbitals does not have any significant influence on the previous orbital analysis.
Thiophenes and their Benzo Derivatives: Structure
2 b 1
Energy (eV)
0
–1
–2
–3 a –4 100
140
180 θ (deg)
220
260
Figure 4 Variation of the calculated total energy as a function of , defined in the linear combinations of thiophene lone pairs A: (a) without 3d-orbitals on the S; (b) with 3d-orbitals on the S. The reference energy was taken as the coplanar geometry ( ¼ 180 ).
Ab initio MO calculations have been carried out on benzo[b]thiophene (BT), 2-methylbenzo[b]thiophene (2-MeBT), 3-methylbenzo[b]thiophene (3-MeBT), and a number of organometallic complexes containing these thiophenic moieties in an attempt to understand the usual preference for insertion of metal fragments into the sulfur–carbon(vinyl) bond of BT and the recent observations of insertion into the sulfur–carbon(aryl) bond <1998OM3798>. The possibility for the existence of two different metal-inserted BT products stems directly from the orbital structure of the BT LUMO and second LUMO (SLUMO) (Table 5). On the basis of Sargent’s predicted insertion mechanism, the character of the LUMO is consistent with S–Cv insertion while the character of the SLUMO coincides with S–Ca insertion. While occupation of the LUMO is energetically preferred, the calculated LUMO/ SLUMO gap is small; the small gap is consistent with the ‘intramolecular’ pathway between the S–Cv and S–Ca products of the rhodium-inserted complex (C5Me5)Rh(PMe3)(Z2-C,S-2-MeC8H5S). Occupation of the SLUMO, therefore, is readily achievable. Table 5 Calculated orbital coefficients for S, Cv, and Ca in the LUMO and SLUMO of BT, 2-MeBT, and 3-MeBT LUMO
S Cv Ca
SLUMO
BT
2-MeBT
3-MeBT
BT
2-MeBT
3-MeBT
0.36 0.80 0.29
0.44 0.84 0.30
0.32 0.75 0.22
0.36 0.20 0.99
0.52 0.23 1.00
0.37 0.21 1.00
Initial Z1-S-coordination of the BT to a transition metal has a minimal effect on the atomic and electronic structure of the ligand. This theoretical evidence for (C5Me5)(CO)2Re(Z1-S-3-MeC8H5S) and previous theoretical and experimental evidence for Z1-S T and DBT complexes suggest that the S–Cv bond is unaffected and certainly not activated by initial coordination through the sulfur atom. In addition, the orbital structure of the ligand persists upon complexation and the BT molecular orbitals responsible for S–Cv and S–Ca insertion products become the LUMO and SLUMO of the complex.
633
634
Thiophenes and their Benzo Derivatives: Structure
When steric interactions do not limit access to either the S–Cv or S–Ca bond, the factor most affecting the stability of a metal-inserted BT complex appears to be the resultant M–C bond strength. Calculations by Seigbahn suggest that the M–C bond strengths can be evaluated in terms of ionic contributions to the bond (reflected in atomic charges) and repulsive interactions between metal–carbon and carbon–substituent bonding orbitals. On the basis of these criteria, Cv is expected to form the strongest M–C bond in BT and 3-MeBT while Ca is expected to form the strongest bond in 2-MeBT and Z6-coordinated BT. These results are consistent with the fact that BT and 3-MeBT have been shown to form S–Cv insertion products exclusively, while 2-MeBT and Z6-coordinated BT are the only BT species known to form S–Ca metal-inserted products.
3.09.2.3 Total Energies The total energy of thiophene obtained by various methods is given in Table 6. CNDO calculations which use only the all-valence electrons give higher energy values (less negative) than the ab initio methods which includes all electrons in its approximations. Table 6 Total energy of thiophene obtained via various methods Method
Basis on sulfur
Total energy (a.u.)a
Reference
CNDO CNDO CNDO Ab initio
3s, 3p 3s, 3p, 3d 3s, 3p, 3d, 4s, 4p Minimal Minimal, 3d Double
Double , H2p Double , 3d Double , 3d, H2p Minimal Minimal, 3d Minimal, STO-3G Minimal, STO-3G Minimal, STO-3G Split valence, 4-31G 4-31G þ d Spin-coupled SCF SCF HF 3-21G 3-21G* TZVP-SCF TZVP-CI
507.148 516.149 517.338 550.417 550.535 550.923 550.946 550.976 550.999 550.075 550.144 545.087 545.092 545.092 550.599 550.662 546.497 546.437 551.064 551.077 548.473 548.515 551.361 551.922
1968T2663 1968T2663 1968T2663 1970CC319 1970CC319 1972TCA171 1972TCA171 1972TCA171 1972TCA171 1972TL4165 1972TL4165 1985JCS(P2)97 1977G55, 1979JA311 1984BCJ1312 1980JCC348 1982JA1375 1989JCS(P2)263 1989JCS(P2)263 1982MP649 1976JEO179 1989JST(186)101 1989JST(186)101 1992ZN(A)203 1992ZN(A)203
Ab initio
Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio Ab initio
1 a.u. ¼ 627 kcal mol1.
a
The neutral and dication species of thiophene oligomers of increasing size (2–12 rings) have been examined and a study made of structural modifications occurring due to the increase in molecular charge. The neutral (nT), radical cation (nTþ), and dication (nT2þ) species of -oligothiophenes with increasing number of rings (n ¼ 2, 4, 6, 8, 10, and 12) (Figure 5) have been considered by means of DFT. These results are important in that they significantly differ from those obtained at the lower HF-SCF theory level <1994JPC7492>.
Figure 5 Molecular structure of the -oligothiophenes (nT).
Thiophenes and their Benzo Derivatives: Structure
The 2T2þ geometry has been optimized at HF, B-LYP, and MP2 levels with the 3-21G* basis set; on these geometries, single-point energy values have been computed at MP4 and coupled-cluster singles and doubles (CCSD) levels (Table 7) <1998SM(92)69>. Table 7 Ab initio total energy values for 2T2þ and 4T2þ computed on geometries optimized at different theory levels. All calculations were carried out using the 3-21G* basis set 2T 2þ
4T 2þ
Energy/geometry
E (hartree)a
E (mhartree)
E (hartree)
E (mhartree)
MP2/HF MP2/B-LYP MP2/MP2 MP3/HF MP3/B-LYP MP3/MP2 MP4/HF MP4/B-LYP MP4/MP2 CCSD/HF CCSD/B-LYP CCSD/MP2
1096.164 12 1096.171 15 1096.172 77 1096.207 93 1096.213 59 1096.215 32 1096.266 56 1096.276 84 1096.277 24 1096.231 48 1096.239 15 1096.240 11
8.65 1.62 0 7.40 1.73 0 10.68 0.40 0 8.64 0.97 0
2192.004 25 2192.019 53 2192.022 12
17.87 2.60 0
a
1.5 mhartree ¼ 1 kcal mol1.
The valence shell photoelectron spectra of thiophene, 2-chlorothiophene (2-Cl-Th), and 3-chlorothiophene (3-Cl-Th) have been investigated theoretically and experimentally. The third-order algebraic-diagrammatic construction approximation scheme for the one-particle Green’s function has been employed to evaluate the vertical ionization energies. The geometry optimization has been performed at the level of the second-order Møller–Plesset perturbation theory (MP2) using the GAUSSIAN program package <1995MI2>. The correlation consistent valence polarized double- (cc-pvDZ) Gaussian basis sets of Dunning <1989JCP(90)1007> with five-component d functions (basis A) were employed. The same basis sets with six-component d functions (basis B) were used in the Green’s function calculations. The total energies of the optimized structures for both basis sets are reported in Table 8 <2001CPH(263)167>.
Table 8 Total energies (a.u.) of the optimized (MP2/basis A) structures Method
Basis
Thiophene
2-Cl-Th
3-Cl-Th
HF HF MP2 MP2
A B A B
551.318 443 551.319 857 551.984 070 551.993 124
1010.231 710 1010.234 354 1011.030 039 1011.041 382
1010.236 295 1010.238 798 1011.033 949 1011.045 189
3.09.2.4 Charge Distribution For the ab initio methods, even a change in the basis set causes large changes in the atomic charges, although, if a large basis set is used, charges calculated with and without d orbitals are about the same. Calculations using the CNDO method gave a positive value for the sulfur atom (0.136) when the d-orbitals of sulfur (method I) were not included in the calculations <1968T2663>. When the basis set included the sulfur 3d-orbitals (method II) the value calculated was 0.0358, and 0.0514 when the 4s- and 4p-orbitals were also included. Density functional theory (DFT) calculations of two types of push–pull chromophores built around thiophenebased p-conjugating spacers rigidified by either covalent bonds or noncovalent intramolecular interactions (Figure 6) have been carried out to assign the relevant electronic and vibrational features and to derive useful information about the molecular structure of these NLO-phores <2003CEJ3670>.
635
636
Thiophenes and their Benzo Derivatives: Structure
Figure 6 p-Spacers and natural bond orbital atomic charges for compounds 12 and 14, as deduced from their optimized DFT//B3LYP/6-31G* molecular geometries.
DFT//B3LYP/6-31G* model chemistry reveals an interesting difference with respect to the rather simple charge distribution associated with the zwitterionic canonical form. Thus, the natural population atomic charges over the donor and the acceptor end groups amount to þ0.051 and þ0.178 e, respectively, for compound 12, whereas for compound 14 the corresponding values are þ0.058 and 0.174 e. The charge distributions for compounds 13 and 15 display a similar behavior. B3LYP/6-31G* calculations indicate that the charge over the malononitrile group is around 3–3.5 times higher than that on the N,N-dimethylaniline group, and that the conjugating spacer is highly polarized since it bears nearly 65–70% of the net positive charge of the whole molecule (probably due to the strong interaction with the acceptor group). Thus, for compound 12, the net charges over the thienyl rings of the open-chain dithienylethylene (DTE) spacer attached to the donor and to the acceptor end groups, respectively, amount þ0.018 and þ0.068 e (without taking into account the net positive charge over the central vinylenic bond), whereas for compound 14 NLO-phore the corresponding values for each thienyl ring of the BT spacer are þ0.034 and þ0.082 e.
Thiophenes and their Benzo Derivatives: Structure
The four types of D-p-A systems showed an intramolecular charge-transfer (CT) band in their electronic absorption spectra, which is influenced by the nature of the p-conjugating spacer. The topologies and energies of the MOs have been studied by means of time-dependent DFT (TDDFT)//B3LYP/6-31G* , showing that the HOMO–LUMO energy gaps account for the observed intramolecular CT from the donor subunit of the NLO-phore including the nearest thiophene unit to the acceptor subunit (i.e., mainly the electron-withdrawing malononitrile group).
3.09.2.5 Dipole Moments The experimental value of the total dipole moment as measured in the gas phase is found to be 0.550 0.040 D <1953JCS1622>. The p–d polarization also contributes to the total dipole moment value. Thus, depending on the method employed, a large variation is expected for thiophene (Table 9).
Table 9 Dipole moments of thiophene obtained from various calculations Method
Basis on sulfur
Experimental HMO PPP
CNDO
CNDO/S CNDO/2 CINDO/SHIFT/UV
2p 2p, 3p, 3d 2p, 3p, 3d, 4p 3d 3s, 3p 3s, 3p, 3d 3s, 3p, 3d, 4s, 4p 3s, 3p, 3d 3s, 3p, 3d 3s, 3p 3s, 3p, 3d 3s, 3p, 3d, C3d
INDO/S MNDO MINDO/3 MP2 Ab initio
6-3lG (þsdþsp) Double
Double , H2p Double , 3d Double , 3d, H2p HF Split valence, 4-31G Minimal Minimal, 3d, H2p Minimal, 3d, H2p, C3d 3-21G 3-21G* SCF/6-31G (þsdþsp)
Dipole moment (D)
Reference
0.55 2.50 0.50 0.18 0.68 0.72 0.63 0.84 2.26 1.84 1.23 0.42 1.94 1.78 1.24 2.71 0.90 0.90 2.22 0.45 0.96 0.97 0.61 0.62 0.65 0.38 0.29 0.07 0.07 1.34 0.75 0.91
1953JCS1622 1952BCJ179 1963T157 1966JA4804 1966JA4804 1966JA4804 1987CHE454 1968T2663 1968T2663 1968T2663 1985CPB3077 1983JST(94)115 1983JST(94)115 1983JST(94)115 1983JST(94)U5 1983JST(94)115 1983JCC84 1986IJQ(29)1599 1980IJQ797 1992JPC7301 1972TCA171 1972TCA171 1972TCA171 1972TCA171 1976JEO179 1980JCC348 1982MP649 1982MP649 1982MP649 1989JST(186)101 1989JST(186)101 1992JPC7301
The fact that dipole moments are generally overestimated at the HF level is shown by the relatively high value of 1.34 D obtained by employing the 3-21G basis set <1989JST(186)101>. When the d polarization function on sulfur is included (the 3-21G* basis set), the value of the dipole moment is 0.75 D. Ab initio calculations that are closest to the experimental value are those obtained by Gelius et al. <1972TCA171> (0.61 D). Among the semi-empirical methods, calculations by the PPP method <1963T157, 1987CHE454> are generally in good agreement with the experimental value. Calculations by other methods gave very high dipole moments which arise due to the noninclusion of the 3d-AOs <1983JCC84, 1986IJQ(29)1599>.
637
638
Thiophenes and their Benzo Derivatives: Structure
The larger values calculated by the PPP method <1966JA4804> when the sulfur 3d- or the 4p-orbitals are included are not surprising, since inclusion of the sulfur 3d-orbitals in the calculations leads to a drift of the s- and p-electrons toward the sulfur atom. With the diffusely polarized 6-31G (þsd þ sp) basis set, a better correlation is obtained with MP2 values than with SCF values 1992JPC730l>. Dipole moments of thiophene have been predicted by DFT(B3LYP) and the conventional ab initio MP2(full) approach. The standard 6-31G(d,p) basis set was used for all atoms. The molecular parameters computed by means of the DFT method are in a good agreement with those predicted by the MP2 approach and with the experimental data (Table 10) 1997JST(436)451>.
Table 10 Geometries, rotational constants, and dipole moments of thiophene Calculated Parametera (thiophene)
DFT
HF
MP2
Experimental b
r(S,C-2) r(C-2,C-3) r(C-3,C-4) r(C-2,H) r(C-3,H) ff(S,C-2,C-3) ff(C-2,C-3,C-4) ff(C-5,S,C-2) ff(S,C-2,H) ff(C-2,C-3,H) A B C m
1.735 7 1.367 2 1.429 6 1.080 8 1.084 0 111.49 112.39 91.52 120.03 123.31 7971.60 5356.53 3203.76 0.623
1.725 2 1.345 1 1.436 6 1.071 1 1.073 8 111.81 112.75 91.31 120.42 123.62 8051.54 5458.54 3253.10 0.899
1.714 1.374 0 1.417 0 1.076 6 1.079 1 111.63 112.53 91.96 120.29 123.16 8098.33 5402.90 3240.78 0.454
1.714 0(14)c 1.369 6(17) 1.432 2(23) 1.077 6(15) 1.080 5(14) 111.47(23) 112.45(18) 92.17(10) 119.85(78) 123.28 8041.77(2)c 5418.12(1) 3235.77(2) 0.55(1)d
a
Bond distances r in angstroms, bond angles ff in degrees, rotational constants A, B, and C in megahertz, and dipole moments in debye. b Experimental uncertainty of the last digits is given in parentheses. c,d From microwave studies <1961JSP58, 1972JSP38>, respectively.
A good agreement with the experimental data is also observed for dipole moments predicted by the DFT approach. Again, for thiophene, the predicted rotational constants and dipole by the MP2 method agree better with the experimental data than the DFT values. The results of extended MO calculations using DFT approximation supported by experimental Raman and 1H and 13 C nuclear magnetic resonance (NMR) studies on thiophene have been reported. Raman spectra of liquid thiophene were reexamined and the performance of a hybrid B3PW91 density functional was compared with the ab initiorestricted Hartree–Fock (RHF) method. With the basis sets of the 6-311þþG** quality, the DFT-calculated dipole moments were predicted in a very good agreement with available experimental data. Additionally, the results on thiophene were extended by calculations on 3-methylthiophene. In this case, a significant change in geometry and charge distribution in the thiophene ring due to a methyl group substituent was observed <2002JST(616)17>. The molecular stability (energy lowering) of thiophene increases with improving the quality of the basis set used for single-point calculations and the DFT-predicted dipole moments and rotational constants are significantly closer to experiment <1997JST(436)451, 1961JSP58> than the corresponding RHF results (Table 11). It is worth noting that the DFT-predicted dipole moment of thiophene is in a very good agreement with experiment. Kwiatkowski et al. <1997JST(436)451> calculated significantly higher dipole moments for thiophene and selenophene using ab initio RHF and B3LYP-DFT methods with smaller basis sets. The dipole polarizability of DBT has been measured experimentally by refractometry techniques, and evaluated theoretically with ab initio and DFT methods in the 1A9 electronic ground state. The molecular dipole polarizability is the linear response of a molecular electronic distribution to the action of an external electric field I. Such an external field causes charge rearrangements in the molecular structure that are reflected in changes in the permanent molecular dipole moment me <2001JPO709>.
Thiophenes and their Benzo Derivatives: Structure
Table 11 Optimized RHF and DFT geometry and dipole moment of thiophene using 6-311þþG** basis set Method (single-point calculations)
Dipole moment (D)
Exp. (1997JST(436)451, 1961JSP58) RHF/6-311þþG** //6-311þþG** RHF/aug-cc-pVTZ//6-311þþG** DFT/6-311þþG** //6-311þþG** DFT/aug-cc-pVTZ//6-311þþGpp
0.55 0.819 6 0.829 0 0.509 2 0.535 5
Table 12 shows the total energy, charge distribution, and dipole moment of DBT. The charge distribution is calculated in terms of the Mulliken atomic population of the S- (Q(S)) and C- (Q(C)) atoms. An analysis of these populations, calculated at the HF/6-31þG(d,p) level, indicates that very small changes in the charge distribution are induced when the benzene rings are fused with the S-atom to form the DBT moiety. However, these charges are very sensitive to the level of calculations, which are reflected in the total dipole moment, as expected. For example, at the HF/6-31þG(d,p) level, the value of dipole moment is 1.16 D, whereas at BLYP/6-31þG(d,p) it is 0.71 D and with B3LYP/6-31þG(3d,3p) it is 0.79 D. This value is in excellent agreement with the experimental high-accuracy dipole moment reported for this molecule by Nagai et al. (0.79 D) <1974BCJ1022>. Table 12 Total energy, dipole moment, and Mulliken atomic charge Q in the S and C atoms for dibenzothiophene
Total energy (a.u.) Dipole moment (D) Q(S-1) Q(C-2) Q(C-3) Q(C-4) Q(C-5) Q(C-6) Q(C-7) a
HF/6-31þG(d,p)
BLYP/6-31þG(d,p)
856.641 381 1.16
860.115 938 0.71 (0.79)a (0.78)b 0.059 0 0.726 1 0.912 6 0.309 0 0.009 3 0.245 7 0.052 4
þ0.247 4 0.664 1 0.986 2 0.319 9 0.133 6 0.272 5 0.161 3
<2001JPO709> with the B3LYP/6-31þG(3d,3p) method. Experimental <1974BCJ1022>.
b
3.09.2.6 Orbital Energies – Ionization Potentials As a general rule, the orbital energy can be (according to Koopmans’ theorem) <1933MI104> assumed to be the negative of the ionization potential, that is, e ¼ IP. The photoelectron spectrum of thiophene has been studied by Eland <1969IJM471> and Derrick et al. <1971IJM177>. The assignments of the first seven bands were of the order 1a2(p), 2b1(p), lb1(p), 6a1, 4b2, 5a1, and 3b2. The assignments of the first two orbitals were unambiguous. The band at 12 eV initially assigned to be the 2b1(p) band was later shown to arise from s-orbitals and subsequent experiments were able to reassign the band at 12.5 eV to that from the lb1(p) orbital. Based on the results observed <1982J(P2)539>, the ordering is assigned as 1a2(p), 2b1(p), 6a1(n), lb1(p), 4b2, 5a1, and 3b2. CNDO calculations show that the MO energies are not affected by the inclusion of the d orbitals <1983JST(105)375> and a modified version of the CNDO/S method show there to be only one s-level which is strongly localized on the sulfur atom and is thus an n-type <1983ACH97>. Calculations were obtained indicating that the d orbitals on sulfur do not affect the orbital energies to any significant extent as they do some of the other molecular properties. The valence shell photoelectron spectra of thiophene, 2-Cl-Th, and 3-Cl-Th have been investigated theoretically and experimentally to evaluate the vertical ionization energies. The ground-state geometrical parameters of the three molecules have been optimized at the level of the second-order Møller–Plesset perturbation theory, and standard
639
640
Thiophenes and their Benzo Derivatives: Structure
cc-pvDZ basis sets have been used throughout. The results for the outer valence region of thiophene agree well with available experimental and theoretical data (Table 13). Very satisfactory agreements have been obtained between the theoretical predictions for the photoelectron spectra of 2-Cl-Th and 3-Cl-Th and the corresponding experimental data. Assignments have been proposed for the major spectral structures <2001CPH(263)167>. Table 13 Calculated (ADC(3)) energies (E, eV) and intensities (P) of the outer- and inner-valence orbital vertical ionization transitions in thiophenea Orbital
E
P
1a2 2b1 6a1 1b2 4b2 5a1 1b1 3b2 1b1 4a1 4a1 2b2 2b2 3a1 2b2 3a1 3a1 4a1 1b2 1b2 2a1 2a1 2a1 1b2 2a1 1b2 2a1 1b2 2a1 1b2 2a1 1a1 1a1 1a1 1a1
8.73 9.09 11.96 12.36 13.32 13.58 13.59 14.11 15.41 16.86 17.54 17.87 18.13 18.15 18.50 19.24 19.39 20.28 22.08 22.68 22.68 22.83 22.93 23.06 23.22 23.36 23.42 23.48 23.68 23.69 24.31 26.71 26.97 28.02 28.32
0.88 0.89 0.89 0.52 0.90 0.89 0.23 0.88 0.13 0.69 0.10 0.19 0.18 0.54 0.31 0.06 0.15 0.04 0.04 0.10 0.07 0.12 0.04 0.05 0.04 0.30 0.12 0.06 0.05 0.06 0.06 0.08 0.04 0.07 0.04
a
Other configurationsb
(1a2)2
(3b1)1, (1a2)2, (1a2)1 (2b1)1 (2b1)2, (1a2)1 (2b1)1 (3a1)1, (1a2)1 (4b2)1, (6a1)1 (2b1)1 (6a1)1 (2b1)1, (6a1)1 (1a2)1 (1a2)1 (2b1)1 (2b1)1 (4b2)1,(1a2)1 (2b1)1 (4a1)1, (1a2)1 (4b2)1, (6a1)1 (2b1)1 (6a1)1 (1a2)1, (2b1)1 (4b2)1 (1a2)1 (4b2)1, (1a2)2 (2a1)1, (4a1)1, (6a1)1 (1a2)1, (2b1)2 (2a1)1, (3a1)1, (1a2)1 (4b2)1, (6a1)1 (2b1)1 (2b2)1, (1a2)1 (2b1)1, (1b1)1 (2b1)1 (3a1)1 (1a2)1, (5a1)1 (2b1)1, (1b1)1 (4b2)1 (1a2)2, (2b1)2, (1b1)1 (2b1)1 (4a1)1 (1a2)1, 1a2)1 (2b1)1, (1a2)1 (2b2)1 (3a1)1, (2b1)1 (4b2)1, (2b1)1 (3b2)1 (1a2)1 (2b1)1, (1b1)1 (2b1)1, (2b1)2 (3a1)1, (6a1)1 (3b2)1, (6a1)1 (4b2)1, (2b1)1 (4b2)1 (6a1)1 (2b1)1, (1a2)1 (1b1)1 (3a1)1, (6a1)1 (3b2)1, (1a2)1 (2b2)1 (1a2)1 (1b1)1, (1a2)1 (2b1)1, (2b1)2 (1a1)1, (3a1)1 (2b1)1 (1a2)1 (4b2)1 (6a1)1 (4b2)1, (6a1)2 (1b1)1 (2b1)1, (1b1)1 (2b2)1 (2a1)1, (4a1)1 (2b1)1, (6a1)1 (1b1)1 (2a1)1, (1a2)1 (2b1)1, (1a2)1 (2b1)1, (2b1)2 (2b1)2, (1a2)1 (2b1)1
Only transitions with P 0.04 are shown. For the sake of brevity, only the hole parts of the 2h–1p configurations are shown.
b
In thiophene, the p-orbital manifold comprises the HOMO 1a2 (p3) describing C(2)–C(3) bonds, the 2b1(p2) orbital related to the 3pz sulfur lone pair, and the deep 1b1(p1) orbital describing the bonding of all the ring atoms. Among the unoccupied orbitals are two antibonding p-orbitals: p* 4(b1) and p* 5(a2). The p-orbital system of the chlorothiophenes is closely analogous: there are three occupied molecular orbitals, 4a0(p3), 3a0(p2), and 1a0(p1), and two unoccupied p* (a0) orbitals. The vertical ionization energies and spectral intensities have been computed using the third-order algebraicdiagrammatic construction approximation scheme (ADC(3)) for the one-particle Green’s function. In the photoelectron spectra of the chlorothiophenes, the assignments of the transitions occurring at low binding energies do not present any diffculties. The two lowest transitions, between 8 and 10 eV, are due to ionization of the p3- and p2-orbitals. Between 11 and 12 eV, ionization of the two 3p-lone-pairs of chlorine takes place. The next transition, between 12 and 13 eV, corresponds to the ionization of the 3p(s)-lone-pair of sulfur.
Thiophenes and their Benzo Derivatives: Structure
Beyond this point, the spectra do not follow so strictly the predictions of the orbital model. In all three molecules, at binding energies slightly greater than those associated with ionization from the sulfur lone-pair orbital, the calculations predict a line with a low intensity and complicated nature. This line is due to transitions characterized by contributions of the (p1)1 configurations with relative intensities of 50%, 20%, and 30% in thiophene, 2-Cl-Th, and 3-Cl-Th, respectively. It is not possible to identify this structure unambiguously in the 80 eV photoelectron spectra due to overlap with stronger transitions. The rest of the intensity associated with this orbital is distributed among states formed by 2h-1p configurations describing ionization of the outermost p2 and p3 MOs accompanied by the p3 ! p4 excitation. Another interesting finding related to the final states of certain p1 transitions are contributions of configurations describing excitation of the p* 4 MO, unoccupied in the HF ground state. Apparently the p* 4 orbital becomes partially occupied when the electron correlation is taken into account. In terms of configuration interaction, this would be described by admixtures of the doubly excited configurations (p3)0(p* 4)2 and (p2)0(p* 4)2 to the main HF configuration. Three more intense transitions are present in the energy region 13–15 eV. All of them are well characterized as ionization of orbitals 4b2, 5a1, 3b2 in thiophene and orbitals 10a9, 9a9, 8a9 in the chlorothiophenes. The total breakdown of the MO ionization picture begins at 16 eV in the spectra of all three molecules.
3.09.2.7 Excitation Energy – UV Spectra Initial calculations on thiophene have been carried out by the PPP method, although calculations by CNDO and intermediate neglect of differential overlap (INDO) have also been done. PPP calculations show four triplet states for thiophene. When only the 3p-orbital is employed in the basis set, the assignments are 3.3, 4.0, 5.4, and 6.0 eV, which correspond to the 3B1, 3A1, 3A1, and 3B1 transitions, respectively. When the 3dxy- and 3dyz-orbitals are included, the four transitions are calculated to be at 3.2, 3.1, 5.5, and 5.7 eV, respectively. The PPP model with configuration interaction (PPP–CI) has been used to predict the long-wavelength excitation energies of thiophene and benzo[c]thiophene <1987MM2023>. TDDFT is a recently developed tool for calculating excitation energies <2001PCA451, 1998JCP(109)8218>. A significant quantitative improvement in the excitation energies from TDDFT over those from HF-based methods has been demonstrated. However <1999JCP(111)10774>, for infinite polymers or sufficiently large systems, the excitation energies to the lowest singlet excited states calculated by TDDFT with the pure exchange-correlation functionals are not better than the corresponding HOMO–LUMO gaps because they tend to converge to the same value. The failure of TDDFT with the pure exchange-correlation functionals in the large systems is attributed to the fact that the exchange-correlation potentials generated by the current approximate exchange-correlation functionals decay too rapidly in the asymptotic region. This problem is partially overcome in TDDFT with the HF/DFT hydrid functionals such as B3LYP, since the incorporated HF exchange potential decays correctly. TDDFT calculations suggest a relative small band gap of 1.52 eV for PTh, 0.17 eV narrower than the predicted band gap of polyfuran. The chain-length dependence of excitation energies of oligomers of thiophene was studied employing the TDDFT with B3LYP functional (Table 14). Band gaps of the corresponding polymers were obtained by extrapolating excitation energies of trimers through pentamers to infinite chain length (Table 15) <2002MM1109>.
Table 14 Excitation energies (eV) of oligomer 16 TDDFT n ¼ 1/2 n¼1 n ¼ 3/2 a
5.76 3.87 3.23
<1983JA6555>. <1997CRV173>.
b
Exptl. a
5.37 4.12a 3.52a
n¼2 n ¼ 5/2 Eg (n ¼ 1)
TDDFT
Exptl.
2.81 2.56 1.52
2.20b
641
642
Thiophenes and their Benzo Derivatives: Structure
Table 15 TDDFT excitation energies, HOMO–LUMO gaps (H–L ), and the negative of HOMO energies ("HOMO) of oligomer 16 (in units of eV ) Oligomer
TDDFT
H–L
"HOMO
n ¼ 1/2 n¼1 n ¼ 3/2 n¼2 n ¼ 5/2
5.76 3.87 3.23 2.81 2.56
5.99 4.13 3.49 3.06 2.18
6.54 5.67 5.29 5.09 4.95
The effects of siloles and doping with positive and negative charges on the electronic structures and band gaps of the silole/thiophene copolymers have also been studied employing the DFT and the TDDFT with B3LYP functional. The calculated excitation energies agree with the available experimental results (Table 16) <2003MM2130>.
Table 16 Excitation energies by TDDFT (eV) of bithiophene dimer 17 and silole/thiophene dimer
16 (n ¼ 0) 17 a
Exptl.
6-31G*
6-31þG*
4.12a
4.02 3.39
3.87 3.28
<1983MI1191>.
TDDFT calculations of the vertical excitation energies are then performed at the optimized geometries of the ground states. Table 16 also lists the excitation energies of bithiophene and silole/thiophene dimer using the basis sets of both the 6-31G* and 6-31þG* at the optimized geometry with the 6-31G* basis set. The excitation energy of bithiophene obtained from TDDFT/6-31G* is close to the experiment value with the variance of 0.10 eV. However, for the unknown silole/thiophene dimer 17, the TDDFT excitation energy calculated at the 6-31G* basis set is only slightly different from that obtained at the basis set of 6-31þG* . The TDDFT excitation energies and HOMO–LUMO gaps of oligomers 16 (n ¼ 1–6) and 18–20 (Figure 7) as well as the extrapolated band gaps for the corresponding polymers are listed in Table 17. The extrapolated band gaps from the TDDFT excitation energies and HOMO–LUMO gaps slightly underestimate the excitation energies by the average values of 0.45 and 0.28 eV, respectively, compared with the available experimental data. Two factors may be responsible for deviations from experiments. One is that there exist systematic underestimates by 0.4–0.7 eV inherent in TDDFT calculations. Another is that the predicted band gaps are for the isolated gas-phase chains, while the experimental band gaps are measured in the liquid phase where the environmental influence and the interchain interactions may be involved. To achieve more quantitative predictions on the lowest excitation energies by partially alleviating the systematic errors, an empirical correction has been introduced. The corrected excitation energies are in better agreement with the experimental data with the average deviation of 0.09 eV. It is worthwhile to notice that with the increase in the silole content, the band gaps of copolymers become increasingly narrower. Electronic states of the fused-silole-thiophene derivatives have been obtained by ab initio MO calculations on model compounds at the level of RHF/6-31G* . Relative HOMO and LUMO energy levels derived from the MO calculations are given in Table 18 <2004OM5622>. For thiophene derivatives (Figure 8), HOMOs are elevated in the order 22 (R ¼ H) < 21 < 23 (R ¼ H), while LUMOs are lowered in the same order, giving rise to the smallest energy gap for 23 (R ¼ H) among them, in accordance with the experimental observations. The difference between LUMO energy levels of 21 (R ¼ H) and bibenzothiophene was calculated to be larger (0.22 eV) than that of HOMO levels (0.11 eV), this being more responsible for the smaller HOMO–LUMO gap of 23 (R ¼ H) as compared with that of bibenzothiophene 21<2004OM5622>.
Thiophenes and their Benzo Derivatives: Structure
Table 17 TDDFT, the empirically corrected excitation energies, and HOMO–LUMO gaps, H–L, of oligomers with B3LYP functional and 6-31G* basis set Oligomer
TDDFT excitation energies (eV )
Corrected excitation energies (eV )
H–L (eV )
Exptl. (eV )
16 (n ¼ 1–6) n¼1 n¼2 n¼3 n¼4 n¼5 n¼6 n¼1
4.02 2.84 2.38 2.15 2.01 1.93 1.53
4.19 3.15 2.75 2.55 2.42 2.35 2.00
4.23 3.03 2.61 2.42 2.31 2.24 1.85
4.12a
18 n¼1 n¼2 n¼3 n¼1
2.63 1.89 1.65 1.33
2.97 2.32 2.10 1.82
2.80 2.11 1.91 1.46
1.83d
19 n¼1 n¼2 n¼3 n¼4 n¼1
2.93 2.06 1.73 1.57 1.31
3.23 2.47 2.18 2.03 1.81
3.09 2.23 1.95 1.82 1.54
1.76d
20 n¼1 n¼2 n¼3 n¼4 n¼5 n¼6 n¼1
3.39 2.38 1.93 1.68 1.52 1.42 1.09
3.64 2.75 2.35 2.13 1.99 1.90 1.61
3.63 2.50 2.07 1.84 1.71 1.63 1.25
1.55c
a
<1983CPL(51)1191>. <1998CEJ1509>. c <1997CRV173>. d <2000AGE1695>. b
Figure 7 Structures of the oligomers 18–20.
Table 18 Relative HOMO and LUMO energy levels for silole derivatives and related energy levels derived from MO calculations at the level of RHF/ 6-31G (in units of eV) Compound
H–L
"HOMO
"LUMO
21 22 (R ¼ H) 23 (R ¼ H)
9.40 9.79 9.06
7.51 7.73 7.39
1.89 2.06 1.67
2.92b
2.20c
643
644
Thiophenes and their Benzo Derivatives: Structure
Figure 8 Bibenzothiophene (BBT), dithienosilole (DTS), and BBTS, compounds having a silole ring condensed with benzothiophene.
3.09.2.8 Vibrational Frequencies Harmonic vibrational frequencies have been calculated by ab initio methods at the MP2 level with a double basis set with one set of polarization functions (DZP) <1988JPC1739>. Semi-empirical calculations involving the QCFF/PI þ CISD method and ab initio calculations using the CASSCF and HF/6-31G* methods have been used to calculate vibrational frequencies of the in-plane modes for thiophene derivatives <1994JCP(100)2571, 1991JCP(94)957, 1991JCP(94)965, 1991JCP(95)4783>. The equilibrium molecular geometry of thiophene has been determined from a combination of gas-phase electron diffraction (ED) vibrational and microwave data and ab initio and DFT calculations (Table 19) <2001JST(567)29>. The chemical structure and vibrational properties of the interface between aluminium and PT, taken as a prototype conjugated polymer, has been investigated theoretically, considering both the deposition of the metal on a polymer substrate and the adsorption of the polymer on the metal surface <1997SM(85)1031>. The results of this DFT study confirm that aluminium and PT oligomers interact preferentially through the formation of covalent bonds between Al-atoms and the -carbons of thiophene rings. This type of reaction is expected to take place when Al is deposited on the polymer layer as well as when PT is adsorbed on the metal surface. In all cases, the formation of the Al–C bonds and the geometric modifications induced in the organic molecules lead to important changes in the vibrational spectra which should allow the experimental detection of the vibrational signatures of the species formed at the Al–PT interface. The calculations indicate that when Al-atoms approach thiophene rings, they preferentially interact with the carbon atoms located in the -positions relative to the sulfur atom. In the case of the thiophene molecule interacting with two Al-atoms, each metal atom forms a single Al–C bond at these positions. In the case of terthiophene, the Al-atoms are found to form bonds with the -carbons of two adjacent rings; they interact to a lesser extent with the neighboring -carbon. In all cases, the Al–C() distance lies in the 2.1–2.3 A˚ range, which indicates the formation of covalent Al–C bonds. Important modifications in the charge density distribution of the conjugated system are also induced by the formation of the Al–C bonds, with significant increases on the carbon atoms involved; consistently, the electron density on the Al-atoms decreases. The calculated vibrational spectrum of the thiophene is dominated by a band at 670 cm1 corresponding to out-ofplane bending of the C–H bonds; in the present context, other important features are the bands typical of CTC stretching around 1500 cm1 and the C–S stretching vibration around 600 cm1. The in-plane C–H bending and the C–C stretching modes lie in the 900–1300 cm1 region. Finally, the peaks related to the stretching of the C–H are located above 3000 cm1. Dramatic differences appear upon Al-bonding to thiophene; the frequency region below 500 cm1 is now populated by a series of strong peaks which correspond to C–Al bending and stretching vibrations, appearing between 160 and 300 cm1 and 300 and 450 cm1, respectively. The remarkable intensity of these peaks is likely related to the strong dipole moment of the Al–C bonds. As a consequence of the geometric changes induced in the thiophene ring by the Al-bonding, its vibrational frequencies are significantly modified: the strong out-of-plane C–H bending band is shifted 35 cm1 upward while the C–S stretching frequency is decreased by 70 cm1. The region of the CTC stretching is also deeply affected: the two bands appearing in the spectrum of thiophene are replaced by a single weak peak at 1600 cm1, which corresponds to the vibration of the newly formed C()–C(9) double bond. Quartic force fields for thiophene have been generated using DFT to evaluate vibrational levels by second-order perturbation theory (PT) and also by the variational method. The results for the fundamental frequencies are in very good agreement with observation <2003SAA1881>.
Thiophenes and their Benzo Derivatives: Structure
Table 19 Calculated and experimental frequencies (in cm1) of thiophene B3LYP/AUG-cc-pVTZ
B3LYP/cc-pVTZ
B3LYP/6-311þG*
MP2( full )/6-311G**
A1 species 1 2 3 4 5 6 7 8
3248 3210 1141 1395 1104 1154 838 614
3249 3210 1145 1397 1106 1055 838 615
3245 3207 1148 1399 1110 1053 835 614
3289 3261 1152 1404 1104 1077 884 626
A2 species 9 10 11
931 697 580
929 694 581
909 680 571
844 649 521
B1 species 12 13 14
893 729 461
889 727 461
871 716 453
828 707 446
B2 species 15 16 17 18 19 20 21
3246 3197 1551 1281 1105 879 751
3247 3196 1556 1283 1108 879 751
3242 3194 1557 1282 1111 878 745
3286 3247 1533 1283 1107 905 777
MP2/6-311þG*
MP2/6-31G*
HF/6-311þG*
Exp.a
A1 species 1 2 3 4 5 6 7 8
3272 3246 1450 1403 1111 1076 882 625
3309 3274 1479 1430 1135 1092 884 628
3412 3377 1573 1522 1202 1099 884 656
3126 3098 1409 1360 1083 1036 839 608
A2 species 9 10 11
800 629 490
841 661 542
1039 794 611
898 683 565
B1 species 12 13 14
801 692 435
836 722 454
1017 800 481
867 712 452
B2 species 15 16 17 18 19 20 21
3269 3233 1526 1287 1112 902 776
3307 3261 1564 1308 1135 911 778
3409 3363 1715 1402 1205 945 802
3125 3086 1504 1256 1085 872 751
a
<1994SAA765>.
645
646
Thiophenes and their Benzo Derivatives: Structure
3.09.2.9 Bond Lengths and Angles The optimized geometry of thiophene and its derivatives has been calculated by both semi-empirical and theoretical methods. Modified neglect of diatomic overlap (MNDO) calculations tend to underestimate the C–S bond due to the noninclusion of the 3d- AOs, which result in smaller sulfur atomic orbitals and hence shorter C–S bonds. Consequently, the C–S–C angles obtained from MNDO calculations are about 1 larger than experimental. Among the ab initio methods, the best correlation between theoretical and experimental values is that obtained by the MP2 method <1988JPC1739>. This is a tremendous improvement over other ab initio calculations, especially those with the 3-21G basis set where the C–S bond is overestimated by 0.08 A˚ due to the absence of d orbitals on sulfur. Inclusion of the d orbitals in the basis set (3-21G* ) reduces the C–S bond length. Similarly, the C–S–C bond angle as calculated with the 3-21G basis set is smaller than the experimental value by about 3 and is reduced to less than 1 when the d orbitals are included. The properties of oligomers of thiophene at the ground and excited states have been investigated by semi-empirical and ab initio methods. Semi-empirical calculations for the ground state of thiophene involve the QCFF/PI þ CISD method, while ab initio calculations are carried out at the HF/6-31G* and the CASSF/3-21G* levels and also at the SCF and the averaged coupled-pair functional (ACPF) levels, with (basis set I) and without (basis set II) the sulfur 3d-orbitals. The molecular geometry of thiophene obtained by the QCFF/PI þ CISD method is in good agreement with experiment <1996CHEC-II(2)451>. Several quantum-chemical methods (ab initio and semi-empirical techniques such as MNDO and CNDO types) have been used to obtain the ground-state geometries of polymers <1997PCB10248>. Because of computational time, the ab initio method may not be suitable for an infinite chain. Ab initio calculations with small basis sets are subject to overestimating the bond length alternation and, thus, quite large basis sets are required to produce reasonable results. Therefore, an oligomeric approach has been widely employed to extract a polymeric structure from the optimized central unit of the corresponding oligomer such as a trimer or a tetramer. However, one should be careful when adopting this approach for determining the ground-state geometries of conjugated polymers and for estimating the relative stabilities of the aromatic and quinonoid structures since these properties strongly depend on the types of terminal groups of an oligomer <1992MM4652, 1995MM4991, 1990MM2237>. Molecular parameters (bond lengths, bond angles, and dipole moments) of thiophene have been predicted by DFT(B3LYP) and the conventional ab initio MP2(full) approach. The molecular parameters computed by means of the DFT method are in a good agreement with those predicted by the MP2 approach and with the experimental data (Table 20) <1997JST(436)451>.
Table 20 Geometries, rotational constants, and dipole moments of thiophene Calculated a
Parameter
DFT
HF
MP2
Experimentalb
r(S,C-2) r(C-2,C-3) r(C-3,C-4) r(C-2,H) r(C-3,H) ff(S,C-2,C-3) ff(C-2,C-3,C-4) ff(C-5,S,C-2) ff(S,C-2,H) ff(C-2,C-3,H) A B C m
1.735 7 1.367 2 1.429 6 1.080 8 1.084 0 111.49 112.39 91.52 120.03 123.31 7971.60 5356.53 3203.76 0.623
1.725 2 1.345 1 1.436 6 1.071 1 1.073 8 111.81 112.75 91.31 120.42 123.62 8051.54 5458.54 3253.10 0.899
1.714 1.374 0 1.417 7 1.076 6 1.079 1 111.63 112.53 91.96 120.29 123.16 8098.33 5402.90 3240.78 0.454
1.714 0(14)c 1.369 6(17) 1.432 2(23) 1.077 6(15) 1.080 5(14) 111.47(23) 112.45(18) 92.17(10) 119.85(78) 123.28 8041.77(2)c 5418.12(l) 3235.77(2) 0.55(1)d
a
Bond distances r in angstroms, bond angles ff in degrees, rotational constants A, B, and C in megahertz, dipole moments m in debye. b Experimental uncertainty of the last digits is given in parentheses. c,d From microwave studies <1961JSP58, 1972JSP38>, respectively.
Thiophenes and their Benzo Derivatives: Structure
The equilibrium molecular geometry of thiophene has been determined from a combination of gas-phase ED, vibrational, and microwave data, and ab initio and DFT calculations (Table 21) <2001JST(567)29>. ˚ angles in degrees) of thiophene Table 21 Theoretical equilibrium geometry (distances in A,
C(2)–H C(3)–H C(2)TC(3) C(3)–C(4) S–C(2) ffC(2)–S–C(5) ffS–C(2)–C(3) ffC(2)–C(3)–C(4) ffS–C(2)–C(3) ffC(4)–C(3)–H
C(2)–H C(3)–H C(2)TC(3) C(3)–C(4) S–C(2) ffC(2)–S–C(5) ffS–C(2)–C(3) ffC(2)–C(3)–C(4) ffS–C(2)–C(3) ffC(4)–C(3)–H
B3LYP/AUG-cc-pVTZ
B3LYP/cc-pVTZ
B3LYP/6-311þG*
MP2(full)/6-311G**
1.0765 1.0797 1.3634 1.4231 1.7257 91.69 111.44 112.72 120.14 123.94
1.0766 1.0799 1.3629 1.4233 1.7260 91.66 111.45 112.72 120.12 123.88
1.0800 1.0832 1.3659 1.4278 1.7331 91.44 111.59 112.69 119.97 123.99
1.0811 1.0834 1.3792 1.4190 1.7113 92.08 111.71 112.26 120.12 124.58
MP2/6-311þþG**
MP2/6-311þG*
MP2/6-31G*
HF/6-311þG*
1.0820 1.0841 1.3820 1.4212 1.7126 92.15 111.70 112.23 120.21 124.58
1.0826 1.0848 1.3818 1.4216 1.7133 92.18 111.64 112.27 120.17 124.57
1.0823 1.0849 1.3763 1.4201 1.7176 91.98 111.57 112.44 119.17 124.40
1.0709 1.0735 1.3459 1.4365 1.7245 91.29 111.87 112.49 120.33 123.85
A theoretical study of a variety of tricyclic polymers with different types of bridging groups has been performed for the fused bithiophene system (Figure 9). Geometrical structures of the polymers were obtained from semi-empirical SCF band calculations and the electronic properties from the modified extended Hu¨ckel band calculations <1997PCB10248, 1997JCP(107)10607>.
Figure 9 Aromatic and quinonoid forms of fused bithiophene polymers.
It is predicted that the ground-state structures of the fused bithiophene polymers are of the aromatic forms, which are more stable than the quinonoid ones by 3.4–7.1 kcal mol1. Optimized structural parameters for both aromatic and quinonoid forms are listed in Table 22. In the aromatic forms, the short bonds are longer than those of PT and the long bonds shorter. Especially, C(2)–C(3) (C(6)–C(7)), C(3)–C(4) (C(5)–C(6)), and C(4)–C(5) bonds of the aromatic forms become similar in length, showing quinonoid character.
647
648
Thiophenes and their Benzo Derivatives: Structure
Table 22 Optimized geometrical parameters for the fused bithiophene polymers A1–A5 (bond lengths in A˚ and bond angles in deg); aromatic (A) and quinonoid (Q) forms A1
A2
Aa 1–2 2–3 3–4 4–5 1–X 4–X 3–Y >CTZb 1–19 1–4 3–6 1–2–3 2–3–4 3–4–5 X–4–3 Y–3–4 7–8–19 rc
A
Q
A3 Q
1.388 1.417 1.414 1.431 1.702 1.654 1.501
1.463 1.349 1.491 1.351 1.724 1.672 1.498
1.386 1.421 1.401 1.431 1.695 1.661 1.802
1.462 1.351 1.477 1.349 1.714 1.683 1.793
1.421 2.447 2.328 111.2 112.0 108.5 111.6 110.6 127.6 0.021
1.344 2.491 2.344 112.3 113.2 109.5 110.1 109.1 126.7 0.129
1.421 2.452 2.645 112.3 111.1 115.7 111.9 107.1 128.1 0.031
1.345 2.496 2.665 113.5 112.3 116.4 110.3 105.6 126.9 0.120
A4
A5
A
Q
A
Q
A
Q
1.391 1.412 1.414 1.440 1.701 1.647 1.494 1.224 1.420 2.445 2.345 110.9 112.3 108.7 111.4 109.6 127.8 0.019
1.464 1.349 1.492 1.351 1.723 1.673 1.487 1.226 1.345 2.492 2.350 112.0 113.5 109.6 109.9 108.2 126.4 0.129
1.389 1.416 1.419 1.436 1.701 1.647 1.476 1.534 1.421 2.444 2.320 111.0 111.9 108.1 111.6 110.1 127.6 0.018
1.462 1.353 1.496 1.351 1.723 1.671 1.471 1.537 1.346 2.490 2.326 112.1 113.2 109.0 110.0 108.7 126.4 0.128
1.388 1.416 1.419 1.433 1.702 1.652 1.473 1.334 1.421 2.449 2.322 111.1 112.0 108.3 111.4 109.7 127.7 0.018
1.461 1.351 1.496 1.351 1.724 1.671 1.469 1.335 1.345 2.491 2.334 112.3 113.0 109.2 110.0 108.2 126.6 0.129
a
Bold-typed are the more stable forms between the isomers. Z ¼ O, S, or CH2. c Average value of the bond-length alternation, defined as r ¼ jR(1–2) R(2–3) þ R(3–4) R(4–5) þ R(5–6) R(6–7) þ R(7–8) R(8–10 )j/4. b
An AM1 semi-empirical calculation method was used to study the structures and electronic properties of N-methyl2-(29-thiophene)-pyrrolidino[3,4]C60 (MTPC) (Figure 10) <2001JST(545)97>.
Figure 10 The atom series numbers and structures of MTPC isomers (A type).
Because of the asymmetry of the thiophene moiety and the relatively larger rotational energy barrier between thiophene and pyrrolidine, eight stable MTPC isomers were obtained by geometry optimization. These MTPC isomers can be divided into two series, A and B (enantiomers), and the series A are named as MTPC-1A, MTPC-2A, MTPC-3A, and MTPC-4A. The calculated bond lengths of MTPC are listed in Table 23. ˚ of MTPC isomers calculated using the AM1 method Table 23 Bond lengths (A)
R(65,72) R(72,73) R(73,74) R(74,75) R(75,65)
MTCP-1A
MTCP-2A
MTCP-3A
MTCP-4A
1.382 1.369 1.377 1.711 1.711
1.357 1.346 1.353 1.682 1.685
1.385 1.375 1.375 1.709 1.713
1.300 1.288 1.294 1.607 1.616
Thiophenes and their Benzo Derivatives: Structure
Introduction of the thiophene ring partly decreases the interaction between C60 and pyrrolidine, and thus lead to a decrease of net charge of the C60 moiety in MTPC isomers. An ab initio computational study on thiophene sulfoxide 25, benzo[b]thiophene sulfoxide 26, and dibenzothiophene sulfoxide 27 have been reported <1996JOC1275>.
Of these molecules, only compound 27 has actually been isolated and characterized. The others are too reactive for ordinary isolation. Simple alkyl substitutions on the thiophene ring of compound 26 are sufficient to allow isolation of its derivatives <1979JOC2887>, but quite bulky substitutions are necessary to achieve sufficient kinetic stabilization to isolate derivatives of compound 25 <1970JA7610>. Geometries were fully optimized for each of the structures 25–27 at the RHF level of theory using 3-21G(d), 6-31G(d), and 6-31G(d,p) basis sets. Several key geometrical parameters for the sulfoxides are presented in Table 24. Table 24 Calculated (RHF) and experimental geometrical parameters of sulfoxides 25–27a Molecule
Basis
r(SO)
r(C1S)
r(C2S)
ffC1SO
ffC2SO
ffCSC
25
3-21G(d) 6-31G(d) 6-31G(d,p) 3-21G(d) 6-31G(d) 6-31G(d,p) 3-21G(d) 6-31G(d)
1.492 1.483 1.483 1.490 1.483 1.483 1.488 1.482
1.763 1.770 1.770 1.772 1.780 1.779 1.778 1.787
1.763 1.770 1.770 1.776 1.784 1.784 1.778 1.787
115.0 113.4 113.4 113.5 112.1 112.1 112.8 111.5
115.0 113.4 113.4 113.4 111.9 111.9 112.8 111.5
90.0 90.1 90.1 89.4 89.5 89.5 89.3 89.3
53.3 55.8 55.7 56.0 58.1 58.1 56.9 59.0
26b
27 a
The angle is between the SO bond vector and the plane defined by the two CS bonds. All distances are in angstroms and all angles in degrees. b C1 is the one not in the benzene ring.
As can be seen from Table 24, there are some significant differences between the geometries obtained with 3-21G(d) and the two bases, 6-31G(d) and 6-31G(d,p).
3.09.3 Experimental Structural Methods 3.09.3.1 Molecular Structure Highly accurate molecular geometries for thiophene, deuteriothiophene, and 13C-labeled thiophene have been obtained by microwave spectroscopy. The molecular structure has also been determined by ED. Results from ED compare reasonably well with microwave spectral analysis, except for the C–H bond lengths, which are somewhat smaller than those determined from microwave spectroscopy. The molecular structure of thiophene has also been determined by liquid crystal LC (liquid chromatography) NMR spectroscopy <1984MP779, 1988MCL267> as well as ED and rotational spectroscopy. Although the molecular structure of thiophene has been actively investigated, there have not been many reports on those of the methyl derivatives. The molecular structure of 2,5-dimethylthiophene has been determined by gas electron diffraction (GED) and the results compared with ab initio calculations carried out at the 3-21G* level. The presence of bulky groups adjacent to each other leads to variations from normal trends due to steric interaction. For example, X-ray results of 3,4-di-t-butylthiophene indicate that the ring is almost planar <1980CC922>. However, results show that the two substituents are also pushed away from each other, the C(3)– C(4)–But angle being 133 as compared to about 124 in other cases.
649
650
Thiophenes and their Benzo Derivatives: Structure
The X-ray structure of tetra-t-butyl thiophene has also been determined <1992TL5947>. The ring is not planar ˚ as compared to any more, the torsional angle being 16.2 . The C–tBu bonds lengths here are also longer (ca. 1.567 A) ˚ 1.49 A in 3,4-di-t-butylthiophene <1980CC922>. The twisting between the t-butyl groups and in the ring releases most of the strain and thus the ring bond lengths are smaller than the di-t-butyl derivative. In tetra-t-butyl 1,1dioxide, the ring becomes nonaromatic and bond alternation is much more pronounced. X-Ray analysis shows that the phenyl rings in 2,5-bis(4-nitrophenyl)-3,4-diphenylthiophene are twisted 72.0 from the thiophene plane, while the angle between the nitrophenyl rings and thiophene is 26.6 <1986AX(C)363>. In ethyl 2-amino-4-phenylthiophene-3-carboxylate 28, steric repulsion between the ethoxy group and the phenyl ring is reduced by the phenyl ring being twisted out of the plane by an angle of 70.2 . Determination of the molecular structure of 2-thiophenecarboxylic acid shows the dihedral angle between thiophene and the carboxyl group to be 1.49 .
The crystal structure of 2-acetyl-3-hydroxythiophene 29 showed the carbonyl oxygen to be cis with respect ˚ to bond to the sulfur atom. Thus the two oxygen atoms within the molecule are too far apart (4.27 A) intramolecularly.
In benzo[b]thiophene 7, both rings are planar. Introduction of a substituent on the thiophene ring usually causes the two rings to be inclined to each other at about 1.0 <1974AXB2058, 1984AX(A)C277>. The average C–S bond length is longer than in thiophene with the S–C(2) bond being the longer of the two. The CTC bond in the five˚ The C(2)TC(3) bond found here is also membered ring which is fused to the benzene ring is longer by 0.044 A. shorter than that in thiophene. The X-ray structure of dibenzothiophene 9 was first determined by Schaffrin and Trotter <1970JCA1561>. Although each of the rings is planar, the molecule is slightly bow shaped with the dihedral angles between the planes being 0.4 and 1.2 . As for benzo[b]thiophene, the C–S bond length at 1.740 A˚ is longer than in thiophene as are the C(l)–C(6) and C(l9)–C(69) bond lengths. The X-ray structure of dibenzothiophene 1,1dioxide 30 <1968AXB981> is quite similar to dibenzothiophene.
Thiophenes and their Benzo Derivatives: Structure
1,9-Bis(dimethylamino)dibenzothiophene (31: X ¼ NMe2) belongs to a group of compounds known as proton sponges. X-Ray structure analysis shows excessive steric strain in this molecule as a result of bulky groups in the 1,9-positions <1988TL1905>. As a result, the torsion amounts to 21.3 and the C-5 and C-59 atoms deviate ˚ This causes the nitrogen atoms to be 28.6 A˚ apart. Protonation causes a relief from the mean plane by 0.33 and 3.0 A. in the strain. The torsion angle is reduced to 7.7 as is the N N distance due to the formation of the N H N bond, which is almost linear (ca. 175 ). Interest in the chemistry of polythiophenes has stemmed from their potential as organic conducting polymers . The simplest polythiophenes are bithienyls, which are 29-16 (n ¼ 0), 2,39-32, or 3,39-33. Furthermore, the molecules can rotate round the intermolecular C–C bond and thus each isomer can possess various conformations.
For 2,39-bithienyl 32, the conformation could not be obtained due to the disorder in the crystals. Similarly, from the X-ray of 3,39-bithienyl 33, it was not possible to determine if the anti-conformation holds for all the molecules. The C–S bond lengths in bithienyl do not differ much from that in thiophene and, consequently, the thienyl substituent does not alter the geometry of thiophene to any extent. X-Ray studies on the structure of 3,39-dimethoxy-2,29-bithienyl show the molecule to lie on a crystallographic center of symmetry and the two rings to be in the anti-form <1988AXB509>. X-Ray structures of bis(thiophenes) and bis[benzo(b)thiophenes] have been determined. In compounds 1,4-bis(2-thienyl)butadiyne 34a, both the thiophene rings are disordered. Thus the position of sulfur and carbon atoms in thiophene rings, adjacent to the diacetylenic backbone, are interchangeable but with unequal occupations. The thiophene rings are planar and the dihedral angle between them is 65.6 . The diacetylene chains are inclined to the ˚ as shortest axis, that is, the a-axis, by 40.5 , and the perpendicular distance between the adjacent chains is 3.823 A, ˚ required for solid-state polymerization. against the respective values of 45 and 3.4 < S1 < 4.0 A,
Preliminary X-ray diffraction data of compound 1,4-bis(3-thienyl)butadiyne 34b indicate that this diacetylene also has a disordered structure in its crystal state. For crystals of 1,4-bis(3-benzothienyl)butadiyne 34c, the distance between adjacent molecules in a stack as well as the angle between the molecular axis and the stack axis are not suitable for 1,4-addition reaction to occur. The structures of naphtho[b-4,5]thieno[2,3-b]pyridine 35 and 4-methyl-5,6,7,8-tetraphenylbenzo[4,5]thieno[2,3-b]pyridine 36b have been obtained by single crystal X-ray crystallography. The X-ray data reveal that the 4-methyl group in the tetraphenyl derivative 36b is located across from the cavity of the 5-phenyl ring, which is perpendicular to the benzo ring. Consequently, the proton chemical shift of the 4-methyl group in 36b occurs at a chemical shift ( ¼ 1.51 ppm) lower than that ( ¼ 2.98 ppm) of the 4-methyl group in 36a <2002JOC3409>.
651
652
Thiophenes and their Benzo Derivatives: Structure
X-Ray diffraction provided the final evidence for the structures of the pentathiepino[6,7-b]benzo[d]thiophene 37 <2002JOC6220>.
Interestingly, two polymorphs of 37 were observed. ‘Form I’ crystallized from a 4:1 mixture of hexane–CH2Cl2 in the space group P21/c with the unit cell parameters a ¼ 4.467(1), b ¼ 13.514(1), c ¼ 18.049(1) A˚ and ¼ 94.59(1) , V ¼ 1086.1(3) A˚ 3, whereas ‘form II’ was obtained from hexane, adopting the space group P21/n with the unit cell dimensions a ¼ 8.997(1), b ¼ 10.115(1), c ¼ 12.116(1) A˚ and ¼ 93.89(1) , V ¼ 1100.1(2) A˚ 3. The molecular conformations of the two forms of 37 are quite similar, and the largest difference in the torsion angles is less than 5 . The X-ray crystal structures of 4,6-bis(trimethylsilyl)dibenzothiophene 38a and 4,6-dibromodibenzothiophene 38b were determined <2003NJC1735>. The nonbonding separation between the two silicon atoms in 38a was ˚ while the distance between the two bromine atoms in 38b is shorter at 6.51 A. ˚ Both these found to be 6.77 A, ˚ distances, however, are longer than the P–P nonbonding distance of 6.38 A in 4,6-bis(diphenylphosphanyl)dibenzothiophene <1993TL2107>. Bond lengths of the dibenzothiophene ring in 38a and 38b fall within the range of typical values reported in the Cambridge Structural Database. Bond angles also compare favorably with the exception of C(3)–C(4)–C(4a) and C(7)–C(6)–C(5a) in 38a at 114.5(2) and 114.7(2) , respectively. These angles are smaller than the values typically reported (mean bond angle approximately 118 with a range of approximately 6 based on 71 structures in the Cambridge Structural Database). The corresponding angles in free dibenzothiophene are 117.8 <1970JCS(A)1561>; thus, dibenzothiophene compounds substituted at positions 4 and 6 contain smaller C(3)–C(4)–C(4a) and C(7)–C(6)–C(5a) bond angles than when substituted at other positions of the heterocycle. Examples include 116.13(7) in 4,6-bis(diphenylphosphanyl)dibenzothiophene <1993TL2107> and 117.6(4) in 4,6-dimethyldibenzothiophene <1996T3953>. In contrast, the C(3)–C(4)–C(4a) and C(7)–C(6)–C(5a) angles in 38b are, at 120.5(4) and 120.6(4) , respectively, larger than in free dibenzothiophene. Consequently, the external C(4a)–C(4)–Br(1) and C(3)–C(4)–Br(1) angles in 38b are larger than the corresponding angles about silicon in 38a. The internal angle at sulfur is smaller in 38b than in 38a (90.6 vs. 91.5 ) and C(9)–C(9a) is longer while C(4a)–C(9b) is shorter. The Br(1)–C(4) bond distance in 38b is almost identical to the Si(3)–C(4) separation in 38a: ˚ respectively. 1.894(5) and 1.890(2) A,
Luminescent organoboron compounds have recently received considerable attention due to their potential applications in organic light-emitting devices (OLEDs) <2005IC601>. In order to understand the electronic effects of substituents and the ligands on the luminescent properties of the BAr2q or BAr2q9 family (Ar, phenyl or 2-benzothienyl; q, 8-hydroxyquinolato; q9, 2-methyl-8-hydroxyquinolato), compounds 39, 40a, and 40b have been prepared by the reaction of 5-(2-benzothienyl)-8-hydroxyquinoline with triphenylborane or by the reaction of 8-hydroxyquinoline or 8-hydroxyquinaldine with benzo[b]thiophene and BBr3 <2005IC601>.
Thiophenes and their Benzo Derivatives: Structure
The crystal structures of the three boron compounds have been determined by single crystal X-ray diffraction analyses. The boron center in all three compounds displays a typical tetrahedral geometry. The hydroxyquinoline groups in all three molecules are chelated to the boron in the same manner to form a five-membered chelate ring. The bond angle N–B–O of the four complexes is similar, ranging from 97.6(3) to 99.6(2) . Each boron center in the three compounds is further bound by two carbon atoms of the two benzothienyl groups. The B–N, B–O, and B–C bond lengths are similar to those reported previously <2000OM5709, 1992IC3162, 1987IC143, 1991CJC1217, 1986TCC39, 1972JCD1639, 1984ZNB1717, 1980ZNB1499>. The five-membered chelate ring in each compound is coplanar with the corresponding quinoline ring. No significant p–p-stacking was observed in the crystal lattices of the three compounds. The benzothienyl ring in compound 39 displays a rotational disorder with 50% occupancy for each disordered site and a dihedral angle of 46.1 (48.1 ) with the quinoline ring. The much smaller dihedral angle in compound 39 is clearly caused by the much-reduced steric interactions between the benzothienyl group and the quinoline ring. As a consequence, the benzothienyl and the quinoline ring form partial conjugation as reflected by the slightly ˚ in compound 39. There are intermolecular p–p-interactions shortened bond length between C(17)–C(22) (1.476 A) involving a few atoms of the benzo portions of the benzothienyl ring with the shortest atomic separation distance ˚ Compounds 40a and 40b have similar structures. In the asymmetric unit of compounds 40a and 40b are being 3.73 A. two independent molecules, which form a p-stacked pair. The p–p-stacking in compound 40a is between two ˚ while in quinoline groups from the two independent molecules (the shortest atomic separation distance is 3.44 A), contrast, the p–p-stacking in 40b is between a quinoline group from one molecule and a benzothienyl group from ˚ These p–p-stacking interactions are limited to another molecule (the shortest atomic separation distance is 3.50 A). two molecules, and no extended p–p-stacking is observed for compounds 40a and 40b. It is likely that the methyl group on the quinoline ligand in compound 40b prevents the p–p-stacking from occurring between two quinoline groups. Both thienyl rings in compound 40b are disordered in a similar manner to the 2-benzothienyl substituent in compound 39. In addition to the p–p-stacking difference, the 2-methyl group in compound 40b has a subtle impact on the structure. For example, the O–B–N angle is about 1 smaller than that in compound 40a, and the B–N and B–O bond lengths are also somewhat longer. Two types of single crystals of 1,2-bis(2-methyl-6-nitro-1-benzothiophen-3-yl)perfluorocyclopentene 41 were obtained, depending on recrystallization solvents. Single crystals obtained from hexane, benzene, toluene, and ethyl acetate were found to show photochromic reactivity in the single-crystalline phases. Upon irradiation with 366 nm light, the single crystal turned green, and the green color disappeared after irradiation with visible (Vis) light (>450 nm). However, single crystals obtained from chloroform and acetone did not show any photochromic reactivity in the single-crystalline phases. These results suggest that the conformation of compound 41 fixed in the crystalline phases is different among the crystals <1999JA8450>.
653
654
Thiophenes and their Benzo Derivatives: Structure
Tetrathieno[2,3-a:39,29-c:20,30-f:3-,2--h]naphthalene 42 forms a 1:1 complex with tetracyano-p-quinodimethane (TCNQ). X-Ray crystal structure determination of the complex confirms the molecular structure and reveals a onedimensional (1-D) structure with columns of alternating donor (D) and acceptor (A) moieties. The flat molecules ˚ As a consequence of this structure, the stack on top of each other with a plane-to-plane D–A distance of 3.32(2) A. material is fully insulating as confirmed by a compressed pellet conductivity measurement.
The molecule 42 is located on an inversion center and appears to be essentially planar, the dihedral angle between the two independent thiophene rings amounting to 2.5(5) . One interesting feature is the short intramolecular ˚ when compared with the Van der Waals distance (S–S 3.7 A), ˚ indicating a degree of S(1)–S(2) distance (3.066(5) A) delocalization between the two sulfur atoms, as already postulated in various molecules with the same 1,5-sulfur– sulfur interaction where S–S distances around 3 A˚ were observed <1996JOC6997>. In the context of organic field-effect transistors (OFETs), two novel 1,4-dithiins, 43-syn and 43-anti, have been prepared as pentacene analogues <2004JOC2197, 2003JOC9813>, consisting of the parent 1,4-dithiin with a benzo[b]thiophene on both sides <2004TL7943>. The structures of the two dithiins, 43-syn and 43-anti, were determined by X-ray crystallographic analyses. The space groups of the two isomers, 43-syn and 43-anti, were Cc and C2/c, respectively. Accordingly, two benzo[b]thiophene rings in compound 43-syn have a distorted structure bending to the dithiin S–S axis. On the other hand, two benzo[b]thiophenes of 43-anti did not show a distorted structure. The bond lengths and angles in the 1,4-dithiin rings were nearly similar to those of the known compounds <1995PS(107)279, B-1997MI(E9a)250, 1999TL9101, 1979AXB1140>. A little difference in the packing structures of compounds 43-syn and 43-anti is observed. There were no intermolecular contacts with sulfur–sulfur and p–p-interaction since interatomic sulfur–sulfur distances in ˚ respectively. the stacking of isomers were 3.90 and 3.88 A,
The crystallographic structure confirms the regular head-to-tail (HT) orientation of the thiophene rings and the expected fully planar geometry of trithieno[1,2-b:3,4-b9:5,6-b0] benzene 44 <2004OL273>.
Similarly, dithieno[1,2-b:4,5-b9]benzene 45 has completely planar molecular structures packed in a herringbone arrangement <2005JOC10569>.
Thiophenes and their Benzo Derivatives: Structure
Crystalline packing of naphthodithiophenes 46a and 46b <2005OL1067> shows a typical herringbone-like motif similar to that of nonfluorinated triphenylene <1954AX595>. However, compound 46a forms face-to-face columnar stacks with disk planes orthogonal to the stacking axis. This arrangement could prove crucial to performance as organic semiconductors <2002PNA5804>.
Compounds 47, the anti- and syn-isomers of a pentacyclic compound consisting of alternating thiophene and benzene rings, have crystal packing of pivotal concern for efficient charge transport in devices such as OFETs <2004JA8546>. Single crystal X-ray analysis revealed that compound 47-anti crystallized in the orthorhombic space group Pmn21 with two molecules in the unit cell. The central atom S-2 resides on the crystallographic mirror plane that relates the two halves of the molecule. Molecules of 47-anti are nearly planar with the highest deviation of atoms ˚ from the best plane through the entire molecule of 0.174(2) A.
The crystals of 47-anti exhibit a herringbone-packing pattern with favorable molecular overlap along the c-axis of the unit cell. The alternating p-stacked columns are tilted at an angle of 50.24 . In comparison, this tilt angle is 51.9 in pentacene <2001AXC939>. Tight packing in the solid state increases the material’s stability toward oxygen in that it decreases the amount of oxygen diffusing into the bulk material. The effective volume occupation is expressed as the Kitaigorodskii packing index (KPI). Compound 47-anti has a packing coefficient of 0.75, whereas pentacene shows with a KPI of 0.76, the highest percent of filled space. Heteroacene 48 has a nearly coplanar structure <2005OL5301>. Notably, this compound forms a herringbone packing structure that is very similar to that of pentacene <1999CEJ3399>. Considering this similarity, the investigation on their solid-state properties, such as carrier mobility, would give important information about the structure–property relationships <2002PNA5804, 2004JA4318>.
Crystal structures of the new salts 49?ClO4(THF)1/2 and 50?BF4(CH2Cl2) hybrid molecules built by insertion of a linear p-conjugated thiophene between two 1,3-dithiole cycles have been reported (THF ¼ tetrahydrofuran) <2002CEJ784>.
655
656
Thiophenes and their Benzo Derivatives: Structure
The stoichiometry and structure of the salts have been determined by single crystal X-ray analysis. Salt 49?ClO4(THF)1/2 crystallizes in the Pbca space group. The structure consists of two independent molecules, two ClO4 anions, and a molecule of solvent. Both molecules adopt a syn-conformation stabilized by two strong S S intramolecular interactions. The nonbonded ˚ but larger than length with a distance about 3.05 A˚ are much shorter than the sum of the van der Waals radii (rS ¼ 1.85 A) ˚ Such 1,5-intramolecular interactions contribute to the planar conformation of the a covalent S–S single bond (2.04 A). donors in these various oxidation states. The molecules are quite planar except for the carbon atoms of the ethylenedithio groups. The torsion angle between the dithiafulvenyl arms and the central thiophene cycle is smaller than 5 . The THF molecule, located in the interstices of one molecule, is stabilized by two S O contacts with distances 3.43 and 3.47 A˚ between the sulfur atoms of the 1,3-dithiole rings and the oxygen atom of the solvent. The structure of salt 49?ClO4(THF)1/2 is characterized by the formation of dimers (492)2þ with a face-to-face ˚ show stacking of monomers. The numerous S S intermolecular contacts close to the van der Waals distance (3.7 A) that, as for dimers of bis(ethylenedithio)tetrathiafulvalene (BEDT–TTF) <2001ICI363, 2000JMC893>, the sulfur atoms of the dithiafulvalenyl groups contribute to the formation of the dimer. On the other hand, short intermolecular ˚ in particular those for thiophene carbons, contacts are observed for the carbon atoms of the spacer (less than 3.5 A); ˚ ˚ the shortest distances are close to 3.14 A and 3.23 A. The X-ray structure of salt 50?BF4(CH2Cl2) reveals that the donors present the syn-conformation of the dithiafulvalenyl groups stabilized by two strong S S intramolecular by the short nonbonded contact with distances 3.039(3) ˚ These interactions contribute to the planarity of the molecule for which the torsion angle between the and 3.092(3) A. dithiafulvalenyl arms and the plane of the central thienylenevinylene system is close to 2 . The structure is characterized by the formation of dimers (502)2þ separated in the [1,0,0] direction by the anions and the solvent. The strongest S S interaction d ¼ 3.400(4) A˚ involves the sulfur atom of the 1,3-dithiole rings while the distance ˚ Concerning the C C intermolecular contacts, the between the sulfur atoms of the thiophene rings is only 3.676(4) A. ˚ involve the carbons of the thienyleneshorter bond lengths, C(3)–C(11), C(6)–C(10), and C(7)–C(8), close to 3.35 A, vinylene spacer and correspond to the overlaps of the p-orbitals. The contribution of the sulfur–sulfur interactions of (502)2þ to stabilize the dimers is less important than in (492)2þ. The structures of compounds 51 and 52 have been confirmed by single crystal X-ray diffraction <2007OL1619>.
There is a slight lengthening of the C–S bond next to the oxygen atom in compound 52 (from mean values of 1.740 and 1.703 in 51 to 1.772 and 1.744 in 52), which implies loss of the aromatic conjugation due to oxidation of the sulfur atom. Various short intermolecular contacts participate in the molecular packing of dioxide 52, including C–H O, C–H S, and C–H p hydrogen bonds and p–p-stacking. The typical C–H O distance of 2.591 A˚ is consistent with ˚ which was observed in the rigid core oligothiophene dioxides. However, no extremely short S O and S S 2.57 A, separations in BSiS compound 52 were observed, which are the main driving forces to promote self-assembled 3-D networks in planar oligothiophene S,S-dioxides. Therefore, it is natural to conclude that spiro frameworks play an important role in interrupting the supramolecular interactions between S- and O-atoms or S- and S-atoms that lead to the formation of excimer emission and the increase of the self-quenching probability in the solid state. In addition, crystallographic data show that dioxide 52 has two different types of recognizable ‘dimers’ with antiparallel HT stacking of fluorene ring interaction planes, in which 3-D organization is achieved through one ˚ respectively, and two pairs of face-to-face p-p stacking intermolecular interaction with distances of 3.499 and 3.439 A, C–H O or C–H S intermolecular interactions. The above X-ray results indicate that the spiro-type spacers render the molecular structure extremely bulky compared to the planar structures, which not only increases the molecular rigidity but also hinders close packing and intermolecular interaction of chromophores. Consequently, the introduction of a spiro-type linkage into thienyl-S,S-dioxides is probably favorable for the improvement of the luminescent quantum yields in the crystallization state.
Thiophenes and their Benzo Derivatives: Structure
The X-ray crystal structure of new bifunctional helicenes, that is, compound 53, constructed from p-excessive 2-(hydroxymethyl)thiophene and p-deficient pyridine rings, shows that the angles between two adjacent planes vary from 6.2 to 12.9 (Table 25), which indicates that the strain seems to be localized in the inner aromatic rings <1996TL5925>. Hence, the outer bonds C(3)–C(4), C(7)–C(8), and C(11)–C(12) are shortened to 1.34–1.38 A˚ to the ˚ whereas the inner bond distances C(17)–C(18), C(19)–C(20), and C(21)–C(22) are bond length in benzene (1.39 A), ˚ The dihedral angles between the terminal rings is 45.3 , which is larger than that of bislengthened to 1.40–1.43 A. (hydroxymethyl)[7]thiaheterohelicene (38 ) <1995CC1873>.
Table 25 Dihedral angles between planes (deg) Plane
1(T )
2(B)
3(T )
4(B)
5(T )
6(B)
2(B) 3(T) 4(B) 5(T) 6(B) 7(P)
6.2 10.3 21.1 30.0 37.8 45.3
7.4 20.2 29.2 38.1 46.9
12.9 21.9 31.0 40.4
9.1 18.3 28.4
10.0 21.2
11.7
T: thiophene, B: benzene, P: pyridine.
˚ The nonbonded distance between the nitrogen atom and the oxygen atom is 2.72 A. The crystal structure of (P)-1,18-bis(hydroxymethyl)dithieno[3,2-e:39,29-e9]benzo[1,2-b:4,3-b9]bis[1]benzo[b]thiophene ((P)-54) (Figure 11) clearly shows that (P)-54 self-assembles through a right-handed helical network of hydrogen bonds <2000J(P2)2492, 1998CC1141>. A full turn of the helix comprises four chiral helicenediols and the pitch of the helix is ˚ The most remarkable feature of compound (P)-54 is that the right-handed helicenediols arrange in a ‘left15.49 A. handed’ helical manner and the cloverleaf motif repeats by the 43 screw axis. In the supramolecular structure, one of the hydroxy functionalities of compound (P)-54 forms an intramolecular bridge to the other hydroxy group of the same molecule and also forms an intermolecular hydrogen bond to one of the hydroxy groups of an adjacent molecule. The interplanar angle between the terminal thiophene rings of (P)-54 is 33.83 (Table 26). This is in contrast with the guest-free racemic heterohelicenediol (PM)-54 which self-assembles to form an alternate-leaf motif. In the crystal of diol (PM)-54, the two stacking columns, consisting of helicenediols of the same helicity, are aligned along the c-axis. Since each hydroxy group of diol (PM)-54 interacts with one of the hydroxy functions of an adjacent molecule via an intermolecular hydrogen bond, the interplanar angle between the terminal thiophene rings increases to 44.70 (Table 26). When the racemic heterohelicenediol (PM)-54 forms an inclusion complex with EtOH through helical hydrogen bonding, the interplanar angle decreases to 37.96 <1995CC1873>. The distortion from planarity locates on the central aromatic rings of the helical framework, and therefore the dihedral angles between two adjacent rings range from 8.73 to 9.73 for diol (P)-54 and from 9.84 to 12.72 for diol (PM)-54. However, the double-bond character of the two helicenediols are unchanged. Thus, the carbon–carbon bond distances of the outer rings range from 1.33 to 1.36 A˚ in the case of (P)-54 and from 1.33 to 1.37 A˚ in (PM)-54, and the inner carbon–carbon bond distances (C(20)–C(21), C(22)–C(23), and C(24)–C(25)) are 1.42 A˚ for (P)-54, and in a range of 1.41–1.43 A˚ for (PM)-54. The inner carbon–carbon bond lengths in the thiophene rings (C(19)–C(20), C(21)–C(22), and C(25)–C(26)) range from 1.43 to 1.47 A˚ for both (P)-54 and (PM)-54. The common feature of this helical geometry is that the carbon–sulfur bond distances in the thiophene rings of (P)-54, (PM)-54, and ˚ (PM)-54?EtOH are uniformly lengthened from 1.71 to 1.73 A.
657
658
Thiophenes and their Benzo Derivatives: Structure
Figure 11 Numbering scheme of heterohelicenediol 54 and thiohelicenes.
Table 26 Interplanar angles between the adjacent rings and the terminal thiophene rings (deg)
Ring(1)–ring(2) Ring(2)–ring(3) Ring(3)–ring(4) Ring(4)–ring(5)
(P)-54
(PM)-54
8.40 6.92 9.73 9.35
5.82 7.70 10.46 12.72
Ring(5)–ring(6) Ring(6)–ring(7) Ring(1)–ring(7)
(P)-54
(PM)-54
8.73 6.33 33.83
9.84 6.61 44.70
The crystal architecture of thiohelicenes trithia[5]-heterohelicene 55, tetrathia[7]heterohelicene 56, pentathia[9]heterohelicene 57, and esathia[11]heterohelicene 58 show ring distortions smaller than in carbohelicenes (Figure 12) <2000CC11392, 2001CM3906>.
Figure 12 Pentathia[9]heterohelicene 55 and numbering scheme of heterohelicenediol 54.
Thiophenes and their Benzo Derivatives: Structure
The tendency to stacking of antipodes <1985J(P2)1999> in interdigitated columnar structures is apparent. The stacking interactions involve especially the third and/or the fourth rings specific interactions engaging sulfur and hydrogen atoms at distances slightly shorter than the sum of the van der Waals radii (1.80 A˚ for S and 1.20 A˚ for H) were found. They always involve atoms of terminal rings and are quite probably attractive, playing a role in molecular recognition and self-assembly. The contacts S S 3.544 A˚ and S H interactions at 2.87 A˚ appear a key feature of the microsegregation of homochiral, tubular molecules in planes parallel to the ab lattice plane. The helical axes within a plane are parallel and form an angle of ca. 40 with c, while the twofold intramolecular axes are all parallel to b. All the thiohelicenes have a C2 molecular symmetry, the twofold axes bisecting the central ring in the molecules. Both helicenes 57 and 58 show evidence of increased twisting as compared to lower racemic oligomers: they are the first studied thiohelicenes for which more than one helical turn is completed. Projection superposition between two thiophene rings, attaining the helical periodicity, will roughly occur after two turns and 14 rings, that is, after seven C6H2S units. The pitch of the helices increases slightly with molecular size ranging from ca. 3.0 A˚ to 3.1 and 3.2 A˚ in thia[x]helicenes, respectively, with x ¼ 7.9 and 11. Short intramolecular contacts occur between atoms close to the helix axis and seven rings apart; in helicene 55, there are only three of these contacts, while a number of different contacts of this kind occur in helicene 57 and in each the two independent molecules of helicene 58 present in the unit cell. The shorter intramolecular contacts of this kind, 0.3 A˚ or more below the sum of van der Waals radii, must be repulsive: they arise because of the tendency inherent in polyconjugated systems to deviate as little as possible from planarity. Deviations from planarity are clearly more concentrated in central rings, whereas terminal rings are more nearly planar. Informative parameters with respect to steric interactions are the dihedral angles p between the least-squares planes of adjacent rings, the bond angles at the benzene–thiophene junction close to the helix axis, and the torsion angle on the C–C bonds at the interior of the helices. The average values of all these parameters (Table 27) tend to increase from helicenes 55 to 58.
Table 27 Average structural parameters in racemic thiahelicenes Parameters
55a
56b
57
58
c (Mg m3) pe (deg) f (deg) jg (deg) ˚ CCav thioph int (A) ˚ CCav benz int (A) ˚ CCav benz ext (A)
1.570 9.2 131.1 14.4 1.442 1.423 1.360
1.576(1.526d) 9.6(8.90d) 131.6 13.2 1.441 1.432 1.368
1.573 9.8 131.4 15.8 1.444 1.422 1.366
1.581 10.0 131.6 15.4 1.446 1.425 1.365
a
Adapted from <1981CL343>. Adapted from <1985J(P2)1999>. c is the density. d Refers to the pure enantiomer crystal structure of compound 56. e p is the average dihedral angle between least-squares planes of contiguous rings. f is the average bond angle at the helix interior. g j is the average torsion angle at the helix interior. b
The crystal structure of compound 58 is unusual because the asymmetric unit is formed by two complete molecules, as opposed to half a molecule in all the lower racemic thiohelicenes. The packing environment of each of the two closely similar but crystallographically independent molecules, and of each of its halves, is unique: thus the C2 axes bisecting the central ring of each helicene 58 molecule are noncrystallographic. This situation is likely to arise in order to optimize the complex network of specific interactions involving S- and H-atoms. It leads to larger than expected asymmetric units and lower crystal symmetry, common occurrences in hydrogen-bonded molecular systems. In the triclinic crystals 58, four nonequivalent short S S and an equal number of S H interactions are found. X-Ray analyses of bridged [7]thiaheterohelicenes 59a–c and 60 indicate that the dihedral angles between terminal thiophene rings of the helical framework vary significantly from 22 for helicene 60 to 59 for helicene 59c. This represents as increase of 37 or 168% <2002JOC1795>.
659
660
Thiophenes and their Benzo Derivatives: Structure
Although the bridged helicenes (PM)-59a–c possess different lengths of spacer, these all crystallize in the space group of P21/n (Z ¼ 4). In the crystals of helicene (PM)-59a, the bridge of one enantiomer of racemic helicenes locates on the central thiophene–benzene–thiophene rings (rings 3–4–5) of the adjacent enantiomer of the same helicity along the crystallographic b-axis. The C(31)–C(32) bond of the bridge locates perpendicularly to the helical axis. The S(28)–C(31)–C(32)–S(30) dihedral angle of helicene (PM)-59a is 175.4 , indicating that two sulfur atoms of the bridge are in an anti-orientation where the dihedral angle of terminal thiophene rings is 53 . The S(28)–C(31)–C(32)–C(33) and C(31)–C(32)–C(33)–S(30) dihedral angles of helicene 59b are 44.1 and 66.1 , respectively, indicating that the 2,6-dithiaheptano-bridge has a gauche-conformation. The benzene–thiophene–benzene rings (rings 2–3–4) of one enantiomer of helicene 59c stack on those of adjacent helicene of the opposite enantiomer alternately along the a-axis. The S(28)–C(31)–C(32)–C(34), C(31)–C(32)–C(34)–C(33), and C(32)–C(34)–C(33)–S(30) dihedral angles of helicene 59c are 68 , 60 , and 68 , respectively, showing that the 2,7-dithiaoctano bridge is gauche-conformation. Due to the flexible conformations of the bridges of compounds 59a–c, the dihedral angles between terminal thiophene rings do not significantly change. Thus the angle increases slightly from 53 for 59a to 58 for 59b and 59 for 59c. Two crystal structures were observed in (PM-60)4?(benzene), where helicene molecules of the same helicity are aligned along the crystallographic c-axis and guest molecules are situated between each enantiomer of helicene molecules. Although the dihedral angle between a benzene ring (ring 6) of helicene 60 and a benzene molecule is 34.7 , the hydrogen atom at C-4 locates on the center of a benzene molecule with 2.67 A˚ of the H p. In the chiral crystals (P)-60, however, right-handed helicene molecules stack along the crystallographic a-axis by p-interaction, which causes the dihedral angle of (P)-60 to increase slightly from 22 for (PM-60)4?(C6H6) to 26.2 . As shown in Table 28, the shortest carbon–carbon distance (C(19)–C(26)) between terminal thiophene rings of ˚ which is very close to the 2.69 A˚ of [2,2]metacyclophane <1977AXB754>. (PM-60)4?(C6H6) and (P)-60 is 2.70 A,
˚ and dihedral angles (deg) Table 28 Selected nonbonded distances between the terminal thiophene rings (A) Helicene
(PM)-59a
(PM)-59b
(PM)-59c
(PM-60)4?(C6H6)a
(P)-60
C(1)–C(18) C(19)–C(26) C(27)–C(29) Ring 1–ring 2 Ring 2–ring 3 Ring 3–ring 4 Ring 4–ring 5 Ring 5–ring 6 Ring 6–ring 7 Ring 1–ring 7
4.33 3.02 5.30 4.42 10.12 12.87 13.32 9.58 7.29 53.5
4.48 3.11 5.54 7.32 9.16 14.33 13.45 11.68 5.77 57.8
4.60 3.22 6.16 10.57 11.11 10.50 12.86 11.45 10.29 59.2
3.29 2.70 2.90 6.26 4.74 10.51 11.69 4.51 6.69 22.5
3.29 2.70 2.89 5.52 9.47 9.13 12.08 2.13 6.18 26.2
a
3.27 2.70 2.87 6.44 4.44 11.49 11.10 5.86 6.63 21.9
Two independent molecules of bridged helicene 60 exist in crystal lattice; space group is P1 and Z ¼ 4.
Thiophenes and their Benzo Derivatives: Structure
The structures of pure thiophene-based [7]-helicene rac-61a, (þ)-61b, and rac-61b have been confirmed by X-ray crystallographic analyses <2004CEJ6531>.
The crystal of rac-61b was found to be essentially identical to that of (þ)-61b, except for its M-helical chirality. This indicates that crystals of rac-61b, which are obtained from isopropanol/benzene, correspond to a conglomerate, that is, each enantiomer crystallizes separately . [7]Helicenes 61a and 61b possess similar but not identical helical structures <2000AGE4481>. The individual benzene and thiophene rings are approximately planar with mean deviations of the least-square planes between 0.01 ˚ The angles between the least-squares planes of neighboring rings are in the ranges 6.8–11.2 and 9.9– and 0.06 A. 12.7 for rac-61a and (þ)-61b, respectively; with the middle ring as a reference, the corresponding inner helix climbs are 3.15 A˚ (C(1)–C(17) for rac-61a), and 3.52 A˚ (C(2)–C(17) for (þ)-61b). Interplanar angles between the terminal thiophene rings are 40.2 and 59.18 for rac-61a, and (þ)-61b, respectively. In the crystal of rac-61a, homochiral [7]-helicene molecules form p-stacked columns along the b-axis; the unit cell contains four such stacks. Consecutive molecules within the stack are rotated around their helical axes, leading to strong p-overlap between the two terminal thiophene rings for the nearest neighbor molecules; for example, each [7]˚ and helicene molecule possesses six short S S contacts (S(2) S(6) ¼ 3.58, S(1) S(5) ¼ 3.60, S(2) S(5) ¼ 3.60 A, their symmetry-related counterparts) with its two homochiral neighbors within the stack. Along the a-axis, inefficient packing of the alkyl groups from the homochiral columns leads to voids (282 A˚ 3 or about 3% of the cell volume) with no significant electron density. The columns of opposite handedness are closely packed along the c-axis; each [7]˚ with its two heterochiral neighbors. helicene possesses two contacts (S(3) S(6) ¼ S(6) S(3) ¼ 3.63 A) In the crystal of (þ)-61b (or conglomerate), homochiral [7]-helicene molecules form herringbone-like chains along ˚ S C (3.396 A), ˚ and Br Br (3.623 A) ˚ contacts with its two the b-axis; each molecule has six short S S (3.585 A), nearest neighbors. Along the c-axis, multiple short contacts (S alkyl group) between the herringbone-like chains are found. The molecules that are related by the translation along the a-axis may be viewed as loosely p-stacked (with ˚ shortest S S contacts of 3.96 A).
3.09.3.2 Molecular Spectroscopy 3.09.3.2.1
Proton NMR spectroscopy
Spectroscopy is an important tool for the structure elucidation of compounds. Modern methods enable determination of conformation, aromaticity, mechanism, and other physical properties. The 1H NMR spectrum of thiophene in CDC13 consists of two multiplets at 7.18 and 6.99 ppm, the one at lower field being assigned to the -hydrogens <1965SA85>. The chemical shifts and coupling constants for thiophene in CDC13 and acetone-d6 are listed in Table 29. The vicinal proton couplings here are much smaller than in benzene. The chemical shifts of the protons in thiophene are solvent dependent <1986BCJ1650>; the H-2 proton resonates at 6.89 and 7.16 ppm in benzene-d6 and cyclohexane <1965BCJ1041, 1974JOM(77)49> and at 7.46 ppm in acetone-d6 <1968ICA(2)12>. The presence of a methyl or an alkyl substituent at the 2-position shifts the other protons upfield by 0.2–0.4 ppm Substituents at the 3-position also cause the protons to shift upfield. With electron-donating substituents, the H-2 hydrogens are found more upfield than the H-4 hydrogens. Electron-withdrawing substituents at the C-2 position cause substantial downfield shifts of the H-3 and H-5 protons while the H-4 proton chemical shift is hardly affected. For 3-substituents, the H-2 and H-4 protons are shifted downfield.
661
662
Thiophenes and their Benzo Derivatives: Structure
Table 29 Proton NMR spectral data for thiophenea
H-2 H-3 J2,3 J2,4 J2,5 J3,4
CDCl3b
CDCl3c
CDCl3d
CDCl3e
Acetone-d6f
7.20 6.96 4.8 1.0 2.8 3.5
7.18 6.99 4.90 1.04 2.84 3.50
7.34 7.12 4.95 1.05 2.85 3.50
7.35 7.14 5.0 0.9 3.0 4.1
7.46 7.14 4.6 1.1 3.6 2.8
a
Chemical shifts in ppm, coupling constants in Hz. <1960AK563>. c <1965SA85>. d <1983BCJ2463>. e <1968ICA(2)12>. f <1968ICA(2)12>. b
For mono- and disubstituted derivatives, the coupling constants for most compounds were as follows: J2,3 (or J4,5) 4.9–5.8 Hz, J2,4 (or J3,5) 1.2–1.7 Hz, J2.5 3.2–3.6 Hz, J3,4 3.4–4.3 Hz <1960AK501, 1960AK563>. In the presence of strongly electropositive or electronegative substituents, values outside this range are observed; a J3.4 of 6.0 Hz is observed for 2-amino-5-nitrothiophene <1981JHC851>. In benzo[b]thiophene, the H-2 and H-3 protons resonate at 7.33 and 7.22 ppm <1966BCJ2316>, while for benzo[c]thiophene the H-l and H-3 protons appear at 7.63 ppm <1976J(P2)81>. The 1H NMR spectra of methyl 3-, 4-, and 5-substituted 2-thiophenecarboxylates 62–64 have been obtained to compare with those of 2- and 3-substituted thiophenes 65 and 66 <1983BCJ2463>.
Although the calculated chemical shifts in compounds 63 and 64 are in good agreement with experimental values, those of compounds 62 show large deviations since the carbonyl group can exist in the S,O-cis-62a or S,O-trans-62b orientation due to the presence of a substituent at the 3-position. Chemical shifts and coupling constants indicate that thiophene 1,1-dioxides possess reasonable diene character <1984ZNB915>. The 1H NMR spectrum in CDC13 shows the - and -protons at 6.64 and 6.38 ppm, respectively, which is about 0.7 ppm upfield from the corresponding resonances in thiophene. Similarly, the H-2 and H-3 protons in 4,5-dihydrothiophene resonate at 6.06 and 5.48 ppm while that of the corresponding dioxide are found at 6.66 and 6.81 ppm, respectively. The NMR spectra of molecules dissolved in liquid-crystalline solvents may be analyzed to yield sets of partially averaged dipolar couplings, Dij (also referred to as residual dipolar couplings), between the magnetic nuclei, and these may be used to determine the relative positions of these nuclei if the molecule is rigid . If there is some internal motion, it may also be possible to determine the conformational distribution. The most interesting and challenging uses of this method of structural characterization are for molecules with internal, large-amplitude motions, as these cannot easily be studied by other experimental techniques.
Thiophenes and their Benzo Derivatives: Structure
There will always be an uncertainty about how precise a structure and conformational probability can be obtained by this liquid crystal NMR method (LXNMR), clearly in part because of the necessary approximations made in the analysis of the data, but also because the conformation and, to a lesser extent, the structure of the flexible molecule will be dependent on the chemical nature of the solvent. The proton NMR spectra of samples of 2-thiophenecarboxaldehyde (TCA) dissolved in a nematic liquid crystalline solvent, including those from all five singly labeled 13C isotopomers, have been studied <2005MI1483>. Bond lengths and angles for TCA, and a probability distribution, Piso(), have been obtained from sets of dipolar couplings obtained by analyzing the proton spectra of the five singly labeled 13C plus the all-12C isotopomers. The analysis of the NMR data involved calculating vibrational corrections and applying the additive potential method to allow for the correlation between molecular conformation and orientational order. The results are in good, although not exact, agreement with the results of B3LYP/6-31G* calculations, which can be regarded as supporting the methodology used for obtaining the structure and conformational distribution of a flexible molecule in a liquid phase (Table 30). ˚ angles (deg), percentage of the cis-isomer and Gaussian function width (Hz) obtained for Table 30 The bond lengths (A), 2-thiophenecarboxaldehyde by using the AP model with: A, the ring geometry optimized previously; B, optimizing the geometry of the whole molecule together; and C, as in B, but fixing R6,3 at the value found by method A. The DFT trans-geometry is also reported for comparison Parameter R2,1 R3,2 R4,1 R6,3 R6,7 R9,1 R10,2 R11,4 ff3,2,1 ff4,1,2 ff6,3,2 ff7,6,3 ff9,1,2 ff10,2,1 ff11,4,1 % cis ht ¼ hc (deg) RMS (Hz) a
A
B a
1.419 1.39 0.01 1.37 0.01 1.45 0.03 1.111 0.002 1.080 0.007 1.075 0.008 1.069 0.006 111.4 0.5 112.7 0.7 125.1 0.6 114.8 0.3 123.9 0.4 125.1 0.3 128.4 0.7 6.0a 0.93
C a
1.419 1.400 0.009 1.38 0.01 1.50 0.03 1.10 0.01 1.086 0.007 1.082 0.008 1.074 0.006 111.4 0.4 112.8 0.7 124.8 0.6 114.1 0.9 124.1 0.4 125.1 0.3 128.5 0.7 9.1 6.0a 0.75
DFT (trans) a
1.419 1.394 0.009 1.37 0.01 1.456[a] 1.116 0.008 1.081 0.007 1.081 0.008 1.072 0.007 111.7 0.4 112.3 0.7 125.7 0.4 115.3 0.5 123.9 0.4 125.1 0.4 128.1 0.7
1.419 1.380 1.374 1.458 1.112 1.084 1.085 1.082 112.98 112.16 127.50 113.81 124.24 124.29 127.49 8.03
6.0a 0.81
Kept fixed.
2-Benzoylthiophenes 67, which have substituents at m- and p-positions of the benzoyl ring, were prepared and their IR and NMR spectra were obtained in chloroform-d solution <2003JHC763>. The chemical shift values of each series were plotted against the Hammett substituent parameters to give good correlation, with the exception of the ortho-H’s. The slopes as well as the differences in chemical shift gave sets of meaningful values for the indices of aromaticity. The 1H chemical shift values are listed in Table 31. The difference in chemical shifts of the 3H and 4H of the thiophene are considered to be a measure of relative aromaticity <1974JCS(P2)332>.
663
664
Thiophenes and their Benzo Derivatives: Structure
Table 31
67a 67b 67c 67d 67e 67f
1
H chemical shift values of substituted benzoylthiophenes 67 in chloroform-d (0.1 M) 3H
4H
5H
7.66 7.64 7.64 7.68 7.68 7.63
7.23 7.19 7.18 7.16 7.12 7.22
7.82 7.82 7.76 7.72 7.61 7.83
67g 67h 67i 67j 67k
3H
4H
5H
7.62 7.63 7.64 7.65 7.65
7.18 7.22 7.16 7.16 7.17
7.74 7.83 7.69 7.70 7.73
The effects of m- and p-substituents in the benzoyl group on the chemical shift of 1H thiophene 67 were analyzed by the Hammett equation (Equation 3). The results are listed in Table 32. ð3Þ
¼ þ o
Table 32 Best fit of the single-substituent-parameter equation for the 1H chemical shifts of 67 in chloroform-d in hertz
ortho-H meta-H para-H
r
2.8 26.3 52.5
0.150 0.939 0.984
The plots of 1H chemical shifts against various substituent parameters show best correlation with the Hammett -values . Other -values such as þ do not show a reasonable correlation. The correlation shows several interesting phenomena. First of all, ortho-H show no correlation while meta- and para-H show fair correlations with -values. The slopes of the para-H are larger than those of meta-H by 26.2 Hz for 67. As listed in Table 33, -H’s of the heterocycles appear downfield and the difference between - and -H’s are 0.22 ppm for thiophene. If an assumption is made that the difference of - and -H’s of benzene is zero because it is fully aromatic and it corresponds to the index of aromaticity of 1.00, then the relative indices of aromaticity may be related to the difference between -H and -H. A set of indexes may be proposed for thiophene 0.89 (¼1.00 0.22/ 2). This seems quite reasonable not only because the difference in chemical shift of - and -H is likely to originate from the presence of the heteroatom but also because the values are in the range of reported sets of aromaticity indexes <1974AHC(17)255, 1993AHC(56)303, 1991H(32)127, 1981JST(85)163, 1985T1409>.
Table 33 Averaged chemical shift values of benzoylthiophenes 67 in chloroform-d (0.1 M) and their differences 2,5(a)-Ha 3,4(b)-Ha (a–b) ortho-H meta-H para-H a
7.35 7.13 0.22 7.65 0.03 7.18 0.05 7.74 0.09
Parent aromatic compounds.
Similarly, a series of m- and p-substituted anilides 68 of thienoic acid were prepared and their 1H NMR spectroscopic characteristics were examined. In general, good correlations were observed between the chemical shifts of proton signals of the acyl aromatic rings and the Hammett <2002JHC1219>.
Thiophenes and their Benzo Derivatives: Structure
The 1H signals of the aromatic region of monodisperse regioregular HT oligo(octylthiophene)s ranging from the dimer to the hexamer were assigned in CDCl3 and THF-d8 on the basis of the proton signals of the monomer octylthiophene 69 (Figure 13). The linear dependence of proton chemical shifts on the reciprocal number of thiophenes is demonstrated in both solvents. Weak signals surrounding the main peak in the spectrum of the regioregular HT poly(octylthiophene) are assigned in CDCl3 and THF-d8 in the light of results obtained for the hexamer. In particular, the end-of-chain protons of the polymer could be assigned. Spin-lattice relaxation times (T1) of aromatic protons of the hexamer were measured in CDCl3 and THF-d8. It was observed that T1 depended on the position of the proton along the main chain. This result was interpreted in terms of molecular motions <2001MRC57>.
Figure 13 Position on the thiophene ring and different oligomers.
Their chemical shifts were roughly the same in oligomers 70 (n ¼ 6) and 71 (n ¼ 6) (Hd6 ¼ 7.160 ppm and Hc6 6.930 ppm). As expected, the spectra of oligomers 70 (n ¼ 6) and 71 (n ¼ 6) showed several differences (Table 34). First, the spectrum of oligomer 70 (n ¼ 6) did not exhibit the characteristic shielded signal related to the proton in c1 ( 6.8 ppm), which was observed in the spectrum of each chlorinated oligomer (at 6.820 ppm in oligomer 71 (n ¼ 6)). This observation confirmed the assignment of Hc1 in compounds 71 (n ¼ 2) to 71 (n ¼ 6) to the most shielded signal. Second, the oligomer 70 (n ¼ 6) spectrum presented two new doublets centered at 6.89 and 6.97 ppm, which did not appear in the spectrum of oligomer 71 (n ¼ 6) . These two doublets were assigned without any ambiguity to protons in c1 and a1 (which does not exist in chlorinated oligomers). The doublet at 6.97 ppm was assigned to the proton in c1 taking into account the shielding effect of chlorine in a1 on the proton in c1 ( 0.14 ppm). Within this assignment, the chemical shift of Hc1 in oligomer 70 (n ¼ 6) was higher than those of the protons in the other cn positions. This result agreed with the data reported in the literature for the regioregular HT ter(hexylthiophene) <1994MM3039>. The value of the coupling constant 4J(H, H) between protons in a1 and c1 (determined on the 1-D spectrum) was equal to 1.5 Hz (in the literature the value reported was around 2–3 Hz <1994MM3039>). Third, some differences were observed between the spectra of oligomers 70 (n ¼ 6) and 71 (n ¼ 6) in the region of protons in c2, c3, c4, and c5: the signal at 6.945 ppm disappeared in oligomer 70 (n ¼ 6) while the signal in the region around 6.96 ppm increased. This result was easily explained by taking into account the slight shielding effect of chlorine in a1 on the proton in c2 ( 0.023 ppm obtained by comparison of the assignments for the oligomer 71 (n ¼ 3) assignments with those of the related nonchlorinated oligomer <1994MM3039>). Therefore, the proton Hc2 was assigned to the signal at 6.945 ppm in oligomer 71 (n ¼ 6) and to the signal at 6.956 ppm in oligomer 70 (n ¼ 6). Table 34 (italics)
1
H chemical shifts of the aromatic region of oligomers 70 (n ¼ 1 and 6) and 71 (n ¼ 1, and 6) in CDCl3 and THF-d8
Oligomer
a1
c1
70 (n ¼ 1) 71 (n ¼ 1) 70 (n ¼ 6)
6.92d
6.93d 6.79b 6.970c 7.020c 6.820a 6.943a
6.898c 7.020c
71 (n ¼ 6) a
Singlet. Doublet. 3J(cn, dn) ¼ 5 Hz. c4 J(c1, d1) ¼ 1.5 Hz. d Multiplet. b
c2a
6.956 7.034 6.945 7.041
c3a
6.956 7.043 6.956 7.049
c4 a
6.956 7.030 6.956 7.036
c5 a
6.936 6.993 6.936 6.995
c6 d
dn
6.929 6.945 6.930 6.945
7.23d 7.15b 7.160b 7.256b 7.160b 7.257b
665
666
Thiophenes and their Benzo Derivatives: Structure
Spin-lattice relaxation times of the aromatic protons of oligomer 70 (n ¼ 6) in CDCl3 and THF-d8 are reported in Table 35. In CDCl3, the highest T1 values (ranging between 5 and 6 s) were observed for protons of the ‘external rings’ in a1 and d6 (-position with respect to the sulfur). This T1 value was approximately 3 times higher than those of the other aromatic protons in c1, c2, c3, c4, c5, and c6 and 10 times higher than T1 value of alkyl-chain protons. Moreover, the T1 values of the protons at the c-position of the ‘external’ rings (c1 and c6) were higher than those of the related protons of the ‘internal’ rings (c2, c3, c4, and c5).
Table 35 Spin-lattice relaxation times (T1) of the aromatic protons of 70 (n ¼ 6) recorded at 400 MHz CDCl3 T1 (s)
Position a1 c1 c2 c3 a
5.95 2.35
THF-d8
Position
CDCl3 T1 (s)
THF-d8
3.7
c4 c5 c6 d6
a 2.1b 5.2
1.87 1.94 2.33 6.3
1.76 1.69
1.65
The value could not be determined. Determined on one of the two peaks of the doublet.
b
In THF-d8, the values of T1 relative to all protons except those in a1 and c1 were close to values obtained in CDCl3. Full and unambiguous asssignment of all 1H signals by combined application of 1-D and 2-D standard NMR techniques of the free bases as well as the hydrochloride salts of the antiarrhythmic agent propafenone 72 and a thiophene analogue 73 in different solutions (dimethyl sulfoxide-d6, (DMSO-d6), CDCl3) has been reported (Table 36) <2001MOL796>.
Table 36 Compound Solvent H-3 H-4
1
H chemical shifts and selected 1H,1H-coupling constants 73 DMSO-d6 7.12 7.86
CDCl3 6.85 7.48
73?HCl DMSO-d6 7.15 7.86
CDCl3 6.87 7.44
3
J(3,4) ¼ 5.5 Hz (73 and 73?HCl/CDCl3 and DMSO-d6).
Poly(3-alkylthiophenes) display properties superior to PT, namely higher conductivity, solubility in organic solvents, and the capability of melting at a higher temperature <1986CC873, 1986CC1346, 1986SM(15)169, 1987MM212, 1987MM965>. In this context, a variety of polymers with functionalized substituents on the 3-position of the thiophene units have been synthesized <1996MM7671> and studied; these unsymmetrical thiophene rings can be incorporated into a polymer chain with two different regioregularities, HT (e.g., 74) and head-to-head (HH), which may cause four regioisomeric triads in the polymer chain: HT–HT, HT–HH, TT–HT, and TT–HH triad. The regioregularity strongly affects the polymer’s properties <1992CRV711, 1987JPC6706, 1990MM1268, 1991JA7064, 1991CM888, 1992MM554, B-1987MI(76)400>.
Thiophenes and their Benzo Derivatives: Structure
1
H NMR data provided important information about the regioregularity of poly(3-substituted thiophenes). The b-protons of thiophene units in different regiochemical circumstances, HT–HT, HT–HH, TT–HT, and TT–HH, had different chemical shifts and showed four singlet peaks in the aromatic area. The ratio of the integration of these peaks has been used to determine the regioregularity of the PTs. Since the b-proton of the thiophene units in an HT regioregular poly(3-substituted thiophene) is located in a unique HT–HT-arranged regio-environment, only one singlet aromatic proton peak will be observed in the 1H NMR spectrum.
3.09.3.2.2
Carbon-13 NMR spectroscopy
The 13C NMR spectrum of thiophene (in acetone-d6) shows the C-2 and C-3 carbons at 125.6 and 127.3 ppm, respectively <1965JA5333, 1975CS76>. The larger value of the 13C–H coupling constants for the 2-position as compared to the 3-position (185 vs. 168 Hz) is helpful in the structure elucidation of trisubstituted derivatives. The 13C NMR chemical shifts of some substituted thiophenes are listed in Table 37. Highly electronegative substituents cause the largest downfield shift on the ipso-carbon atom but the adjacent carbons are upfield as compared to thiophene. For substituents at the 2-position, the C-4 carbon resonances are the least affected, while for 3-substituted thiophenes, the C-5 resonances do not change much.
Table 37 Carbon-13 NMR chemical shifts (ppm) of some substituted thiophenesa,b Substituent
C-2
C-3
C-4
C-5
H 2-Me 2-F 2-C1 2-NO2 2-OMe 2-Phc 3-Me 3-F 3-Cl 3-NO2 3-OMe 3-Phc 2,5-di-Med
125.6 139.8 (þ14.2) 166.5 (þ40.9) 129.7 (þ4.1) 151.2 (þ25.6) 167.4 (þ41.8) 143.5 (þ17.9) 121.3 (4.3) 104.2 (21.4) 120.9 (4.7) 129.2 (þ3.6) 97.3 (28.3) 120.1 (5.5) 137.4 (þ11.8)
127.3 125.9 (1.4) 108.0 (19.3) 127.4 (þ0.1) 129.9 (þ2.6) 104.2 (23.1) 123.9 (3.4) 138.2 (þ10.9) 159.2 (þ31.9) 125.7 (1.6) 149.7 (þ22.4) 159.8 (þ32.5) 142.3 (þ15.0) 125.3 (2.0)
127.3 127.3 (0) 124.7 (2.6) 129.6 (þ2.3) 128.7 (þ1.4) 125.5 (1.8) 126.5 (0.8) 130.1 (þ2.8) 117.8 (9.5) 128.1 (þ0.8) 123.1 (4.2) 119.9 (7.4) 126.2 (1.1) 125.3 (2.0)
125.6 123.7 (1.9) 114.9 (10.7) 125.3 (0.3) 134.2 (þ8.6) 112.4 (13.2) 122.2 (3.4) 126.1 (þ0.5) 126.4 (þ0.8) 127.5 (þ1.9) 128.9 (þ3.3) 125.6 (0) 126.2 (þ0.6) 137.4 (þ11.8)
a
Value in parentheses corresponds to shifts relative to thiophene. <1975CS76>. c <1986HC(44/2)135>. d <1965JA5333>. b
The C-2 carbon atom is 2.4 ppm downfield with respect to the C-3 carbon atom in benzo[b]thiophene <1979OMR647>. The 13C chemical shifts for benzo[b]thiophene 7 <1976OMR252> and dibenzothiophene 9 are given.
667
668
Thiophenes and their Benzo Derivatives: Structure
The 13C NMR spectra of thiophene, and their 2-methyl and 2,5-dimethyl derivatives, have been obtained and completely assigned (Table 38). The initial assignment of chemical shift values for the 2-methyl series was based on additive substituent relationships and 13C–H coupling constants. Aromatic character in these compounds is inferred from the similarity of the corresponding chemical shift values with those of the ordinary benzenoid aromatics. Failure of the chemical shift data to correlate in every detail with estimates of the p-electron charge densities argues for the importance of -bond effects <1965JA5333>.
Table 38
1
JCH of thiophene and 2-methyl and 2,5-dimethyl derivatives
Compound
Position
Ha( ppm)
1
Thiophene
2,5 3,4 2 3 4 5 Me 2,5 3,4 Me
7.04 6.92
189 168
6.60 6.73 6.82 2.29
164 170 186 129
6.40 2.25
162 125
2-Methylthiophene
2,5-Dimethylthiophene
a
JCH (Hz)
Relative to TMS.
Anisotropy, resonance, and inductive effects affect 13C chemical shifts of carbon atoms of aromatic and heteroaromatic rings: the superimposition of these effects usually prevents the occurrence of mono- (Hammett) or biparametric (DSP, dual-substituent-parameter) <1973MI1> linear free energy relationships (LFERs) for the relevant substituent-induced chemical shift (SCS) values, when substituent and probe carbon atom are in the same ring. In contrast, the effect of a substituent not directly linked to the ring containing the probe carbon atom leads to SCS values (possibly small) that can be correlated by means of mono- or biparametric LFERs <1993MI229, 1995MRC883, 1990BCJ328, 1997G331>. The 13C NMR data of 2-nitro- 75 and 3-nitrobenzo[b]thiophenes 76 in DMSO-d6 solutions have shown <2003T7189> the occurrence of an alternate polarization, which can involve carbons C-3, C-2, C-3a, C-7a, C-4, and C-5 of the 2-nitrobenzo[b]thiophen-3-yl moiety. A dual-substituent-parameter treatment of the 13C SCS indicates a large and a low resonance contribution for aryl para- and meta-substituents, respectively, while the inductive component remains constant throughout <1995MRC883>.
Thiophenes and their Benzo Derivatives: Structure
In Table 39, 13C SCS data of compounds 75 and 76 in DMSO-d6 are collected. A rough examination of data shows the absence of the expected substituent effects on SCS: for example, in the 75 series, both electron-withdrawing and -repelling substituents cause shielding and deshielding of C-2 and C-3, respectively. Also, in the case of 76, the SCS variations cannot be related to the electronic effects of the substituents, essentially paralleling the situation observed for compound 75.
Table 39
13
C NMR SCSs for 3-anilino-2-nitrobenzo[b]thiophenes 75 and 2-anilino-3-nitrobenzo[b]thiophenes 76 in DMSO-d6
Compound
X
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
75f 75a 75b 75c 75d 75e 75g 75h 75i
H OH NH2 OMe Me Et F Cl Br SCSa
124.42 22.53 22.65 21.89 22.55 22.53 20.22 20.75 20.98 2.65
142.71 2.70 2.40 1.95 2.47 2.72 0.18 0.82 0.89 2.72
129.35 20.21 20.51 20.29 20.57 20.76 0.16 20.23 20.41 0.92
126.19 20.40 0.25 20.57 20.38 20.05 21.03 20.81 20.71 1.28
124.59 0.13 0.18 0.15 0.24 0.12 0.50 0.54 0.44 0.54
130.72 0.30 0.42 0.33 0.32 0.35 0.20 0.33 0.30 0.42
123.78 20.03 20.02 0.07 0.16 0.19 0.16 0.29 0.23 0.32
137.49 0.08 0.52 0.05 0.46 0.57 20.25 0.05 0.07 0.82
76f 76c 76d 76e 76g 76h 76i
H OMe Me Et F Cl Br SCSa
162.42 20.79 1.75 2.08 0.14 0.41 0.45 2.87
119.94 0.10 20.77 20.72 0.07 20.15 20.25 0.87
130.94 20.26 0.13 0.37 20.05 0.11 0.04 0.63
121.23 0.15 0.02 0.01 0.00 0.17 0.11 0.17
126.69 0.17 0.00 0.01 20.03 0.21 0.16 0.24
124.74 0.16 20.16 20.13 20.12 0.10 0.05 0.32
122.34 0.13 0.09 0.07 20.11 0.22 0.16 0.33
125.02 0.24 0.24 0.22 20.01 0.25 0.25 0.26
a
SCS – range of substituent effect on chemical shifts.
In order to lower the proximity effects caused by the solvent, 13C chemical shift values of compounds 75 and 76 have also been collected in CDCl3 solutions (Table 40). In the compound 75 series, electron-withdrawing and -repelling substituents cause shielding and deshielding of C-3 (SCS 3.27 ppm), respectively, while the usual inverted effect can be evidenced for C-2 (SCS 2.74 ppm).
Table 40
13
C NMR SCSs for 3-anilino-2-nitrobenzo[b]thiophenes 75 and 2-anilino-3-nitrobenzo[b]thiophenes 76 in CDCl3
Compound
X
C-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
75f 75b 75c 75d 75e 75g 75h 75i
H NH2 OMe Me Et F Cl Br SCSa
125.00 21.06 20.59 21.51 21.47 0.74 1.09 1.23 2.74
144.26 1.71 0.36 1.19 1.35 20.69 21.52 21.56 3.27
128.78 0.02 0.17 20.04 20.12 0.13 0.08 0.07 0.29
127.17 20.39 20.60 20.64 20.35 21.07 20.83 20.69 1.07
124.33 0.46 20.03 0.28 0.16 0.33 0.31 0.30 0.49
130.61 0.24 0.04 0.18 0.14 0.05 20.02 20.04 0.28
123.49 20.15 20.18 20.03 20.01 0.04 0.01 0.07 0.25
138.87 0.04 20.31 0.08 0.18 20.34 20.46 20.38 0.64
76f 76c 76d 76e 76g 76h 76i
H OMe Me Et F Cl Br SCSa
160.92 22.05 1.72 2.08 20.86 22.01 21.65 4.13
121.75 0.26 1.20 1.17 0.65 0.71 0.59 1.20
131.06 20.24 0.34 0.28 20.03 20.23 20.17 0.58
122.64 20.12 20.04 20.16 0.15 0.05 0.02 0.31
127.06 20.06 20.02 20.09 0.18 0.13 0.11 0.27
125.22 20.11 20.07 20.10 0.14 0.14 0.13 0.25
121.49 0.06 0.11 0.11 0.11 0.06 0.08 0.11
125.28 0.16 0.25 0.19 0.11 0.08 0.00 0.25
a
SCS – range of substituent effect on chemical shifts.
669
670
Thiophenes and their Benzo Derivatives: Structure
In the compound 75 series, the small SCS values (0.3–1.1 ppm) and the occurrence of some scattered behavior for the other carbons of the benzo[b]thiophene moiety discourages the search for LFERs, except for C-7a. In this instance, only a rough correlation has been observed by means of a monoparametric LFER treatment ( R 0.96, r 0.78). Interestingly, a dissociation of electronic effects in their components (inductive and resonance contributions) strongly improves the statistical results ( I 1.17 and R 0.29, R 0.945): this occurrence can be related to the peculiar R/ I ratio observed ( ca. 0.25), unusually low for conjugated systems. As a matter of fact, the -value calculated recalls the figure observed in meta-substituted compounds <1995MRC883>, indicating that some significant steric hindrance operates, thus lowering the resonance effects. For compounds of the 76 series, a somewhat different behavior has been observed: only the C-2 chemical shift shows the expected substituent effects. Complete assignment of the 13C chemical shifts of thiophene-substituted p-xylenes by different NMR techniques has been reported (Table 41) <2004MRC931>.
Table 41 1H and 13C NMR chemical shifts and T1C values of the aromatic part of the carbon and proton spectra of monomers 77a and 77b 77a Entry 2 3 4 5 29 39 49 59 69 a
Proton
6.83 6.94 7.18 7.25
7.42
77b Carbon
T1Ca (s)
140.21 (Cq) 126.10 (CH) 126.97 (CH) 124.51 (CH) 139.99 (Cq) 131.10 (CH) 132.78 (Cq) 128.41 (Cq) 132.72 (CH)
7.54 2.17 2.06 1.32 3.44 0.67 4.54 2.80 0.88
Proton
6.92 7.28 6.98 7.19
7.41
Carbon
T1Ca (s)
137.95 (Cq) 128.02 (CH) 125.88 (CH) 122.02 (CH) 140.14 (Cq) 131.04 (CH) 132.57 (Cq) 127.99 (Cq) 132.57 (CH)
8.55 3.11 1.89 2.49 3.57 0.68 5.03 2.80 0.58
Average error is about 2%.
Some degree of classification of the aromatic carbon resonances can also be found in the T1C decay times. The protonated carbons C-39 and C-69 have T1C values below 1 s, whereas those of the thiophene ring are situated between about 1 and 3 s. The quaternary carbons next to the methylene carbon (C-29 and C-59) relax with a decay time between 2.8 and 3.6 s, whereas those next to a methine carbon have much longer decay times of >4.5 s. Since the relaxation of carbon nuclei mainly occurs via neighboring protons, the higher the surrounding proton density, the shorter is the T1C decay time. An overview of the T1C values for both monomers is presented in Table 41. Spin–spin carbon–carbon coupling constants across one bond and carbon–proton coupling constants across one, two, and three bonds have been measured for a large series of derivatives of five-membered heterocyclic compounds. This included 2-methyl (ethyl) and 2-lithio derivatives of thiophene and a series of 2-R-substituted thiophenes where R ¼ O-But, Cl, Br, I, Si(CH3)3, MgBr, MgTh, and BTh2 <1999SAA91>. The one-bond CC coupling data for the lithium and 2-methyl derivatives of thiophene are collected in Table 42. The 1JCC couplings for a series of substituted thiophenes are presented in Table 43. The nJCH (n ¼ 1–3) couplings are given in Tables 44 and 45. In Table 44, the couplings 2,3JC2Hm (m ¼ 3–5) are collected; in Table 45, the 1JCH and in Table 46 the 2–3JCH couplings connected with carbons 3, 4, and 5 are given. In Table 47, the 13C NMR chemical shifts for the lithium, magnesium, silyl, and t-butoxy derivatives (compounds 79, 80, 81, 82, and 88) are included.
Thiophenes and their Benzo Derivatives: Structure
Table 42 One-bond carbon–carbon spin–spin couplings in thiophene 1, 2-methylthiophene 78, and in 2-lithiothiophene 79. All values are given in Hz Compound
2-R
1
1 78 79
H Me Li
64.2 65.3 27.6
a
JC(2)C(3)
1
1
a 56.3 50.5
64.2 62.7 67.2
JC(3)C(4)
JC(4)C(5)
Reference B-1995MI(30)131 1999SAA91 1999SAA91
Could not be determined.
Table 43 One-bond carbon–carbon spin–spin coupling constants in 2-substituted thiophenes. All values are given in Hz Compound
R
1
1 78 79 80 81 82 83 84 85 86 87 88
H Me Li MgBr MgTh SiMe3 BTh2 Et I Br Cl O-But
64.2 65.3 27.6 35.8 35.6 52.1 53.8 65.2b 66.0 70.5 74.1 78.8
a
JC(2)C(3)
1
1
a 56.3 50.5 51.9 51.7 55.6 55.8 56.7 54.7 55.7 a 60.2
64.2 62.7 67.2 a 66.1 64.6 61.0 62.9 63.4 63.2 63.0 64.7
JC(3)C(4)
JC(4)C(5)
Reference B-1995MI(30)131 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1996ZNB1811 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1999SAA91
Could not be determined. JC(2)CH(2) ¼ 47.5 Hz.
b1
Table 44 Two- and three-bond C(2)–H(3–5) coupling constants, 2JC(2)H(3), 3JC(2)H(4), and 3JC(2)H(5), in thiophene and 2-substituted thiophenes. All values are given in Hz Compound
R
2
1 78 79 81 82 85
H Me Li MgTh SiMe3 I
86
Br
87
Cl
88
O-But
þ7.61 þ7.2 þ21.8 þ19.8 þ11.5 3.7 3.9 þ2.22 2.2 þ1.9 þ1.91 þ2.3
a
JC(2)H(3)
3
JC(2)H(4)
þ11.51 þ10.3 þ4.4 þ5.5 þ8.3 13.6 13.6 þ14.10 14.1 þ13.6 þ13.84 þ12.2
3
Reference
þ3.91 þ4.8 þ1.6 a þ3.4 6.5 6.5 þ7.51 7.4 þ7.8 þ7.88 þ7.0
1976JST(31)161 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1985M685 1981MR396 1975OMR572 1999SAA91 1981MR396 1999SAA91
JC(2)H(5)
Has not been observed.
Table 45 One-bond C–H coupling constants corresponding to carbons 3, 4, and 5 in thiophene and 2-substituted thiophenes. All values are given in Hz Compound
R
1
1 78
H Me
79 81
Li MgTh
166.95 164.2 164 157.3 158.5
JC(3)H(3)
1
1
166.95 167.2 165 156.8 159.0
184.70 185.4 186 176.5 178.8
JC(4)H(4)
JC(5)H(5)
Reference 1976JST(31)161 1999SAA91 1975CS76 1999SAA91 1999SAA91 (Continued)
671
672
Thiophenes and their Benzo Derivatives: Structure
Table 45 (Continued) Compound
R
1
82 85
SiMe3 I
86
Br
87
Cl
88
O-But
164.9 172.7 172.4 173 171.5 172.3 172.4 172 171.0 172.4 171.69 172 166.8
JC(3)H(3)
1
1
164.9 170.1 170.3 170 170.0 169.9 170.4 171 169.6 169.5 169.91 171 167.5
183.2 188.3 188.9 189 186.9 188.1 188.1 190 189.7 190.2 188.333 190 186.9
JC(4)H(4)
JC(5)H(5)
Reference 1999SAA91 1999SAA91 1985M685 1975CS76 1970JPC2765 1981MR396 1975OMR572 1975CS76 1970JPC2765 1999SAA91 1981MR396 1975CS76 1999SAA91
Table 46 Two- and three-bond C–H coupling constants corresponding to carbons 3, 4 , and 5 in thiophene and 2-substituted thiophenes. All values are given in Hza Compound
R
2
1 78
H Me
79 81 82 85
Li MgTh SiMe3 I
86
Br
87
Cl
88
O-But
þ5.81 þ5.7 5.2 5.8 þ6.2 þ6.0 þ5.6 5.9 6.2 5.6 6.1 þ5.8 5.8 5.6 6.1 þ5.7 þ5.67 5.5 þ5.3
JC(3)H(4)
2
JC(4)H(3)
þ5.81 þ6.3 5.3 5.55 þ9.6 þ9.1 þ6.1 5.2 4.8 5.0 3.8 þ4.7 4.7 4.7 4.0 þ4.6 þ4.60 4.5 þ4.9
2
2
3
3
Reference
þ4.66 þ3.4 3.5 3.8 þ6.7 þ6.2 þ5.3 3.8 4.8 3.5 3.8 þ3.5 3.0 3.3 4.0 þ4.0 þ3.29 3.1 þ2.6
þ7.61 þ6.2 6.8 9.8b þ8.9 þ8.5 þ8.1 6.8 7.0 6.7 6.9 þ6.4 6.5 6.5 6.6 c þ6.24 6.4 þ5.3
þ9.79 þ8.7 9.0 8.2 þ11.8 þ11.4 þ9.7 8.9 9.1 9.0 8.9 þ8.5 8.4 8.5 8.5 8.3 þ8.31 8.2 6.9
þ10.04 þ10.3 10.0 6.8b þ7.6 þ8.5 þ9.4 10.3 10.0 10.0 10.4 þ10.6 10.6 10.3 10.1 þ11.2 þ10.83 10.5 þ11.0
1976JST(31)161 1999SAA91 1975CS76 1985JST(133)125 1999SAA91 1999SAA91 1999SAA91 1999SAA91 1985M685 1975CS76 1970JPC2765 1981MR396 1975OMR572 1975CS76 1970JPC2765 1999SAA91 1981MR396 1975CS76 1999SAA91
JC(4)H(5)
JC(5)H(4)
JC(3)H(5)
JC(5)H(3)
a
All one-bond C–H coupling constants are assumed to be positive; the signs of all remaining coupling constants are related to them. b These two couplings have been interchanged. c Could not be observed.
Table 47 Chemical shifts in 13C NMR spectra of 2-lithiothiophene 79, 2-thienylmagnesium bromide 80, di(2-thienyl)magnesium 81, 2-trimethylsilylthiophene 82, and 2-t-butoxythiophene 88 Compound
C-2
C-3
C-4
C-5
79 80 81 82 88
175.1 160.9 161.2 141.4 116.1
135.8 133.5 134.0 136.0 115.7
126.5 126.2 126.7 130.0 124.7
129.0 126.8 127.2 132.3 116.8
Thiophenes and their Benzo Derivatives: Structure
It is well known that the lithio derivatives may exist in solution as various aggregates whose structures depend on both solvent and concentration. In the case of the aryllithium compounds, the most typical aggregates are dimers and tetramers, the 13C NMR chemical shifts of the lithiated carbons being typically larger by several ppm for dimers than for tetramers <1987OM2371, 1990JOM(393)C35>. The lithium-induced chemical shift effects (CSEs) reported by Harder et al. <1989OM1688> for the lithiated carbons, C-2, in the dimers of lithiobenzothiophene–TMEDA (TMEDA ¼ tetramethylethylenediamine), are 55.2 ppm. As a result, the corresponding signals appear at dramatically lower field than the signals in nonsubstituted compounds, viz. at 181.4 ppm. The CSE values observed for C-2 in the spectra of the lithiated thiophene are considerably smaller at 49.0 ppm (Table 47). Though this result cannot be used as unequivocal proof of the state of aggregation of the compounds under study, it strongly indicates that in the THF solution they both exist in the form of tetramers. It should also be added that a similar problem concerns the magnesium derivatives; for example, according to Ashby and Walker <1980PAC545, 1969JA3845>, phenylmagnesium bromide in THF exists as a monomeric species, whereas in diethyl ether it forms polymeric aggregates. Unlike the 13C NMR chemical shifts, the carbon–carbon couplings across one bond only insignificantly depend on the state of aggregation of the compound. In an attempt to get a deeper insight into the trends occurring in the heteroaromatic rings upon substitution, 1JCC couplings were measured for a series of variously 2-substituted thiophenes bearing more electronegative substituents. The 1JC(2)C(3) coupling values increase monotonically on passing from 2-lithio derivative, 1JC(2)C(3) ¼ 27.6 Hz, to 2-tbutoxythiophene, 1JC(2)C(3) ¼ 78.8 Hz, in accord with the increasing electronegativity of the first atom of the substituent, ELi ¼ 0.98 and EO ¼ 3.41; 1JC(2)C(3) of 53.8 Hz, measured by Wrackmeyer et al. <1996ZNB1811> for tri(2-thienyl)borane, fits very well in this scheme, EB ¼ 2.04. Analysis of the J data obtained revealed that the dramatic decrease observed for the 1JC(2)C(3) couplings upon passing from 2-t-butoxy- to 2-lithiothiophene is accompanied by a sharp increase of the two-bond coupling between C-2 and H-3 nuclei: a very large coupling constant is observed for the 2-lithium compound, 2JC(2)H(3) ¼ þ21.8 Hz, and a coupling 10 times smaller for the t-butoxy derivative, 2JC(2)H(3) ¼ þ2.3 Hz. A significant dependence upon the electronegativity of the substituent is also revealed by three-bond couplings involving carbon 2, 3JC(2)H(4), and 3JC(2)H(5): the coupling between C-2 and H-4 increases about 3 times and that between C-2 and C-5 about 4 times when passing from 2-lithio- to 2-chlorothiophene. Reasonably good linear relationship is observed for the 3JC(2)H(5) coupling (Equation 4). 3
JCð2ÞHð5Þ ¼ 2:7Ex –1:41
n ¼ 8; R-squared ¼ 0:899
ð4Þ
The C–H couplings connected with carbons 3, 4, and 5 including those across one bond are much less sensitive toward the influence of the substituent at position 2, though the changes observed are not negligible. In general, all one-bond C–H couplings and three-bond C(5)–H(3) coupling increase and all two-bond C–H couplings and threebond C(3)–H(5) coupling decrease with the increasing electronegativity of the 2-substituent. The 13C chemical shifts and some selected 13C–1H spin coupling constants of compound 73 and its hydrochloride are collected in Table 48. The data show a high degree of consistency – in nearly all cases the chemical shifts for carbons of the amino alcohol chain (carbons C–H) are somewhat reduced when switching from the free bases to the hydrochloride salts (the opposite trend is observed for the corresponding H chemical shifts) <2001MOL796>. Plots of the chemical shift values of the carbonyl carbons of the benzanilides against those of the 2-thienamides 68 gave an excellent correlation and the values of the slopes are 0.72 in DMSO-d6. The slopes could be considered as a set of aromaticity indexes <2002JHC1219>.
673
674
Thiophenes and their Benzo Derivatives: Structure
Table 48
13
C NMR chemical shifts and selected 13C,1H-coupling constants 73
73?HCl
DMSO-d6
CDCl3
DMSO-d6
CDCl3
1 2 3 4
121.5 159.8 118.1 133.7
122.9 159.2 116.9 132.5
121.7 159.0 118.0 133.4
121.4 159.3 117.1 132.2
1
171.7 4.5 4.5 188.8
169.7 4.5 4.5 186.3
171.7 4.5 4.5 188.9
170.7 4.5 4.5 187.1
J(C-4,H-4) J(C-4,H-5) 2 J(C-5,H-4) 1 J(C-5,H-5) 2
3.09.3.2.3
Sulfur-33 NMR spectroscopy
Sulfur-33 is the only naturally occurring isotope of sulfur with a nonzero spin (I ¼ 3/2). Since it has a moderate quadrupole moment (5.5 1030 m2), a low natural abundance (0.76%), and a low magnetogyric ratio (2.055 l07 rad T1 s1), it is clearly an intrinsically insensitive nucleus. The 33S NMR spectrum of thiophene was initially studied as a solution in carbon disulfide <1970Ml379> and its chemical shift relative to carbon disulfide was 220 þ 6 while those of 2- and 3-methylthiophene were 178 þ 9 and 197 þ 26, respectively. The 33S chemical shift of neat thiophene (relative to aqueous cesium sulfate) was found to be 119 ppm, while that of tetrahydrothiophene was 354 ppm (Table 49) <1985J(F2)63>. Table 49 Sulfur-33 chemical shift and line-width dataa Compound
Concentration
Chemical shift ( ppm)
line widthb (Hz)
Tetrahydrothiophene Thiophene
Neat Neat
354 (422)c 119 (113)c
4800 (2600) 1450 (620)
a
Literature value in brackets. Defined as the full width at half height. c <1972JA6579>. b
The 33S chemical shift of neat tetrahydrothiophene 1,1-dioxide is 36.7 ppm and shifts upfield when the solution is diluted. A shift of 6.5 ppm is observed when the solvent system is changed from water to dioxane. The chemical shift data from some sulfur compounds previously reported are summarized in Figure 14 <1985J(F2)63>.
Figure 14 Sulfur-33 chemical shift data.
Chemical shifts were measured relative to external 2 mol dm3 aqueous cesium sulfate.
Thiophenes and their Benzo Derivatives: Structure
Careful choice of solvent and dilution is particularly important for some samples. In general, the spectra of the sulfones show a marked solvent dependence. The line width is especially sensitive to the nature of the solvent. For example, the line widths for 5 mol dm3 solutions of sulfolane in acetone and water are 16 and 60 Hz, respectively. A shift difference of 6.5 ppm is observed between 5 mol dm3 solutions of sulfolane in water and dioxane. Table 50 shows how the chemical shift (quoted relative to that for neat sulfolane) and line width vary with concentration of sulfolane in acetone. No nuclear Overhauser effect is observed for sulfolane, which suggests that sulfur–hydrogen dipolar interactions are not significant as a relaxation mechanism.
Table 50 Variation of relative chemical shift and line width with concentration for sulfolane 89 in acetonea Concentration (mol dm3)
Chemical shift ( ppm)b,c
Line widthb(Hz)
1 2 3 4 5 6 7 8 9 10
1.7 1.6 1.2 1.1 0.9 0.8 0.6 0.3 0.2 0.0
17 14 16 19 16 17 19 20 24 32
a
Data derived from measurements using the CXP200 spectrometer. Estimated error in chemical shifts, 0.1 ppm; estimated error in line widths, 2 Hz. c Relative to neat sulfolane, which is ca. 10 mol dm3. b
Sulfur–hydrogen scalar coupling has been observed for a solution of 2 mol dm3 2,5-dihydrothiophene 1,l-dioxide (butadiene sulfone) 90, in acetone. A partially resolved triplet, of total width 18 Hz, collapses to a singlet, width 7 Hz, when proton decoupling is applied. The major coupling is attributed to a vicinal interaction between the sulfur and olefinic protons, by comparison of the carbon spectrum of diethyl ketone (the carbonyl carbon resonance exhibits a septet) and the sulfur spectrum of sulfolane (the sulfur peak shows no structure). This was confirmed by selectively decoupling at the two relevant proton frequencies in turn.
Quadrupolar nuclei are frequently difficult to observe by NMR spectroscopy owing to their broad resonances, which result from efficient quadrupolar relaxation. Since the quadrupolar relaxation rate is dependent upon the molecular correlation time, which is, in turn, directly proportional to the solvent viscosity, lowering the solvent viscosity will decrease the line width and make the resonance easier to observe. Typically, this might be accomplished by judicious choice of solvent or raising the solution temperature. However, the range of accessible viscosities using common organic solvents below their boiling points is necessarily limited. Much lower viscosities, and a wider range of viscosities, are available in supercritical fluids by adjusting the temperature and pressure. Thus, the use of supercritical fluid solvents affords a means of narrowing resonances from quadrupolar nuclei.
675
676
Thiophenes and their Benzo Derivatives: Structure
The first demonstration of line narrowing for solid and liquid solutes containing quadrupolar nuclei dissolved in supercritical fluid solvents has been reported <1987MR345>. Using this technique, the 33S spectra of thiophene (b.p. 84 C) dissolved in supercritical ethylene and carbon disulfide was obtained. Because of the intrinsic insensitivity of the sulfur nucleus, 2 l06 transients were acquired for these spectra, which resulted in signal-to-noise ratios of 4:l. The line widths obtained at 60 C and 200 bar were approximately 200 Hz for thiophene in ethylene which correspond to narrowing factors of 7, when compared to the literature values <1985J(F2)63> for the line widths of the neat liquids at ambient conditions. Sulfur NMR chemical shieldings have been determined at the correlation-including DFT-scaled B3LYP/6311þG(nd,p)//B3LYP/6-311þG(d,p) and modified MP2/6-311þG(nd,p) estimated infinite order Møller–Plesset levels with n ¼ 2 for sulfur (Table 51). The calculations span the range of sulfur shieldings and show agreement with experiment of about 3% of the shielding range. The atoms-in-molecules delocalization index and a covalent bond order from specific localized orbitals in the DFT approach are used to characterize sulfur’s bonding and to relate it, where possible, to the calculated shieldings <2004HAC216>. The sulfur chemical shieldings (, ppm) and bond delocalization indexes () for thiophene are 328.5 and 1.27.
Table 51 Observed 33S chemical shieldings and those calculated from the DFT (B3LYP/6-311þG(2d,p)//B3LYP/6311þG(d,p) scaled by k ¼ 0.871) and EMPI (RHF and MP2/6-311þG(d,p)//MP2/6-311þG(d,p)) approachesa
Thiophene a
DFT
EMPI
Obs.
328.5
309.6
324
A set of 2d polarization functions was used on sulfur in both cases.
3.09.3.2.4
Mass spectrometry
Thiophene, along with the other five-membered heterocycles in its group, shows similar ring fragmentation patterns, the first step being cleavage of the C–S bond (Figure 15). From there, it can proceed by three different pathways to afford three principal peaks: C3H3þ (m/z 39) 91, HCUSþ (m/z 45) 92, and C2H2Sþ (m/z 58) 93.
Figure 15 Fragmentation pattern in thiophene.
A quantum-chemical interpretation of the MS fragmentation of organic molecules has been reported <1987CHE512>. Based on the bond orders, the weakest bond is the C(3)–C(4) bond and hence should fragment first and to a much greater extent than the S–C or the C(2)–C(3) bond. This then forms the divinyl sulfide radical cation which cyclizes to intermediate 94 and then eliminates acetylene to form thiirene 93 (Figure 16). On the other hand, it is also possible that the bicyclic intermediate 95 is formed first, which could fragment to form radical cation 96 and/or intermediate 94 both of which lose acetylene to form thiirene 93.
Thiophenes and their Benzo Derivatives: Structure
Figure 16 Fragmentation pattern based on bond orders.
For 2- and 3-alkyl thiophenes, the base peak at m/z 97 is assigned to the C5H5Sþ ion, which arises from the -cleavage of the alkyl substituent (Figure 17), and the thiopyrylium structure 97 is proposed. The thiopyrylium cation 97 is the base peak for long chain alkyl groups at the 2-position. If another such group is present at the 5position, the molecular ion is found to be the base peak .
Figure 17 Fragmentation pattern for 2-alkylthiophenes.
For benzo[b]thiophenes, there is very little systematic information available <1981AHC(29)171>. Dibenzothiophene undergoes surface-catalyzed oxidation when subjected to negative chemical ionization (NCI) with oxygen <1993JAM949>. The m/z ion at 184, initially attributed to M, is now shown to be the anion of 2-sulfobenzoic acid cyclic anhydride 98. Formation of anhydride 98 is presumed to arise by initial oxidation of dibenzothiophene to the sulfone 30 followed by oxidation of the angular carbon atoms to form the bicyclic intermediate 99. Further attack by oxygen cleaves the ring to form anhydride 98 (Scheme 1).
Scheme 1
As a typical organosulfur compound, thiophene has been extensively studied on model or real catalyst surfaces to understand the details of the industrially important hydrodesulfurization (HDS) process. Laser-induced thermal desorption/Fourier transform mass spectrometry (LITH/FTMS) has been developed as one of the most sensitive probes to yield time-dependent molecular information from surfaces. This technique shows that the low-temperature decomposition of thiophene on Pd(111) proceeds via C–S bond scission forming a C4Hx (x ¼ 4 or 5) intermediate which hydrogenates and desorbs as 1,3-butadiene. The cleavage between the C–S bonds of thiophene results in the deposition of sulfur, which remains on the Pd(111) surface (Scheme 2) <1997POL3197>. Likewise, several studies involving thiophene decomposition on Ni-, Re-, and Mo-surfaces suggest an intermediate C-4-metallocycle species as well <1984MI2161, 1987MI75, 1987L555, 1989MI127, 1989MI297>.
677
678
Thiophenes and their Benzo Derivatives: Structure
Scheme 2
In this context, the adsorption of thiophene on almost stoichiometric TiO2 surfaces has been studied with a combination of synchrotron-based high-resolution photoemission spectroscopy and thermal desorption mass spectrometry (TDS). The bonding nature between thiophene and Ti- or O-sites of TiO2 has been investigated. Over an almost stoichiometric TiO2 surface, the adsorption and desorption of thiophene is completely reversible. In the submonolayer regime, four adsorption states were identified in TDS. The results of density functional calculations indicate that at small coverage the molecule should be bonded with its ring nearly parallel to the surface <2003JMO215>. A variant of coordination electrospray ionization mass spectrometry (ESI-MS), in which Pd(II) in methanol is introduced into the ESI source of an ion trap mass spectrometer, have been used for the structural determination of polyaromatic sulfur heterocycles (PASHs) <2003JMP167>. For ESI, proton-transfer reactions are a common ionization mechanism in the gas phase. However, according to the MS results acquired for the organosulfur compounds, radical cations form in the presence of palladium. A possible formation mechanism involves CT from the sulfur compounds to Pd(II). The process is depicted for DBT in Scheme 3.
Scheme 3 Charge transfer between Pd(II) and DBT.
Three-ring organosulfur compounds have an ionization potential (IP) that ranges around 8 eV, which is lower than that of methanol (10.85 eV), so that electron abstraction from an organosulfur compound should be favored over abstraction from methanol when an organosulfur compound is present. Thiophene and benzo[b]thiophene have an oxidation potential in excess of þ1.8 V versus NHE and are not oxidized prior to the solvent in the mixture. DBT, 2-DBT (2-methyldibenzo[b]thiophene), and 4,6-DBT (4,6-dimethyldibenzo[b]thiophene) in ESI tandem mass spectra have a a consistent 32 Da neutral loss, which is believed to be sulfur. Based on the tandem mass spectrum of the PASH compounds, the mechanism of fragmentation is considered to be a charge site-initiated reaction followed by a radical site-initiated fragmentation. Taking the example of DBT, Scheme 4 shows a possible mechanism.
Scheme 4 Mechanism for sulfur loss from DBT.
Unlike the other species in the mixture, 2-DBT and 4,6-DBT showed both the parent ion and a fragment missing a hydrogen. It is suspected that the methyl groups on these two compounds lose one hydrogen during the ionization and collision-induced dissociation (CID) process as depicted in Scheme 5.
Scheme 5 Mechanism for H loss from 2-DBT.
Thiophenes and their Benzo Derivatives: Structure
The fragmentation processes for 2-DBT and 4,6-DBT are more complicated than those of the unalkylated species. The precursor ion may lose hydrogen, methyl, sulfur, or HS. In addition, the M-1 fragment may lose methyl, sulfur, or HS. Some possible fragmentation pathways for the M-species of 2-DBT are outlined in Scheme 6.
Scheme 6 Fragmentation pathways for 2-DBT.
3.09.3.2.5
Ultraviolet spectroscopy
The ultraviolet (UV) spectrum of thiophene and its derivatives has been extensively investigated <1972J(F2)2009, 1978JCP(69)5077, 1981BCJ1511, 1982J(P2)761, 1986HC(44/3)1, 1991HC(44)1>. In the gas phase, the UV spectrum consists of three bands originating at 240, 207, and 188 nm, respectively. High-resolution and temperature-dependence measurements were recorded for the lowest-energy UV transition (230–250 nm) of thiophene. Based on these results, the first system of the UV spectrum is assigned to the 4 3 (B2) transition <1982J(P2)76l>. The electronic absorption spectra of 2,29-bithienyl and its derivatives have also been investigated <1985BCJ2126> and the transitions in the spectra of 5- and 5,59-substituted 2,29-bithienyl compounds assigned to intramolecular CT, locally excited transitions, and n ! s* -transitions. 2,29-Bithienyl with alkyl or chloro substituents shows similar patterns. The presence of formyl or acetyl groups at the 5- and 5,59-positions causes a significant shift for the lowest-energy transition due to the perturbation caused by the carbonyl group which is shifted in polar solvents. Silylthiophenes have attracted much attention as useful reagents for organic synthesis <1979S841, 1988BCJ3549, 1997JOC1940>, the precursors of PT and related polymers <1996JOM(521)11, 1990JEI293, 1991JEI277, 1992PSA1667, 1993SM(55)1246, 1993SM(55)1596, 1993AM637, 1994SM(62)233, 1995SM(72)129, 1995JMC797, 1991JA7064, 1992MM1901>, and the precursors of silylenethienylene copolymers <1989PB133, 1991MM2106, 1994JOM(468)55, 1996OM2000>. The dimethylsilyl groups of compounds 100–102 (Figure 18) considerably affect the structure and the electronic properties of the thiophene ring, which was revealed by MO calculations and UV spectroscopy.
Figure 18 Some dimethylsilyl derivatives of thiophene.
Thiophene shows an absorption band at 230 nm <2006OM2761>. As the number of dimethylsilyl groups on the thiophene ring progressively increases, the absorption band shifts bathochromically: the absorption maxima of compounds 100, 101, and 102 exist at 245, 252, and 254 nm, respectively. In the cases of compounds 102 and 101, another absorption band, which might be in the vacuum–UV region in the cases of compound 100 and thiophene, appears in the UV region by the bathochromic shift. The extinction coefficients of the lowest-energy absorption bands of compounds 100, 101, and 102 are much larger than that of thiophene. These results indicate that the p-electron system of thiophene is considerably perturbed by the dimethylsilyl groups <2006OM2761>. The electronic effects of dimethylsilyl groups on the thiophene ring have also been studied by MO calculations. As the number of dimethylsilyl groups progressively increases, the HOMO is more destabilized and the LUMO is more stabilized. The destabilization of the HOMO is caused by the s–p-conjugation <1998CL471> between Si–C(methyl) s-orbitals and a p-orbital of thiophene. The LUMO of thiophene is stabilized by the s* –p* -conjugation <1996BCJ2327> between Si–C(methyl) s* -orbitals and a p* -orbital of thiophene. As a result of these effects, the
679
680
Thiophenes and their Benzo Derivatives: Structure
energy gap between the HOMO and the LUMO successively decreases as the number of dimethylsilyl groups progressively increases. The bathochromic shift of the lowest-energy absorption band in the UV spectra is explained by this decreasing energy gap. The s–p-conjugation in the HOMO and the s* –p* -conjugation in the LUMO also affect the extinction coefficients of the lowest-energy absorption bands of the UV spectra. The MO calculations at the CNDO/S level considering configuration interaction showed that the lowest-energy absorption bands of compounds 100, 101, 102, and thiophene are due to the transition from the HOMO to the LUMO. The UV–Vis spectrum of undoped polythiophenes usually exhibits a p–p* transition peak in a range of 400–450 nm. On the other hand, the p-doped polymer gives peak(s) at a longer wavelength, which is accounted for by formation of polaron and/or bipolaron state(s) in the polythiophene main chain . The UV–Vis absorption spectrum of polythiophene derivative 103 in 2-methyltetrahydrofuran at 300 K reveals a single broad absorption at max ¼ 386 nm (" ¼ 61300 l mol1 cm1). Note that, as a consequence of the finite angle (of the order of 67 ) between the conjugated chromophores, both components of the exciton splitting are dipole allowed in compound 103 <1997CPL(272)463, 1998JA1289, 1996SM(76)47>. At 100 K, a hypsochromic shift and significant sharpening of the absorption spectrum occur, resulting in the appearance of two vibronic peaks at ¼ 426 nm (0–0) and ¼ 400 nm (0–1) and an additional shoulder at ¼ 383 nm (0–2) <1998AM1343>. Regioregular poly(3-alkylthiophene)s have received a lot of attention, especially because of their high electrical conductivities in the doped state, and because of their unusual solvatochromic and thermochromic behavior . Hence, a lot of research has been focused on clarifying the structure of these materials, both in the solid state and in solution. Today, it is agreed that supramolecular aggregation of polythiophene chains plays an important role in their physical properties. UV–Vis absorption spectra show that the polythiophene films exhibit an absorption band at 535 nm, corresponding to the first p–p* transition, with a clear vibronic fine structure. This absorption can be attributed to a structure that mainly consists of stacks of nearly coplanar extended chains, with the transition dipole moment oriented along the polymer backbone <2005AM708>. The introduction of vinylene bridges between thiophene moieties improves the electronic properties of the resulting thienylenevinylene polymers <1993MM2704, 1994SM(62)223, 1989JPC(91)1303, 1994JPC10102, 1997APL379, 1997SM(84)199>. The electronic absorption spectra of compounds 104 (Figure 19) are characterized by an absorption band with a max in the range 422–436 nm, indicating that, despite the planarity and therefore increased conjugation of the styryl group, the nature of the para-substituent on the benzene ring has little effect on the HOMO–LUMO gap in these compounds. Previous work has shown that the position of the absorption maximum of alkyl-substituted thienylenevinylene oligomers is largely determined by the number of carbon atoms in the conjugated chain <1997JA10774>, with max for (E,E)- 2,5-bis(29-thienylvinyl)-3,4-dibutylthiophene (16 carbon atoms in the conjugated chain) being 423 nm <2006T2190>.
Figure 19
The UV–Vis spectrum of a thin film of compound 105 (Figure 19) shows several absorption maxima at 545, 411, and 370 nm. The position of the first absorption peak at the low-energy side of the spectrum at 545 nm indicates that the molecule is fully conjugated <1997SM(89)193>. Several new oligothiophenes blocked by cyclophane end groups with two, three, four, or six thiophene rings in the chain have been studied by UV–Vis spectroscopy (Figure 20) <2003NJC1000>.
Thiophenes and their Benzo Derivatives: Structure
Figure 20
Table 52 summarizes the main features of the new ,!-cyclophanyl oligothiophenes 106 and compares them with the spectral data obtained in dioxane by Becker et al. <1996JPC18683> for unfunctionalized oligothiophenes 16.
Table 52 Main features of the spectra of the new cyclophane-derivatized oligothiophenes 106 at 293 K in dichloromethane Abs. max. (nm) 16 (n ¼ 0)a 16 (n ¼ 1/2)a 16 (n ¼ 1)a 16 (n ¼ 2)a a
3.09.3.2.6
303 354 392 436
Abs. max. (nm) 106 (n ¼ 2) 106 (n ¼ 3) 106 (n ¼ 4) 106 (n ¼ 6)
374 404 421 453
Data from <1996JPC18683> for the unsubstituted oligothiophenes in dioxane at room temperature.
IR spectroscopy
The IR spectra of thiophene derivatives were first studied by Gronowitz in the early 1960s <1963AHC(1)l> and have been reviewed again <199lHC(44)1>. The 21 fundamental vibrations of thiophene are composed of eight vibrations of A1 symmetry, seven of B1 symmetry, and three each of A2 and B2. The assignments of all 21 vibrations are listed in Table 53. The complete vapor-phase assignment, including IR vapor, Raman vapor, and liquid spectra, has been determined to obtain a complete set of vibrational frequencies in the vapor and liquid states of thiophene <1994SAA765>. The results confirm the assignments made earlier by Rico et al. <1965SA689>. For 2- and 3-substituted thiophenes, the three C–H ring stretching bands are observed in the region 1350– 1550 cm1, the intensities of which depend on the type of substitution <1970SAA1651>. In addition to this, up to two bands corresponding to in-plane C–H deformations are observed in the region 1030–1085 cm1. Furthermore, the absorption pattern in the region 750–900 cm1 is different for 2- and 3-substituted derivatives, making it easy to identify the substitution pattern. Similarly, 2,5-dialkylthiophenes display a strong absorption at ca. 800 cm1 <1964CB3263>. Frequencies and assignments of IR absorption bands of the 3-(6-methoxyhexyl-2,29-bithiophene and alternating methoxyhexylthiophene–thiophene copolymer 107 <1999SM(104)1> are listed in Table 54. The absence of absorption due to C–H stretching (3104 cm1) together with the presence of C–H out-of-plane bending of both 2,5- and 2,3,5-substituted rings (792 and 829 cm1, respectively) confirm the 5,59-polymerization of the monomer. Qualitative information regarding backbone conjugation as compared to that of polymer 108 was gathered both from the frequency of the antisymmetric ring stretching and from the intensity ratio between the symmetric and antisymmetric ring stretching (Isym/Iasym). Both these values were seen to decrease as conjugation length increased, a finding which had already emerged from previous analyses on polythiophene and its oligomers <1987SM(18)151> and on regiorandom and regioregular poly(3-alkylthiophenes) <1995JA233>. In the case of polymer 107, the antisymmetric stretching (1499 cm1) is red-shifted by 12 cm1 compared to that of polymer 108 (1511 cm1) <1997SM(89)181>. The findings thus suggest that the conjugation length of the two polybithiophenes is the same and that it is longer than that of PT 108, in agreement with the results of the UV–Vis spectroscopy (Figure 21). In situ reflectance FTIR spectroscopy has been found to be a valuable tool for characterizing electrogenerated polythiophenes <1992JCF595, 1993JCF921, 1994SM(62)141, 1996JCF773, 2001JMC2253>.
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Thiophenes and their Benzo Derivatives: Structure
Table 53 Experimental and theoretical vibrational frequencies (cm1) of thiophene Assignment A1
A2
B1
B2
C–H str. C–H str. CTC , C–C, ring str. CTC str., CCH bend CCH bend in plane CCH bend C–C str C–S str. Ring def. in plane C–H wag out of plane C–H wag out of plane Ring def. out of plane C–H str. C–H str. CTC, ring str. CCH bend in plane CCH bend in plane C–S str. Ring def. in plane C–H wag out of plane C–H wag out of plane Ring def. out of plane
Assignment A1
A2
B1
B2
C–H str. C–H str. CTC, C–C, ring str. CTC str., CCH bend CCH bend in plane CCH bend C–C str. C–S str. Ring def. in plane C–H wag out of plane C–H wag out of plane Ring def. out of plane C–H str. C–H str. CTC, ring str. CCH bend in plane CCH bend in plane C–S str. Ring def. in plane C–H wag out of plane C–H wag out of plane Ring def. out of plane
Exptl.a
Force fieldb
MINDOc
MP2d
3126 3098 1409 1360 1083 1036 839 608 898 683 565 3125 3086 1504 1256 1085 872 763 867 712 452
3127 3104 1427 1364 1072 1030 844 642 893 698 565 3129 3089 1532 1254 1069 857 745 865 712 450
3561 3501 1677 1348 1058 988 778 460 802 712 435 3558 3490 1729 1100 970 774 605 795 699 315
3328 3302 1471 1420 1111 1079 885 628 822 596 516 3325 3287 1542 1296 1114 909 780 768 680 447
SCFe
SCFf
ACPFg
QCFF/PIþCISDh
3125 3092 1421 1359 1077 1023 829 605 908 703 550 3123 3078 1504 1262 1076 870 757 877 687 452
3130 3099 1422 1356 1077 1027 833 604 901 697 575 3126 3085 1504 1262 1074 865 761 878 692 446
3135 3095 1415 1361 1088 1032 837 603 878 726 564 3132 3083 1499 1251 1084 872 753 873 696 451
1420 1352 1089 1006 825 556 1092 846 491
1536 1310 1061 936 677 1086 728 398
a
<1965SA689>. <1969ACS3139>. c <1977JA1685>. d <1988JPC1739>. e <1991SM(43)3491>. f <1992JST(259)181>. g <1992JST(259)181>. h <1994JCP(100)2571>. b
In the spectral region (ca. 900–6000 cm1), a strong electronic band (or its low-energy edge) is generally observed during the oxidation of a conducting polymer film, owing to the lowest-energy transition, regardless of the identity of the charge carrier in the doped polymer. In addition, the movement of charge carriers along polymer chains gives rise to large dipole changes in those vibrations that can couple to the carrier motion (the so-called T-modes)
Thiophenes and their Benzo Derivatives: Structure
<1986MI415>. The corresponding infrared bands are selectively enhanced, such that difference spectra usually show only the gain of these very intense IR activated vibrations (IRAV’s) <2002JMC758>. Table 54 Characteristic FT-IR frequencies (cm1) for the monomer and polymer 107 Monomer (neat) 3104m 3069m 2976s 2932vs 2857vs 1515vw,1505w 1461s,1447s 1387m 1198m 1119vs 883m,831s,716sh 849m,694vs
(107 film)
3063m 2975m 2930vs 2857vs 1499m 1460s 1387m 1196m 1119vs
829m 792s 728w
Assignment C–H stretching (aromatic, -hydrogen) C–H stretching aromatic, -hydrogen C–H antisymmetric stretching methyl C–H antisymmetric stretching methylenes C–H symmetric stretching methylenes Thiophene ring antisymmetric stretching Thiophene ring symmetric stretching Methyl deformation Aromatic C–H bending in plane C–O-C stretching mode Aromatic C–H out-of-plane bending in 2,3-disubstituted thiophene Aromatic C–H out-of-plane bending in -monosubstituted thiophene Aromatic C–H out-of-plane bending in 2,3,5-trisubstituted thiophene Aromatic C–H out-of-plane bending in 2,5-disubstituted thiophene Methylene rocking
vw ¼ very weak; w ¼ weak; m ¼ medium; s ¼ strong; vs ¼ very strong; sh ¼ shoulder.
Figure 21 Poly[3-(6-methoxyhexyl)-2,20-bithiophene] and poly[3-(6-methoxyhexyl)-2,5-thienylene].
The adsorption of thiophene (C4H4S) on g-Al2O3 has been investigated in ultrahigh vacuum (UHV) using IR spectroscopy and temperature-programmed desorption (TPD) <1996L1500>. IR spectroscopy of adsorbed thiophene at sub-monolayer coverages provides further evidence that thiophene interacts only weakly with the alumina support; no decomposition of the thiophene overlayer is observed upon heating to 600 K under UHV conditions or a partial pressure of thiophene of 3.0 Torr. A direct correlation has been established between the IR and TPD data, permitting integrated extinction coefficients to be determined for adsorbed thiophene in both the monolayer and multilayer coverage regimes. Extinction coefficients in the two coverage regimes are markedly different, underscoring the need to use care when interpreting the IR spectral intensities for adsorbed species. While, as expected, this study has shown that thiophene adsorbs only weakly on g-Al2O3, more importantly it has shown that the combined IR–TPD methods can be used to determine both the thiophene coverage and the mode of bonding with the surface. The growth of thiophene films on ice depends on both the structure of the ice and the deposition temperature. A specific adsorption state of thiophene on amorphous ice at 125 K is deduced from the distinct reflection–adsorption infrared spectroscopy (RAIRS) in the range between 700 and 900 cm1 <2001MI160>. Variation of the conditions under which the films are prepared leads to changes in the spectral pattern that are most obvious in the 700–900 cm1 range. Here the out-of-plane CH wagging band 19 and the most intense in-plane mode
3 are located. The intensity distribution among the detected in-plane modes reveals only minor variations. When a multilayer thiophene film is grown at 85 K, the resulting RAIRs spectra closely resemble IR spectra of liquid <1965SA689> and matrix-isolated thiophene <1999MI59>. In these spectra, 19 has a somewhat higher intensity at the peak maximum and a larger bandwidth than 3. This close similarity suggests that an amorphous sample is grown at 85 K. At 125 K and high thiophene dose, 3 is much stronger than 19, and the latter also reveals a characteristic splitting. Transmission IR spectra were recorded to investigate the origin of the splitting. The results
683
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Thiophenes and their Benzo Derivatives: Structure
show that the splitting occurs when a thiophene film initially deposited at 9 K is annealed to a temperature between 82 and 112 K or if deposition takes place at 125 K. This suggests that the splitting is associated with the formation of a crystalline phase.
3.09.3.2.7
Photoelectron spectroscopy
The photoelectron spectra (PESs) of thiophene derivatives have been well studied <1969IJM47l, 1970T4505, 1971IJM177, 1976JEO179, 1979CPL(61)355>. The UV PES of thiophene (using He(I) (21 eV) photon excitation) was first measured up to 18 eV by Eland <1969IJM47l>, and later up to 25 eV by Derrick et al. using He(II) (40 eV) photon excitation <1971IJM177>. Theoretical studies have been carried out to assist in assigning the ionization energies to the appropriate occupied MOs and this has been discussed in Section 3.09.2.6. Photoelectron spectroscopy is an efficient tool for the gas-phase characterization of various elusive compounds <1989CSR317>. It has also been used to investigate the products formed on flash vacuum pyrolysis of alkylthio derivatives of Meldrum’s acid <1991JOC3445>. The PESs of the thiophen-3(2H)-ones formed were similar to authentic samples from which it is apparent that no keto–enol tautomerism occurred in the gas phase and that only the keto tautomers are formed in the gas phase. The IPs of benzo[b]thiophene <1969IJM47l> and DBT <1973J(F2)1155> have also been determined and the assignments compared with various theoretical calculations <1983JST(105)375>. The X-ray photoelectron spectrum (XPS) of thiophene has been measured in the vapor phase using Mg-K X-ray excitation <1970MI379>. The complete valence shell binding energy spectra and the outer valence orbital momentum profiles of thiophene have been measured, using a high-resolution binary (e, 2e) electron momentum spectrometer, at an impact energy of 1200 eV plus the binding energy and using symmetric non-coplanar kinematics. Binding energy spectra of the complete valence shell have been obtained. The summed experimental momentum profile of the HOMO 1a2 and next HOMO (NHOMO) 3b1 is compared with the theoretical momentum distributions calculated using HF and DFT methods with various basis sets <2005CPL(401)80>. The point group symmetry of thiophene is C2v. According to MO theory, the ground-state electronic configuration can be written as
In the ground state, the 44 electrons are arranged in 22 double-occupied orbitals in the independent particle description. The valence electrons in thiophene are distributed in 13 MOs. All the canonical molecular orbitals (MOs) are either a-type or b-type. There is no degeneracy in these orbitals; therefore, the spectra of thiophene are not complicated by the Jahn–Teller effect. The average vertical IPs of the 1a2 þ 3b1, 11a1 þ 2b1 þ 7b2 þ 10a1 þ 6b2, 9a1 þ 5b2, and 8a1 outer orbitals are determined by electron momentum spectroscopy (EMS) measurement to be 9.2, 12.9, 16.6, and 18.4 eV, respectively. The vertical IPs of the 7a1, 4b2 and 6a1 inner valence orbitals are determined to be 20.2, 22.2 and 26.3 eV. In addition, some rather weak satellite structures due to many-body correlation effects in the target or in the residual ion final states are also observed above 30.7 eV in the binding energy spectra. This satellite is likely due to ionization from the 6a1 orbital <1992CPH(164)283>. The IPs of five orbitals, 11a1, 2b1, 7b2, 10a1, 6b2, are very close and bands due to these orbitals have not been clearly resolved even in high-resolution PES <2001JEO221, 1992CPH(164)283>. The same is true of the next two orbitals, 9a1 and 5b2. The differences in FWHM (Full width at half maximum) are due to the vibrational broadening of the lines. The IPs measured by PES <1989JEO129, 1992CPH(164)283> and present EMS, as well as the HF and DFT orbital energies for the outer valence orbitals, are shown in Table 55 <2006CPH(327)269>. The experimental momentum distributions are compared with the associated calculations with the HF and DFT methods. The binding energies are in excellent agreement with previously published PES data and the synthesized theoretical spectrum are compared with the experimental binding energy spectrum, from which it can be seen that the DFT-B3LYP/aug-cc-pVTZ calculation is in reasonably good agreement with the experimental binding energy
Thiophenes and their Benzo Derivatives: Structure
spectra in the outer valence region while the calculation predicted significant splitting of ionization transitions from the 6a1 inner valence orbital due to strong electron correlation effects in the inner valence region. The agreements between theory and experiment for the shape and intensity of the orbital electron momentum distributions are generally good. HF and DFT calculations with B3LYP hybrid functional using saturated and diffuse basis sets provide some better descriptions of the experimental data. Furthermore, in the outer valence orbital momentum distributions, the aug-cc-pVTZ calculations give somewhat better fit to the experimental results, which indicates that a basis set including saturated diffuse and Dunning’s correlation consistent polarization is essential for the sulfurcontaining five-membered aromatic heterocyclic molecule thiophene. The inner valence orbital ionizations are considered with the pole strengths for ionization from these orbitals being split into higher-energy satellite processes, which is due to many-body ion states associated with the inner valence orbital ionization.
Table 55 Outer valence IPs for thiophene (eV ) Experiment Orbital 1a2 3b1 11a1 2b1 7b2 10a1 6b2 9a1 5b2 8a1
Orbital energy
EMS
PES a
PES b
OVGFc IP
Pole strength
HF d
DFT e
9.2
9.0 9.5 12.0 12.5 13.2 13.9 14.4 16.6 17.6 18.4
8.87 9.52 12.1 12.7 13.3 13.9 14.3 16.6 17.6 18.3
8.834 9.065 11.983 12.824 13.312 13.354 14.126 17.114 18.347 19.019
0.901 0.906 0.900 0.826 0.901 0.896 0.893 0.854 0.845 0.047
8.926 9.419 12.912 14.251 14.397 14.971 15.698 19.010 20.464 20.859
6.633 7.022 9.474 10.498 10.671 10.800 11.355 14.155 15.158 15.423
12.9
16.6 18.4
a
From <1992CPH(164)283>. From <1989JEO129>. c <2006CPH(327)269>, calculated by OVGF method and the 6-311þþG** basis set. d <2006CPH(327)269>, calculated by HF method and the aug-cc-pVTZ basis set. e <2006CPH(327)269>, calculated by DFT/B3LYP method and the aug-cc-pVTZ basis set. b
The vibrational structures of the electronic ground states X˜ 2A2 of the thiophene cation have been studied by a zero kinetic energy (ZEKE) photoelectron spectroscopic method. In addition to the strong excitations of the symmetric a1 vibrational modes, an other three symmetric vibrational modes (a2, b1, and b2) have been observed unambiguously. These results, which cannot be explained by the Franck–Condon (FC) principle, illustrate that the vibronic coupling and the Coriolis coupling may play important roles in understanding the vibrational structures of the thiophene cation. The vibrationally resolved ZEKE spectra are assigned with the assistance of the DFT calculations, and the fundamental frequencies for many vibrational modes have been determined for the first time. The first adiabatic ionization energy for thiophene was determined as 8.874 2 eV. The assigned band origins are listed in Table 56 along with the previous measurements from the PES spectrum. Ultraviolet photoelectron spectroscopy (UPS) has been used to study the evolution of the valence electronic states as a function of conjugation length for thiophene, bithiophene, terthiophene, and sexithiophene films deposited in vacuum on gold substrates at 130 K. The binding energy scale is referenced to the spectroscopic Fermi level. The peak in the range of 4–5 eV is attributed to p-orbitals localized on the sulfur atoms and the -carbons of the thiophene rings <1993JCP(99)664>. This peak shifts slightly to lower binding energy as the length of the molecule increases. The bithiophene and terthiophene spectra contain a distinct peak at 2.9 and 2.3 eV, respectively, due to orbitals delocalized along the carbon backbone of the chain. For sexithiophene, this feature is peaked at ca. 1.7 eV. However, in this case, it is broad and extends toward the Fermi level <2005SM(150)259>. The binding energies relative to the vacuum level (i.e., ionization energies) of the thiophene ring p-orbitals for the four molecules have essentially the same value, 8.1 eV. In contrast, the ionization energies of the orbitals corresponding to electrons delocalized along the backbone strongly depend on the length of the molecule. For bithiophene, terthiophene, and sexithiophene, the ionization energies of these HOMOs are 6.7, 6.3, and 5.8 eV, respectively. These results are summarized in Table 57.
685
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Thiophenes and their Benzo Derivatives: Structure
Table 56 Vibrational band origins of C4H4Sþ (X˜ 2A2) observed in the ZEKE spectrum and assignments ZEKEa
PESb
Energy
Assignment
82(2) 106(2) 0 372(2) 407(2) 463(3) 483(1) 522(1) 602(1) 841(1) 956(5) 973(2)
14(452) 14 þ 11(567) 11 IE þ 14 þ 11(567)2 21 þ 11 þ 21 þ 14(452)2 21 þ 8 þ 20 þ 19 þ þ 8þ 14 2þ21 þ 6 þ þ 8þ 11 þ þ 8þ 21 þ 5 2þ8 þ 18 þ 4 þ 17 þ þ 8þ 20 3þ21 þ 3 2þ8þþ14 þ þ 8þ 19 þ þ 21þ 5 þ þ 8þ 6 2þ8þþ11 þ þ 8þ 5 þ þ 21þ 4 þ 3 8 þ þ 8þ 18 þ þ 8þ 4 þ þ 8þ 17 þ 2 8þþ20 2þ21þþ5 þ þ 8þ 3 2þ8þþ19 3þ8þþ14
1050(1) 1062(5) 1071(2) 1117(1) 1204(1) 1260(5) 1307(1) 1342(1) 1429(2) 1456(2) 1505(1) 1567(1) 1611(3) 1653(2) 1663(3) 1718(1) 1792(1) 1801(2) 1858(3) 1902(5) 1935(1) 2023(2) 2092(2) 2101(2) 2159(5) 2169(3)
Energy
Assignment
þ
581c 645 877c
þ 8
1137
þ 5
1290 1395
2þ8 þ 3
1760
þ þ 8þ 5
2017
þ þ 8þ 3
a
From ZEKE experiments <2006JCP(125)174313>. The digits in the parentheses represent the uncertainties in the last digits quoted. b From PES experiments; see <1971SAA2525> and <1971IJM177>. c Peaks found by Trofimov et al.; see <1998JCP(109)1025>.
Electron loss spectroscopy (ELS) has also been performed using an electron gun typically employed for Auger electron spectroscopy, and it is found that the lowest-energy-loss feature shifts to lower energy as conjugation length increases. The results obtained are in general agreement with theoretical and higher-resolution experimental studies, and the thresholds of the lowest-energy ELS peaks provide estimates of the bandgaps of the films. These results show that the combination of UPS and ELS provides a convenient means of evaluating the conjugation length of short-chain oligothiophenes. The electronic and geometric structures of poly[3-(4-octylphenyl)thiophene] (POPT) 109 (Figure 22) have been studied by X-ray and ultraviolet photoelectron spectroscopy (XPS and UPS, respectively). Thermochromic effects, and new charge-induced states generated by potassium doping, have been observed by direct UPS measurement <1996SM(76)263>.
Thiophenes and their Benzo Derivatives: Structure
Table 57 Summary of UPS results for the HOMO peak and ELS measurement of the lowest-energy-loss feature for condensed thiophene and -oligothiophene films HOMO
Thiophene -Bithiophene -Terthiophene -Sexithiophene
(EF)a (eV )
(VL)b (eV )
Loss peakc (eV )
Thresholdd (eV )
Bandgap (lit.)e (eV )
4.6 2.9 2.3 1.7
8.1 6.7 6.3 5.8
5.4 4.1 3.5 2.7
4.9 3.2 2.8 2.0
4.86e 3.74e, 3.5f 3.13e, 3.20g 2.27h
a
HOMO energy level with respect to the Fermi level. HOMO energy level with respect to the vacuum level. c Energy of the lowest-energy-loss feature. d Onset of the lowest-energy-loss feature. e <2003MCL113>. f <1993PRB13323>. g <1994AM846>. h <1998MI291>. b
Figure 22 Structure of POPT and 2,5-(2,20-dithienyl)diethynylthiophene.
The DOUS (density of the valence states) obtained from the calculations was in good agreement with the direct measurements by UPS spectra. By studying temperature-induced changes in the UPS spectra, it can be deduced that the torsion angles of the POPT backbone decrease at elevated temperatures, leading to an increase of crystallinity. This conversion process was found to be irreversible, in contrast to the real thermochromism in poly(3-hexylthiophene), which is reversible. The evolution of the doping-induced new states is different, depending upon whether the starting films are of the unconverted or converted form. For unconverted POPT, polaron states are seen at low doping levels, and bipolaron bands at high doping levels. Starting with thermally converted POPT, on the other hand, no polaron states could be detected at low doping levels, but bipolaron bands were seen at high doping levels. In addition, the maximum level of doping was found to be higher, by a factor of 2, in thermally converted samples compared to unconverted samples. This effect arises from the fact that thermal conversion leads to a improved crystallization of the films, which in turn affects the ability of dopant ions to diffuse throughout the films. The higher levels of doping obtained for converted POPT can be explained by the shorter distances between the potassium ions and the polymer chains in the more planar thermally converted POPT, which leads to better Madelung stabilization and also lower energy levels for the polaron and bipolaron states. The X-ray photoelectron spectra of gaseous 2,5-(2,29-dithienyl)diethynylthiophene 109 (TRIM) (Figure 22) in the C 1s and S 2p core level regions have been recorded by means of synchrotron radiation (SR) <2001CPL(340)449>. A main and rather broad peak is evident at a binding energy value just below 291 eV; a well-resolved but lower-inintensity component occurs at higher binding energy in close proximity of 291.5 eV and is interpreted as due to more positive carbon atoms. The signal splitting, as well as the broadening of the first peak, is due to the presence of different IPs of the eight inequivalent carbon atoms of diyne 110. For the thiophene, the shift in energy between the contribution by the - and -carbon atoms (i.e., bonded to sulfur and not) was reported as being 0.34 eV <1971MI237>. This splitting was found somewhat smaller than the 0.59 eV separation obtained from ab initio calculations performed by Gelius et al. <1970CPL(4)471> but larger than
687
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Thiophenes and their Benzo Derivatives: Structure
the results coming from ab initio calculations of Clark and Armstrong discussed by Clark and Lilley <1971CPL(9)234>, who also reported an experimentally determined value of energy shift equal to 0.1 eV. It should be taken into consideration that the central thiophene brings two chemically bonded ethyne groups on each side of the ring, while the two terminal heteroaromatic rings are linked to only one –CUC– group. This is expected to produce a perturbation on the charge distribution around the thiophene ring. A good agreement between experiment and theory is observed by comparing the spectra experimental and calculated both for the position of the bands and for their intensity ratios that are fairly similar. The assignment of the peaks, made on the basis of both the IP calculations and the chemical structure, is given in Table 58, with details about the different components of the line as derived from calculation of the theoretical spectrum and deconvolution of the experimental one.
Table 58 Comparison between experimental and calculated IPs for the three spectral bands (a–c) attributed to the eight chemically different types of carbon atoms of compound 109a Peak type
Experimental IP
Calculated IP
FWHM (eV )
Area (%)
a (C-3, C-8) b (C-1, C-2, C-5, C-6) c (C-4, C-7)
290.33 290.59 291.43
290.72, 290.72 291.15, 291.10, 290.96, 291.03 292.06, 291.81
0.55 0.66 0.61
22.61 45.13 22.61
a
Data are in eV. Intensity of bands a–c are also given in %.
Photoelectron spectroscopy employing synchrotron radiation was applied to learn about the electronic structure of regioregular poly(3-hexyl-thiophene) (P3hT) <2003SM(138)135>. The data allow the determination of the energetic position of the occupied and the unoccupied states. The electronic structure is determined by the existence of two valence and conduction bands with a total width of about 20 eV. The atomic parentage of the valence states arises from the C 2p and S 3p states while the lower valence band includes the s states (C 2s, S 3s) as well. Also, the conduction band consists of at least two almost-separated sub-bands. The Auger processes are found to involve predominantly the localized states of the monomeric subunits and not the band-like states that are significant for the existence of long-range covalent interactions. The nature of vibronic coupling in fused polycyclic benzene–thiophene structures, including benzodithiophene 45, naphthodithiophene 111, and anthradithiophene 112, has been studied using an approach that combines highresolution gas-phase photoelectron spectroscopy measurements with first-principles quantum-mechanical calculations <2006CEJ2073>. The photoelectron spectra of the isomers 45 are nearly identical. The same must hold true for the isomers 112; indeed, even though compound 112 has been obtained as an inseparable mixture of anti- and syn-isomers, the sharpness of its PES demonstrates that the cation spectra of the isomers 112 are equivalent. This conclusion is further supported by the electronic-structure calculation; the DFT results indicate that the energy spectrum becomes less dependent on isomer constitution as the size of the system increases. In contrast to the acenedithiophenes, the difference between the PESs of the isomers 47 is substantial (Figure 23). In compound 45, however, the effect of replacing a CTC bond with S is somewhat larger; the energy EH/H–1 of the HOMO–HOMO-1 gap, for instance, is 0.4 eV smaller in compound 45 than in anthracene. Nevertheless, the PES of both isomers overall resemble that of anthracene. The first ionization potential in compound 47 is shifted by 0.8 eV to higher energies with respect to pentacene (the linear pentaphene) and compound 112. The 7.27 eV first ionization in pentaphene <1977JCP(66)828> in fact matches very well with the corresponding values of 7.36 and 7.43 eV derived for the isomers 47. In addition, the EH/H–1 value of 0.12 eV estimated for pentaphene is also in good agreement with the corresponding energy gaps in isomers 47. The DFT calculations indicate that heterocycles 114–116 share the same kind of similarity with pentaphene 113. The degree of geometry relaxations calculated when going from the neutral to the cation or anion states in compounds 45, 111, and 112 is similar to those observed in the corresponding oligoacenes. As the size of the systems increases, when going from tricycle 45 to pentacycle 112, the Huang–Rhys factors (the electron- and hole-vibration constants) for high-frequency vibrations decrease as expected. In contrast, the vibronic interaction with low-energy vibrational modes shows an opposite trend for both electrons and holes. The electron– vibrational interaction with low-energy vibrations is much larger than the hole–vibrational interaction; a similar pattern is also characteristic for oligoacenes.
Thiophenes and their Benzo Derivatives: Structure
Figure 23
In the results of the simulation performed in the framework of the Born–Oppenheimer and FC approximations (see <2004JCP(120)7490> for more details), the positions of the peaks and the difference between the isomers are remarkably well reproduced. The overall agreement between the simulated and experimental spectra increases the confidence in the reliability of DFT-derived vibronic constants and relaxation energies. The DFT estimates of the reorganization energies obtained from the adiabatic potential (AP) calculations for the isomers 47 and related systems are collected in Table 59. As in the case of acenedithiophenes, (ET) is much larger than (HT). The replacement of a CTC bond with a S-atom in the terminal rings of pentaphene has only moderate influence on the relaxation energies. In contrast, replacement in the central ring results in a significant reduction of both (ET) and (HT): these two quantities in compound 116 are about 25% and 50%, respectively, smaller than in pentaphene. Both (ET) and (HT) in compounds 47 are also smaller than in pentaphene, while larger than in compounds 112 and pentacene. The influence of the isomer constitution on the reorganization processes is more significant in compounds 47 than in compounds 112. It appears, however, that the substitution of different CTC bonds affects (ET) and (HT) in different ways. For instance, (ET) in anti-47 is similar to that in compound 114, and is thus not affected by substitution in the middle ring. At the same time, (HT) in anti-47 is identical to that in compound 116, indicating that the substitution in the terminal rings has no influence on the reorganization, as is further supported by the comparison of (HT) values in compounds 113 and 114.
Table 59 B3LYP/6-31G** estimates of the reorganization energies (eV) related to electron transfer (ET) and hole transfer (HT) in pentaphene derivatives Molecule
(ET )
(HT )
Molecule
(ET )
(HT )
anti-47 syn-47 113
0.237 0.213 0.249
0.118 0.148 0.178
114 115 116
0.239 0.259 0.198
0.181 0.204 0.119
689
690
Thiophenes and their Benzo Derivatives: Structure
3.09.4 Thermodynamics 3.09.4.1 Aromaticity Qualitatively, the concept of aromaticity is quite clear <1974AHC(17)255, B-1985MI1>. A compound is considered aromatic if it: 1. 2. 3. 4. 5. 6.
is a cyclic compound with a large resonance energy; possesses an aromatic sextet; follows the Hu¨ckel rule; is capable of sustaining an induced ring current; has a lack of marked bond-length alternation; and displays enhanced thermostability.
Aromaticity, defined as a structural feature, has been used as a predictive tool for compounds that had not been prepared previously, whereas reactivity, bond length, or magnetic criteria had to await the isolation of a compound and its experimental investigation. Only recently has the development of quantum-chemical methods reached the point where one can predict with sufficient accuracy the magnetic properties, the bond lengths, and the reactivity patterns of aromatics. The multidimensional character and the definition and measurement of aromaticity generated confusion and conflicts <1989JA7, 1990JPR853, 1990JPR870, 1990JPR885, 1991JPO163, 1995JCI203, 1998JOC5228, 2002JOC1333>. Actually, the concept of aromaticity continues to evolve over time. New aspects await discovery <2004CRV2777>. Nevertheless, ‘‘it would be inconceivable to discontinue the use of the concept of aromaticity because of difficulties in its definition and/or measurement’’ <1998JOC5228>. The following qualitative definition covers various aspects of the concept and is compatible with the rapid further developments of this field of research. Aromaticity is a manifestation of electron delocalization in closed circuits, either in two or three dimensions. This results in energy lowering, often quite substantial, and a variety of unusual chemical and physical properties. These include a tendency toward bond-length equalization, unusual reactivity, and characteristic spectroscopic features. Since aromaticity is related to induced ring currents, magnetic properties are particularly important for its detection and evaluation. The main criteria characterizing aromaticity comprise four main categories. The following are illustrative, but each has its drawbacks: 1. Structures’ tendency toward bond-length equalization and planarity (if applicable). Bond-length equalization cannot be used as the only criterion for aromaticity because some bond-equalized systems are not aromatic. Moreover, bond-length equalization due to p-electron delocalization is found not only in cyclic systems but also in highly conjugated acyclic compounds. 2. Energy-enhanced stability and reactivity criteria such as enhanced resonance energies (REs) and the aromatic stabilization energies (ASEs) have long been recognized to be the cornerstone of aromaticity. However, ASEs and REs, even of unstrained and uncomplicated systems, are difficult to evaluate unambiguously. Predominance of substitution versus addition reactions; thermal stability; stabilizing ability for aryl- or heteroaryl-substituted free radicals, anions, or cations (such as carbenium, halonium, oxonium, and diazonium cations) are some of the characteristics. Reactivity is dominated by the transition state rather than the initial state energy. Since aromaticity is a property of the initial state, criteria based on chemical reactivity are not straightforward to quantify. The traditional reactivity characteristic of aromatic compounds is the electrophilic aromatic substitution. 3. Magnetic properties (exaltation and anisotropy of magnetic susceptibility, diatropic ring current, nucleus-independent chemical shifts (NICSs) at a distance (angstroms) from the molecular plane indicated in brackets (NICS(0) and NICS(1) values) <1996JA6317, 1997OM2362, 2001CRV1349> are also assessed. Several methods for the evaluation of magnetic aromaticity <2001CRV1349, 2005CRV3842>, including proton chemical shifts <2005OL1457, 2005OL3457, 1956JCP(24)1111>, exaltation of magnetic susceptibilities <1956JCP(24)1111, B-1967MI1>, NICSs, <2005CRV3842, 1996JA6317, 1997JA12669, 2001OL2465, 2001J(P2)1893, 2002JOC1333, 2003PCA6470, 2003PCP246, 2004PCP273>, ring current density plots <1999MP1099, 2000MP945, 2001AGE362,
Thiophenes and their Benzo Derivatives: Structure
2001CC2220, 2004JOC6634, 2005JPO886>, and aromatic ring current shieldings (ARCSs) <1999PCP3429>. Since its introduction in 1996 <1996JA6317>, NICS continues to gain popularity <2005CRV3842> as an easily computed, generally applicable criterion to characterize aromaticity and antiaromaticity of rings <1996AGE2638, 1997AGE2761, 1998JA9634, 1998JOC3417, 2000JMM67>, clusters <1998CEJ734, 2000JA4781, 2000AGE3915, 2001CRV1153, 2001AGE2834>, transition states <1998JPO655, 1999JA6737, 1999JA864, 2000JOC7971, 2001AGE557, 1998JA11130>, and transition metal complexes <2000JA510>. NICS is based on the magnetic shielding (with the sign reversed) computed at chosen points in the vicinity of molecules. Significantly negative (shielded) NICS values inside rings or cages are due to induced diatropic ring currents and denote aromaticity, whereas positive (deshielded) values denote paratropic ring currents and antiaromatic behavior. Isotropic NICS values can be computed readily using commonly available programs and do not require model compounds for evaluation. However, due to its conceptual imperfections, NICS has been refined considerably <2005CRV3842> since its introduction in 1996 <1996JA6317>. The original NICS index <1996JA6317> (now termed NICS(0)iso) was based on the total isotropic shielding (average shielding) computed at ring centers. But this index is not a ‘pure’ measure of p-aromaticity, as the local contributions of the -framework are ignored. Consequently, isotropic NICS(1) values (i.e., at points 1 A˚ above ring centers) were recommended in 1997 as being better measures of p-effects than NICS(0) <1997JA12669, 2001OL2465, 2001J(P2)1893>. However, NICS(1) is still based on the total isotropic shielding value, rather than on just the contributions arising from the zz-component of the shielding tensor as envisioned by Pople <1956JCP(24)1111>. The most refined index <2004PCP273, 2001AGE362>, designated NICSpzz, eliminates this contamination by using localized molecular orbital (LMO) or CMO dissection to select only the p-contribution to the zz-component of the tensor. The final index, NICS4"pzz, is based on the contributions from only the two highest energy p-MOs. NICS4"pzzis expected to correlate most closely with the induced ring current densities <2001CC2220>. All of the p-based methods share the disadvantage of requiring LMO or CMO dissection. All isotropic magnetic indexes used to characterize p-aromaticity of 2-D systems have conceptual limitations. As the response to a magnetic field applied along each of the three principal directions may be quite different, important features inherent to each direction (tensor component) can be masked when considering the averaged isotropic values of NICS and other magnetic measures. Alternative magnetic indexes based on the out-of-plane tensor component have a physical origin closer to the current density. These indexes not only are more sound conceptually, but they also perform better in practice for planar rings. They may also be applied to cyclic planar moieties within clusters and cages. Isotropic NICS is highly useful for spherical (isotropic) systems. Important criteria for heterocycles include hybridization, electronegativity, and stereochemistry. For thiophene, the matter is further complicated by the question whether the 3d-orbital of sulfur also participates in bond formation. If so, then the two resonance structures 119 and 120 in Scheme 7 should also be considered in determining the degree of aromaticity.
Scheme 7
Qualitatively, heterocycles with five- and six-membered rings have been considered as modified benzenes, where a pair of carbon atoms (for five-membered systems) plus any number of carbon atoms are substituted with a heteroatom. Hence, most heterocycles could be classified as p-excessive 121 or p-deficient 122 (Scheme 8) . This approach is useful in assessing the aromatic properties of monocycles but lacks generalization.
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Scheme 8 Heteroaromatic compounds as modified benzenes.
In heterocyclic chemistry, a quantitative evaluation of the aromatic character is a necessity as new heterocyclic systems are designed and synthesized and need to be evaluated in connection with property predictions. Three major approaches to the quantization of aromaticity exist: 1. The increased thermodynamic stability of aromatic compounds is the basis of the energy scale. 2. The geometry of the ring was proposed as a criterion for the degree of aromaticity. Today, inter- and intramolecular bond-length data are easily collected by routine X-ray measurements. On the basis of these measurements, the harmonic oscillator model of aromaticity (HOMA) concept has been successfully used as evidence of the aromatic character in many p-electron systems. This model relates the decrease of aromaticity to two geometric/ energetic factors: one describing the bond-length alternation (GEO) and the other describing the extension of the mean bond length (EN). 3. Magnetic property measurements led to a quantitative approach to aromaticity. Diamagnetic susceptibility was the first magnetic property studied in connection with the concept of resonance energy. More recently, 1H NMR spectroscopy has become a tool in the study of ring currents in cyclic p-conjugated systems. Structures and nomenclature for the most important five-membered monocycles with one or more heteroatoms are depicted in Figure 24. The aromaticity scale in five-membered heterocycles has long been debated <2001PCA5486, 1996CHEC-II(2)471, 1984CHEC(4)28, 1974AHC(17)255, B-1986MI2>.
Figure 24 Monocyclic aromatic compounds.
Thiophenes and their Benzo Derivatives: Structure
The decreasing order of aromaticity based on various criteria is (Dewar resonance energy (DRE) values in kcal mol1): benzene (22.6) > thiophene (6.5) > selenophene > pyrrole (5.3) > tellurophene > furan (4.3) (see Figure 25).
Figure 25 Aromaticity scales in five-membered heterocycles.
A larger covalent radius such as that of sulfur, selenium, or tellurium reduces the ring strain; d orbital participation in thiophene is not significant in the ground state, and thiophene exhibits a pronounced aromatic character that is substantiated by its physical and chemical properties . In the benzo[b]-annulated series the order of aromaticity is similar, as described by the DRE values (kcal mol1): naphthalene (33.6) > benzo[b]thiophene (24.8) > indole (23.8) > benzo[b]furan (20.3); for the dibenzo series, phenanthrene > dibenzothiophene (44.6) > carbazole (40.9) > dibenzofuran (39.9) (Figure 25). Benzo[c]-annulation causes an inversion between NH- and S-heterocycles: isoindole (11.6) > benzo[c]thiophene (9.3) > benzo[c]furan (2.4) . On converting 1-phenylbenzo[b]thiophene into 1-phenyl-1-benzo[b]thiophenium triflate 123, this salt becomes a dienophile and reacts readily with cyclopentadiene or 1,3-diphenylbenzo[c]furan to give the adduct 124 (Scheme 9) <1999OL257>. This example of the dienophilic nature of the double bond in the benzo[b]thiophene ring arises from reduced aromaticity. Thiophene 1-oxide and 1-substituted thiophenium salts present reduced aromaticity <1970JA7610>.
Scheme 9 The olefinic nature of the thiophenium ring.
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Several aromaticity indexes (bond lengths, bond orders, Jug and Franc¸ois’s aromaticity index) indicate that, despite the nonplanarity of the five-membered ring in 2,5-diphenylthiophene-1-oxide 126, this compound is intermediate in aromaticity between the corresponding thiophene 127 and the nonplanar 1,1-dioxide 127 (Figure 26) <1997JHC1567>. The theoretical calculations were supported by experimental electrochemical data <2000CC439>.
Figure 26 Thiophene derivatives.
The NICS of each ring, as a criterion of aromaticity, has been used to explain the stability order of benzo[b]thiophene and its isomer. The results indicate that the benzene ring is aromatic in all the systems. The five-membered ring of benzo[b]thiophene is also aromatic, whereas in benzo[c]thiophene it is nonaromatic. This could be an explanation of the stability of the former molecule. The MOS and the condensed Fukui functions derived from the electronic-structure calculations explain the expected electrophilic substitution of these compounds. The theoretical structure, ionization energies, order of aromaticity, stability, and reactivity are in good agreement with the experimental results <2003T6415>. Benzo[c]thiophene is less stable than benzo[b]thiophene by 9.3 kcal mol1. This result is in agreement with the experimental information concerning the reactivity of these systems, namely, benzo[b]isomers are more stable than the corresponding benzo[c] derivatives (Table 60). Table 60 NICS (total) RB3LYP/6-311þG** values for thiophene and derivativesa A ring
a
B ring
NICS(0)
NICS(1)
NICS(0)
NICS(1)
12.87
10.24
9.10
10.63
10.35
8.85
5.06
7.62
14.86
12.61
6.64
9.19
10.61
11.55
11.71
8.90
9.93
6.75
1.18
0.89
All structures are fully optimized local minima (RB3LYP/6-311þG**).
Thiophenes and their Benzo Derivatives: Structure
Theoretical ionization energies are in good agreement with the experimental values. For all the molecules, the HOMO–LUMO gap is larger for the most stable isomers. This confirms previous results that claim that the stability of aromatic hydrocarbons depends on the HOMO–LUMO gap. The principle of maximum hardness establishes that the system would be more stable if the global hardness, related to the HOMO–LUMO gap, is a maximum. As shown in Table 61, the HOMO–LUMO gap correlates well with the expected stability of these molecules and the energy difference between the HOMO and HOMO-1 for benzo[b]thiophene is smaller than for benzo[c]thiophene (Figure 27). Therefore, it is possible to use hardness as a criterion of stability.
Table 61 HOMO–LUMO gap (H–L) and HOMO–[HOMO-1] energy difference (H–H’) in eV, for benzo[b]thiophene and benzo[c]thiophene. All calculations with Perdew–Wang 1991 <1995MI2>
Benzo[b]thiophene Benzo[c]thiophene a
H–L
H–H
Ionization energiesa
3.8 2.7
0.5 1.1
7.83 (8.13) 7.40 (7.75)
Theoretical ionization energies with available experimental results (in italics) <2001PCA3838, 1999T6205, 2000T1783>.
LUMO –0.06
HOMO –0.20 HOMO-1 –0.22
LUMO –0.09
HOMO –0.18 HOMO-1 –0.23
Figure 27 HOMO, LUMO, and HOMO-1 orbitals of benzo[b]thiophene and benzo[c]thiophene. PW91 results are shown.
Again, these results are in agreement with the NICS values for both rings of these molecules. With this MO analysis, the stability and aromaticity of these compounds are explained. The p-molecular delocalization agrees with the aromatic behavior of the two rings in these systems. It is possible to see the delocalization with two frontier MOs. However, caution is required for other systems where perhaps more occupied MOs are required. A Mulliken population analysis was used to estimate the condensed reactivity indexes. In Table 62, the absolute values for the condensed Fukui function for electrophilic attack are shown for the relevant atoms in the heterocyclic compounds.
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Table 62 Calculated Fukui functions (absolute values), f q , for electrophilic attack at the qth atom, from the Mulliken population analysis for benzo[b]thiophene and benzo[c]thiophene (PW91/ 6-311þG(2d,p))
Benzo[b]thiophene Benzo[c]thiophene
S
C-2
C-3
0.20 0.12
0.07 0.12
0.07 0.15
For benzo[b]thiophene, S and C-3 are the most reactive sites. Note the large condensed Fukui function on the S-atom of benzo[b]thiophene. The results concur with the experimental information concerning the reactivity and stability of these systems. The principle of maximum hardness establishes that the system would be more stable if the global hardness, related to the HOMO–LUMO gap, was a maximum. The HOMO–LUMO gap correlates well with the expected stability of these molecules. This is an indication of the possibility to use hardness as a criterion of stability. The stability order of these molecules can be explained using the NICS values of each ring. The NICSs indicate that the benzene ring is aromatic in all of the systems. However, for the benzo[c] derivative, only the benzene ring is considered aromatic, whereas for the benzo[b] compound both rings are considered aromatic. One can say that one ring gains aromaticity, whereas the other loses it, when we proceed from benzo[b] derivatives to benzo[c] compounds. The aromaticity of benzene increases when it is bonded to a five-membered heterocyclic ring, while the aromaticity of the five-membered rings decreases when they are bound to benzene. (Figure 28).
˚ and point groups for B3LYP/6-31G* optimized structures. Figure 28 Bond lengths (A)
For benzo[b]thiophene, there is a p-MO delocalization between the two aromatic rings. For benzo[c]thiophene, the orbitals of the five-membered rings are localized on the heteroatom, C-1 and C-3, and there is no p-MO delocalization on the heterocyclic five-membered rings. These results are in agreement with the theoretical aromaticity of these molecules as are theoretical results from the reactivity indexes. Aromaticity of thiophene, benzo[b]thiophene, benzo[c]thiophene, and dibenzothiophene has been examined via their NICS values (NICS(0) and NICS(1)) calculated at gauge-independent atomic orbital (GIAO)–HF/6-31G* // B3LYP/6-31G* and GIAO-HF/6-31þG* //B3LYP/6-31G* levels (Table 63) <2003JST(638)157>. A serious loss of aromaticity is seen in the thiophene ring when it is fused to benzene to form benzo[b]thiophene (10.5 ! 8.4 ppm; NICS(1) ¼ 2.1 ppm) and dibenzothiophene (10.5 ! 6.2 ppm; NICS(1) ¼ 4.3 ppm). The aromaticity of benzene ring in these compounds, however, remains virtually the same. As has been the case in the pyrrole and furan analogues, an opposite NICS trend is observed for benzo[c]thiophene; the NICS(1) value of the thiophene ring becomes more negative (more aromatic: 10.5 ! 13.0 ppm, NICS(1) ¼ 2.5 ppm) and the NICS(1) value of the benzene ring becomes less negative (less aromatic: 11.5 ! 7.2 ppm, P NICS(1) ¼ 4.3 ppm). The NICS(1) values of benzo[b]thiophene and benzo[c]thiophene are virtually the same (20.3 and 20.2 ppm, respectively). When a benzene ring is fused to 2,3- and/or 4,5-positions of a thiophene, the aromaticity of the five-membered ring is reduced to some extent. This reduction is almost cumulative depending upon the number of benzo groups fused to it. The aromaticity of the benzene ring in these compounds, however, remains virtually the same. When a benzene ring is fused to the 1,2- or 3,4-positions of a thiophene, the aromaticity of the five-membered ring increases while the aromaticity of the benzene ring decreases. In these compounds, it is noteworthy that the reduction in the aromaticity P of benzene ring is greater than the gain of the aromaticity in the five-membered ring. The NICS values of benzoand dibenzo-substituted heterocycles are close to or lower than the sum of NICS values of corresponding monocycles.
Thiophenes and their Benzo Derivatives: Structure
Table 63 Electronic energies (hartree) for B3LYP/6-31G*-optimized geometries and GIAO–SCF-calculated NICS (ppm), P NICS (ppm), and NICS (ppm) values GIAO–HF/6-31G* //B3LYP/6-31G* NICS(0) (NICS(0)) Structure
B3LYP/6-31G*
Thiophene
553.002 628 5
Benzo[b]thiophene
706.653 648 0
Benzo[c]thiophene
706.635 744 6
Dibenzothiophene
860.306 860 4
5MR 14.7a (0.0) 10.9 (3.8) 16.6 (1.9) 7.3 (7.4)
NICS(1) (NICS(1)) 6MR
5MR
6MR
12.2 (0.7) 5.9 (5.6) 11.6 (0.1)
11.1 (0.0) 9.1 (2.0) 13.8 (2.7) 6.7 (4.4)
13.1 (0.3) 8.3 (4.5) 12.6 (0.2)
6MR
P NICS(1)
GIAO–HF/6 31þG* //B3LYP/6-31G* NICS(0) (NICS(0)) Structure Thiophene Benzo[b]thiophene Benzo[c]thiophene Dibenzothiophene
5MR 13.6a (0.0) 10.1b (3.5) 15.8b (2.2) 6.9 (6.7)
NICS(1) (NICS(1)) 6MR
P NICS(0) 13.6
10.7b (1.0) 4.6b (5.1) 10.2 (0.5)
20.8 20.4 27.3
5MR 10.5 (0.0) 8.4 (2.1) 13.0 (2.5) 6.2 (4.3)
10.5 11.9 (0.4) 7.2 (4.3) 11.4 (0.1)
20.3 20.2 29.0
a
Taken from <1996JA6317>. Taken from <1996AGE2638>. NICS (ppm): difference between NICS value in fused-ring system and NICS value in reference compound (benzene, pyrrole, P furan, and thiophene); NICS (ppm): sum of NICS values of rings in compound. For NICS values, 5MR indicates five-membered ring while 6MR indicates six-membered ring. b
Quantitative relationships among the magnetic, energetic, and geometric criteria of aromaticity have been noted for a variety of monocyclic heterocycles <1996JA6317, 2002JOC1333>. However, these criteria sometimes give different predictions on aromaticity when it comes to polycyclic systems <2002CPL(365)34, 2003BCJ1363, 2004BCJ101>. This aspect of polycyclic species has been explicitly revealed by theoretical investigations carried out on the isomers of thienothiophenes 128a–d (Figure 29, Table 64) <1996AGE2638, 1997JST(398)315, 2001CRV1385>. These species are the simplest among polycyclic p-systems, being iso-p-electronic with aromatic naphthalene. For these heterobicycles, the lowest energy isomer is not always the most aromatic.
Figure 29 NICS values for thienothiophenes (128a–b), all calculated at the CSGT-HF/6-31þG** level of theory. Values in parentheses are TREs in units of jj.
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Table 64 TREs and related quantities for thienothiophenes (all in units of jj) Species
Total p-binding energy
HOMO–LUMO gap
TRE
Thieno[3,2-b]thiophene 128a Thieno[2,3-b]thiophene 128b Thieno[3,4-b]thiophene 128c Thieno[3,4-c]thiophene 128d
8.223 8.199 8.076 7.690
1.283 1.547 1.134 0.568
0.311 0.309 0.251 0.267
The stability orders of thienothiophene isomers are 128a 128b > 128c > 128d, respectively <1996AGE2638, 1997JST(398)315, 2001CRV1385>. The low-energy isomers 128a and 128b satisfy the topological charge stabilization (TCS) rule <1983JA1979>. However, the relative aromaticities of compounds 128a–d as predicted by their NICS <1996JA6317, 2002JOC1333> values show the highest-energy isomer 128d to be the most highly aromatic (Table 64). Note that NICS has been used widely as a magnetic criterion for estimating the degree of aromaticity. The lowest-energy isomer 128a proved not to have the largest aromatic or resonance stabilization. If the relative aromaticities thus determined were fully reliable, it would imply that highly aromatic molecules are not always thermodynamically very stable. This does not conform to our image of aromatic molecules. The aromaticities of compounds 128a–d have been critically evaluated using the graph theories of aromaticity and magnetotropicity <1976JA2750, 1977JA1692, 1995JA4130, 1996J(P2)2185, 1983BCJ1853, 1985JA298> and this has established that at least some aromatic molecules might be energetically or kinetically very unstable. The term ‘magnetotropicity’ has been used when diatropicity and paratropicity are referred to collectively <2005JPO235>. Topological resonance energy (TRE) and bond resonance energy (BRE) are typical energetic quantities defined by the graph theory. TRE represents a stabilization energy due solely to cyclic p-conjugation <1976JA2750, 1977JA1692>, which is evaluated relative to the p-binding energy of the graph-theoretically defined polyene reference. TRE is used as a standard measure of aromaticity. BRE represents the contribution of a given p-bond to the TRE <1995JA4130, 1996J(P2)2185>. If the smallest BRE in a p-system has a large negative value, the p-system will be kinetically very unstable with chemically reactive sites. Both TRE and BRE are given in units of jj, where is the standard resonance integral in Hu¨ckel theory. It has been assumed that all five-membered rings are regular pentagons in shape. Hu¨ckel parameters employed for compound 128 are those determined consistently by VanCatledge <1980JOC4801>: hO ¼ 2.09, kC–O ¼ 0.66, hS ¼ 1.11, and kS ¼ 0.69. A graph-theoretical variant <2002CPL(365)34, 2003BCJ1363, 2004BCJ101, 1983BCJ1853, 1985JA298> of the Hu¨ckel–London theory is utilized to calculate the intensities of p-electron currents magnetically induced in polycyclic p-systems. According to this, a p-electron current induced in a polycyclic p-system can be partitioned formally among all possible circuits in the p-system. Here a circuit stands for any cyclic path in a p-system. Let a p-system from which one or more circuits can be chosen be denoted by G. A current assigned to the ith circuit, ri, may be called the ith circuit current. The intensity of the ith circuit current, Ii, can be expressed in the form <1983BCJ1853, 1985JA298>. occ PG–ri Xj Ii Si ri ¼ 18 km I0 S0 m j P9G Xj
where I0 is the intensity of a current induced in the benzene ring; Si and S0 are the areas of ri and the benzene ring, respectively; Gri is the subsystem of G, obtained by deleting ri from G; PG(X) and PGri(X) are the characteristic polynomials for G and Gri, respectively; km is the heterobond parameter for the mth p-bond; m runs over all p-bonds that belong to ri; Xj is the jth largest zero of PG(X); and j runs over all occupied p-orbitals. If there are degenerate p-orbitals, this formula must be replaced by others <1983BCJ1853, 1985JA298>. Positive and negative values for Ii signify diatropicity and paratropicity, respectively. NICS values at the ring centers of thienothiophenes 128a–d are summarized graphically in Figure 29, which are those calculated by Subramanian et al. at the continuation set of gauge transformations (CSGT)–HF/6-31þG** level of theory <1996AGE2638>. It is noteworthy that compound 128d exhibits the largest negative NICS values at the ring centers. On this basis, Subramanian et al. predicted that this isomer must be the most aromatic although it is the energetically least stable isomer. As shown in Table 64, 128d has the smallest total p-binding energies. For these species, large negative NICS values never represent thermodynamic stability. They do not conform to the TCS rule <1983JA1979>.
Thiophenes and their Benzo Derivatives: Structure
Current density maps for 128a–d are shown in Figure 30, where the intensities of all p-electron currents are given in units of that induced in the benzene ring. These maps were obtained by superposing all possible circuit currents.
Figure 30 p-Electron currents induced in the isomers of thienothiophene 2a–d, all in units of that for benzene (l0). Values in parentheses are the BREs in units of jj.
Why does the TRE order of aromaticity differ from the NICS order? A clue to this problem is obtained by partitioning the p-electron currents among the circuits. All heterobicycles studied have three circuits: two fivemembered circuits and one eight-membered circuit. Current intensities induced in the individual circuits, that is, intensities of all circuit currents, are given in Figure 31. All circuits sustain diamagnetic currents when compounds 128a–d are placed in the magnetic field. In compounds 128a and 128b, strong currents are induced in two fivemembered circuits and a weaker one in the eight-membered circuit. In compound 128c, a strong current is induced in only one of the two five-membered circuits. In marked contrast, compound 128d sustains very large diatropic currents not only along the two five-membered circuits but also along the peripheral eight-membered circuit, and is thus different in the relative intensities of circuit currents from other isomers. Therefore, it follows that it is not always meaningful to predict the aromaticity order from the relative NICS values.
Figure 31 Circuit currents for thienothiophenes (2a–d), all in units of that for benzene (l0).
BRE is a useful measure for estimating the contribution of individual circuits to aromaticity <1995JA4130, 1996J(P2)2185>. If a p-bond is shared by two or more aromatic circuits, the BRE will have a large positive value. BREs for all species are added in Figure 30. All p-bonds in the heterobicycles studied have positive BREs, which is consistent with the view that all these molecules are aromatic with positive TREs. As for compounds 128a and 128b, the central CC bond, that is, the bond shared by two rings, has a large BRE, which indicates that the two fivemembered circuits are highly aromatic on which ca. six p-electrons reside. In contrast, the central bonds in compound 128d have much smaller BREs, suggesting that the two five-membered circuits are much less aromatic. In fact, the chemistry of compounds 128a–d is fully consistent with the above interpretation of TREs and HOMO– LUMO gaps <1975ACR139, 1976AHC(19)123>. Thienothiophenes 128a and 128b, which have the largest positive TREs and the largest HOMO–LUMO gaps, are kinetically very stable and undergo electrophilic substitution, whereas isomer 128c, with the smallest positive TRE and a smaller HOMO–LUMO gap, is sensitive to air. Isomer 128d, whose polyene reference must be extremely reactive, is available only as a transient or heavily substituted species <1975ACR139, 1976AHC(19)123>. It is much more reactive than isomers 128a or 128b. It can be seen that the TREs calculated for polycyclic p-systems cannot always be associated with the thermodynamic or kinetic stability of the p-system. Heterobicycle 128d has large negative NICS values at all ring centers in accord with the large positive TREs. However, they must be kinetically very unstable because the nonclassical
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Thiophenes and their Benzo Derivatives: Structure
polyene references are supposed to be extremely reactive. The TCS rule <1983JA1979> proved to be a rule of thermodynamic stability but not that of aromaticity. It has repeatedly been pointed out that NICS is not always a good indicator of aromaticity for polycyclic p-systems <2002JOC1333, 2002CPL(365)34, 2003BCJ1363>. However, when thiophenes are transformed into the corresponding S-oxides, the aromaticity of the thiophene ring is destroyed. In fact, thiophene monoxides formed by oxidation of thiophenes successfully undergo the Diels–Alder cycloaddition as a diene component <1954JA1936, 1980JOC856, 1980JOC867, 1996SL461, 1997JOC7926, 1998H(47)793, 2000J(P1)2968>. There are a few reports on the theoretical study of thiophenium salts <1995JPO753, 1995JHC483, 1995J(P2)455>, demonstrating that the aromaticity of the thiophene ring is destroyed. However, there is no experimental evidence for the lack of aromaticity. The triflate salt of 1-phenylbenzo[b]thiophenium ion 123 (R ¼ Ph) shows a tetrahedral structure around the sulfur atom with the phenyl group being out of the plane and a large bond alternation <1993CL1703>. The C(2)–C(3) bond ˚ calculated value) length of 1.308 A˚ is much shorter than the corresponding values of benzo[b]thiophene 7 (1.354 A, ˚ <1974AXB2058>, thiophene 1 (1.369 A) ˚ <1970ACS23>, 5-bromo-2,3-dimethylbenzo[b]thiophene 130 (1.355 A) ˚ <1970AXB1010>, and 2-methylbenzo[b]thiophene 129 (1.382 A) (Figure 32) <1985AXC929>.
Figure 32
This structural outcome suggests a lack of aromaticity of the thiophene ring in the 1-phenylbenzo[b]thiophenium ion. A novel [4þ2] cycloaddition reaction of 1-phenyl-1-benzothiophenium salts with cyclopentadiene or 1,3-diphenylbenzo[c]furan has been reported which experimentally confirmed the olefinic nature of the thiophene ring arising from a lack of aromaticity <2003JOC731>. The aromaticity of 1,3,4-thiadiazole-2-thione and thiophene has been examined by harmonic oscillator model of aromaticity (HOMA), ASE, differential heat of hydrogenation (HH), and nucleus-independent chemical shifts (NICS (0)), calculated at the HF/6-31G** , B3LYP/6-31G** , B3LYP/6-311G** , and B3LYP/6-311CCG** levels <2005JST(726)233>. A principal component analysis (PCA) of the data set generated from these aromaticity results has been presented and compared with similar analyses in the recent literature. It has been shown that aromaticity is at least a 2-D phenomenon, independent of the level of the computational method employed. It has been observed that the sulfur-containing heterocyclic compounds are more aromatic than their oxygen analogues according to geometrical aromaticity measurements.This can be ascribed to the larger covalent radius of sulfur that will reduce the ring strain. On the other hand, all the sulfur-containing heterocycles are located in the close vicinity of the model aromatic structure, the cyclopentadienyl anion 131. Thus, one can assign higher aromaticity to the sulfur-containing heterocycles relative to the oxygen-containing ones, not only on the basis of geometric criteria but also from the 2-D dimensional perspective.
An MO multicenter bond index involving the þ p electron population is proposed as a measure of aromaticity. It is related both to the energetic and to the magnetic criteria <2000PCP3381>. This index, an invariant in the tensor sense <1984ZNA1259>, gives the electronic population along the AB bond and gives values agreeing with chemical expectation. The multicenter bond index <1990STC423>, an extension of IAB to multicenter bonds, involves the total electron population (despite admitting –p-separation).
Thiophenes and their Benzo Derivatives: Structure
In Table 65, Iring values for heterocycles with five-membered rings containing one heteroatom are shown. These values show clearly three groups, pyrroles being the one with highest values and furans the one with lowest values. It has been suggested that the lower aromaticity of furan compared with pyrrole is due to the contraction of the oxygen pz orbital, while the pz of nitrogen would have the optimal size for the delocalization in the p-system <1981JST(85)163, 1998JOC2497>.
Table 65 Aromaticity index (Iring) for heterocycles with five-membered rings Indexes Molecule
Iring
RCIa
RCVb
IAc
REd
"ple
f
g
Pyrrole Furan Thiophene
0.0962 0.0541 0.0696
1.464 1.431 1.450
1.124 1.081 1.173
85 53 81.5
40.5 27.2 43.0
0.0860 0.0597 0.1123
7.12 7.42 6.74
10.2 8.9 13.0
a
RCI means ring current index <1983JOC1344>. RCv, bond valence criterion <1990JA6772>. c IA unified aromaticity index <1992T335>. d RE, resonance energy <1992T335>. e "pl, steps from natural localized MOs <1990IJQ(24)843>. f , hardness <1997T3319>. g , magnetic susceptibility exaltation <1996T9945>. b
Results in Table 65 (IA and resonance energy) agree in assigning the lowest aromaticity to furan. Alternatively, the Bird index , based on absolute hardness reformulated in terms of molar refractivity, ascribes the highest values to this group and the lowest to the thiophene <1997T3319>, while "p, which is the difference between the lowest natural MOs’ eigenvalues and the corresponding lowest p-delocalized MOs’ eigenvalues, ascribes the highest values (i.e., highest aromaticity) to thiophene <1990IJQ(24)843>. The geometrical criteria RCI <1983JOC1344> and RCv <1990JA6772>, as with the magnetic quantity , do not lead to a separation according to the three families. The relative aromaticity of pyrrole and thiophene has been a controversial subject for at least 30 years. According to some authors, pyrrole is more aromatic <1995AGE337, 1997JST(398)315>, while others assert that it is thiophene <1990IJQ(24)843>. Even within the same criterion, discrepancies arise between different indexes; for example, in contrast to the resonance energy values of Table 65, ASE assigns the highest value to pyrrole (Table 66) <1998JOC5228>. In addition, the same magnitude gives different ordering when comparing the results obtained by different authors; this happens, for instance, with the in Tables 65 and 66. If the uniformity of delocalization through the ring has something to do with aromaticity, pyrrole is the most aromatic and furan the least <1981JST(85)163>. As has been reported in Table 67, the IAB values and their mean variation for the three systems and the results agree with the above assertion.
Table 66 Aromaticity indexes for some five-membered-rings and benzene
Pyrrole Thiophene Furan Cyclopentadienyl anion Benzene a
ASEa
NICSb
c
25.5 22.4 19.8 28.8 26.6
17.3 14.7 13.9 19.4 11.5
12.1 10.0 9.1 17.2 13.6
ASE, aromatic stabilization energy <1998JOC5228>. NICS, nucleus-independent chemical shift <1996JA6317>. c , magnetic susceptibility exaltation <1998JOC5228>. b
701
702
Thiophenes and their Benzo Derivatives: Structure
Table 67 IAB and its mean variation IAB along the ring for furan, thiophene, and pyrrole Molecule
I12
I23
I34
IAB
Furan Thiophene Pyrrole
1.10 1.17 1.26
1.69 1.64 1.52
1.19 1.24 1.33
0.545 0.385 0.220
Nevertheless, the values in Table 65 for the pyrrole are higher than expected, above that of benzene. As benzene is the established paradigm for aromaticity, this is not satisfactory. Other indexes suffer from the same drawback. For instance, Bird’s molecular hardness reported in Table 65 <1997T3319> ascribes higher aromaticity to the fivemembered heterocycles than to benzene ( ¼ 6.60); the same thing happens with NICS in Table 66. The diamagnetic susceptibility exaltation, , which has been recognized as particularly appropriate as an aromaticity measure <1996PAC209>, assigns in Table 66 much more aromatic character to the cyclopentadienyl anion than to benzene and predicts for pyrrole a value near to that of benzene. The same objection applies to some energetic indexes, such as ASE (Table 66), TREPE <1977JA1692>, and Parr’s hardness <1989JA7371>. Estrada and Gonza´lez <2003JCI75> have analyzed the numerous possibilities of using graph-theoretic descriptors for aromatic compounds in the framework of quantitative structure–property relationship/quantitative, (QSPR/ QSAR) theory, and some misunderstandings on the role of this theoretical approach in chemistry were clarified. In ˜ an effort to quantify aromaticity in oxocarbons, Quinonero et al. have reported ASE results for a set of representative five-membered heteroaromatic compounds using molecular descriptors describing the previous features <2002CEJ433>. The electrotopological approach has been shown to make up a substantive method within the QSPR/QSAR field and results reported up to now have been shown to be quite useful and precise <2003CPL(369)325>. Of particular importance for the study of aromaticity is the definition of atom-type indexes, since when choosing the atom-type classification scheme, the valence-state identification includes a representation of resonance forms and/or aromaticity . ASE for thiophene (20.2–22.4 kcal mol1) is calculated using molecular descriptors such as magnetic susceptibility exaltation (6), NICSs, and electrotopological indexes (EIs) via linear, quadratic, and cubic fitting polynomials. Theoretical estimations compare fairly well with experimental data when three variable multilinear regression equations are employed <2004MI145>. NMR spectroscopy also provides an experimental tool capable of assessing aromaticity of the structure. Aromatic compounds are characterized by their capacity to exhibit a diamagnetic ring current. The ring current effect is responsible for the large magnetic anisotropy in the aromatic compounds. The nuclei in the cone above and below the plane of an aromatic ring are shielded by the induced field and appear at the higher field region in the NMR spectrum. However, the nuclei in the ring occur ar relatively low field positions. This effect can be taken as evidence for the aromaticity, although this criterion should be applied with some care <1979JA1722, 1981JA5704>. It has been demonstrated that the B3LYP is a reliable method when the geometries and energies of chemicals are computed <1981IJQ161, 1995CPL(236)206, 1995JCS1223, 1995JOC4721>. The computed values were correlated with the experimentally determinated heat of combustion <1949CB358>. An excellent correlation between the computed and the experimental values was obtained, demonstrating that this method can correctly estimate the relative magnetic properties of five-membered heterocycles. It is well known that thiophene is the most aromatic heterocycle in this series. This approach was extended to evaluate the relative stability and reactivity of fused five-membered heterocycles and benzene, based on the computed physical properties of their ground states <1996JHC1079>. The computed structures are presented in Figure 33.
Figure 33 The B3LYP-computed geometries of benzo[b]thiophene and benzo[c]thiophene.
Thiophenes and their Benzo Derivatives: Structure
In b and c benzo heterocycles, the b heterocycle is much closer to the benzene structure (Figure 33); in particular, a large distortion is obtained for benzo[c]thiophene. To confirm this finding based on the degree of the benzene ring C–C distortion, the magnetic susceptibility anisotropies and the relative energies for the benzene-fused five-membered heterocycles have been computed (Table 68). A similar approach was used by Schleyer et al. <1995AGE337> to evaluate the aromaticity of fivemembered heterocycles using the ab initio methods.
Table 68 The heat of combustion and the computed magnetic susceptibility anisotropies (cgs) Compounds
IGAIM
CSGT
E (a.u.)
E kcal mol1
Benzo[b]thiophene Benzo[c]thiophene
55.7 53.9
55.7 53.9
706.653 621 6 706.635 747 0
11.2
According to both the computed magnetic susceptibility anisotropies and relative energies, the benzo[b]thiophenes lie between the benzo[b]pyrroles and benzo[b]furans: the benzo[c]thiophene should be more stable than the benzo[c]furan; benzo[b]thiophene should be the more stable isomer. Of the two benzo[b]thiophenes, the benzo[c]thiophene is more reactive <1995JHC1455> as was predicted by the computed magnetic susceptibility anisotropies (Table 68). The NMR shielding tensors and magnetic properties were calculated using the CSGT and individual gauges for molecules (IGAIM) methods <1993CPL(210)223, 1992CPL(194)1>. It can be concluded that the B3LYP/6-31G* will produce high-quality structural parameters for the five-membered rings and their benzo derivatives. Based on the structural uniformity principle and magnetic susceptibility anisotropies, the predicted relative aromaticity of these systems is found to be reliable. From the computed values, the relative stability of thiophene, benzo[b]thiophene, and benzo[c]thiophene is accurately predicted. In a pioneering study, Abraham and Thomas <1966JCB127> compared the chemical shifts of the H-2 and 2-methyl protons in thiophene and their methyl derivatives (Figure 34) with those of similarly placed protons in the 4,5-dihydro compounds where there is no ring current. They proposed that the observed differences in the proton chemical shifts were a measure of the ring currents in these compounds and found that the ring currents in thiophene ‘‘did not differ significantly’’ from the benzene ring current.
Figure 34 Thiophene and some derivatives.
A large set of rigid molecules with fully assigned 1H NMR spectra provides sufficient data (Table 69) for an analysis of the proton chemical shifts in heteroaromatics based on the CHARGE model <2001MRC421, 2000J(P2)803, 1999MI85>. In this model, it is necessary to identify and separate the various mechanisms responsible for the 1H chemical shifts in these molecules. These are the ring current shifts, the p-electron densities, the direct , and -effects of the heteroatoms and the long range steric, electrostatic and anisotropic effects at the protons. It is possible to identify and quantify these effects and the resulting model gives a very good account of the 1H chemical shifts in the molecules investigated <2002J(P2)1081>. The agreement of the observed versus calculated proton chemical shifts is very good and shows very clearly that the CHARGE model can be applied to heteroaromatic compounds. The ring current calculations provide further evidence for the accuracy of the simple equivalent dipole model of the benzene ring current and also demonstrate that the ring current effect is not the only factor responsible for the difference between the chemical shifts in the aromatic and nonaromatic heterocyclic compounds. The use of suitable dihydro compounds as reference compounds is a useful method for determining the ring currents in these systems.
703
704
Thiophenes and their Benzo Derivatives: Structure
Table 69 Observed vs. calculated 1H chemical shifts () for sulfur compounds Compound
1
Observed
Calculated
Thiophene 1
2 3 2 3 4 5 3 4 5 3 4 5 3 2 4 5 2 3 4 5 6 7
7.310 7.090 6.170 5.630 2.740 3.220 6.720 6.870 7.040 5.250 2.790 3.260 6.560 6.870 6.870 7.190 7.422 7.325 7.780 7.330 7.310 7.860
7.263 7.044 6.076 5.717 2.592 3.169 6.733 6.970 7.017 5.248 2.657 3.195 6.655 6.898 7.020 7.305 7.523 7.347 7.642 7.302 7.340 7.996
4,5-Dihydrothiophene 4
2-Methylthiophene 78
2-Methyl-4,5-dihydrothiophene 132
2,5-Dimethylthiophene 133 3-Methylthiophene 134
Benzo[b]thiophene 7
H number
A series of m- and p-disubstituted anilides of thienoic acid and of 2-benzoylthiophenes, which have substituents at the m- and p-position of the benzoyl ring, have been prepared and their IR and NMR spectra obtained in 0.1 M chloroform-d solutions and DMSO-d6. The chemical shift values of each series were plotted against the Hammett substituent parameters to give good correlation. The slopes as well as the differences in chemical shift gave a set of meaningful values for the indexes of aromaticity <2002JHC1219>. Carbon-13 NMR studies have also been used as a quantitative measure of electron deficiency and excessiveness <1982OMR192>. The difference in the chemical shifts observed between a given unsubstituted carbon atom and its substituted counterpart varies significantly for different aromatic compounds. The presence of an electron-withdrawing substituent X will cause a larger chemical shift at the substituted carbon if the ring is electron rich. If the ring is electron deficient, the extent of deshielding will be less since there is a counter effect here. Based on this, the ratio up is defined by Equation (5). ðppmÞ ðhet – XÞ – ðppmÞ ðhet – HÞ 13 ¼ ð5Þ ðppmÞðbenzene – XÞ – ðppmÞðbenzene – HÞ For p-deficient systems this ratio is <1, while for p-excessive it is >1. As a result, it is possible to obtain a quantitative measure of the p-excessiveness or -deficiency and thus the degree of aromaticity. Based on this, the aromaticity indexes for 2- and 3-substituted thiophenes were calculated to be 1.35 as compared to 1.14 and 1.31 for the corresponding furan derivatives, indicating thiophene to be more aromatic than furan. Calculated chemical NMR shifts were considered to be reliable parameters, as they can be measured with high accuracy in NMR spectroscopy and calculated shifts are in good agreement with experiment <1996JCP(104)5497>. Magnetic susceptibility exaltation , the difference between the magnetic susceptibility of a cyclic conjugated system and that of a hypothetical cyclic system with localized double bonds in which the ring current vanishes, is yet another parameter which was once considered to be the only uniquely applicable aromaticity criterion <1995PAC209, 1969JA1991, 1968JA811>; aromatic compounds are characterized by significantly enhanced diamagnetic susceptibility. Flygare et al. advocated the utilization of diamagnetic anisotropy, aniso, and the susceptibility component perpendicular to the ring plane, zz <1974CRV653, 1971JA5591>. However, it has been pointed out that electron delocalization influences only the out-of-plane component of the susceptibility and that the local and nonlocal contributions to aniso must be differentiated and only the latter can constitute aromaticity indexes <1973JA7961, 1974TL2885>.
Thiophenes and their Benzo Derivatives: Structure
A quantitative measure of electron delocalization in a planar, cyclic molecule may be obtained by comparing the measured out-of-plane magnetizability component or magnetic anisotropy with the value predicted for a hypothetical structure in which the electron distribution is completely localized. The difference between the observed and calculated values, ani and zz, is the estimate of the extent of electron delocalization and of the relative aromaticity. Currently, the enhancement of magnetic susceptibility, , has been calculated by comparing corresponding susceptibilities of the reagents of corresponding homodesmotic reactions, and so have ani and zz <2004JPO303>. Other magnetic characteristics calculated are the following: susceptibility, iso, equalling 1/3(11 þ 22 þ 33), where nn are elements of the magnetic susceptibility tensor; anisotropy of the susceptibility tensor, equaling the out-of-plane minus the average in plane magnetic susceptibility tensor components, aniso, and the component of magnetic susceptibility perpendicular to the ring plane, zz, in addition to NICS and NICS(1). To these parameters, three other ‘excess’ parameters based on the homodesmotic reactions, , ani, and zz, have been added. The last three were derived from the comparison of iso, ani, and zz for the compounds in the set with those calculated for the localized structures in which the ring current vanishes. Magnetic parameters for thiophene are given in Table 70.
Table 70 Calculated magnetic parameters of thiophenes: magnetic susceptibility iso; anisotropy of magnetic susceptibility aniso; the susceptibility component perpendicular to the ring plane, zz; exaltation of the three parameters, , aniso, and zz; and nuclear-independent magnetic shift calculated at ring centers (NICS) and 1 A˚ above the ring centers (NICS(1)) in ppm
Thiophene
iso
aniso
zz
NICS
NICS(1)
aniso
zz
53.04
10.49
50.83
86.93
12.92
10.28
33.78
33.01
An excellent linear correlation between the dilution shift parameters (A) for thiophene and the aromaticity index IA has been observed <1992T335, 1996T9945>. The A parameters are clearly magnetic in origin, while IA has been commended <1989JA7, 1990JPR853, 1990JPR870, 1990JPR885, 1990TCM247> as a measure of classical aromaticity. The experimentally derived data concur with a theoretical analysis <1995AGE337> in demonstrating that ‘classical’ and ‘magnetic’ concepts of aromaticity are not ‘orthogonal’ as proposed <1989JA7, 1990JPR853, 1990JPR870, 1990JPR885> earlier.
3.09.4.2 Conformational Analysis Organic carbonyl compounds in which the carbonyl group is not part of a cyclic structure possess interesting conformational properties depending on the system. 2-Formylthiophene or thiophene-2-carbaldehyde can exist either as the S,O-trans- 135a or S,O-cis- 135b conformer (Figure 35).
Figure 35 Different conformations of thiophencarbaldehyde and 2-acetylthiophene.
The energy barrier for the trans–cis-isomerization was determined to be 10 kcal mol1 as determined by ultrasonic pulse techniques <1969JCA713>. It has been shown that the molecule is planar and that >90% of the molecule exists in the S,O-cis-orientation <1985J(P2)1839>. For thiophene-3-carbaldehyde 136, there are two adjacent hydrogen atoms while for the 2-formyl derivatives there is only one. Thus in the ground state, the latter displays greater stabilization than the former <1984J(P2)819>.
705
706
Thiophenes and their Benzo Derivatives: Structure
The presence of a substituent at the adjacent position tends to alter the conformation due to hydrogen-bonding, steric, and electrostatic effects. Thus a C-3 substituent in thiophene-2-carbaldehyde 135 increases the stability of the S,O-cis-form. In ketones, the coplanarity between the ketone group –C(O)R and the heterocycle depends strongly on steric interactions. For 2-acetylthiophene, the S,O-cis-form 137 is preferred, and the molecule is practically planar. As in the 3-formyl derivatives, both conformers are observed in 3-acetylthiophene, the ratio of S,O-trans to S,O-cis being roughly 3:2 <1976OMR(8)525>. Furthermore, the presence of an alkyl group reduces the energy barrier for cis–trans-isomerization for 2- and 3-keto substituents as compared to their formyl analogues <1985J(P2)1839>. For aroyl derivatives, the phenyl ring is too large to be planar with the heterocycle. X-Ray studies show the 2-aroyl derivatives 138 and 139 to favor the S,O-cis-orientation and the 3-aroyl compounds 140 and 141 to adopt the S,O-trans-form (Figure 36).
Figure 36 Acylthiophene and benzo[b]thiophene derivatives.
The conductor-like continuum solvation model, modified for ab initio in the quantum-chemistry program GAMESS, implemented at the Møller–Plesset order 2 (MP2) level of theory, has been applied to a group of push– pull thiophene systems to illustrate the effects of donor/acceptor and solvation on the stability and energetics of such systems. The most accurate theoretical gas- and solution-phase data to date have been presented for the parent thiophene-2-carbaldehyde system <2000JCP(113)7519>. The sulfur-substituted system 135 (Figure 35) shows a relatively small cis–trans energy difference of 4.93 kJ mol1 at MP2/TZV(2d,2p) and 4.57 kJ mol1 at B3PW91/TZV(2d,p), which is in very good agreement with the experimental value of 4.1 0.4 kJ mol1 (Table 71) <1986JST(145)45>.
Table 71 Experimental and calculated energy differences for thiophene-2-carbaldehydea Method
Erel,trans
Erel,ts
HF/DZV(2d,p) HF/TZV(2d,2p)b MP2/6-31G(d;p) MP2/DZV(2d,p) MP2/TZV(2d,2p)b B3PW91/aug-cc-pVDZ B3PW91/TZV(2d,2p)c B3LYP/TZV(2d,2p)c Expt.d
6.84 6.26 7.04 6.10 4.93 4.67 4.57 4.86 4.1 0.4
40.54 38.75 44.28 44.14 40.09 46.59 45.67 46.11
E relative to the cis-isomer in kJ mol1 (1 kJ ¼ 0.24 kcal). Data obtained with GAMESS, standard polarization exponents from <1984JCP(80)3265>. c Data obtained with GAUSSIAN 94, with correlation consistent polarization exponents from <1989JCP(90)1007> and <1993JCP(98)1358>. d <1986JST(145)45>. a
b
Thiophenes and their Benzo Derivatives: Structure
o-Aminothioaldehydes derived from thiophene and benzo[b]thiophene rings have been found to be chemically stable, owing to stabilization of the thioformyl group brought about by the mesomeric effects of the aminosubstituted heterocyclic rings (Scheme 10) <1996S1185>.
Scheme 10
These compounds (e.g., 142) seemed particularly well suited for the investigation of the carbon–carbon rotational barrier about the Ar–CHS bond as well as the carbon–nitrogen rotational barrier about the adjacent Ar–NH2 bond, but these have not been reported as yet. For thioaldehyde 142 and aldehyde 143, the C–N rotational barriers were only determined for the major rotamers E <1997JOC2263>. Ratios of the E- and Z-rotamers (whose structures were assigned on the basis of nuclear Overhauser effect (NOE) experiments, 13C chemical shifts, and 5J values, as previously discussed) as well as C–C and C–N rotational barriers for compounds 144 and 143 are collected in Table 72. The G‡ values measured for the C–C rotation in the furan derivatives 144 and 145 are significantly greater than those of the corresponding thiophene derivatives 142 and 143. This reflects a greater ability of the furan than the thiophene moiety to release electron density to the thioformyl or formyl substituent. An analogous trend had been observed for the unsubstituted 2-furyl and 2-thienyl carbaldehydes, although in these cases the corresponding G‡ values are much more similar, being 10.9 and 10.15 kcal mol1, respectively <1984J(P2)819>. Furthermore, the G‡ (C–C) values are larger for thioaldehydes 144 and 142 than for the aldehyde analogues 145 and 143. This suggests greater electron donation by the heteroaryl ring to the thioformyl than to the formyl function. This trend parallels that observed for thioamides with respect to amides <1967JPC2318, 1970CRV517, 1974JOC929, 1996JA8891>, which has been recently explained on the basis of ab initio MO calculations <1995JA2201>. Contrary to the G‡ (CC) values, the corresponding G‡ (C–N) values were found to remain virtually constant, or even increase, on going from 144-E to 142-E and 145-E to 143-E. This trend suggests that delocalization of the amino nitrogen lone pair occurs to a comparatively larger extent with thiophene than with furan derivatives as a result of the competing delocalization of the adjacent CTS or CTO group with the same heteroaromatic rings.
Table 72 E,Z-Rotamer ratio (at room temperature) and free energies of activation (G‡) for C–C and C–N rotation of 142, 143, 144, and 145
E/Z ratioa G‡ (C–C) (kcal mol1) G‡ (C–N)c kcal mol1) a
72:28 17.9a 11.2
In DMSO. In CD3CN, at 20 C. c Barrier referred to the E-rotamers in CD2Cl2. d Barrier for the 1-Z rotamer. e In CD3CN. b
85:15b 13.7e 9.7
78:22 22.2a (9.0d) 11.4
57:43 16.2a 8.4
707
708
Thiophenes and their Benzo Derivatives: Structure
The UV photoelectron spectra of two isomeric styrylthiophenes, 146 and 147, and six isomeric (thienylethenyl)pyridines, 148–153, have been recorded and analyzed, making use of DFT Becke3LYP calculations <2001EJO121>. In a surprising common result for all methods, only planar conformers were found for all compounds. Most stable are the conformers 148d, 149c, 150b, 151a, 152b, and 153a (Figure 37). For the 2-substituted pyridine derivatives 148 and 149, the conformers c and d with sp pyridine rings are favored over the ap conformers a and b, because of very short H- - -H distances of about 216 pm in the latter forms. In conformer 148d, both heterocyclic rings are in their preferred sp orientations, as in 2-vinylpyridine 155b and 2-vinylthiophene 158b. With regard to conformational preferences, the total energies E (B3LYP results) of the isomeric (2-thienyl-ethenyl)pyridines 148–153 permit the following conclusions:
the sp orientation of the 2-substituted pyridine ring is favored by about 5 kJ mol1, the sp orientation of the 2-substituted thiophene ring is favored by about 5 kJ mol1, the ap orientation of the 3-substituted pyridine ring is favored by about 1.5 kJ mol1, the ap orientation of the 3-substituted thiophene ring is favored by about 4.5 kJ mol1.
Figure 37
Thiophenes and their Benzo Derivatives: Structure
The relatively strong preference of the 3-substituted thiophene ring for the ap orientation is certainly unexpected and difficult to explain. However, this result is confirmed by inspection of the two conformers of 3-vinylthiophene, 159a and 159b, for which an energy difference of 4.87 kJ mol1 is calculated by B3LYP; both conformers are found to be planar. The nonbonded H- - -H distances, H1- - -H3 and H2- - -H4 (Figure 38), in conformer 159a are 236.3 and 258.8 pm, and in conformer 159b 254.2 and 245.0 pm, so the energy difference cannot simply be ascribed to steric effects. Since some reservation with respect to noncovalent interactions is appropriate to DFT methods <2000CRV143>, calculations for conformers 159a and 159b have been repeated at the MP2/6-31G* level. Here, again, planar conformers resulted, and the energy difference was found to be 3.89 kJ mol1, not much at variance with the B3LYP result.
Figure 38 Structures of compounds 154–160.
Generally, it is found that 3-substituted thiophenes are less stable than 2-substituted ones by 3.5–4.4 kJ mol1. The structure parameters of 146–153 (Figure 39) summarized in Table 73 reveal a rather uniform picture with only minor differences in individual data. The length of the central CTC bond varies only between 135.0 and 135.3 pm. In the thiophene derivatives, the largest value is found for 2-substituted molecules and the smallest for 1-substituted ones.
Figure 39 Atom numbering for 1,2-bis(hetero)arylethylenes 146–153.
Using quantum-chemical analyses, planar molecular structures were obtained for all these compounds. However, from the separation, IP, of the ionization bands associated with the p7 and p3 MOs, it is possible to make a distinction between planar and twisted molecular structures. Accordingly, in these compounds, 2-substituted pyridine rings and 3-substituted thiophene rings are nearly untwisted, whereas phenyl rings, 3- and 4-substituted pyridine, and 2-substituted thiophene rings are twisted to an extent similar to that in trans-stilbene. The apparent distortion of the molecules is probably caused by torsional vibrations, so that twisted average geometries correspond to planar equilibrium structures. The B3LYP data permit detailed conclusions to be drawn with regard to the conformational preferences of 2- and 3-substituted thiophene and pyridine rings in heterocyclic analogues of trans-stilbene, as well as the to relative stabilities of isomers 148–153. The results clearly indicate that PE spectroscopy is a powerful method for analysis of conformational properties of stilbene-like molecules.
709
710
Thiophenes and their Benzo Derivatives: Structure
Table 73 Selected structure parameters (pm, deg) of compounds 146–153 (B3LYP results)a Compound
CTC
C(S)–C
C(N)–C
C(S)–CTC
C(N)–CTC
146b 147a 148d 149c 150b 151a 152b 153a
135.3 135.1 135.2 135.0 135.3 135.1 135.3 135.0
144.8 145.9 144.5 145.7 144.7 145.8 144.6 146.1
146.5 146.7 146.5 146.7 146.2 146.4 146.3 146.5
126.8 126.1 127.2 126.3 126.9 126.1 126.9 126.7
127.2 127.2 124.2 124.2 126.9 126.8 126.5 126.6
Compound
H1---H3
H1---H5
H2---H4
H2---H6
232.5 232.5 240.3 239.9 233.7 233.5 237.5 237.3
256.8 257.2 258.8 259.6 256.6 257.2 256.5 252.8
215.9 214.9
146b 147a 148d 149c 150b 151a 152b 153a a
228.5 232.7 229.0 237.2
219.5 218.8 218.1 217.3
For atom numbering, see Figure 39.
In 3,4-alkylenedioxy- and 3,4-dialkoxy-2,5-bis[di(tert-butyl)hydroxymethyl]thiophenes 161 and 162 (Figure 40), there are three rotational isomers, SS, AS/SA, and AA, in relative amounts which depend on structure in much the same way as the corresponding 3,4-alkylenedioxy- and 3,4-dialkoxy-2-[di(tert-butyl)hydroxymethyl]thiophenes 163 and 164. The shorter the alkylene bridge and the more hydrogen-bonding the solvent, the greater the overall amount of syn-forms. Solvent effects, however, show different behavior for the two equilibria. While the sensitivity of the AA . AS/SA equilibrium to solvent variations is similar to that of monosubstituted derivatives previously studied, that of the AS/SA . SS equilibrium is smaller, the SS rotamer being less favored by hydrogen-bonding solvents than expected. Work on the corresponding BiEDOT derivative 165, where the two –C(t-Bu)2OH rotors are completely independent, suggests that this is due to the proximity of the two OH groups in the SS isomer, which precludes fully effective solvation of both. The relative instability of the SS isomer in DMSO and pyridine is reflected in the unusually low barrier for its transformation into the AS/SA form <2004JPO102>.
Figure 40
Thiophenes and their Benzo Derivatives: Structure
Vibrational circular dichroism (VCD) has been used for the independent verification of the absolute configuration and the determination of the predominant conformations of chiral 3-(2-methylbutyl)thiophene <2002PCA5918>. The comparison of experimental and ab initio-predicted absorption and VCD spectra indicates that (þ)-3-(2methylbutyl)thiophene 166 and (þ)-3,4-di(2-methylbutyl)thiophene 167 are of (S)-configuration, in agreement with the known absolute configuration <1988CC917>; the repeating units in polymers 168 and 169 have the same configuration and conformation as those for the corresponding monomers; at least six conformations are present for (S)-3-(2-methylbutyl)thiophene in CDCl3 solution, with each contributing more than 5% to conformer population.
Static and dynamic light scattering measurements have been undertaken on dilute solutions of poly(3-dodecylthiophene) (PDDT) to evaluate its conformation over a range of temperature and to learn whether a reversible thermochromic effect is associated with any conformational change <1996MM933>. The thermochromic effect in solutions of poly(3-alkylthiophene)s has been attributed to an intramolecular conformational transition to an extended chain conformation, principally on the basis of an observed isosbestic point <1987PSB1071, 1992MM2141>, but evidence for supramolecular aggregates was noted <1987PSB1071>. The light-scattering characterization of dilute solutions of regioregular poly(3-dodecylthiophene) has shown that metastable aggregation is obtained under all of the conditions studied, including temperatures as high as 65 C, with a range of supramolecular structures dependent on solution history. The aggregation may be associated with the chemically disparate character of the polythiophene main chain and the alkyl side chains. The reversible thermochromic effect observed here and in the solid state is associated with enhanced order of the alkyl side chains with decreasing temperature, facilitating coplanar conformers in the polythiophene backbones, with the attendant enhancement in the p–p* -transition of the thiophene ring electronic absorption spectra and improvement in electronic conduction of the doped film. Conformations, structural parameters, and charge distributions of 2-acetylthiophene 137, di-2-thienyl ketone 170, and higher oligomers 171 and 172 (Figure 41) have been determined by ab initio calculations at the HF/6-31** level of theory <1998JST(455)131>.
Figure 41 Structure of thienyl ketones.
2-Acetylthiophene 137 has two stable planar rotamers, the S,O-cis being more stable than the S,O-trans one by 5.53 kJ mol1 (MP2/6-31G** ) (relative abundance 89% and 11%, respectively). A large steric hindrance occurs between the O and C/CH3 atoms of the acetyl group and the faced S and C-3 atoms of the ring in both conformations. The S,O-cis-conformer is more stable because of a strong O/Sþ stabilizing electrostatic interaction, and a smaller repulsion between the C(2)TC(3) and CTO bonds, with respect to the S,O-trans-rotamer. Conversely, di-2-thienyl ketone 170 has three stable, nonplanar conformations (relative abundance: cc ¼ 84.0%, ct ¼ 15.1%, and tt ¼ 0.9%, 6-31G** ), in which the two thiophene rings are conrotated by 19–24 with respect to the carbonyl group plane. The larger steric demand of the thienyl with respect to the methyl group and the electrostatic interactions between faced atoms of the three groups cause rotation of the rings out of the main plane and small variations of the bond angle values around the carbonyl group with respect to ketone 137. The total energy increases while the distortion from planarity decreases with the S,O-trans-orientations, in agreement with the changing nature of the dominant electrostatic interaction. The (cc), (ct), and (tt) planar conformations correspond to saddle points and lie higher in energy with respect to the adjacent minima by 2.3–9 kJ mol1 (6-31G** ).
711
712
Thiophenes and their Benzo Derivatives: Structure
Bond distances and angles of both molecules reproduce well available experimental data. In both compounds, the charge density difference between the oxygen (d) and the sulfur (dþ) atom increases in the S,O-trans one because of the synergy between the p* CO pring and through-space Sþ O CT iterations. In all the oligomers, the lower energy conformations are stabilized by electrostatic interactions between the oxygen atoms, bearing a partial negative charge (ca. 0.54 e), and the sulfur (ca. þ0.32 e and þ0.44 e, for terminal and central rings, respectively) and hydrogen (ca. þ0.18 e) atoms, bearing partial positive charges, from which they are separated by distances shorter than the sum of the corresponding van der Waals radii. The main features of geometry, S,O-orientation, deviation from planarity (av), and charge distribution observed for 137 and 170 are also reproduced in longer oligomers, indicating that the balance among mesomeric, electrostatic, CT, and steric interactions is responsible for the geometrical and conformational similarity of oligomers of different length. Stacks formed by oligo-2-thienyl ketones appear, therefore, propitious for high electrical conductivity, when properly doped. The conformational analysis of oligothiophenes by use of a combined molecular dynamics (MD)/NMR spectroscopic protocol has been carried out. A series of MD simulations were performed for 2-(2-thienyl)-3-hexylthiophene 173, 2,5-bis(39-hexyl-29-thienyl)thiophene 176, and 2,5-bis(49-hexyl-29-thienyl)-thiophene 177, with a new MM2 torsional parameter set developed earlier for unsubstituted and methyl-substituted 2,29-bithiophene. The new parameter set for the MM2 force field, developed in an earlier work <2002PCA1266>, accurately predicted the conformational properties of 2-(29-thienyl)-3-hexylthiophene 173, 2,5-bis(39-hexyl-29-thienyl)thiophene 176, and 2,5-bis(49-hexyl-29-thienyl)thiophene 177. Thus, NOE buildup curves, calculated from average conformations obtained from molecular dynamics simulations, gave excellent or very good agreement with experimentally derived curves for almost all proton pairs. The 1/6 averaging scheme for inter-proton distances provided a better fit with experimental data than the 1/3 scheme, suggesting that internal motion occurs at a lower rate than the overall molecular tumbling. Although the new parameter set was developed for methyl-substituted molecules containing two heterocyclic rings, it provides an excellent model for the hexyl-substituted tricyclic systems, and this is expected to hold true for alkyl substituents of different lengths. The new MM2 torsional parameter set models accurately the dynamics of conformational exchange in oligothiophenes and oligo(thienyl)furans, and it should, therefore, permit the study of the conformational properties of longer oligomers and perhaps even polymers. Ab initio calculations have been carried out to predict various torsion potentials existing in poly(thiophene– phenylene–thiophene) (PTPT). The calculated torsion potential curves give a comprehensive explanation to the optical properties in point of substituent effects. Especially, it was found that the length of the hexyl and cyclohexyl groups on the bithiophene segment is the dominant factor that determines the distance of co-facial solid packing which affect the conformation of polymer chain. This is the theoretical evidence for the conjecture that the cyclohexyl-substituted thiophene-based polymers have higher tendency of crystallization than the corresponding hexyl-substituted ones <2000MM2462>. Conformational analysis was carried out on the molecules shown in Figure 42 <2002CPL(363)18>. One group consists of thiophene–phenylene–thiophene (TPT) 178, dimethyl-substituted TPT (DMTPT) 179, and dimethoxysubstituted TPT (DMOTPT) 180, and the other group is composed of dihexyl-substituted bithiophene (DHBT) 175 and dicyclohexyl-substituted bithiophene (DCBT) 181. The calculated bond lengths and bond angles of the two substituted bithiophene structures are quite similar. Both structures are largely twisted with the cyclohexyl-substituted derivative having an even larger equilibrium torsion angle. The calculated equilibrium of the hexyl-substituted bithiophene 175 is 76 , nearly the same as that calculated for the corresponding ethyl-substituted derivative 174 (DE33BT, 78 ) <1997CPL(275)533>. The torsion potential curve of compound 175 is very similar to that of 3,39-diethyl-2,29-bithiophene (DE33BT) 174 obtained with the same calculations <1997CPL(275)533>. The most stable conformation is the one with the two rings twisted by 76 . The coplanar energy barriers are quite high. They are about 10 kcal mol1 for the 0 (anti-)conformation and 16 kcal mol1 for the 180 (syn-)conformation. All these values are quite comparable with those of 174 <1997CPL(275)533>. In comparison with that of compound 175, the energy barriers toward coplanar conformations increase, and the equilibrium torsion angle becomes larger in the torsion potential curve of compound 181, around 85 . The thiophene rings are even more twisted by cyclohexyl groups than by hexyl groups. It is noticed that in both hexyl- and cyclohexyl-substituted bithiophenes, the substituent is largely twisted in the free molecules. Due to the large coplanar energy barriers, the substituent is most probably largely twisted in the solid state. The lengths of the hexyl group and the cyclohexyl group become the dominant factor that determines the co-facial packing distances.
Thiophenes and their Benzo Derivatives: Structure
Figure 42 Oligothiophene derivatives.
Fully relaxed single-bond torsional potentials of oligothiophenes 16 (n ¼ 0–2) under the interaction of the parallel external electric field (EF) constructed by point charges have been evaluated with semi-empirical AM1 and PM3 calculations <2004SM(145)253>. Consistent evolutions of the torsional potential surfaces have been observed for three lineal oligothiophenes (Figure 43) as the EF increases. In particular, the equilibrium molecular geometries are deformed toward planar conformations, and the torsional barriers around the central C–C9 bond are elevated. These features are sensitive to the conjugation length as expected. For the longer conjugation, the equilibrium geometries become more planar and the torsional barrier increases more rapidly. In addition, the electronic structures of oligothiophenes 16 can also be modulated by the application of an external EF. The increase of EF leads to reduction of the energy gap between the LUMO and HOMO.
Figure 43 Linear and cyclic oligothiophenes.
713
714
Thiophenes and their Benzo Derivatives: Structure
Cyclic oligothiophenes 182 (n ¼ 6–30, only even) in syn- and anti-conformations have been studied theoretically at the B3LYP/6-31G(d) level of theory <2006JOC2972>. Strain energies, IPs, HOMO–LUMO gaps, bond-length alternations, NICS values, and IR and Raman spectra have been studied. The properties of anti-conformers change systematically with increasing ring size and have been studied in detail in neutral, radical cation, and dication forms. In syn-conformation, the oligomers lose their nearly planar ring shape and bend significantly for n > 14, and thus properties cannot be related to ring size. anti-Cyclic oligothiophenes are curved in order to make a full cycle. The smaller cyclic oligothiophenes require larger dihedral inter-ring angles to achieve curvature within the oligomer (the diameter of the rings varies from 0.6 to 4 nm for 6- to 30-monomer units). Consequently, they are also twisted. The average dihedral angle is 33.7 in anti-182 (n ¼ 8) and decreases gradually to 19.1 in anti-182 (n ¼ 30). The optimized geometries in the syn-conformers (s-cisoid) exhibit a systematic decrease in the dihedral angle and increase in planarity. However, molecules larger than syn-182 (n ¼ 14) lose their nearly planar cyclic nature and circular shape significantly as oligomer size increases. The calculated shapes of syn-182 (n ¼ 8) and syn-182 (n ¼ 10) are similar to the experimentally reported, nearly planar structure of cyclo[8]pyrrole <2002AGE1422>. Compound syn-182 (n ¼ 14) possesses a completely planar ring shape. Compared to linear oligothiophenes, cyclic oligothiophenes should have strain energies due to their curvature. In the solid state, all linear oligothiophenes are planar, with an anti-conformation of thiophene rings being the most stable . In planar systems, there is maximal conjugation, which stabilizes the system. The deviation of dihedral inter-ring angles from planarity affects the electronic properties of cyclic oligomers and should increase the HOMO–LUMO gap. In short syn-conformers, from syn-182 (n ¼ 8) up to syn-182 (n ¼ 14), the HOMO–LUMO gaps decrease steeply with increasing chain length. All thiophene rings in both syn-182 and anti-182, as well as in linear oligothiophenes 16, show an aromatic nature, while inter-ring bonds and the middle bonds in the rings have more of a single-bond nature. The calculated vibrational spectra of p-conjugated cyclic oligomers constitute a very rich source of information on their structure and properties and can be used to differentiate between syn- and anti-conformers. In the IR spectra of cyclic oligothiophenes, two intense bands are observed, one for symmetric C–C stretching and the other for antisymmetric C–C stretching. For the syn-conformation, these bands appear at 1435–1455 (symmetric) and 1500– 1525 cm1 (asymmetric), whereas the corresponding bands for the anti-conformation are slightly shifted to lower energies, 1420–1445 and 1460–1480 cm1, respectively. There are two more characteristic regions in the IR spectra of the syn- and anti-conformations, the out-of-plane and in-plane C–H bending vibrations (at 765–785 and 1105– 1165 cm1 for syn and at 775–795 and 1165–1195 cm1 for anti, respectively). Two intense bands at 505–575 cm1, which are associated with the symmetric and antisymmetric ring deformations, are not present in the more planar structures (syn-182 (n ¼ 10) and syn-182 (n ¼ 12)) but are present in all syn-182 (nonplanar), syn-182 (n ¼ 6), and syn182 (n ¼ 8) (nonplanar) structures. The 10-membered ring cyclophanes 183–185 are novel compounds bearing unique molecular structures (Figure 44) <2006JOC6110>.
Figure 44 Membered ring cyclophanes.
X-Ray analysis revealed that compound 184 possesses a chairlike C2h conformation with an anti-arrangement of the two methylene bridges <2000CC2329>. The crystal contains two crystallographically independent molecules, which locate at crystallographic symmetric centers. Both molecules show essentially the same C2h structures with torsional angles at the bithiophene units of 53.7 (C(1)–C(2)–C(6)–C(5)) and 56.3 (corresponding angle for another molecule). Three possible conformations for compound 184 are present (Figure 45). The most stable conformation is the chairlike C2h structure obtained by B3LYP/6-31G(d)-level DFT calculations. The other two conformers, boatlike C2
Thiophenes and their Benzo Derivatives: Structure
and twisted D2 structures, are less stable than the C2h conformer by 0.8 and 7.1 kcal mol1, respectively. The 1H NMR spectrum of compound 184, which is composed of two sets of AB pattern signals ( 7.30 and 6.89 for the thiophene ring protons and 4.45 and 4.02 for the methylene protons), clearly shows the C2h conformation in solution.
Figure 45 Optimized molecular structures of 184 by B3LYP/6-31G(d)-level DFT calculations. The symmetry for each conformer is shown with the relative energy (kcal mol1) in parentheses.
Thiophene oligomers 16 (n ¼ 0–5/2) have been optimized by using Hartree–Fock and restricted configuration interaction/singles (CIS) for their ground (S0) and first singlet excited (S1) states geometries <2005JMT(726)161>. This was followed by conformational and optical studies using an ab initio method in combination with CIS, TDB3LYP, and Zerner’s intermediate neglect of differential overlap (ZINDO) approaches. It is found that bithiophene 16 (n ¼ 0) and terthiophene 16 (n ¼ 1/2) are nonplanar in the S0 states, whereas they almost reach planarity in the S1 states. The geometry relaxation after excitation contribute much to the Stokes shift observed in their absorption and emission spectra. The global potential energy surface studies show bithiophene and terthiophene have high inter-ring torsional flexibilities, in both the ground states (S0) and first excited states (S1); the cis-conformers should have evident contribution to the absorption and emission spectra of bithiophene and terthiophene molecules. These conclusions are also applicable to larger oligomers by a basis study extended to oligothiophenes 16 (n ¼ 1–5/2).
3.09.4.3 Tautomerism The presence of a hydroxy-, thio-, or amino substituent in the thiophene ring leads to various tautomeric forms. Compounds which are less aromatic would be more prone to tautomerize than the more aromatic ones.
3.09.4.3.1
Compounds with a hydroxy group
The 2-substituted hydroxythiophene systems 186 (Scheme 11) gives rise to three different tautomeric forms. In contrast to phenol, 2-hydroxythiophene exists almost exclusively in one of its carbonyl forms. These forms predominate because of the very stable thiolactone moiety. Several papers have discussed how different substituents influence the tautomeric equilibrium of this system, particularly for monosubstituted compounds.
Scheme 11 2-Hydroxy- and 3-hydroxythiophenes.
For 3-substituted hydroxythiophene systems 189, there are only two tautomeric structures possible, one hydroxy form and one carbonyl form. Many papers have shown that the hydroxy form dominates these equilibria . Hydroxy thiophenes are very unstable compounds <1996CHEC-II(2)483>. 2-Hydroxythiophenes are generally found in the tautomeric forms 186–188, while the 3-hydroxy isomer can exist in either the hydroxy form 189 or the keto form 190. Although some of these systems could exist as mixtures or exclusively in the keto form, we shall generically refer to them as hydroxythiophenes for simplicity.
715
716
Thiophenes and their Benzo Derivatives: Structure
3.09.4.3.1(i) 2-Hydroxythiophenes For the 2-hydroxythiophenes, the equilibrium is almost completely in the keto form. Furthermore, the conjugated isomer 2(5H)-thiophenone 187 is generally more stable due to the conjugation between the keto group and the double bond. In the parent molecule where there is no substituent, only form 187 is detected <2000AHC(76)105, 1974JHC291>. In general, the 2(5H)-thiophenones 187 have higher dipole moments than the 2(3H)-thiophenones 188. Thus the equilibrium shifts to the former with increasing polarity of the solvent <1968AK461>. The base-catalyzed rearrangement of 5-alkyl-2(3H)-thiophenone 188 to the corresponding 2(5H)-form 187 is first order in substrate and also in base. For 5-alkyl compounds, only the keto forms are present, whereas with R ¼ phenyl, thienyl, and ethoxycarbonyl, substantial almounts of the enol forms were detected. Computations for the parent system (R ¼ H) showed that the most stable form is 187 (Table 74) <2000AHC(76)105>.
Table 74 DFT results for 2-hydroxythiophene and the corresponding keto tautomersa
Method (basis) Energiesb 6-31G* a
628.208 88
628.209 95
628.228 26
628.235 00
B3LYP functional. Values in hartree.
b
The enolic form, 2-hydroxythiophene 191 (Figure 46), has been generated from its trimethylsilyl ether 192 in DMSO-d6 at 32 . This may be regarded as the enolic form of a thioester and it is converted in more than 99% into the keto forms 193 and 194 at equilibrium <2000AHC(76)105, 1968MI343, 1967JOC3028>.
Figure 46
The kinetics of ketonization has been studied by UV spectroscopy. The pH rate profiles are inverted bell-shaped curves with Hþ-, HO-, and H2O-catalyzed reactions. The values of kHþ and the equilibrium constants are given in Table 75 <1986TL3275>.
Table 75 Rate and equilibrium constants for the ketonization of hydroxy thiophene compounds at 25 C (I ¼ 1.00 M) kHþa (M1 s1) 2-Hydroxythiophene 3-Hydroxythiophene 2-Hydroxybenzo[b]thiophene a
kHþb (M1 s1) c,d
5.83
11.5 1.78c 12.4
Water, I 1.00 M. Water–acetonitrile (10–90% v/v). c Water–acetonitrile (50–50% v/v). d Total rate constant to yield 3-thiolene-2-one (20%) and 4-thiolene-2-one (80%). b
Kenol(H2O) 2
Kenol(DMSO) <2 102 >102 <2 102
Thiophenes and their Benzo Derivatives: Structure
2-Hydroxythiophene undergoes ketonization to yield a mixture of 3- and 4-thiolene-2-ones 187 and 188 (R ¼ H), the composition of which depends on the catalyst and the solvent. The H3Oþ-catalyzed ketonization with protonation at C–3 to yield 4-thiolene-2-one 188 (R ¼ H) is ca. 5 times faster in water–acetonitrile (50–50% v/v) than the H3Oþ-ketonization of 3-hydroxythiophene which occurs with protonation at C-2. The initial protonation steps in these reactions are similar to the initial steps of proton exchange and other electrophilic substitutions, which normally occur much faster at C-2 of thiophene than at C-3 <1971AHC(13)272, 1971AHC(13)284>. The presence of the hydroxy groups is therefore affecting the relative rates, and the formation of the thioester group at C-2 is kinetically as well as thermodynamically favored over formation of the keto group at C-3. According to the IR spectra (neat), nitriles 195 and 196 exist as 195b and 196b. For nitrile 195 in CDCl3 solution, only the keto tautomer 195b has been found; however, addition of DMSO-d6 shifts the equilibrium toward 195a. Nitrile 197 exists exclusively as hydroxy tautomer 197a (Figure 47).
Figure 47 2-Hydroxythiophene derivatives.
Halo substituents do not influence the general tautomeric patterns of the hydroxythiophenes <2000J(P2)1453>. The trichlorinated hydroxythiophenes are stable when kept under nitrogen. The hydroxythiophenes with a bromine substituent, however, started to polymerize quite rapidly, even when kept at temperatures below 0 C under nitrogen. The carbonyl structure of 2,5-dihydrothiophen-2-one 198bis the only detectable tautomer of compound 198. In the 1H NMR spectrum of compound 187, the coupling constant between the hydrogen atoms at the 3- and 4-position are larger (ca. 6.1 Hz) than those found in thiophene <1964AK211>. Carbonyl substituents at the 3-position, which generally cause the equilibrium to shift exclusively to the hydroxy form 186 (R ¼ H), show unusually large (>6.0 Hz) J45 coupling constants <1967T871>. The carbonyl absorption in 2(5H)-thiophenones 187 is found in the region 1670–1695 cm1, while that in the 2(3H)-thiophenones 188 is found between 1730 and 1750 cm1 <1963AK239>. In general, the 2(5H)-thiophenones 187 display a band around 220 nm in the UV spectra, which shifts to higher wavelength when substituents at the 3- and 4-position (including hydroxy groups) are introduced. The second band at 265 nm is generally unaffected by the introduction of substituents <1963AK239>.
3.09.4.3.1(ii) 2-Hydroxybenzo[b]thiophenes As is well kown <1976AHC(S1)232>, 2-hydroxybenzo[b]thiophene 199 exists in both the solid state and in solution exclusively as its keto tautomer 200. According to DFT calculations, tautomer 200 is more stable than 199 by E ¼ 15.0 kcal mol1 (E199 ¼ 781.863 90; E(200) ¼ 781.887 75 (B3LYP/6-31G* , in hartree)). The 2-hydroxybenzo[b]thiophene 201 was generated from the O-trimethylsilyl derivative 202 in DMSO-d6–D2O at 34 C. After 15 min at 25 C, the spectra had changed to that of [3D]-2-benzothiophenone 203 (Figure 48) <1989JA5346, 2000AHC(76)106>.
Figure 48 2-Hydroxybenzo[b]thiophene derivatives.
717
718
Thiophenes and their Benzo Derivatives: Structure
Benzo[b]thiophene normally undergoes electrophilic substitution at the 3-position more rapidly than at the 2-position <1971AHC(13)284>, so both this and formation of the thioester group favor ketonization of 2-hydroxybenzo[b]thiophene which occurs 40 times faster than ketonization of 3-hydroxybenzo[b]thiophene. The rapid rate of ketonization of the thio-ester enol 2-hydroxybenzo[b]thiophene is also indicated by its 4.4-fold greater rate of ketonization compared to 2-hydroxyindene, which contrasts with what is found with 3-hydroxybenzo[b]thiophene and 1-hydroxyindene <1986TL3275>. Rates of the reversible deprotonation of benzo[b]-2,3-dihydrothiophene-2-one 200 by OH, primary aliphatic amines, secondary alicyclic amines, and carboxylate ions have been determined in water at 25 C <2006JOC8203>. Compound 200 (pKaKH ¼ 8.82) is significantly more acidic than compound 204 (pKaKH ¼ 11.68). Kresge and Meng <2002JA9189> have attributed the higher acidity of compound 200 to the greater aromatic stabilization of the thiophene ring in the anion compared to that of the furan anion from compound 204 <1974J(P2)322, 1985T1409, 1987T4725, B-1994MI217>. A contributing factor to the acidity difference may be the stronger p-donor effect of the ring oxygen in compound 204 compared to that of the ring sulfur in compound 200; the greater stabilization of the former should reduce its acidity more. 2-Hydroxybenzo[b]thiophenes with carbonyl groups at C-3 (e.g., COCHTCHPh) have been formulated as enols <1979LA965, 1981CCC118>. In some cases, mixtures of enol and oxo forms have been observed <1984CCC603>. Aldimines of type 205 exist predominantly as keto tautomers 206 (Figure 49) <1974JPR971>.
Figure 49
3.09.4.3.1(iii) 3-Hydroxythiophenes Spectral evidence for 3-hydroxythiophenes shows them to exist as mixtures of both forms 207 and 208 and the keto form 208 to predominate by a factor of 2.9 <1986TL3275, 1989JA5346>. It is, however, unstable and tends to dimerize to the bithienyl 209 <1990CC375>. 3-Hydroxythiophene was prepared from the trimethylsilyl derivative and was sufficiently stable for its NMR spectrum to be obtained in a variety of solvents <1989JA5346>. In most cases, 100% of the enol form was detected, but in CCl4 both tautomers were observed.
Alkyl- and dialkyl-3-hydroxythiophenes are more stable, but they still exist as mixtures of both forms in the liquid state and in solution. Lantz and Ho¨rnfeldt <1972CS9> determined the equilibrium constants for the tautomerization of a series of 2,5-dialkyl-3-hydroxythiophenes in CS2 solution. It has been reported that the keto–enol equilibria were established very rapidly. The 2,5-dimethyl compound was studied in five solvents (C6H12, CS2, CHCl3, CH3COCH3, CH3CN) and the values of K (keto (K)/enol (E)) varied from 8.09 in CHCl3 to 1.04 in acetone. Crude 3-hydroxythiophene has been prepared by the method of Ford and Mackay <1956JCS4985> and converted into its trimethylsilyl ether, which was purified by distillation. This was methanolyzed, and evaporation of the methanol and trimethylsilanol yielded 3-hydroxythiophene with an IR spectrum identical with that reported by Ford and Mackay <1956JCS4985>. This compound resinifies rapidly, but it is sufficiently stable to have its NMR spectrum run in a solvent. The percentage enol present was estimated to be as indicated in the following solvents: DMSO-d6, (100%); CD3COCD3 (100%); CH3OH (100%); dioxane–water (9:l) ( 95%); CC14 ( 60%) <1986TL5155>. 3-Deuteroxythiophene 211 can also be generated from its trimethylsilyl derivative 210 in acetone-d6–D2O (4:l v/v)– DCl 103 M) (Scheme 12). The keto form 212 was not detectable in this solvent, but the signal of H-2 of the enol form ( ¼ 6.35) slowly disappeared through exchange with the solvent and the signals of H-4 and H-5 were simplified.
Thiophenes and their Benzo Derivatives: Structure
Scheme 12
3.09.4.3.1(iv) 3-Hydroxybenzo[b]thiophenes As in the case of 3-hydroxythiophenes, the benzo analogue is also unstable. There have been conflicting reports as to whether the hydroxy tautomer 213 or the keto form 214 is more stable. IR evidence indicates that in the solid state, it exists in the keto form <1958JCS1217>. A strong carbonyl absorption is observed at 1690 cm1 and the absence of a band between 3000 cm1 and 4000 cm1 indicates the absence of a hydroxy group. The 1H NMR spectrum run in DMSO-d6 also implies the exclusive existence of the keto form, but it is gradually converted into the enol form 213. The rate of conversion depends on the amount of water present in the solvent. The effect of solvent on the equilibrium constants has been studied for the 3-hydroxybenzo[b]thiophenes <1986TL3275, 1989JA5346>. The enol is much more stable in hydrogen-bonding solvents than in aprotic solvents. Thus, while enol 213 is barely detected in C6D6, CCl4, or CDCl3, it is predominant in C5D5N and DMSO-d6. For acid-catalyzed ketonization, the 3-hydroxy monocyclic compounds tautomerize 10–103 times faster than their benzo analogues, presumably via a mesomeric effect due to the lone pair on the heteroatom. The rate of ketonization of the hydroxythiophenes and benzo[b]thiophenes in acetonitrile–water (9:1) is as follows: 2-hydroxybenzo[b]thiophene > 2,5-dihydroxythiophene > 2-hydroxythiophene > 3-hydroxybenzo[b]thiophene > 3-hydroxythiophene <1987PAC1577>. 3-Hydroxybenzo[b]thiophene could be generated in 100% yield as the enol form 216 by hydrolysis of its trimethylsilylether 215 (Scheme 13). After 15 min at 32 C, the trimethylsilyl ether 215 in 90% acetone-d6–10% D2O (5 104 M DCl) was converted into compound 216 ((CH) ¼ 6.45), and no keto form, 217 ((CH2) ¼ 3.92), could be detected. Under these conditions, the enol form has a half-life of ca. 1 day and changes slowly to an equilibrium mixture which contains approximately 40% of the keto form <1989JA5346>.
Scheme 13
The acylation of ortho-substituted 2-arylaminomethylene-2,3-dihydrobenzo[b]thiophen-3-ones with acyl chlorides (Scheme 14) results in formation of the corresponding N-acyl enaminoketones 218. The structure of compounds 218 as (Z)-enaminoketones is confirmed by the presence in the IR spectra of absorption bands of the amide (1710 cm1) and endocyclic carbonyl groups (1650 cm1), as well as by a characteristic chemical shift of the methine proton ( 9.2 ppm) in the 1H NMR spectrum. Structures Z-218 show a characteristic maximum at 418–428 nm in the electron-absorption spectrum. Irradiation at that band ( exc 436 nm) induces fast (Z,E)-isomerization of compounds 218 with subsequent thermal N ! O transfer of the acyl group and formation of O-acyl isomers 219 which absorb at 360–370 nm. However, unlike most previously studied analogues, the photochemical transformation goes until equilibrium (Scheme 14) establishes between the N- and O-acyl isomers. The state of the equilibrium strongly depends on the solvent nature and compound structure. The equilibrium constants K0 ¼ [219]/[218] and Gibbs energies G0294 are given in Table 76. In the presence of CCl3CO2H, the equilibrium is displaced completely toward initial isomer (Z)-218.
719
720
Thiophenes and their Benzo Derivatives: Structure
Scheme 14 Table 76 Thermodynamic parameters of the equilibria involving compounds 218 (R1 ¼ OMe) and 218 (R1 ¼ TsNH) G0294 (kJ mol1)
K0
Toluene Acetonitrile DMSO
218b
218c
218b
218c
1.04 1.63 a
7.3 1.03 0.07
0.001 1.15 a
4.7 0.001 6.3
a Irradiation of compound 218 (R1 ¼ OMe) in DMSO at exc 436 nm induces both acylotropic N ! O migration and partial decomposition. b R ¼ MeO. c R ¼ TsNH.
Compound 220 in solution gives rise to a dynamic equilibrium between the enaminoketone (E)-220 and N-acyl forms (Z)-221 in the ground state (Scheme 14). In nonpolar solvents, such as hexane, benzene, and toluene, the equilibrium is displaced toward isomer (E)-220, which is stabilized by intramolecular hydrogen bond; it absorbs in the region of 470 nm. In polar solvents like DMSO, the equilibrium shifts almost completely toward the N-acylated form (Z)-221. The enaminoketone structure of compound 220 in the crystal state was derived from the IR spectrum which contained the following absorption bands: 1760 (ester carbonyl), 1640 (exocyclic carbonyl group), 1630 (lactone carbonyl in the pyran ring), and 3350 cm1 (strongly broadened (N–H) band) <2001RJO1318>. The acetyl derivative of 3-hydroxybenzo[b]thiophene-2-carbaldehyde 222 undergoes acylotropic acid-catalyzed rearrangement to the 2-acetoxymethylenebenzo[b]thiophen-3(2H)-one 223, which is stable in hydrocarbon solvents up to 100 C (Scheme 15) <1985JOU862>.
Scheme 15
Thiophenes and their Benzo Derivatives: Structure
The IR spectrum of the 3-hydroxy(benzo[b]thiophen-2-yl) aryl methanones 224 showed peaks due to hydroxyl and carbonyl functions at 3440–3450 and at 1590 cm1, respectively, suggesting intramolecular hydrogen bonding between the two functionalities. The existence of hydrogen bonding was further corroborated by the 1H NMR spectra, which displayed signals due to a hydrogen-bonded OH as a one-proton singlet at ca. 13.5 ppm <2005T1493>.
3.09.4.3.2
Compounds with more than one hydroxy group
3.09.4.3.2(i) 2,3-Dihydroxythiophenes Theoretically, 2,3-dihydroxythiophenes can exist in four tautomeric forms 225–228 (Scheme 16), and it has been unequivocally proved that 2,3-dihydroxythiophene does exist in form 226 (3-hydroxy-3-thiolene-2-one). The NMR spectrum shows peaks at 3.87 (d, CH2) 6.52 (t, H-4), and 6.40 (OH) with J4–5 ¼ 3.3 Hz. No peaks corresponding to other tautomers were observed. The IR spectrum in KBr shows two strong peaks at 1680 and 1645 cm1, corresponding to CTO and CTC, respectively, and a broad band with maximum at 3320 cm1 (the O–H stretching vibration of the enol group). In Table 77 are spectroscopic data, and a comparison with already known data of 3-thiolene-2-ones <1963TL1867, 1960AK499, 1967AK239> shows that the 3-OH or 3-OMe substituents do not have any marked influence on the CO stretching frequency, while the CTC frequency is about 40 cm1 higher in the substituted compound. The UV spectrum of thiolene-2-ones usually shows one band at 220 nm and another at 265 nm. Methoxyl and hydroxyl substituents in the 3-position of 3-thiolene produce a hypsochromic shift of the 220 nm band, while the 265 nm band is unaffected by the substituents <1971T3839>. 2,3-Dihydroxy-5-methylthiophene can also exist in four tautomeric forms. The NMR spectrum in CDCl3 shows a doublet at ¼ l.55 (CH3), a double quartet at 4.10 (H-5), a broad signal at 6.1 (OH), and a doublet at 6.32 (H-4). No other peaks were observed, and together with the IR and UV data (Table 77) the true structure of 2,3-dihydroxy-5methylthiophene is 3-hydroxy-5methyl-3-thiolene-2-one 229.
Scheme 16
Table 77 Spectroscopic data of 2,3-dihydroxythiophenes Compound
IR (cm1)
UV, nm (log ") (EtOH)
NMR (, ppm)
Reference
1645a 1680
248 (3.9) 266 (sh.)
3.87 (2H)c 6.40 (1H) 6.52 (1H)
1966ACS261
1640b 1690
247 (3.9) 264 (sh.)
1.55 (3H)c 4.10 (1H) 6.10 (1H) 6.32 (1H)
1971T3839
4.74 (1H)d 6.44 (1H) 6.50 (1H)
1965T3331
1665a 1695 1740
(Continued)
721
722
Thiophenes and their Benzo Derivatives: Structure
Table 77 (Continued) Compound
IR (cm1)
UV, nm (log ") (EtOH)
NMR (, ppm)
Reference
1650a 1680
249 (3.9) 266 (sh.)
2.10 (3H)c 3.89 (2H) 6.20 (1H)
1971T3839
1645a 1680
244 (3.9) 268 (3.3)
1967AK239
a
KBr. Liquid. c CDCl3. d CCl4. b
The structure of 2,3-dihydroxy-5-ethoxycarbonyl-thiophene was assumed to be <1965T3331> that of a a 4-thiolene 2-one (type 227). By inspection of the IR spectra of ethyl 4,5-dihydroxythiophene-2-carboxylate and related compounds (Table 77), it is now possible to distinguish between the two possibilities and show which is 3-hydroxy-5-ethoxycarbonyl-3-thiolene-2-one 230. The observed strong absorptions at 1695 and 1740 cm1 in the CO frequency area only fit structure 230. The band at 1695 cm1 is assigned to the thiolactonecarbonyl group and is in good accordance with known data <1968AK427, B-1958MI1>. The unconjugated ester function also shows the characteristic absorption at 1740 cm1. The thiophene and the 3-substituted thiophenes 233 have been found to undergo ring dihydroxylation yielding the cis/ trans-dihydrodiol metabolites 234. Evidence is provided for a dehydrogenase-catalyzed desaturation of a heterocyclic dihydrodiol 234-cis/234-trans (R ¼ Me) to yield the corresponding 2,3-dihydroxythiophene 235 as its preferred thiolactone tautomer 236. A simple model to allow prediction of the structure of metabolites, formed from Toluene dioxygenase (TDO)-catalyzed bacterial oxidation of thiophene substrates, has been presented (Scheme 17) <2003OBC984>.
Scheme 17
3.09.4.3.2(ii) 3,4-Dihydroxythiophenes Recently, 3,4-dihydroxythiophenes have received considerable attention due to their photophysical properties <1997MM2582> and biological activity <2006MI6883>. Mono- and disubstituted-3,4-dihydroxythiophenes can potentially exist in four tautomeric forms, 237–240 (Scheme 18). For unsubstituted and for most disubstituted derivatives, the hydroxyketo form 238 or 239 is observed. In monosubstituted products (R1 6¼ H, R2 ¼ H), 238 is the only one observed <1971T3839>. However 3,4-dihydroxy2-thiophenecarboxylic acid ethyl ester existed as the dihydroxy tautomer 241.
Thiophenes and their Benzo Derivatives: Structure
Scheme 18
The 1H NMR spectrum of 241 shows a sharp aromatic C–H singlet at 6.65 assigned as the C-5 methine, and in acetone-d6 the hydroxyl hydrogen resonances are well resolved at 8.65 and 9.49; no C-5 methylene resonance was detectable. The 13C NMR spectrum is completely resolved with the ester CTO resonance at 166.l ppm and no ketone resonance detectable. The 1H NMR spectrum obtained in various solvents (CDCl3, acetone-d6, DMSO-d6, methanol-d4, C5D5N) are identical, except for the expected changes in the OH resonances <1993TL8229>. Two lines of evidence suggest that a less stable keto tautomer 242 may be accessible from (or in equilibrium with) the stable dihydroxy tautomer 241. First, the C-5 hydrogen of 241 is rapidly exchanged for deuterium upon solution of 241 with NaOD–D2O in an NMR tube. However, the C-5 hydrogen is not exchanged (at 25 C) when D2O is added to a solution of ester 241 in CDCl3. Second, following an acid-catalyzed hydrolysis of diester 243 using ethanol as co-solvent, a 37% yield of 241 was obtained along with 20% of the monoethyl ether 244. The surprising formation of 244 under aqueous conditions is the result of reaction between ethanol and a low-equilibrium concentration of the keto tautomer 242 (Scheme 18). Likewise, 2-cyano-3,4-dihydroxythiophene predominantly existed in the dihydroxy tautomeric form 245, as shown by 13C and 1H NMR studies performed in methanol, as well as IR analysis (Scheme 19) <2000BML349>.
Scheme 19
An X-ray structure of diethyl 3,4-dihydroxythiophene-2,5-dicarboxylate 246 shows that the hydroxy groups lie in the plane of the molecules. This planarity leads to a larger number of potential intra- and intermolecular hydrogen bonds; each hydroxy group is involved in one intra- and one intermolecular contact <2004AXCo338>.
723
724
Thiophenes and their Benzo Derivatives: Structure
An X-ray structure of some 2,5-dicarboxy-3,4-dihydroxythiophene derivatives 247 suggests the presence of three distinct intramolecular hydrogen bonds, namely [Namide–H O] (A), [O–H Oamide] (B), and [Namide–H S] (C) (Scheme 19) <2006BKC243>.
3.09.4.3.3
Compounds with a thiol group
Unlike the hydroxy derivatives, no tautomerism tends to exist in the simple 2- and 3-thiophenethiols <1977ACB198>, nor in benzo[b]thiophene-3-thiol <1970JC2431>. Quantum-chemical calculation of the relative stabilities <1989JST(184)179> of tautomeric forms B and C of substituted 2-hydroxy- and 2-mercaptothiophenes have been carried out by the AM1 and PM3 methods. The calculation results shown in Table 78 indicate a definite preference for the thiol form in the case of 2-thiophenethiols 248 and similar H values for the formation of all three tautomeric forms in the case of 2-hydroxythiophenes, which corresponded to the experimental data . The effect of substituents on the relative stabilities for hydroxy- and mercaptothiophenes is identical and in complete qualitative accord with the empirical data obtained for hydroxythiophenes: substituents at C-3 and C-4 stabilize to form 249, while substituents at C-5 stabilize to form 250 (Scheme 20) <1997CHE1047>.
Table 78 Quantum-chemical calculation of the relative stabilities of tautomeric forms 248–250 of R-substituted 2-thiophenethiols and analogously substituted potential 2-hydroxythiophenes 186a AM1 Calculation
PM3 Calculation
H249–250 (kcal )
H249–248 (kcal )
H249–250 (kcal )
H249–248 (kcal )
R
186
Thiol
186
Thiol
R
186
Thiol
186
Thiol
3-Ph 3-Me 3-Br 3-Cl 4-Ph 4-Me H 4-Cl 5-Cl 5-Me 5-Ph 5-SH 5-MeS
3.58 2.52 2.11 1.63 1.19 0.93 1.04 1.48 4.14 4.43 5.34 7.73 6.65
1.94 0.86 0.34 0.02 2.58 2.80 2.97 3.52 6.03 6.23 7.23 8.65 8.71
12.99 11.66 13.39 13.28 11.00 10.42 11.08 11.57 14.44 14.14 15.69 18.21 18.52
1.93 0.30 3.47 2.59 0.35 0.29 0.31 1.23 4.05 3.29 5.20 8.28 8.56
3-Me 3-Ph 3-Cl 4-Me 4-Ph H 4-Cl 3-Br 5-Cl 5-Me 5-Ph 5-SH 5-Mes
4.29 2.52 3.26 0.10 0.29 0.17 0.16 3.52 3.81 4.38 4.59 5.67 5.65
2.33 2.02 1.50 2.33 2.52 2.53 2.79 4.99 6.01 6.62 6.79 9.12 9.21
19.11 21.99 19.93 17.74 17.86 18.49 18.67 19.98 22.17 22.31 23.02 24.68 25.29
3.99 2.75 2.81 4.64 5.06 4.10 3.46 2.59 1.32 1.10 0.41 1.65 3.07
a
The tautomeric forms for 186 are the hydroxy and oxo forms analogous to tautomeric forms 248–250 for 2-thiophenethiol (Scheme 20).
Scheme 20
The presence of a proton-acceptor site external to the ring such as an aldimine group at the 3-position leads to the possibility of four tautomeric forms, 251–254 (Scheme 21) <1970CHE1232>. A similar behavior is also observed in the corresponding benzo[b]thiophene analogues <1974JPR970>. Benzo[b]-2,3-dihydrothiophene-2-thione 255 proved to exist solely as the enethiol in aqueous solution, and only the enethiol ionization constant pQaE ¼ 3.44 could be determined for this substance; the limits pKE < 1.3 and pQaE < 2.1 K < 2.1, however, could be set.
Thiophenes and their Benzo Derivatives: Structure
Scheme 21
Neither the IR nor the 1H NMR spectra of benzo[b]thiophene-2-thiol shows any sign of the thio-keto isomer, which indicates that this substance exists essentially completely in the ene-thiol form. The reversible UV spectral change that this substance undergoes, from max ¼ 275 nm in 0.1 M HCl to max ¼ 305 nm in 0.1 M NaOH, may therefore be attributed to ionization of the enol to its enolate ion (Scheme 22) <2002JA9189>.
Scheme 22
Because the system exists essentially completely as the thiol isomer, a carbon-acid acidity constant for ionization starting with the thio-keto form as the initial state, QaK, could not be measured, and a keto–enol equilibrium constant, KE, could not be determined. A lower limit for KE can nevertheless be estimated on the assumption that 5% of the keto isomer would have produced a detectable signal in the 1H NMR spectrum of the enol form. Because no such signal was seen, KE must be greater than 20, which makes pKE less than 1.3. The relationship QaK ¼ KEQaK then leads to QaK > 7.2 103 M, pQaK < 2.1.
3.09.4.3.4
Compounds with an amino group
MO calculations on simple aminothiophenes show them to exist in the aromatic amino form rather than in the nonaromatic imino tautomeric form <1981AQ105>. The 2- and 3-aminothiophenes are generally unstable in air. They are much more stable as salts or as their N-acyl derivatives and are also more stable in solution than in the neat liquid state. 2-Aminothiophenes 256 can, in principle, occur in equilibrium with the tautomeric forms 257 and 258 (Scheme 23).
Scheme 23
Since the chemical behavior of these unstable compounds deviated in many respects from that of the arylamines, it was first thought that they preferably exist in the imino form 257. In 1960 <1960AK515>, it was proved by NMR spectroscopy that the parent aminothiophene occurs exclusively in the amino form 256. This was confirmed later by more detailed investigations <1967TL5201, 1969JHC147>. Several other 2-N-substituted thiophenes have been
725
726
Thiophenes and their Benzo Derivatives: Structure
synthesized <1986HC(44/2)1>, but in none of the cases amino–imino tautomerism has been mentioned. The strong preference for the amino tautomers may be explained by assuming that the –M-effect of the electron-withdrawing substituents present compensates the þM-effect of the amino group, which stabilizes the amino form. On the other hand, one would expect that the presence of electron-donating substituents (OCH3, SCH3) at suitable positions of the ring could stabilize the imino tautomers. The tautomeric equilibrium between the forms 259 and 260 was studied in detail by lH and 13C NMR spectroscopy for compounds 259a and 259b, using CCl4, 1:1 mixtures of CCl4 and CDCl3, pure CDCl3, or (CD3)2 CTO as solvents. The NMR spectra of compounds 259c and 259d showed only signals, assignable to the amino structures. In a 1:1 mixture of CCl4 and CDCl3 form, 259a is in equilibrium with its tautomer 260a (ratio 1:7) <1998TL2433>. Replacement of the solvent (CDCl3/CCl4 1:1 mixture) by the more polar CDCl3 slightly shifts the tautomeric equilibrium toward the imino form (259a:260a ¼ 1:15). In neat CCl4, the population of the NH tautomer form increases (259a:260a ¼ 1:1). In the case of compound 259b, the amino form predominates in neat CDCl3 (259b:260b ¼ 10:7). The 3-methoxy-substituted derivatives 259a and 259b are the first examples of tautomeric systems in the 2-thiopheneamine series. Proton NMR studies on 2- and 3-thiophenamine <1967TL5201> as well as their substituted derivatives all indicate the exclusive existence of the amino form <1960AK515>. Proton NMR studies of 2-thiopheneamines bearing only an electron-withdrawing substituent in the ortho-position, that is, the ester 261, indicate the existence of the imino form <2001M279, 2006T11311, 2006MI139>. Due to the push–pull effect, the imino form 262 can be generated (Scheme 24).
Scheme 24
A series of yellow to greenish-blue aziridinyl azo dyes and their azo precursors containing a thienyl coupling moiety (i.e., 263), which have been prepared from 2-aminothiophenes, are relatively bathochromic. From the viewpoint of solvatochromism, a clear contrast existed between max values in different solvents; thus, a positive solvatochromism was observed in aprotic solvents, whereas a hypsochromic shift was brought about in polar protic solvents <1999DP(40)99>. These bathochromic shifts strongly suggest that the lone pair electrons of the terminal nitrogen atom are effectively conjugated with the p-electron system of the thiophene ring, giving rise to bathochromic shifts. In the hydroxyamino compounds, it is usually the hydroxy system that tautomerizes to the keto form rather than the amino function to the imine. Thus, 5-amino-2-hydroxythiophene may exist in three tautomeric forms, 264–266 (Scheme 25).
Scheme 25
Analysis of spectral data showed that products exist in the keto form 264 and not in the tautomeric enol form 265. This is indicated by the presence of a two-proton singlet for the methylene group of the thiophene ring at 3.69–3.92 ppm, and by an absorption band for a conjugated keto group in the IR spectra at 1620–1630 cm1. At the
Thiophenes and their Benzo Derivatives: Structure
same time, the presence of two absorption bands for the amino group at 3150–3400 cm1 excludes the imine form 266 <2005CHE173>. The single crystal X-ray diffraction of carboxamide 267 indicates that this type of thiophene exists only in the ketone form, 5-aminothiophen-3(2H)-one, which is consistent with the results of the 1H and 13C NMR spectra <2006JOC8006>.
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Y. Cui, Q. D. Liu, D. R. Bai, W. L. Jia, Y. Tao, and S. Wang, Inorg. Chem., 2005, 44, 601. S. S. Erdem, G. A. Oezpinar, and M. T. Sacan, J. Mol. Struct. Theochem, 2005, 726, 233. K. Takimiya, Y. Konda, H. Ebata, N. Niihara, and T. Otsubo, J. Org. Chem., 2005, 70, 10569. A. Jun-ichi, J. Phys. Org. Chem., 2005, 18, 235. T. M. Krygowski, B. T. Stepien, M. K. Cyranski, and K. Ejsmont, J. Phys. Org. Chem., 2005, 18, 886. F. Liu, P. Zuo, L. Meng, and S. J. Zheng, J. Mol. Struct., 2005, 726, 161. M. Concistre, G. De Luca, M. Longeri, G. Pileio, and W. Emsley James, Chemphyschem, 2005, 6, 1483. D. M. Cho, S. R. Parkin, and M. D. Watson, Org. Lett., 2005, 7, 1067. C. S. Wannere, C. Corminboeuf, W. D. Allen, H. F. Schaefer, and P. v. R. Schleyer, Org. Lett., 2005, 7, 1457. F. Faglioni, A. Ligabue, S. Pelloni, A. Soncini, R. G. Viglione, M. B. Ferraro, R. Zanasi, and P. Lazzeretti, Org. Lett., 2005, 7, 3457. 2005OL5301 T. Okamoto, K. Kudoh, A. Wakamiya, and S. Yamaguchi, Org. Lett., 2005, 7, 5301. 2005SM(150)259 A. Chandekar and J. E. Whitten, Synth. Met., 2005, 150, 259. 2005T1493 T. K. Pradhan and A. De, Tetrahedron Lett., 2005, 46, 1493. 2006BKC243 S. Ko, S. H. Park, H. J. Gwon, J. Lee, M. J. Kim, Y. Kwak, Y. Do, and D. G. Churchill, Bull. Korean Chem. Soc., 2006, 27, 243. 2006CEJ2073 V. Coropceanu, O. Kwon, B. Wex, B. R. Kaafarani, N. E. Gruhn, J. C. Durivage, D. C. Neckers, and J.-L. Bredas, Chem. Eur. J., 2006, 12, 2073. 2006CPH(327)269 S. F. Zhang, X. G. Ren, G. L. Su, C. G. Ning, H. Zhou, B. Li, G. Q. Li, and J. K. Deng, Chem. Phys., 2006, 327, 269. 2006JCP(125)174313 J. Yang, J. Li, and Y. Mo, J. Chem. Phys., 2006, 125, 174313. 2006JOC2972 S. S. Zade and M. Bendikov, J. Org. Chem., 2006, 71, 2972. 2006JOC6110 Y. Miyake, M. Wu, M. J. Rahman, Y. Kuwatani, and M. Iyoda, J. Org. Chem., 2006, 71, 6110. 2006JOC8006 Y. Li, F. Liang, X. Bi, and Q. Liu, J. Org. Chem., 2006, 71, 8006. 2006JOC8203 C. F. Bernasconi and H. Zheng, J. Org. Chem., 2006, 71, 8203. 2006MI139 K. M. Khan, Z. Nullah, M. A. Lodhi, S. Jalil, M. I. Choudhary, and R. Atta Ur, J. Enzym Inhib., 2006, 21, 139. 2006MI6883 S. Kehlenbeck, U. Betz, A. Birkmann, B. Fast, A. H. Goller, K. Henninger, T. Lowinger, D. Marrero, A. Paessens, D. Paulsen, V. Pevzner, R. Schohe-Loop, H. Tsujishita, R. Welker, J. Kreuter, H. Rubsamen-Waigmann, and F. Dittmer, J. Virol., 2006, 80, 6883. 2006OM2761 S. Kyushin, T. Matsuura, and H. Matsumoto, Organometallics, 2006, 25, 2761. 2006T2190 P. Wagner, A. M. Ballantyne, K. W. Jolley, and D. L. Officer, Tetrahedron, 2006, 62, 2190. 2006T11311 D. M. Barnes, A. R. Haight, T. Hameury, M. A. McLaughlin, J. Z. Mei, J. S. Tedrow, and J. D. R. Toma, Tetrahedron, 2006, 62, 11311. 2007OL1619 L. H. Xie, X. Y. Hou, Y. R. Hua, Y. Q. Huang, B. M. Zhao, F. Liu, B. Peng, W. Wei, and W. Huang, Org. Lett., 2007, 9, 1619. 2005IC601 2005JMT(726)233 2005JOC10569 2005JPO235 2005JPO886 2005JST(726)161 2005MI1483 2005OL1067 2005OL1457 2005OL3457
737
738
Thiophenes and their Benzo Derivatives: Structure
Biographical Sketch
Pedro Molina Buendı´a was born in Totana (Murcia), Spain, in 1945. He received his Ph.D. in organic chemistry at the University of Murcia in 1973. After a postdoctoral stay at the University of East Anglia (UK) with Professor A. R. Katritzky (1975–77), he joined the University of Murcia where he became full professor in 1982. His interests focus on the development of iminophosphorane-bassed synthetic methods and their applications to the synthesis of marine alkaloids. nitrogen-substituted metallocenes, and chemosensors.
Antonio Arques Adame was born in Badajoz in 1952. He studied chemistry at the University of Murcia (Spain), from where he also obtained his Ph.D. in 1980. He joined the group of Prof. P. Molina at the University of Murcia and from 1984 he held a position as an assistant professor at the University of Murcia. The major focus of his research interest relates to heterocyclic chemistry using iminophosphorane methodology. His current research interest is focused on the development of hetero-difunctional ferrocene-coordination ligands and their application to organic synthesis.
Thiophenes and their Benzo Derivatives: Structure
Inmaculada Cartagena Travesedo was born in Madrid, Spain, on 21 April 1951. She studied chemistry at the University of Murcia and gained her B.Sc. in 1973 and her Ph.D. degree in chemistry in 1981 from the same university. She is a professor at the University of Murcia. Her research has been devoted to the field of heterocyclic chemistry.
739
3.10 Thiophenes and their Benzo Derivatives: Reactivity S. Rajappa B-1, Melody Apartments, ICS Colony, Pune 411007, India A. R. Deshmukh National Chemical Laboratory, Pune, India ª 2008 Elsevier Ltd. All rights reserved. 3.10.1
Introduction
3.10.2
Reactivity of Fully Conjugated Rings
3.10.2.1
743 743
General Survey of Reactivity
3.10.2.1.1 3.10.2.1.2 3.10.2.1.3 3.10.2.1.4
3.10.2.2
743
Photodissociation and photoisomerization of thiophene Sigmatropic rearrangements Electrocyclizations Didehydrothiophenes and 3,4-dimethylenethiophene
One-Electron Oxidation of Thiophenes
3.10.2.2.1 3.10.2.2.2
3.10.2.3
754
Thiophene radical cation and oligothiophene dications Oxidative polymerization
Electrophilic Attack on Carbon
3.10.2.3.1 3.10.2.3.2 3.10.2.3.3
743 744 744 752 754 756
756
Protonation Alkylation Acylation
756 756 758
3.10.2.4
Electrophilic Attack on Sulfur
758
3.10.2.5
Nucleophilic Attack on Ring Atoms
758
3.10.2.5.1 3.10.2.5.2 3.10.2.5.3 3.10.2.5.4
Ring-opening reactions Addition of nucleophiles across the 2,3-double bond Reaction of nucleophiles with cationic species Nucleophilic attack on sulfur
758 758 758 759
3.10.2.6
Nucleophilic Attack on Hydrogen Attached to Carbon
759
3.10.2.7
Reactions with Radicals and Electron-Deficient Species
760
3.10.2.7.1 3.10.2.7.2 3.10.2.7.3 3.10.2.7.4 3.10.2.7.5 3.10.2.7.6
3.10.2.8
Homolytic substitution Reaction with carbenes and nitrenes Catalytic hydrogenation Reactions at surfaces Electrochemical reactions at cathodes Desulfurization
760 761 761 761 762 762
Reactions Involving a Cyclic Transition State with a Second Molecule
3.10.2.8.1
3.10.2.9
Cycloadditions
762 762
Reactions of Strained Thiophenes
763
3.10.2.10
Sulfur-Extrusion and Sulfur-Transfer Reactions
764
3.10.2.11
Reactions Brought About under Transition Metal Catalysis
765
3.10.2.11.1 3.10.2.11.2 3.10.2.11.3
3.10.3
Addition reactions of thiophenes brought about by palladium catalysis Introduction of substituents on the thiophene ring through cross-coupling reactions Homocoupling reactions
Reactivity of Nonconjugated Rings
766 766 777
777
3.10.3.1
Thiophene 1-Oxides
777
3.10.3.2
Thiophene 1,1-Dioxides
782
741
742
Thiophenes and their Benzo Derivatives: Reactivity
3.10.3.3
Thiophene S,N-Ylides and S,C-Ylides
787
3.10.3.4
Dihydrothiophenes
790
3.10.3.4.1 3.10.3.4.2
3.10.3.5 3.10.4
2,5-Dihydrothiophenes 2,3-Dihydrothiophenes
Tetrahydrothiophenes Reactivity of Substituents Attached to the Ring Carbon Atoms
3.10.4.1
C-Linked Substituents
3.10.4.1.1 3.10.4.1.2 3.10.4.1.3 3.10.4.1.4
3.10.4.2
Alkyl, alkenyl, and alkynyl groups Halomethyl groups Hydroxymethyl groups Aldehydes and Ketones
N-Linked Substituents
3.10.4.2.1 3.10.4.2.2 3.10.4.2.3
Nitro compounds Amines and derivatives Azides and nitrenes
790 793
793 797 797 797 799 800 801
805 805 807 809
3.10.4.3
O-Linked Substituents
810
3.10.4.4
Halo Groups
813
3.10.4.4.1 3.10.4.4.2 3.10.4.4.3 3.10.4.4.4
Nucleophilic displacement Halogen–metal exchange Generation and reactivity of thienyl radicals (Diacetoxyiodo)thiophenes
813 814 815 816
3.10.4.5
Si-Linked Substituents
816
3.10.4.6
Metallo Groups
819
3.10.4.6.1 3.10.4.6.2 3.10.4.6.3 3.10.4.6.4
Metal–metal exchange Formation of C–C bonds Ni- and Pd-catalyzed cross-coupling reactions Formation of C–halogen bonds
819 820 820 820
3.10.5
Reactivity of Substituents Attached to the Thiophene Sulfur Atom
820
3.10.6
Reactivity of Transition Metal Complexes of Thiophene
823
3.10.6.1
General Survey
823
3.10.6.2
Metal Insertion into the C–S Bond: C–S Bond Activation
823
3.10.6.3
Hydrogenolysis of Thiophenes to Thiols
826
3.10.6.4
Catalytic Hydrogenation of the Thiophene Ring
827
3.10.6.5
Transition Metal-Mediated C–H Activation
828
3.10.6.6
Nucleophilic Attack at C-2 and Cleavage of the Thiophene Ring
828
3.10.6.7
Nucleophilic Attack at Sulfur
829
3.10.6.8
Nucleophilic Attack at Benzenoid Carbon in Benzo[b]thiophene Complexes
830
3.10.6.9
Nucleophilic Attack on Hydrogen Attached to Carbon: Deprotonation
830
3.10.6.10
Electrophilic Attack on Metal Complexes of Thiophene
3.10.6.10.1 3.10.6.10.2 3.10.6.10.3
3.10.7
Electrophilic attack on 2-complexes Electrophilic attack on 4-complexes Electrophilic attack on metallathiacycles leading to conjugated thioaldehydes and thioketones
Further Developments
References
831 831 832 833
834 836
Thiophenes and their Benzo Derivatives: Reactivity
3.10.1 Introduction The reactivity of thiophenes and benzothiophenes had been dealt with at great length in CHEC(1984) <1984CHEC(4)741> and CHEC-II(1996) <1996CHEC-II(2)491>. The present chapter therefore is concerned mainly with the progress in this field since the publication of CHEC-II(1996), with appropriate cross-references to the earlier reviews. The organization of the present chapter follows the same general pattern as in CHEC-II(1996), except for the deletion of those subsections where no significant new results have been reported in the period under review. Inevitably, new sections had to be introduced, without disturbing the overall arrangement, in order to discuss aspects of thiophene chemistry that have shot to prominence in the last few years. It has been our endeavor to gather and report all significant research results in this field during the past decade. We wish to tender our apologies to those authors who feel their own contributions have not received adequate appreciation. All relevant publications in major journals up to April/May 2006 have been included in this survey.
3.10.2 Reactivity of Fully Conjugated Rings 3.10.2.1 General Survey of Reactivity Three major topics have dominated research activity on thiophenes since 1996: the design and synthesis of dithienylethene molecules for application as photochromic systems (Section 3.10.2.1.3); reactions brought about under transition metal catalysis (Section 3.10.2.11); and the synthesis, characterization, and reactivity of a plethora of transition metal complexes of thiophenes (Section 3.10.6). All three had received brief mention in CHECII(1996) (Sections 2.10.2.2.3, 2.10.4.7.3, and 2.10.6, respectively), but together account for almost one-third of the chapter now. In addition, shorter sections have been introduced to cover the following topics: one-electron oxidation of thiophenes (Section 3.10.2.2); electrochemical reactions at cathodes (Section 3.10.2.7.5); sulfurextrusion and sulfur-transfer reactions (Section 3.10.2.10); and reactivity of silicon-linked substituents (Section 3.10.4.5).
3.10.2.1.1
Photodissociation and photoisomerization of thiophene
The photofragmentation of thiophene on irradiation at 193 nm has been studied <1995JPC1760>. The primary products are vinylacetylene, acetylene, thioketene, and sulfur (Equations 1 and 2).
The various modes of photoisomerization of thiophene and substituted thiophenes have been discussed in detail in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. To summarize the data, irradiation of thiophene in the liquid phase or in an argon matrix gives Dewar thiophene; in the latter case, cyclopropene 3-thiocarbaldehyde is also obtained. Irradiation of 2-substituted thiophenes leads to the corresponding 3-substituted isomers; this mechanistically intriguing isomerization takes place from the singlet excited state of the molecule. During this process, the bond between C-2 and the substituent is not broken, and the interchange between C-2 and C-3 occurs without the concomitant interchange between C-4 and C-5. Irradiation of thiophenes in the presence of an amine gives the corresponding pyrroles; very likely, this proceeds through the initial formation of Dewar thiophenes. D’Auria has attempted to provide a unified description of the photoisomerization of several p-excessive heterocycles <2001AHC(79)41, 1999H(50)1115>. His proposal, based on the available experimental data and on the results of his calculations of the energy levels of the possible intermediates, can be summarized as shown in Scheme 1.
743
744
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 1
The initially formed singlet excited state 1 can convert either to the corresponding triplet state 2 by intersystem crossing, or to the Dewar isomer 4. In the former case, homolytic cleavage of the S–C(5) bond in 2 can lead to the biradical 3 and ultimately result in ring-opened or ring-contracted products. The Dewar isomer 4 is responsible for the formation of the isomeric thiophene 6 via 5 obtained by a ‘sulfur walk’.
3.10.2.1.2
Sigmatropic rearrangements
A [3,3]-sigmatropic rearrangement has been postulated to account for the products of the reaction of aryl Grignard reagents with 3,4-dinitrothiophene (see Section 3.10.4.2.1). No other interesting sigmatropic rearrangement has come to light since the topic was covered in CHEC-II(1996).
3.10.2.1.3
Electrocyclizations
3.10.2.1.3(i) 1,3,5-Hexatriene/cyclohexadiene interconversion The term ‘photochromism’ refers to the light-induced reversible isomerization between two forms having different absorption spectra. This topic has been discussed extensively in CHEC-II(1996) <1996CHEC-II(2)491>. The photochemical conrotatory electrocyclization of dithienylethene and the light-induced ring opening of the product form the basis for one of the most extensively studied photochromic systems. Thermal irreversibility of the cyclization and fatigue resistance are essential requirements for the application of photochromic compounds to optoelectronic devices such as memories and switches. Other desirable properties include high sensitivity and rapid response, high quantum yields, and a large difference in max between the open and closed isomers. The dithienylethenes, and especially the di(benzo[b]thienyl)ethenes, seem to meet most of these requirements. In general, photogenerated colored isomers are thermally unstable and return to the initial isomers in the dark. However, dithienylethenes and their photocyclized products, as well as their benzo[b]thiophene analogs, are quite stable thermally, the half-life at 80 C being more than 12 h <2000CRV1685>.
Thiophenes and their Benzo Derivatives: Reactivity
Fatigue resistance refers to the nonoccurrence of photoinduced side reactions to any significant extent. Earlier, the problem of the waste of the starting material by the photoisomerization of the central double bond from the cis- to the trans-configuration had been solved by incorporating it into a five-membered ring <1996CHEC-II(2)491>. Still another source of fatigue in such systems is the formation of thiophene endoperoxide through reaction with photogenerated singlet oxygen. Replacement of the thiophene ring with benzo[b]thiophene improves the fatigue resistance by preventing the formation of endoperoxide <2000CRV1685>. Recently a photochromic system in which one of the benzo[b] thiophene units is replaced by an indene has been synthesized <2006TL1267>. The cyclization and cycloreversion quantum yields were, however, slightly less than the values for the bis(benzo[b]thienyl)ethene system. Another unexpected side reaction was the formation of a six-membered ring in the system, shown in Scheme 2. On repetition of the ring-closure/ring-opening sequence by alternate irradiation with ultraviolet (UV) and visible (Vis) light, the absorbance of 7a gradually declined. At the same time, a photostable violet product with max at 547 nm was formed. X-Ray crystallography revealed the structure of this product to be 8. In contrast, the analogous system (Equation 3) in which the free -positions of the thiophene rings bear methyl groups does not show any fatigue even after 850 cycles; the absorbance remained almost constant.
Scheme 2
ð3Þ
In the last decade, several new avenues have been explored to increase the efficiency of the system. The role of extending the conjugation in the heteroaryl part has been investigated by synthesizing dithienylethenes in which the thiophene rings of the photochromic core are attached to one or more thiophenes at either end. The two terminal thiophene rings carry nitrile groups (Equation 4) <1997T12263>. The open form 9a has max at 374 nm, and on irradiation with 366 nm light the pale yellow solution turned green to form the closed isomer 9b with max at 653 nm when n ¼ 2. The process could be reversed by irradiation at >550 nm.
ð4Þ
However, the ring-opening quantum yields decreased dramatically with the increasing number of the thiophene rings. It is therefore not well suited for use as a photoswitch unit in molecular wire systems. A further innovation is to connect two (or more) dithienylethene units through another conjugating moiety attached to the thiophene units. Scheme 3 shows one such system in which the linker is a benzene ring
745
746
Thiophenes and their Benzo Derivatives: Reactivity
<2003T8359>. The open isomer 10a has max at 271 nm. Upon irradiation with 313 nm light, the colorless hexane solution of 10a turned purple-blue and a new absorption band appeared at 570 nm. Upon further prolonged irradiation, the color changed to blue, and the max shifted to 580 nm. This suggests two electrocyclization stages, leading to 10b and 10c. Photocycloreversion of 10c to 10a via 10b could also be achieved by irradiation with light of 570 nm.
Scheme 3
Earlier studies had been carried out with dithienylethenes and di(benzo[b]thienyl)ethenes in which the ethene unit had been attached to C-3 of the thiophenes or the benzo[b]thiophenes. The photochromism of the 2-substituted analogs have been studied now <2001T4559>. Irradiation of 11a (max 370 nm) with UV light led to 11b
Thiophenes and their Benzo Derivatives: Reactivity
(max 438 nm). Photocyclization and reversion could be repeated 400 times without any fatigue effect being observed. At the photostationary state, the ratio of 11a to 11b was 18:82.
Dithienylethene molecules in the open form can adopt two different conformations – parallel and antiparallel. As mentioned in CHEC-II(1996), photocyclization of the hexatriene system can occur only from the antiparallel conformer. Normally the population of the two conformers in solution is about 1:1. Several strategies have been adopted to fix the molecule in the antiparallel mode. One of them has already been mentioned in CHEC-II(1996). Another strategy is to link the two thiophene units in di(2-thienyl)ethene through their free -positions (Equation 5). The thiophene rings in the open form do not have the freedom to take up the parallel conformation because of the –CH2-S-CH2– linkage. The quantum yield for the photocyclization in this case was 1.6 times higher than that of the corresponding dithienylethene without a bridge <2004CSR85>.
ð5Þ
Until now the ethene part of the dithienylethene system has been provided by maleic anhydride, maleimide, cyclopentene, or perfluorocyclopentene units. Now a new photochromic compound with a thiophene ring as the bridging unit has been described <2005TL5409>. The advantage with compound 12a is that it is easy to synthesize from readily available starting materials. The terthiophene exhibits good photochromic properties and could be switched to the ring-closed form by irradiation with UV light. The yellow ring-closed molecule 12b can be reconverted to the ring-opened terthiophene by irradiation with visible light. The ring-closed form 12b appears to be thermally stable.
Photochromic systems have been described in which a 2,5-dihydrothiophene acts as the bridging ethene unit between two thiophene rings. The novelty here is that the core system has two 2-iodothiophene moieties which can be used to couple with a variety of other aromatic systems by standard reactions <2006SL737>. An example is given in Equation (6).
747
748
Thiophenes and their Benzo Derivatives: Reactivity
ð6Þ
Dithienylethenes have assumed importance for designing switch units with light-controlled electrochemical and optical properties. Useful properties that lend themselves to such control include luminescence, viscosity, and optical rotation. Some examples of such systems are given below. But the full range of their potential applications can be appreciated only by going through the reviews provided by the experts in the field <2000CRV1685, 2004CSR85, 1998BCJ985>. Amide groups with long hydrophobic chains have been attached to the thiophene rings in order to promote the formation of supramolecular assemblies in solution. The reversible photoswitching of 13 from the open form to the closed form causes a change in the extent of aggregation; this in turn causes a decrease in viscosity. Thus the viscosity could be modulated by appropriate illumination <2004CSR85>.
The intriguing possibility of a diastereoselective photochemical conrotatory cyclization of a dithienylethene having a chiral substituent has been investigated. The chiral substituent chosen was (S)--phenylethylamine, attached through an amide bond. This is thus capable of forming intermolecular hydrogen bonds. In preliminary experiments, it was evident that cyclization of 14 in solution showed no diastereoselectivity, giving the (S,S,S,)-15b and (S,R,R)15a in equal amounts. However, on irradiation of (S)-14 in the crystalline phase, the (S,S,S)-isomer was the major product (82% de) at 10% conversion. Obviously the crystal lattice regulates the reaction <2001TL7291>. A higher diastereoselectivity (97% de) was realized in the photocyclization of 16 (X ¼ F) in the crystalline state, although the conversion was only 2.3% <2006OBC1002>.
Thiophenes and their Benzo Derivatives: Reactivity
Photochromic switches can be used in erasable memory media to generate a write–read–erase system. If the ‘read’ event is dependent on the use of UV/Vis spectroscopy to record the spectral changes near the absorption bands corresponding to the two photochromic states, the act of reading itself will cause partial switching of the photochromic compound and erase the stored information. With the goal of realizing a nondestructive write–read–erase system, a chiral oxazoline has been attached to the thiophene rings, resulting in the generation of a pair of enantiomeric [(R,R) and (S,S)] photochromic compounds. The Cu(I) complexes of these enantiomers strongly rotate light throughout the UV/Vis spectrum. The Cu(I) complex of one enantiomer is shown in structure 17. The possibility now exists of measuring the optical rotation at wavelengths that do not disturb the photochromic system <2004CSR85>.
A dithienylethene-based liquid crystal material has been synthesized. This provides a morphologically stable, photoresponsive glassy nematic system in which the refractive index and optical birefringence can be modulated by photochemical means (Equation 7) <2004CSR85>.
ð7Þ
749
750
Thiophenes and their Benzo Derivatives: Reactivity
Multicolor photochromism is useful for optoelectronic devices such as multifrequency optical memories and displays. Such systems can be obtained by mixing photochromic compounds with different colors. But an interesting possibility is to incorporate two photochromic units in the same molecule. This has now been realized <2003AGE3537, 2004CSR85> in the nonsymmetric molecule 18 in which both bis(2-thienyl)- and bis(3-thienyl)ethenes are present, with one thiophene ring being common to both. From previous experience, it was known that the closed-ring isomer of bis(2-thienyl)ethene has max at shorter wavelength than that of bis(3-thienyl)ethene.
Matsuda has come out with an ingenious idea to use a photochromic biradical molecule as a switching system to be used for molecular-scale information processing <2005BCJ383>. If the two termini of the photochromic molecule are attached to units carrying unpaired electrons, then the photochromic moiety acts as a ‘spin-coupler’. The magnetic exchange interaction between the spins of the two unpaired electrons can be controlled by photoirradiation. With this in view, two nitronyl nitroxide radicals have been stitched on to the di(benzo[b]thienyl) system in 19. The open (19a) and closed (19b) forms could be interconverted almost completely by irradiation with light of appropriate wavelength. Experimentally, it was confirmed that the interaction between the two spins in the open-ring isomer 19a was weak, while the spins of the closed-ring isomer 19b had a remarkable antiferromagnetic interaction. The former thus has an ‘OFF’ state, while the latter corresponds to ‘ON’. The concept has been extended to a system having two dithienylethenes with nitroxyl radicals attached at the ends. Three photochromic states are available corresponding to open–open, open–closed, and closed–closed positions of the switches. A photochromic, fluorescent organogel has recently been described <2006CC1497>. The system consists of two naphthalimide units bearing cholesteryl groups, bridged through a bithienylcyclopentene unit. The naphthalimide is an excellent fluorescent chromophore, while the cholesteryl groups are expected to assemble through van der Waals interaction. The organogel system exhibits excellent photochromic properties and defined thermoreversible properties. A remarkable photochromic system in which molecular and supramolecular chirality seem to communicate with each other has recently been described <2004SCI278>. The compound 16 (X ¼ H) shows exceptional stereoselectivity upon aggregation of the molecules during gel formation in toluene. This supramolecular chirality is translated into molecular chirality on photocyclization wherein a diastereoselectivity of 96% is obtained.
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.1.3(ii) [1,7]-Electrocyclizations Nitrile ylides, when given the option of cyclizing either on a phenyl or on a 2-thienyl ring, prefer the latter. Thus 20 gives exclusively 21. The mechanism might involve a [1,7]-electrocyclization followed by a [1,5]-sigmatropic shift of hydrogen <1995J(P1)2565>. Carbonyl ylides behave similarly. Thus 22 obtained by flash vacuum pyrolysis (FVP) of the oxirane at 625 C gave 23 as the major product (Scheme 4) <1997J(P1)3025>. The 3-thienyl analog gave similar results.
Scheme 4
751
752
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.1.4
Didehydrothiophenes and 3,4-dimethylenethiophene
3.10.2.1.4(i) Didehydrothiophenes Evidence for the formation and trapping of 2,3-didehydrothiophene (thiophyne) was presented in CHEC-II(1996) <1996CHEC-II(2)491>. Similar evidence has now been adduced for the formation of 3,4-didehydrothiophene 24 in solution <1996JA2511, 1997JOC1940>. This is the smallest cyclic cumulene to have been characterized. Treatment of 3,4-bis(trimethylsilyl)thiophene with iodobenzene diacetate in the presence of triflic acid gave phenyl [4-(trimethylsilyl)thien-3-yl] iodonium triflate 25. This, on fluoride ion-induced desilylation, generated 3,4-didehydrothiophene 24. As anticipated, this was extremely reactive and could be trapped by dienes as well as olefins. The structures of the resultant products proved that 24 had indeed been formed in the reaction. Thus generation of 24 in the presence of anthracene gave a mixture of the 9,10-adduct and the 1,4-adduct in a total yield of 10% (Scheme 5). 3,4-Didehydrothiophene reacted even with benzene to give the 1,4-adduct in 7% yield. With 2,3-dimethyl-1,3butadiene it gave two products: one was the [2þ2] adduct, and the other was the product of an ene reaction. With furan, it gave the 1,4-adduct in 31% yield (Scheme 5). There was no evidence of the formation of a dimer from 24 in the absence of any trapping agent.
Scheme 5
The photo-Bergman cyclization of enediynes has been utilized for the generation of 2,5-didehydrothiophene 26 <2003OL2195>. Irradiation of bis(phenylethynyl) sulfide at 300 nm in hexane in the presence of 1,4-cyclohexadiene leads to 3,4-diphenylthiophene and phenylacetylene in 16% and 33% yields respectively. It has been postulated that irradiation of the diethynyl sulfide sets in motion two competing reactions: cycloaromatization to the 2,5-didehydrothiophene and cleavage of the -bond between an sp-carbon and sulfur. The five-membered ring diradical intermediate is trapped by the hydrogen donor to form 3,4-diphenylthiophene, while the ethynyl radical leads to a terminal alkyne (Scheme 6). The electronic structures and possible rearrangement pathways of several C4H2S isomers including 2,5-didehydrothiophene have been investigated through computational methods <2005JOC8171>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 6
3.10.2.1.4(ii) 3,4-Dimethylenethiophene The preparation and cycloaddition reactions of the p-conjugated non-Kekule´ molecule, 3,4-dimethylenethiophene, have been reported in CHEC-II(1996) <1996CHEC-II(2)491>. A comprehensive account of this and other similar molecules has now become available <1997ACR238>. Molecular orbital (MO) calculations indicate that the ground state of 3,4-dimethylenethiophene is a singlet. This singlet biradical 28 can indeed be observed directly, when it is generated by photolysis of the diazene 27 in a matriximmobilized state. It has an intense purple color, with max at about 560 nm, with an extinction coefficient of about 5000. It does not show any electron spin resonance (ESR) signal attributable to a triplet. The 13C nuclear magnetic resonance (NMR) spectrum of this diradical has been recorded on an isotopically enriched sample using lowtemperature solid-state, magic angle spinning techniques. Unbroadened (and hence not from a triplet species) signals were seen at 105 ppm (CH2) and 115 ppm (CH). If fumaronitrile is incorporated in the matrix containing 28, the adduct 29 is formed quantitatively as shown by the disappearance of the 13C signal at 105 ppm and the corresponding appearance of a new signal at 28 ppm. This conclusively establishes the singlet biradical as the reactive entity in the cycloaddition.
Other biradicals such as 30 bearing substituents on the thiophene ring could be prepared by photolysis of the corresponding diazene precursors <1996JA265>.
Incorporation of singlet biradicals such as 28 in a polymer chain might lead to antiferromagnetic low-spin nonclassical materials which might exhibit metallic conduction without doping <1997ACR238>. With this in view, the tetraradical 32 has been prepared as the prototype of the putative polymer <1996JA265, 1997JA1428>. Irradiation at 350 nm of the diazene 31 at low temperature in a frozen glass of 2-methyltetrahydrofuran gave the intense green tetraradical 32. Like the monomer 28, this too was ESR-silent. In the UV–Vis spectrum, it showed max at 386 and 675 nm; the extinction coefficient of the 675 nm band was almost double that of the model biradical 30. This singlet tetraradical could be trapped by acrylonitrile, maleonitrile, or fumaronitrile.
753
754
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.2 One-Electron Oxidation of Thiophenes 3.10.2.2.1
Thiophene radical cation and oligothiophene dications
One-electron oxidation of oligothiophenes inside zeolite channels has been reported in CHEC-II(1996) <1996CHEC-II(2)491>. The direct investigation of the electrochemical oxidation of thiophene itself is extremely difficult because the initially formed radical cation is highly reactive and polymerizes rapidly. In the case of 2,5dimethylthiophene the radical cation loses a proton and then undergoes a further oxidation; the final products result from a nucleophilic attack by the solvent or other nucleophiles present in the solution. Such nucleophilic substitution can take place either on the side chain or on the nucleus itself <1984CHEC(4)741>. Several groups have therefore been studying the oxidation of 2,29-bithiophenes and related oligothiophenes in which the thiophene units are linked through their -positions <1995SM(75)95; 1998J(P2)169>. In one such study, the electrochemical oxidation of a series of such 2,29-bithiophenes 33 in which the 5,59-positions are blocked toward polymerization by the presence of methyl groups has been investigated <1998J(P2)169>. Electroanalytical methods showed the presence of two oxidation stages. The first one, leading to the formation of a radical cation was reversible, whereas the second electron transfer was found to be irreversible. The stability of the radical cation increased as the number of -methyl groups increased. Chemical oxidation of the same substrates with FeCl3?6H2O led to the isolation of several products. For instance, compounds 33 in which R2 and R3 are methyl groups give 2,29-bithiophene-5-carbaldehyde; if either R2 or R3 (or both) is H, mainly bithienylmethanes such as 34 are formed.
One of the most significant recent results in this context is the preparation and ESR study of a stable radical cation of thiophene in solution. Even more surprisingly, stable crystalline salts of the dications of oligothiophenes have been isolated and their structures determined by X-ray crystallography <2005SL187>. The concept underlying this spectacular outcome was this: if instead of having just alkyl substituents, the thiophene ring is surrounded completely by an array of rigid bicycloalkenes, the highest occupied molecular orbital (HOMO) energy level of the p-system is likely to be elevated; and the cationic system derived from this by removal of an electron is likely to be stabilized. A further benefit is likely to result from the fact that collapse of the cation through deprotonation from the -position of the substituent would be inhibited because such a process would have to go through a species having a double bond at a bridgehead position.
Thiophenes and their Benzo Derivatives: Reactivity
The annelated thiophene 35 was synthesized in 91% yield as shown in Equation (8). In cyclic voltammetry, it showed a well-defined reversible oxidation wave in contrast to the irreversible oxidation waves obtained for thiophene analogs having only alkyl substituents at all four positions.
ð8Þ
Chemical one-electron oxidation of 35 by SbF5 in CH2Cl2 gave a yellow solution of the corresponding radical cation 35?þ, whose ESR signal has been recorded. This reacted with triplet oxygen to give the SbF6 salt of the stable carbocation 36, whose structure was established by X-ray crystallography. The mechanism of formation of 36 from 35?þ most probably involves the addition of triplet oxygen to the spin-localized 2,5-positions of the radical cation to give the thioozonide radical cation, followed by cleavage of the O–O bond and extrusion of sulfur (Scheme 7).
Scheme 7
This concept has been extended to oligothiophenes as well. A series of oligothiophenes, containing two to six thiophene units, and entirely surrounded by bicyclooctene frameworks have been constructed using a combination of Stille coupling (see Section 3.10.2.11.2) and oxidative coupling <1996CHEC-II(2)491>. Representative examples are 37 and 38. The cyclic voltammetry of these oligothiophenes exhibited two-step reversible oxidation stages, occurring at lower potentials compared to the analogous oligothiophenes bearing only fused cyclohexene rings at the ends. This strongly suggests the formation of stable radical cations and dications. Oneelectron oxidation of 37 with 1 equiv of NOþSbF6 in CH2Cl2 under vacuum afforded the radical cation salt 37?þSbF6 as deep green crystals, which were stable in air at room temperature. X-Ray crystallography showed that the whole p-system was planar, and the inter-ring bond was shorter than in the neutral 37. There is thus greater double-bond character in the inter-ring bond in the radical cation.
755
756
Thiophenes and their Benzo Derivatives: Reactivity
Similar oxidation of the tetramer 38 led to the isolation of the dication salt 382þ2SbF6 and not the radical cation. X-Ray crystallography again showed the extended p-system to be planar, with the thiophene rings in anti-conformation <2005SL187>. These results are expected to lead to novel applications in the design and synthesis of various types of molecular devices.
3.10.2.2.2
Oxidative polymerization
Polymerization of thiophenes by oxidative coupling has been discussed earlier <1996CHEC-II(2)491>. The generally accepted mechanism for the electropolymerization of thiophene may also be valid in the case of chemical oxidative polymerization. The steps involved are: formation of a radical cation, spin-pairing of two such radical cations to form a dihydrodimer dication, loss of protons with concomitant rearomatization, and repetition of this cycle with the dimer. Couplings take place at the position of highest unpaired-electron spin density. Regioregularity of the thiophene units in the polymer is one of the most important factors in influencing the conductivity of the polymer chain. It follows from the mechanism outlined above that in order to attain a high regioregularity (e.g., head to tail), the difference in the reactivity of the 2- and 5-positions of the monomer must be large. This has been verified both experimentally and by theoretical calculations <1997SM(84)223>. The synthesis and electropolymerization of thiophenes with pendant functional groups have been reviewed <1997CSR247>. The pendant groups can consist of metal complexes or biomolecules for protein binding and such polymers may find application in the development of sensors. One particularly interesting application makes use of the fact that the electronic absorption maxima of the polymers depend on the degree of conjugation. In chemically generated polythiophenes, this is controlled mainly by the inter-ring twist angle – the more twisted adjacent monomer units are with respect to each other, the lower is the degree of conjugation. Polythiophenes in which the -positions of adjacent rings are linked by a polyether chain <1996CHEC-II(2)491> can change their conformation by capturing a suitable alkali metal ion. This would result in twisting of the chain away from optimal conjugation. Similarly, calixarene-functionalized bithiophenes have also been incorporated into polymer chain.
3.10.2.3 Electrophilic Attack on Carbon 3.10.2.3.1
Protonation
Thiophene and substituted thiophenes are protonated at C-2. The NMR spectra of the protonated species have been recorded <2000AHC(76)85, 1996CHEC-II(2)491, 1984CHEC(4)741>.
3.10.2.3.2
Alkylation
The gas-phase reactivity of radiolytically generated ethyl cations C2D5þ toward thiophene has been studied in CH4–C2D6 systems <1998PCA6464>. The pressure ranged between 760 and 1520 Torr. Oxygen (4 Torr) was introduced as a radical scavenger and triethylamine (TEA) to ensure a fast deprotonation of the ionic intermediates. Under these conditions there is a competition between deuteration and alkylation (Equations 9 and 10). At low TEA concentrations, the product mixture contained more monodeuterated thiophene 39 than the d5-ethylated species 40. Irrespective of the amount of TEA, the latter consisted of - and -isomers in the ratio 54:46. For the monodeuteration, the : selectivity was 64:36.
ð9Þ
ð10Þ
Thiophene itself undergoes Mannich reactions more sluggishly than furan or pyrrole. The Mannich reaction of 3-alkoxythiophenes and 3,4-dialkoxythiophenes has been investigated in detail <2001J(P1)2595>. The reaction of 3-methoxythiophene with secondary amines and formaldehyde in acetic acid at room temperature led to the
Thiophenes and their Benzo Derivatives: Reactivity
2-alkylated products 41 in 62–87% yields, the highest yield being obtained with morpholine. Surprisingly, 3,4dimethoxythiophene gave much lower yields of the Mannich products 42 under the same conditions; while 42c was obtained in 53% yield, 42a and 42b were produced in meagre yields of just 5%. This has been attributed to steric crowding imposed at the 2- and 5-positions of the thiophene. In confirmation of this, better yields of the Mannich products were obtained when the two oxygen-linked substituents were ‘tied back’ as in 3,4-(ethylenedioxy)thiophene (EDOT) 43 or the larger ring analog 44 (Equations 11 and 12). For instance, 43 gave 72% and 82% yields of the Mannich products with dimethylamine and piperidine respectively. In fact, with the more reactive morpholine, it even gave a 13% yield of the bis-Mannich product (Equation 11) at room temperature and at higher temperatures only the bis-Mannich base could be isolated.
ð11Þ
ð12Þ
Earlier, Cava and co-workers had shown that EDOT 43 reacts with formaldehyde and dimethylamine to give the Mannich base 45 in 84% yield <1999T11745>. Subsequently, Cava and co-workers have converted the Mannich base 45 in two steps to the synthetically useful phosphonium salt 46. In an extension of this method, the diammonium salt 47 obtained from bis-EDOT has been treated with diethyl phosphite to give the bis-phosphonate 48 <2005T3045>.
757
758
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.3.3
Acylation
As part of a program on replacing AlCl3 with ecologically acceptable catalysts, the acylation of thiophene with 4-fluorobenzoyl chloride in the presence of commercial acid-treated clays has been investigated. Complete conversion could be achieved, leading to almost complete formation of the 2-acylthiophene with only traces of the 3-isomer (Equation 13) .
ð13Þ
Vilsmeier formylation of the thienylpyrroles 49 gives only the pyrrole-formylated products (Equation 14) <2006T3493>. The formyl group could be introduced on the thiophene ring by lithiation and subsequent treatment with DMF.
ð14Þ
3.10.2.4 Electrophilic Attack on Sulfur The reaction of thiophene with dimethyldioxirane (DMDO) to form thiophene 1,1-dioxide is discussed under Section 3.10.3.2. Trifluoroperacetic acid in MeCN in the absence of water is an effective reagent for the oxidation of thiophenes bearing electron-withdrawing groups (EWGs) to the corresponding thiophene 1,1-dioxides (Equations 15 and 16) <2001TL4397>. However, thiophenes bearing a nitro group appear to resist oxidation even under these conditions. Subsequently, the method has been extended to substrates bearing two EWGs <2004RCB2241>.
ð15Þ
ð16Þ
3.10.2.5 Nucleophilic Attack on Ring Atoms 3.10.2.5.1
Ring-opening reactions
The ring-opening reactions of nitrothiophenes and nitrobenzo[b]thiophenes are discussed in Section 3.10.4.2.1. Another interesting ring opening is initiated by a nucleophilic attack on sulfur; this is discussed in Section 3.10.2.5.4.
3.10.2.5.2
Addition of nucleophiles across the 2,3-double bond
The oxidative nucleophilic substitution of hydrogen (ONSH) in 2-nitrobenzo[b]thiophene involves the initial reversible addition of the nucleophile to the 2,3-double bond. This is discussed in Section 3.10.4.2.1.
3.10.2.5.3
Reaction of nucleophiles with cationic species
The reaction of various nucleophiles with S-trifluoromethyldibenzothiophenium triflate constitutes an excellent general method for the ‘electrophilic perfluoroalkylation’ of nucleophilic substrates. This forms the subject matter of Section 3.10.5.
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.5.4
Nucleophilic attack on sulfur
The ring opening of 3-thienyllithium leading to acetylenic products is well known <1984CHEC(4)741, 1996CHECII(2)491>. Two recently reported reactions resulting in diphenylacetylenes are however initiated by nucleophilic attack on the sulfur <1998SL407, 2005SL247>. Treatment of 3-chloro-2-phenylbenzo[b]thiophene with butyllithium, followed by quenching with NH4Cl, gave a 71% yield of the diphenylacetylene 50 (Equation 17). This is obviously the result of nucleophilic attack at the sulfur with cleavage of the ring and elimination of Cl.
ð17Þ
The same product 50 was also obtained in 66% yield when 2-fluoro-3-phenylbenzo[b]thiophene was treated with excess BuLi. It has been suggested that this reaction involves a rearrangement of a carbene intermediate (Scheme 8).
Scheme 8
3.10.2.6 Nucleophilic Attack on Hydrogen Attached to Carbon Deprotonative zincation and magnesiation have been developed as alternatives for the lithiation of thiophenes. The drawbacks associated with lithiation are that it usually requires the reactions to be performed at 78 C, and the lithium derivatives so formed cannot be directly used for cross-coupling reactions. Kondo et al. have reported the formation of thienylzincates using the new reagent lithium di-tert-butyltetramethylpiperidinozincate (TMP-zincate) 51 <1999JA3539>. This new ate-complex is prepared by adding di-tert-butylzinc to a solution of lithium tetramethylpiperidine in tetrahydrofuran (THF) at 78 C and allowing the solution to warm to room temperature. Ethyl thiophene-3-carboxylate was easily metalated at C-2 by treatment with TMP-zincate at room temperature. Subsequent reaction with iodine gave ethyl 2-iodothiophene-3-carboxylate in 89% yield. Similarly ethyl thiophene-2-carboxylate gave the 5-iodo derivative in 62% yield.
759
760
Thiophenes and their Benzo Derivatives: Reactivity
Chemoselective magnesiation of thiophene can similarly be achieved using (diisopropylamino)magnesium chloride 52 <2001J(P1)442>. Ethyl thiophene-2-carboxylate, on brief treatment with 2 equiv of this reagent at room temperature, followed by quenching with an electrophile gave the 5-substituted thiophene-2-carboxylic ester. The reagent did not attack the ester group. Similarly, metalation of ethyl thiophene-3-carboxylate selectively gave the 2-substituted products.
Lithium tributylmagnesate 53 has been successfully used for deprotonation of thiophene <2005T4779>. The reaction is conducted in THF at room temperature preferably in the presence of tetramethylethylenediamine (TMEDA), using 1/3 equiv of lithium tributylmagnesate. The resulting lithium tri(2-thienyl)magnesate can either be reacted with electrophiles, or be directly used for cross-coupling reactions (Scheme 9).
Scheme 9
3.10.2.7 Reactions with Radicals and Electron-Deficient Species 3.10.2.7.1
Homolytic substitution
The homolytic substitution reactions of thiophene have been extensively surveyed in CHEC(1984) and CHECII(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Not much work seems to have been done in this area since. The photochemical heteroarylation of thiophenes has been further exemplified. Irradiation of 4,5-diiodopyrrole 2-carbaldehyde with thiophene or 2-chlorothiophene leads to the pyrrole-substituted thiophenes in high yield (Equation 18) <1997J(P1)2369>. Similarly, irradiation of 4(5)-nitro-2-iodoimidazole in the presence of thiophene or 2-chlorothiophene produces the imidazole-substituted thiophenes 54 in good yields <1998J(P1)271>.
ð18Þ
Base-promoted, regioselective, photostimulated homolytic t-butylation of thiophenes has been reported <2001J(P1)2035>. Photolysis of alkylmercury(II) halides is a convenient method for the generation of alkyl radicals.
Thiophenes and their Benzo Derivatives: Reactivity
These radicals can undergo oxidative homolytic reactions with unsaturated compounds in the presence of a base, such as 1,4-diazabicyclo[2.2.2]octane (DABCO). This type of radical chain reaction seems to work well on electrondeficient aromatic species. The substrates chosen were therefore thiophenes carrying an aldehyde or ketone at C-2. Photolysis of ButHgCl–KI in the presence of these thiophenes along with DABCO gave good yields of the 5-tertbutylated products (Equation 19). Thiophene 2-carbaldehyde was found to be very reactive, giving 3,5-di-tertbutylthiophene 2-carbaldehyde in nearly quantitative yield.
ð19Þ
The gas-phase reaction of CF3 radicals with thiophene has been studied <2003CJC1477>. The CF3 radicals were generated by photolysis of CF3I or CF3COCF3. At thiophene conversions of less than 20%, mainly 2-trifluoromethyland 3-trifluoromethylthiophene were produced in the ratio 16:1.
3.10.2.7.2
Reaction with carbenes and nitrenes
The reactions of thiophene with carbenes and nitrenes were discussed in detail in CHEC-II(1996). The preparation of S,N-ylides by an improved method is discussed in Section 3.10.3.3.
3.10.2.7.3
Catalytic hydrogenation
Catalytic hydrogenation of thiophenes is discussed in Sections 3.10.6.3 and 3.10.6.4.
3.10.2.7.4
Reactions at surfaces
The normal Ullmann reaction is the formation of an Ar–Ar bond by a thermally activated coupling of a thienyl halide in the presence of Cu, Ni, Pd, or their compounds, but this method is not suitable for the preparation of oligothiophene and polythiophene films of nanoscale thickness. A photoactivated Ullmann coupling has now been described for the in situ synthesis of such polythiophene films <2006CC729>. The concept involves the selective photodissociation of the C–I bond in 2,5-diiodothiophene on a copper surface; the resultant thienyl radicals react with the copper to produce thienyl–Cu intermediates in a thin monomer film at room temperature. These intermediates react with the monomer and produce polythiophene. Electrochemical generation of a radical cation at a suitable location on a 2-substituted thiophene can lead to cyclization products not observed if a similar cation is generated by traditional means through a Lewis acid or a protic acid. This is because the radical cations are generated on an electrode surface and not in the bulk solution. Also, the conditions of electrolysis are quite unique and differ substantially from typical cationic conditions since the solvent itself is highly nucleophilic, consisting of a mixture of isopropanol and acetonitrile. Electrolysis of the silyl enolether 55 led to the ring-closed spiro products 56 and 57 via the initially generated radical cation. A minor product was 58, the expected cyclization product of a cation generated by conventional means. Treatment of a mixture of 56 and 57 with a Lewis acid led to the rearranged thiophene 59 <2006CC194>.
761
762
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.7.5
Electrochemical reactions at cathodes
Unusually stable thiophene radical anions have been encountered in the cyclic voltamograms of 2,3-diferrocenylbenzo[b]thiophene 60 and 1,3-diferrocenylbenzo[c]thiophene 61 <2006TL2887>. The cyclic voltamogram exhibited a well-defined reversible cathodic step, indicating good stability of the negatively charged reduction products.
3.10.2.7.6
Desulfurization
Benzo[b]thiophene has been used as a scaffold for the synthesis of various other heterocycles; the final step is the removal of sulfur <2006TL1015>. An example is given in Scheme 10.
Scheme 10
3.10.2.8 Reactions Involving a Cyclic Transition State with a Second Molecule 3.10.2.8.1
Cycloadditions
Thermal [4þ2] cycloadditions of thiophenes are not very common. Earlier, it had been reported that 2,5-dimethoxythiophene undergoes cycloaddition with maleic anhydride <1984CHEC(4)741>. It has now been shown that the dienic capacity of thiophene is greatly enhanced if electron-releasing anisyl groups are present at the 3- and 4-positions of the ring. 3,4-Bis(2-methoxyphenyl)-2,5-dimethylthiophene 62 reacts with methyl acrylate in the presence of BF3?Et2O to give the pentasubstituted benzene 63 in 65% yield. This obviously arises by loss of H2S from the initial cycloadduct. Cycloaddition failed to take place if either or both the anisyl groups in 62 were replaced by phenyl groups <1997TL1099>.
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.9 Reactions of Strained Thiophenes It had been mentioned in CHEC-II(1996) <1996CHEC-II(2)491> that some circumstantial evidence was available for the formation of cyclopropa[c]thiophene. This consisted of the isolation of a bis- [2þ4] cycloadduct 65 when the dehydrobromination of 64 was conducted in the presence of benzo[c]furan. The details of this investigation have now been discussed in a review of nonbenzenoid cycloproparenes <2001EJO849>. The author feels that the results are more consistent with the stepwise formation of the double bonds followed immediately by their capture through cycloaddition (Scheme 11), rather than the generation of a strained thiophene which then reacts with two molecules of the diene.
Scheme 11
A further attempt through photochemical extrusion of N2 from 66 also did not provide any evidence for the formation of the fugitive cyclopropa[c]thiophene. Only the alkene 69 was isolated in 60% yield. This presumably arose via the diradical 67 and the carbene 68.
763
764
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.10 Sulfur-Extrusion and Sulfur-Transfer Reactions The oxidative ring opening of 2,5-dimethylthiophene through reaction with singlet oxygen has been referred to in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. The first step is the cycloaddition of 1 O2 to thiophene to give the endoperoxide 70 (a thiaozonide), which then undergoes thermal decomposition to give the cis-enedione 72 and sulfur, presumably via the oxathiirane 71 (Scheme 12).
Scheme 12
Adam et al. have developed an ingenious method for putting such oxathiiranes to use as sulfur-transfer agents for the episulfidation of strained alkenes <1996CC177, 1998JA8914>. This was made possible by the isolation of the reasonably stable endoperoxide 74 from the thiophene 73 by reaction with singlet oxygen. The yield was quantitative. The endoperoxide could be isolated by silica gel chromatography at 30 C. It was stable in CDCl3 solution at 20 C for several days. Both as a solid and in solution, it decomposed readily at 0 C; the products were elemental sulfur and the labile ene-trione 75, which isomerized reversibly to 76. No sulfine could be isolated as a decomposition product (see CHEC(1984)). Direct reaction of the freshly generated endoperoxide with norbornene gave the episulfide 77 in about 60% yield. Other strained alkenes could similarly be converted to the corresponding episulfides in good to excellent yields. The diastereomeric pair, cis- and trans-cyclooctene, reacted stereoselectively (>95% d.s.), indicating that the sulfur-transfer step is a concerted process, and does not involve open dipolar or diradical intermediates. Detailed investigation of the kinetics of the reaction proved that the endoperoxide itself was
Thiophenes and their Benzo Derivatives: Reactivity
not the sulfur-transfer reagent. What seems to happen is that it is transformed thermally into two species, one of which is responsible for the sulfur transfer, while the other leads to the extrusion of sulfur in the elemental form. Although unequivocal evidence is currently not available for the structure of the former, there is reason to believe that it could be either of the two oxathiiranes 78 or 79 (Scheme 13).
Scheme 13
Another example of the extrusion of sulfur from a thiaozonide intermediate is given in Section 3.10.2.2. In that sequence, the endoperoxide radical cation resulted from the addition of triplet oxygen to the radical cation of a tetrasubstituted thiophene.
3.10.2.11 Reactions Brought About under Transition Metal Catalysis The reactivity of specific transition metal complexes of thiophenes is discussed in Section 3.10.6. Apart from these, there are several other reactions of thiophenes and benzo[b]thiophenes that take place in the presence of transition metals. Although it is quite likely that these reactions also proceed through the initial formation of complexes with the metals, no specific information is available on the isolation, characterization, and further transformation of such intermediates. These reactions are discussed in this section.
765
766
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.11.1
Addition reactions of thiophenes brought about by palladium catalysis
The addition of thiophene to ethylene mediated by a 2-thienylruthenium complex is discussed in Section 3.10.6.5. The reaction of thiophenes and benzo[b]thiophenes with alkylidenecyclopropanes in the presence of catalytic amounts of Pd(PPh3)4 and tributylphosphine oxide has been reported (Scheme 14) <2002JOC3445>. Yields are around 60%. The role of tributylphosphine oxide in the detailed mechanism is not clear, but it certainly served to accelerate the addition reaction.
Scheme 14
3.10.2.11.2
Introduction of substituents on the thiophene ring through cross-coupling reactions
3.10.2.11.2(i) C–C bond formation Transition metal-catalyzed cross-coupling reactions of thiophenes have been extensively covered in CHEC-II(1996). These include:
the cross-coupling of 2-thienylmagnesium (Kumada) or zinc derivatives (Negishi) with vinyl, ethynyl, or aryl halides in the presence of either NiCl2(dppp) [dppp ¼ 1,3-bis(diphenylphosphino)propane] or a Pd-catalyst <1996CHEC-II(2)491>, as well as the reverse coupling of thienyl halides with Grignard reagents; the Pd(0)-catalyzed reaction of heteryl halides with thienylboronic acids (Suzuki) or with stannylthiophenes (Stille); the cross-coupling of thienyl halides with terminal alkynes in the presence of PdCl2(PPh3)2 and CuI in an amine (Et3N, pyrrolidine) as solvent (Sonogashira); and the Pd-catalyzed synthesis of alkenylthiophenes by reacting thienyl halides with suitable alkenes (Heck reaction) (also included in this is the arylation of thiophenes by means of aryl halides).
In the decade since then, the major focus has been twofold: improving the scope of such reactions and application of the cross-coupling reactions for the synthesis of thiophene dendrimers, thiophene polymers, and thiophenes as optoelectronic materials. The Suzuki coupling of thiopheneboronic acids with a range of aryl bromides has been carried out efficiently by the use of [Pd(C3H5)Cl]2 in the presence of cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl)cyclopentane (Tedicyp) (Equations 20 and 21) <2005SL2057>.
ð20Þ
ð21Þ
Thiophenes and their Benzo Derivatives: Reactivity
The direct arylation (Heck) of thiophene by means of aryl halides and substituted thiophenes has been extensively studied by Lemaire and co-workers <1997TL8867, 1998JOM(567)49,2002TL1829, 2004T3221>. EWGs facilitate the reaction. With a 3-substituted thiophene, the major product was the 2-aryl derivative; with 2-substituted thiophenes, the only product was the 5-aryl derivative. Yields ranged from 40% to 95%. The reaction has been extended to the synthesis of 2-arylbenzo[b]thiophenes as well (Equations 22 to 25). The yield improved on replacing the quaternary ammonium bromide by dicyclohexyl-18-crown-6.
ð22Þ
ð23Þ
ð24Þ
ð25Þ
In the reverse cross-coupling, 2-bromothiophene has been reacted with 1,2-dimethyl-1H-imidazole to give the product 80 in 45% yield <1998BCJ467>.
The same authors also found that the phenylation of benzo[b]thiophenes and thiophene 2-carbaldehyde proceeded in >80% yields in the presence of CuI (Equations 26 and 27).
ð26Þ
ð27Þ
An interesting extension of the Heck reaction is the multi component assembly developed by Tonogaki et al. <2006JA1464, 2006OL1419>. This is based on an allenylboronate platform and results in the regioselective and stereoselective synthesis of alkenylboronates. Treatment of allenylboronate pinacol ester with N-benzylmethylamine and 3-iodothiophene in the presence of Pd2(DBA)3, P(2-furyl)3, and i-Pr2NEt in toluene at 80 C for 24 h gave the product 81 in 82% yield (DBA ¼ dibenzylideneacetone). Carbon nucleophiles could be used instead of amines. Thus, sodium ethyl 2-cyclohexanonecarboxylate gave 82. Both 81 and 82 are poised for further transformations.
767
768
Thiophenes and their Benzo Derivatives: Reactivity
A novel catalytic reaction of 3-iodothiophene-2-carboxylic acid with terminal alkynes leading to 4-alkynylthieno[2,3-c]pyran-7-ones has been described <2006TL83>. This extension of the Sonogashira coupling occurs under Pd–Cu-catalysis (Equation 28). The reaction seems to proceed through an initial Sonogashira pathway to 3-(1-alkynyl)thiophene-2-carboxylic acid, which then reacts with a Pd(II) species formed by insertion of a Pd(0) complex into the C–H bond of the second molecule of alkyne. Both Pd- and Cu-catalysts played crucial roles, since the reaction failed if either was omitted.
ð28Þ
Pd-catalyzed tandem cyclization of dithienylhexadienynes provides an efficient route to dithienylethenes (Equations 29–31) <2006OL1197>.
ð29Þ
ð30Þ
ð31Þ
The original Sonogashira protocol involves palladium–copper co-catalysis. Attempts have been made over the last few years to overcome some of the limitations in this method, specifically to eliminate the undesired dimerization of terminal alkynes. Various copper-free conditions have been developed in order to reduce the amount of diacetylene formation. The focus seems to have been on changing the ligand. 2-Iodothiophene reacts with several terminal alkynes at room temperature in the presence of a bulky phenanthrylimidazolium hexafluorophosphate-derived ligand (Equation 32) <2003OL3317>.
Thiophenes and their Benzo Derivatives: Reactivity
ð32Þ
3-Bromothiophene has been coupled with phenylacetylene in a copper-free reaction to give a 96% yield of the product (Equation 33) <2003OL4191>. A Pd(II) complex containing the ferrocene-based phosphinimine-phosphine ligand 83 has proved very efficient for the reaction of 2-iodo- and 2-bromothiophene with phenylacetylene; the coupling takes place under copper- and amine-free conditions (Equation 34) <2004TL4337>.
ð33Þ
ð34Þ
Excellent yields have also been obtained using the tetrapodal phosphine ligand Tedicyp, in which four phosphinomethyl groups are attached to the same face of the cyclopentane ring. The couplings were performed in the presence of [(allyl)PdCl]2, Tedicyp, and 5% Cu(I) as co-catalyst <2005TL1717>. Finally, Sonogashira coupling of 2-iodothiophene with phenylacetylene has also been carried out in an ionic liquid without copper salts or a phosphine. The catalyst was [(bisimidazole)PdClMe] <2004CC1306>. In symmetrically substituted 3,4-dihalothiophenes, several stepwise cross-coupling reactions have been performed <2005T2245>. Thus, 3,4-dibromothiophene undergoes a Negishi coupling with benzylzinc bromide to yield the monobromothiophene 84. This can be subjected to a Kumada cross-coupling to give the unsymmetrically substituted thiophenes 85.
769
770
Thiophenes and their Benzo Derivatives: Reactivity
Similar selectivities for the first cross-coupling have been observed for Suzuki and Sonogashira reactions. The Stille coupling of 3,4-diiodo-2,5-dimethylthiophene with 2-trimethylstannylthiazole stops at the monosubstitution stage. The reason for this selectivity might be that the carbon at the 3-position retards the oxidative addition and transmetalation at the adjacent 4-position. A different strategy has been reported for the synthesis of various 3,4-disubstituted thiophenes by Wong and coworkers <1997LA459>. They make extensive use of 3,4-bis(trimethylsilyl)thiophene as the building block. This can be prepared from 3,4-dibromothiophene in two successive lithiation/silylation steps. A regiospecific monoipso-iodination gave 86, which could be transformed by a combination of cross-coupling reactions into various 3,4disubstituted thiophenes. Two such examples are shown in Scheme 15. The formation of the product 87 involves a Heck reaction after an initial Suzuki coupling.
Scheme 15
Thiophenes and their Benzo Derivatives: Reactivity
The situation with 2,5-dihalothiophenes is somewhat different since the two halogen-bearing carbons are not adjacent to each other. Therefore a second cross-coupling can occur readily, leading to mixtures in which the symmetrical disubstituted thiophene may be a major by-product <2005T2245>. If the newly introduced group deactivates the molecule toward further coupling by increasing the electron density, then there might be a selectivity in favor of the monosubstituted product. Thus the Sonogashira coupling of 2,5-diiodothiophene leads to the monoalkynylated thiophene 88 in 50% yield; subsequent Stille coupling gives the product 89 <2005T2245>.
Similarly, Negishi cross-coupling of 2-furylzinc chloride with 2,5-dibromothiophene in the presence of PdCl2(dppb) proceeded in moderate yield (45%) to give the monosubstituted product (dppb ¼ 1,4-bis(diphenylphosphino)butane). In 2,3- or 2,4-dihalothiophenes, the 2-position is more electrophilic and so coupling reactions proceed with high regioselectivity. Thus 2,3-dibromothiophene has been subjected to regioselective reaction under the Sonogashira conditions with various terminal alkynes to yield the 2-alkynyl-3-bromothiophenes as the major products; the most common by-products are the alkyne dimers <2001T7871>. Similarly, coupling with different organostannanes under the Stille conditions, and with different boronic acids under the Suzuki conditions, gave regioselectively substituted products. The remaining bromine could then be replaced by using stronger reaction conditions (Scheme 16).
Scheme 16
771
772
Thiophenes and their Benzo Derivatives: Reactivity
Polyhalothiophenes can similarly be selectively reacted at the 2- and 5-positions (Scheme 17) <2005T2245>. Further prolonged reaction can lead to the fully substituted product.
Scheme 17
As with thiophene, 2,3-dibromobenzo[b]thiophene also exhibits a high regioselectivity in coupling reactions <2005T2245>. For example, Sonogashira coupling with t-butylacetylene leads exclusively to the 3-bromo derivative 90. 2,3-Unsymmetrically substituted derivatives of benzo[b]thiophene can be obtained by two successive crosscoupling reactions (Scheme 18).
Scheme 18
Thiophenes and their Benzo Derivatives: Reactivity
The synthesis of conjugated thiophene-based dendrimers has received special attention because of their nonlinear optical and electronic properties. A successful route to such dendrimers is based on Stille cross-coupling; an example is shown in Scheme 19 <2004TL3109>.
Scheme 19
The cross-coupling reactions easily lend themselves to use in controlled synthesis of polymers containing thiophene nuclei <2002JOM(653)195, 1994MM6620, 1997T10357>. Equations (35)–(37) provide representative examples. ð35Þ ð36Þ
ð37Þ
Bimetallic complexes containing a cationic (6-arene)Mn(CO)3þ complex at one end, a ferrocenyl group at the other end, and a thiophene ring as part of the conjugated linker chain have been recently synthesized using the Stille and Sonogashira coupling reactions <2004OM184>. The synthesis uses a new concept: during the coupling stages, the manganesecarbonyl complex is retained as the (5-cyclohexadienyl) complex and is oxidized by means of trityl fluoroborate in the penultimate step. This two-step procedure was found to be essential because the cationic (6-chlorobenzene) tricarbonylmanganese forms a stable bimetallic Mn/Pd-complex that refuses to take part in the coupling reaction. The successful synthesis involved the following steps: a Stille reaction with the (5)-manganese complex 91 and 2-(tributylstannyl)-5-bromothiophene gave 92; this was subjected to a Sonogashira coupling with ethynylferrocene; oxidation of the product 93 with triphenylcarbenium tetrafluoroborate gave the desired product 94 (Scheme 20). Compound 95 has been synthesized through a similar series of reactions. The conventional Sonogashira coupling has been used to construct bipyridine oligomers in which a thiophene ring is attached to the bipyridine through an acetylene link, for example, 96 <2005S1169>.
773
774
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 20
Reaction conditions have been optimized for the Suzuki coupling of pentafluorophenylboronic acid with 2,5dibromothiophene and with oligothiophenes carrying bromine substituents at the -positions of the terminal thiophene rings (Equation 38) <2005S1589>.
ð38Þ
Thiophenes and their Benzo Derivatives: Reactivity
Terminally nitro-substituted oligothiophene moieties having an ethynyl group at the other terminus, for example, 97, have been synthesized by using a combination of Negishi and Sonogashira couplings <2005JA9710>.
It has been found that oligothiophenes having terminal isocyanide groups bind to a platinum surface forming a selfassembled monolayer via chemisorption <2004JA11796, 2006OL183>. A series of such oligothiophenes 98 have been synthesized through the application of Sonogashira coupling procedures.
3.10.2.11.2(ii) C–N bond formation A facile transition metal-catalyzed formation of C–N bonds has been reported <2005T2931>. 3-Bromothiophene can be coupled with 2-pyridone to form the N-(3-thienyl) derivative in a CuI-catalyzed reaction. The catalyst consists of CuI in the presence of N,N9-dimethylcyclohexane-1,2-diamine and KOAc or K2CO3 (Equation 39).
ð39Þ
Earlier, a one-pot procedure based on consecutive Pd-catalyzed aryl–aryl coupling followed by N–C bond formation had been described for the synthesis of phenanthridones and their thiophene analogs <2004OL4759>. The starting materials were 2-iodotoluene and 3-bromothiophene-2-carboxamides or 3-bromobenzo[b]thiophene-2-carboxamides (Equations 40 and 41). The conditions were rather critical: in order to prevent the nucleophilic amide group from coordinating with the palladium, tri-2-furylphosphine had to be added to the reaction mixture. Norbornene serves to form a palladacycle which then reacts with the bromoamide.
ð40Þ
ð41Þ
775
776
Thiophenes and their Benzo Derivatives: Reactivity
The reaction took a different course in the absence of norbornene <2006JA722>. Symmetrically condensed pyridones were obtained in 30–75% yields (Equations 42 and 43) when 3-bromothiophene-2-carboxamides alone were treated with the palladium catalyst. Evidently this involves a palladium-catalyzed homocoupling followed by an intramolecular aromatic substitution by the amide nitrogen.
ð42Þ
ð43Þ
3.10.2.11.2(iii) C–P bond formation Pd-catalyzed C–P bond formation (Equation 44) has been used to synthesise several highly active thiophene- and benzo[b]thiophene-based phosphine ligands, for example, 99 and 100, for use in asymmetric allylation reactions <2004SL1113, 2002SL2083>. The catalyst used was 101.
ð44Þ
Thiophenes and their Benzo Derivatives: Reactivity
The chiral center can also reside in the phosphine fragment. 2,5-Dimethyl-3,4-bis[(2R,5R)-2,5-dimethylphospholano] thiophene 102 has been synthesized and used as the ligand for Rh and Ru in asymmetric hydrogenation reactions (Scheme 21) <2005JOC5436>.
Scheme 21
3.10.2.11.3
Homocoupling reactions
The hexabutylditin-mediated synthesis of 5,59-diaryl-2,29-bithiophenes through a homocoupling reaction has been described (Equation 45) <2006TL795>.
ð45Þ
3.10.3 Reactivity of Nonconjugated Rings 3.10.3.1 Thiophene 1-Oxides The [2þ4] (thiophene ring contributing 2p-electrons) and the [4þ2] (4p-electrons of the thiophene taking part) cycloadditions of thiophene 1-oxides have been covered in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Since then, several reviews have been published on thiophene 1-oxides and related compounds <1997SR349, 2000BCJ1, 2002CHE632, 2002JCM303>. Much of the work is devoted toward the synthesis of stable thiophene 1-oxides and their application in cycloaddition reactions with various dienophiles. [4þ2] Cycloaddition of thiophene 1-oxides with electron-deficient dienophiles can be performed at much lower temperature (20 C) in the presence of a Lewis acid such as BF3?Et2O. The Lewis acid greatly improves the yields and allows for a large choice of dienophiles. Where the noncatalyzed reaction provides yields of just 10–30%, the addition of BF3?Et2O improves the yields of the cycloadduct to nearly 75%. The thiophene 1-oxides are usually generated in situ by m-chloroperbenzoic acid (MCPBA) oxidation of the corresponding substituted thiophenes. Because of the complexation with the Lewis acid, the sulfur of the sulfoxide moiety becomes less nucleophilic and so is less prone to be oxidized further to the 1,1-dioxide. However, in some cases, stable thiophene 1-oxides are isolated first and then reacted with the dienophile in a second step (Equation 46) <1997JOC7926>.
777
778
Thiophenes and their Benzo Derivatives: Reactivity
ð46Þ
In an interesting application of this reaction, fullerene (C60) has been used as the dienophile with 3,3-dimethylthiophene 1-oxide <1997SL175>. Oxidative extrusion of the sulfoxy group from the cycloadduct leads to the formation of an aromatic compound. An application of this reaction to the synthesis of non-natural arylamino acids from 2-methylthiophene has been described by Thiemann and co-workers (Scheme 22) <2003JCM527>.
Scheme 22
If the dienophile is an alkyne or benzyne, the cycloadduct directly eliminates sulfur monoxide and gives the aromatic product <2003NJC1377>. When thiophenes are treated with MCPBA in the presence of alkynes, arenes are formed, but in rather low yields (23–41%) (Equation 47).
ð47Þ
The reaction is successful only if the alkynes have EWGs attached and the thiophenes are substituted at least at C-2 and C-5 with electron-donating groups. The yields are much lower (5–15%) if the thiophene carries a CO2Me group at C-2. Better yields of the aromatic products are obtained if a preformed thiophene 1-oxide is used in the cycloaddition (two examples are provided in Scheme 23). Benzo[b]thiophene 1-oxides also undergo facile [4þ2] cycloadditions with alkynes, the products being naphthalenes (Equation 48).
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 23
ð48Þ
In the same way, benzyne reacts with thiophene 1-oxides to give aromatic products (Equation 49).
ð49Þ
Allenes too react with thiophene 1-oxides to give cycloadducts; in some cases, the products are stable and do not lose SO, while in others only the arenes could be isolated (Equations 50 and 51).
ð50Þ
ð51Þ
779
780
Thiophenes and their Benzo Derivatives: Reactivity
Thermally stable 3,4-di-tert-butylthiophene-1-oxide 103 has been prepared by oxidation of the corresponding thiophene and used for investigation of p-facial selectivity in Diels–Alder reaction (Figure 1). It has been shown that 3,4-di-tert-butylthiophene 1-oxide undergoes Diels–Alder reaction with electron-deficient <2003JA8255> as well as electron-rich dienophiles with very high p-facial selectivity <2005TL4165>. The approach of dienophile in each case is from syn-p-face with respect to the STO bond. The preference for the syn-p-face approach and the endoselectivity in the cycloaddition reaction have been explained on the basis of theoretical calculations. Thioaldehydes and thioketones also react with 3,4-di-tert-butylthiophene 1-oxide to give cycloadducts with syn-p-face selectivity (Scheme 24) <2003TL5159>. However, in the case of thiobenzophenone, a small amount of anti-adduct was also observed along with the major syn-p-face-selective product.
Figure 1
Scheme 24
Thiophenes and their Benzo Derivatives: Reactivity
The addition of bromine to 3,4-di-tert-butylthiophene 1-oxide takes place exclusively in 1,4-cis-mode to give 1:1 mixture of two isomers (Equation 52) <2003BCJ619>. However, a single 1,4-cis-addition product, syn-face to STO bond, was obtained in the bromination of 3,5-bis(trimethylsilanyl)thiophene 1-oxide <1998H(48)227>.
ð52Þ
An unusual methylene-transfer reaction along with [4þ4] cyclodimerization was observed, when 3,4-di-tertbutylthiophene 1-oxide was refluxed in toluene with 2-methylene-1,3-dimethylimidazolidine <2001CL758>. Initially a Michael adduct is formed by the addition of 104 to 103. This adduct upon intramolecular cyclization gives the cyclopropyl compound with elimination of a carbene. This on further oxygen-transfer reaction gives products 105 and 106. The 1,4-Michael adduct on further Michael reaction with 103 produces another adduct, which on cyclization followed by elimination of 104 gives 107 (Scheme 25).
Scheme 25
781
782
Thiophenes and their Benzo Derivatives: Reactivity
The electron-withdrawing STO group helps the nucleophilic substitution of bromide with sodium phenolate in 3-bromobenzo[b]thiophene 1-oxide (Scheme 26). Nucleophilic substitution of bromine could also be carried out using secondary amines such as piperidine and morpholine <2005JOC3569>.
Scheme 26
3.10.3.2 Thiophene 1,1-Dioxides Thiophene 1,1-dioxides are nonaromatic compounds and hence undergo a wide variety of reactions as unsaturated cyclic sulfones. All these reactions have been exhaustively covered in CHEC-II(1996) <1996CHEC-II(2)491> and also in some reports <1999TCC131, 2000BCJ1, 2002CHE632>. The unsubstituted thiophene 1,1-dioxide 108 is highly unstable and difficult to isolate as it rapidly undergoes [4þ2] self-dimerization. Nakayama et al. <1997JA9077> prepared this compound for the first time by direct oxidation of thiophene with dimethyldioxirane (DMDO) at 20 C under neutral conditions, and studied the spectral data <1999BCJ1919>. The compound has a very short half life and further undergoes [2þ4] dimerization followed by SO2 extrusion to give the dihydrobenzothiophene 1,1-dioxide 109, which on further [4þ2] cycloaddition with 108 gives the adduct 110 (Scheme 27).
Scheme 27
Thiophene 1,1-dioxide did not undergo cycloaddition with electron-deficient dienophiles. In most of the cases the dihydrobenzothiophene derivative 109 was obtained as the major product. This shows that self-dimerization is faster than cycloaddition with a different molecule. In the case of dimethyl acetylenedicarboxylate (DMAD) and 4-phenyl3H-1,2,4-triazole-3,5(4H)-dione (PTAD), the Diels–Alder adducts 111 and 112 of 109 were obtained <1997JA9077>. However, cyclopentadiene gave the Diels–Alder adduct 113 with thiophene 1,1-dioxide. The DMAD adduct 111 on thermolysis undergoes a retro-Diels–Alder reaction to give dimethyl phthalate and thiophene 1,1-dioxide. Azulene was isolated in the thermolysis of 108 in the presence of 6-(dimethylamino)-fulvene; this was the result of a [4þ6] cycloaddition of the thiophene 1,1-dioxide formed in the reaction followed by elimination of SO2 and dimethylamine (Scheme 28) <1999BCJ1919>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 28
Other monosubstituted thiophene 1,1-dioxides 114a–d have also been prepared by direct oxidation of the corresponding thiophenes with DMDO. 2-Methylthiophene 1,1-dioxide 114a undergoes dimerization via [4þ2] cycloaddition followed by elimination of SO2 to give a mixture of regioisomers 115 and 116 <2000H(52)365>. The former reacts with another molecule of 114a to give 117 (Scheme 29).
Scheme 29
783
784
Thiophenes and their Benzo Derivatives: Reactivity
Sterically congested thiophene 1,1-dioxides are less prone to dimerization; the most stable is the tetrachlorothiophene 1,1-dioxide. Other congested thiophenedioxides such as 3,4-di-t-butyl, 3,4-diadamantyl, and 3,4-dineopentylthiophene 1,1-dioxide undergo [4þ2] cycloaddition with electrophilic dienophiles followed by SO2 extrusion to produce highly substituted aromatic compounds (Scheme 30) <1998JOC4912>.
Scheme 30
3,4-Di-neopentylthiophene 1,1-dioxide on reaction with benzyne gives the ene reaction product in 68% yield along with the [4þ2] adduct (28%) and the further adduct of the latter with benzyne. 2,5-Dimethylthiophene 1,1-dioxide gives a tetraadduct with C60-fullerene <1997SL175>. Stable bis(trimethylsilyl)thiophene 1,1-dioxides have been prepared by lithiation of thiophene followed by silylation and oxidation with peracetic acid or MCPBA. These thiophenedioxides also undergo a [4þ2] Diels–Alder reaction with N-phenylmaleimide to produce monoadducts with elimination of sulfur dioxide (Scheme 31) <1994TL4425>. 3,4-Di-t-butylthiophene 1,1-dioxide reacts with 2-methylene-1,3-dimethylimidazolidine in refluxing toluene to give a cycloadduct, which spontaneously eliminates SO2 and aromatizes (Scheme 32) <2001CL758>. Russian workers have examined the reactivity of thiophene 1,1-dioxides bearing one or two EWGs toward various dienes <2005T10880; 2006T4139>. With open-chain dienes, both types of substrate undergo chemo-, regio-, and stereoselective [2þ4] cycloaddition, with the thiophenedioxide acting exclusively as the dienophile (Equations 53 and 54).
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 31
Scheme 32
ð53Þ
ð54Þ
However, there was a remarkable difference in their reactivity toward cyclopentadiene. While 2,5-bis(methylsulfonyl)thiophene 1,1-dioxide still reacted as a dienophile (Equation 55), substrates in which only one EWG is attached to the ring react as dienes (Equation 56), ultimately forming indene derivatives by extrusion of SO2.
ð55Þ
785
786
Thiophenes and their Benzo Derivatives: Reactivity
ð56Þ
Thiophene 1,1-dioxides are also very good Michael acceptors. The addition of MeSNa to 3,4-di-t-butylthiophene 1,1-dioxide <2000CL744> takes place in 1,6- and 1,4-fashion to give a 56:44 mixture of adducts in 94% yield (Equation 57). The addition of molecular bromine to 3,4-di-t-butylthiophene 1,1-dioxide also takes place exclusively in 1,4-cis-fashion (Equation 58) <2003BCJ619>.
ð57Þ
ð58Þ
Nucleophilic addition of secondary amines to 2,5-dialkylthiophene 1,1-dioxide is rather difficult. However, addition to 2,5-bis(trimethylsilyl)-, 2-trimethylsilyl-5-trimethylgermyl-, and 2,5-bis(trimethylgermyl)thiophene 1,1-dioxides (Scheme 33) occurs smoothly. Selective desilylation of 3-piperidino-2-trimethylsilyl-5-trimethylgermylthiophene
Scheme 33
Thiophenes and their Benzo Derivatives: Reactivity
1,1-dioxide on a silica gel column provided 3-piperidino-5-trimethylgermyl-2,3-dihydrothiophene 1,1-dioxide. Similarly desilylation of 3-piperidino-2,5-bis(trimethylsilyl)thiophene 1,1-dioxide gave 3-piperidino-5-trimethylsilyl-2,3-dihydrothiophene 1,1-dioxide <2000EJO3139>. In an unusual reaction, 3-(piperidinomethyl)-2,5-dihydrothiophene 1,1-dioxide was obtained when 2,5-bis(trimethylsilyl)thiophene 1,1-dioxide was reacted with excess piperidine in an aprotic solvent (Equation 59) <2000EJO3139>.
ð59Þ
3.10.3.3 Thiophene S,N-Ylides and S,C-Ylides The thiophene S,N-ylides include 1-imino (118), 1,1-diimino (119), and 1-imino-1-oxo (120) derivatives.
More formally, these compounds have been referred to as 1-imino-1,1-dihydrothiophene, 1,1-bis(imino)-1,1dihydrothiophene, and 1-imino-1,1-dihydrothiophene 1-oxide, respectively <1999TL5549, 1999TL3785>. An excellent account of the chemistry of these substances has been given by Nakayama <2000BCJ1>. The synthesis and cycloaddition reactions of the stable S,N-ylide 121a (R ¼ CO2Et) and 121b (R ¼ Ts) have already been reported in CHEC-II(1996) <1996CHEC-II(2)491>. The synthesis of 121 involves thermal generation of the corresponding nitrene by decomposition of the azide in tetrachlorothiophene at 130 C. However, the instability of the S,N-ylides except in the case of tetrachlorothiophene has prevented the extension of this procedure to the preparation of other analogs without the chlorine substituents.
An improved procedure has now been developed for making the sterically congested 3,4-di-t-butyl-1-iminothiophenes <1999TL5549>. The procedure involves reaction of 3,4-di-t-butylthiophene with tosylnitrene generated from [N-(p-tolylsulfonyl)imino]phenyl-3-iodinane (TsNTIPh) 122 at room temperature in the presence of a Cu(I) or Cu(II) catalyst. The preferred catalyst is Cu(MeCN)4PF6. Under the best conditions, this led to the 1-tosylimino derivative 123 in 61% yield, along with small amounts of the 1,1-diiminothiophene 124 and the N-tosylpyrrole (Equation 60). The 1-tosylimino derivative 123 on further reaction with 122 in the presence of 5 mmol% of the Cu(I) catalyst gave the diimine derivative 124 in low yield (10%), with most of the starting material being recovered. This method has some disadvantages: for obtaining reasonably good yields of the product 123 the molar ratio of the thiophene substrate and 122 has to be 20:1, that is, a large excess of the substrate thiophene has to be used. Furthermore, the purification of the product is rather cumbersome.
ð60Þ
787
788
Thiophenes and their Benzo Derivatives: Reactivity
An alternative method has therefore been developed, which makes use of the easily obtainable 1-oxide 103 as the starting material <2000TL8461>. The 1-oxide is treated with trifluoroacetic anhydride (or with triflic anhydride) at 78 C, and then with a sulfonamide, carbamate, or carboxamide (Equation 61). The N-unsubstituted parent compound 126 could be obtained from the t-butyl carbamate 125 in two steps (Equation 62).
ð61Þ
ð62Þ
Both the thiophene 1-imide 123 and the 1,1-diimide 124 are thermally stable. X-Ray crystallography showed that the geometry of the former is similar to that of thiophene 1-oxide with a pyramidal configuration at the sulfur atom indicating loss of aromaticity. The C–C bond lengths also confirm this. The compound 123 acts as a Michael acceptor toward alkoxides and thiolates <2000CL744>. Treatment with refluxing methanolic NaOH or with MeSNa at room temperature leads to 1-methoxy-3,4-di-t-butylthiophene 127 and 1-methylthio-3,4-di-t-butylthiophene 128, respectively. The suggested mechanism involves addition of the nucleophile to C-2, followed by hydrogen migration and a Stevens rearrangement (Scheme 34).
Scheme 34
Using reagent 122, thiophene 1-sulfoximides have been prepared from the corresponding thiophene 1-oxides. Thus the two stable di-t-butylthiophene 1-oxides 103 and 130 have been converted to the corresponding di-t-butyl1-[(p-toluenesulfonyl)imino]-1,1-dihydrothiophene 1-oxides 129 and 131 <1999TL3785>. The tosyl group in both the products could be cleaved by treatment with conc. H2SO4 (Equations 63 and 64). The free imino group in the products could be methylated by treatment with Me3OþBF4.
Thiophenes and their Benzo Derivatives: Reactivity
ð63Þ
ð64Þ
In contrast to the thiophene 1,1-dioxides, the tetracoordinated sulfur atom in the unsymmetrically substituted sulfoximide 132 is chiral. The compound could be separated into two enantiomers, and the absolute configuration established by X-ray crystallography. The addition of bromine to the thiophene 1-imide 123 and the 1-sulfoximide 129 has been investigated <2003BCJ619>. With a 1.1 molar amount of bromine, the imide gave a mixture of bromothiophenes shown in Equation (65). In order to explain this, it has been proposed that the initial reaction occurs on the nitrogen atom; subsequent steps are shown in Scheme 35.
ð65Þ
Scheme 35
Addition of bromine to the N-tosylsulfoximide 129 was much slower than to the corresponding sulfoxide or sulfone. The product in this case was the 1,4-cis-adduct 134 (Equation 66).
ð66Þ
789
790
Thiophenes and their Benzo Derivatives: Reactivity
In contrast, the N-unsubstituted sulfoximide showed only a small p-face selectivity, leading to the two cis-adducts in the ratio 1:2 (Equation 67).
ð67Þ
3.10.3.4 Dihydrothiophenes The synthesis and properties of dihydrothiophenes have been reviewed by Shvekhgeimer <1998CHE1101>.
3.10.3.4.1
2,5-Dihydrothiophenes
Conformationally constrained 29-deoxy-4-thia -anomeric spirocyclic nucleosides have been synthesized by Dong and Paquette <2005JOC1580>. Osmium-catalyzed dihydroxylation of the spirocyclic dihydrothiophene 135 in the presence of DABCO gave the cis-diol 136 in 53% yield which was protected as an acetonide; hydrolysis using LiOH in aqueous THF and subsequent Meerwein–Ponndorf–Verley reduction of the keto compound 137 gave a diastereomeric mixture of alcohols (Scheme 36).
Scheme 36
The pure major diastereomer 138 on -elimination gave the dihydroxythiaglycal 139, which on electrophilic glycosidation using phenylselenyl chloride and silylated nucleobase provided the major -phenylseleno--anomer 140, along with a small amount of the -phenylseleno--anomer. In a similar reaction, the iodo compound was obtained when PhSeCl was replaced with N-iodosuccinimide (NIS) (Scheme 37).
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 37
Reductive removal of the PhSe group from 140 followed by deprotection of hydroxyl groups afforded the spirocyclic nucleoside (Scheme 37). Several analogs have been prepared by following the above synthetic protocol using different nucleobases. FVP of (5-methyl-2-thiophene-yl)methyl benzoate at 650 C and 105 Torr pressure has provided 2,5-dimethylene-2,5-dihydrothiophene (S-monomer) in 75% yield via a double [3,3]-sigmatropic shift (Scheme 38). A solution of this compound in a mixture of CHCl3 and CS2 was relatively stable at 78 C. The structure was confirmed by
791
792
Thiophenes and their Benzo Derivatives: Reactivity
1
H NMR, 13C NMR, gas chromatography (GC) IR, and GC MS. The solution of S-monomer at room temperature gave a mixture of the SS-dimer, SSS-trimer, and a polymer (Scheme 38). Evidence for formation of an SSSS-tetramer (Mþ 440) was only obtained by GC MS. Similar results were obtained on FVP of (5-ethyl-2-thiophene-yl)methyl benzoate <1997JOC8980>.
Scheme 38
Photochromism in 1,2-bisthienylethenes has been discussed in Section 3.10.2.1.3. This property is also observed in dithienylethenes with a 2,5-dihydrothiophene bridging unit (Equation 68) <2003OL1435, 1997JPH35>.
ð68Þ
2,5-Dihydrothiophene 1,1-dioxide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) reacts with CO2 to give the carboxylic acid (Equation 69), which is a stable precursor to 1,3-butadiene-2-carboxylic acid <2003SC3643>. The reaction proceeds through initial deprotonation at the 2-position; the resonance-stabilized carbanion thus generated reacts with CO2 to form the carboxylate. Abstraction of a proton from the 3-position by another molecule of the base generates a dianion, which isomerizes to the stable dianion as shown in Scheme 39. Final protonation produces 3-sulfolene-3-carboxylic acid.
ð69Þ
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 39
3.10.3.4.2
2,3-Dihydrothiophenes
The antioxidant profile of the analogous series of compounds 141a–d has been determined by studies of their redox properties, their capacity to inhibit lipid peroxidation, etc. From these studies, it has been concluded that the antioxidant capacity varies as follows: 141d > 141c ¼ 141b > 141a <2001JA3434>.
Biocatalytic asymmetric oxidation of 2,3-dihydrobenzo[b]thiophene to ()-(R)-sulfoxide in excellent yield has been reported. The enzyme used is a chloroperoxidase from the marine fungus Caldariomyces fumago. This enzyme is relatively stable and does not require any cofactor. Hydrogen peroxide was the oxygen source. Using this system, 2,3-dihydrobenzo[b]thiophene was converted to the ()-(R)-sulfoxide in 99.5% yield, with an ee of 99%. Similarly, 1,3-dihydrobenzo[c]thiophene could be oxidized to the corresponding sulfoxide in 80% yield <1998CH246>.
3.10.3.5 Tetrahydrothiophenes The reactivities of tetrahydrothiophene (THT) (thiolane), tetrahydrothiophene 1-oxide, and tetrahydrothiophene 1,1-dioxide (sulfolane) have been discussed in detail in CHEC(1984) <1984CHEC(4)741> and also in CHECII(1996) <1996CHEC-II(2)491>. The present review deals only with some new contributions in this area. Recently, salacinol 142, a sulfonium salt of THT, was isolated from the herb Salacia reticulata and shown to be a new type of -glucosidase inhibitor. This compound was later synthesized from 1,4-epi-thio-D-arabinitol and the cyclic sulfate derived from either D- or L-glucose. D-Glucose gave the correct natural stereoisomer (salacinol) while the other diastereomer was obtained from L-glucose <2000TL6615>. Encouraged by the glycosidase inhibitor activity associated with salacinol, other sulfonium salts 143–145 of thiophenes have been prepared and evaluated for biological activity <2006JOC1111, 2006JOC1262>.
793
794
Thiophenes and their Benzo Derivatives: Reactivity
Thiophene sulfonium salts have also been used for alkylation of phenols, thiophenols, and other nucleophiles (Equation 70) <2001T2871>. Ylides generated from THT and alkyl or allyl halides are known to react with aldehydes to form oxiranes. However, a modified procedure has been developed in which only a catalytic amount of THT is used for the preparation of vinyloxiranes from allyl bromides and aldehydes. In most of the cases, a cis– trans-mixture of vinyloxiranes was obtained. Optically pure C2-symmetric trans-2,5-dimethyltetrahydrothiophene has also been used for the asymmetric version of this reaction, but the enantioselectivity was poor (25% ee) (Equation 71) <2003CC2074>.
ð70Þ
ð71Þ
trans-Glycidic amides were obtained when diazoacetamides were reacted with aldehydes in the presence of a catalytic amount of Cu(acac)2 (5 mol%) and THT (20 mol%) (acac ¼ acetylacetonate) <1998TL8517>. Similarly, cyclopropanation of electron-deficient alkenes has been achieved by reaction of phenyldiazomethane or ethyl diazoacetate in the presence of a catalytic amount of Rh2(OAc)4 or Cu(acac)2 and THT (Equation 72) <2000J(PI)3267>.
ð72Þ
The alkylidenecarbene generated from alkenyl(phenyl)iodonium tetrafluoroborate by base adds irreversibly to THT to form a sulfonium ylide, which further gives the sulfonium salt along with a small amount of a thioether (Scheme 40). This was in contrast to the corresponding oxonium ylide where the reaction was found to be reversible <1996JA10141>. The thiosugar 146 on reaction with ozone followed by treatment with Ac2O gave a mixture of three Pummerertype products 147–149. The sulfoxide of 146 did not yield the Pummerer products 147–149 on treatment with Ac2O. Therefore, it has been postulated that these products arise from the ozonide as shown in Scheme 41 <2006JA227>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 40
Scheme 41
795
796
Thiophenes and their Benzo Derivatives: Reactivity
A Pummerer rearrangement has been shown to occur on the sulfoxide 150 anchored onto C60-fullerene <1999TL1543>.
Chiral bis(phosphinites) derived from (2R,5R)-2,5-di(hydroxymethyl)tetrahydrothiophene have been prepared (Equation 73). These ligands have been used in the synthesis of rhodium complexes from Rh(COD)2X (COD ¼ cyclooctadiene; X ¼ OTf, SbF6) and tested in the asymmetric hydrogenation of methyl -acetamidocinnamate. A maximum of 55% enantioselectivity was observed <1998OM4976>.
ð73Þ
Tetrahydrothiophene-3-one reacts with 6-aryl-2H-pyran-2-ones in the presence of base to give dihydrobenzothiophene (Equation 74). The reaction proceeds through the addition of the carbanion generated from tetrahydrothiophene3-one to pyran-2-one followed by base-induced intramolecular annulation <2001JOC5333, 2002J(P1)1426>.
ð74Þ
THTs are well known to undergo desulfurization with Raney-Ni. Recently this has been used in the asymmetric synthesis of the sex pheromones of Macrodiprion nemoralis (Scheme 42) <2000S1863>.
Scheme 42
Apart from these reactions of THT, it has also been used as a good coordinating ligand in a large number of metal complexes such as those of gold, palladium, platinum <2004OM3521, 2002OM5887, 2002JOM(663)164, 2001JCD1196, 1999HCA1202>, cobalt, titanium, tungsten, and zirconium <2004OM4349, 2002EJI678, 1999OM4275>. A complete reversal of reactivity of bis(iodozincio)methane with acid chloride by the addition of THT in THF has been reported (Scheme 43). In a normal reaction, the bis(iodozincio)methane reacts with PhCOCl in THF to give the iodoester (99%) with a trace amount of the diketone. However, under similar reaction conditions, the diketone was formed in more than 98% yield when a small quantity of THT was added in THF solvent <1999SL1471>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 43
3.10.4 Reactivity of Substituents Attached to the Ring Carbon Atoms 3.10.4.1 C-Linked Substituents 3.10.4.1.1
Alkyl, alkenyl, and alkynyl groups
Michael additions of various aldehydes and ketones to 2-(-nitrovinyl)thiophene have been carried out in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate. Yields were in general better with aldehydes than with ketones. The best catalyst was L-proline <2004EJO1577>. The first successful osmium-catalyzed asymmetric aminohydroxylation and dihydroxylation of thiophene acrylates have been reported. The aminohydroxylation of 2-thienyl-, 5-bromo-2-thienyl-, and 3-thienylacrylates proceeds with high regio- and enantioselectivity (Equation 75) <1999SL1907. Yields were about 67–68%, with the regioselectivity of 151 over 152 being >15:1. The ee was 99%.
ð75Þ
Asymmetric dihydroxylation of the three thiophene acrylates 153–155 at 0 C under the standard conditions was very slow. Increasing the temperature only led to decomposition of the thiophene ring. However, satisfactory results could be attained by increasing the ligand twofold (up to 2 mol%). The yields of the (2R,3R)-dihydroxy derivatives (Equations 76–78) were in the 50–60% range, with an ee of 99% <2002TL3813>.
ð76Þ
ð77Þ
797
798
Thiophenes and their Benzo Derivatives: Reactivity
ð78Þ
Two processes have been reported recently in which a benzene ring is constructed on an existing thiophene by cyclization of tetrayne or enyne side chains. The tetrayne 156 was prepared by using a standard Stille coupling followed by addition of the lithio derivative of (trimethylsilyl)butadiyne. Oxidation of 156 to the ketone and stirring at room temperature in benzene resulted in cycloaromatization, leading to the indenothiophene 157 in 90% yield. In the presence of anthracene, the cycloaromatization gave 158. It has been suggested that these cycloaromatizations proceed via diradical intermediates (Scheme 44) <2005TL1233>.
Scheme 44
Thiophenes and their Benzo Derivatives: Reactivity
The second benzoannulation results from the coupling of Fischer carbene complexes with conjugated dienyne systems in which the central double bond is part of a thiophene ring. Thus reaction of the 2-alkenyl-3-alkynylthiophene 159 with the Fischer carbene complex 160 and acid treatment of the resulting product gives the thienobenzofuran 161. The reaction is compatible with a variety of substituents on the double bond (159: R ¼ CO2Me, CN, Ph, H, Me) and generally proceeds in good yields <2005TL2211>. Several other analogous thiophene substrates have similarly been converted to thienobenzofurans (Equations 79 and 80).
ð79Þ
ð80Þ
3.10.4.1.2
Halomethyl groups
An interesting difference in the chemical behavior between ,9-dibromo-o-xylene and 3,4-bis(bromomethyl)-2,5dimethylthiophene toward Meldrum’s acid has been brought to light <2003JOC7455>. As expected, the former leads to a spiroindane through C,C-dialkylation. But the thiophene derivative gives the C,O-dialkylated product 162 in 93% yield. 3,4-Bis(chloromethyl)-2,5-dimethylthiophene behaves similarly, giving 162 in 74% yield. This difference has been attributed to the slightly greater distance between the two halomethyl groups on the 3,4-positions of a thiophene compared to two halomethyl groups on the ortho-positions of a benzene ring. The tricyclic compound 162 undergoes some interesting transformations. Refluxing in methanol for 5 min leads to the methoxymethylthiophene 163. Thermolysis leads to the ketene 164 by a retro-Diels–Alder reaction. The ketene can be trapped as a t-butyl ester by t-BuOH (Scheme 45).
799
800
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 45
3.10.4.1.3
Hydroxymethyl groups
The acid-catalyzed reaction of 2,5-di(acetoxymethyl)thiophene with a substituted pyrrole has been briefly mentioned in CHEC-II(1996) <1996CHEC-II(2)491>. This type of reaction has now found extensive application in the synthesis of thiaporphyrins and other macrocycles containing one or more thiophene rings. A few examples are given below. Porphyrins in which one or more of the pyrrole rings are replaced by thiophene have been intensely studied in recent years for potential application in various electronic systems and as photosensitizers in photodynamic therapy. In a recently reported synthesis of several such thiaporphyrins, the starting material is 2,5-bis(hydroxymethyl)-3,4-ethylenedioxythiophene 165. The N3S porphyrin (three pyrrole rings and one thiophene) 166 could be synthesized by condensing 1 equiv of the diol 165 with 2 equiv of benzaldehyde and 3 equiv of pyrrole in CHCl3 in the presence of BF3–Et2O, followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The desired thiaporphyrin 166 was obtained in 8% yield <2003EJO3730>. Condensation of the diol 165 with pyrrole alone under mild acidic conditions led to the thiaporphyrin 167 containing two thiophene units. The yield was 9%. The unsymmetrical diol 168 has been condensed with the 16-thiatripyrrin 169 in refluxing propionic acid to give the thiaporphyrin 170 in 14% yield <2004EJO2223>.
Thiophenes and their Benzo Derivatives: Reactivity
Condensation of 2,5-bis(acetoxymethyl)thiophene with the pyrrole 171 having a free -position in the presence of a catalytic amount of p-toluenesulfonic acid gave the tricyclic compound 172. Hydrolysis and decarboxylation of this and subsequent condensation with 5-formylsalicylaldehyde gave the thiaoxybenziporphyrin 173 in 15% yield <2004JOC6079>.
Macrocyclic molecules that have the ability to bind anions continue to attract considerable synthetic effort. During the course of such studies, it has been found that hybrid calixpyrroles in which some pyrrole units are replaced by thiophenes are good receptors for Y-shaped anions such as carboxylates <2005JOC1511>. One such macrocyle is compound 176. The synthesis of this compound utilizes the same type of chemistry as has been adopted for the thiaporphyrins. The bis(bipyrrolyl)furan 174 was reacted with the diol 175 (1.1 molar ratio) in MeCN in the presence of a catalytic amount of BF3–Et2O at 0 C to give 176 in 44% yield.
3.10.4.1.4
Aldehydes and Ketones
The normal reactions of aldehydes and ketones attached to thiophenes or benzo[b]thiophenes have been discussed exhaustively in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Only novel reactions, or those leading to products with special applications, are discussed here.
801
802
Thiophenes and their Benzo Derivatives: Reactivity
Nitration of thiophene 2-carbaldehyde has been reported to give a mixture of all three mononitro isomers in the ratio 3-nitro (62%), 4-nitro (15%), and 5-nitro (23%). This mixture could not be condensed with 2-acetylpyridine in NaOH; instead, the thiophene ring was ruptured <2006S1295>. Conjugated oligomers based on various combinations of thiophene, EDOT, and ethylenic units have attracted attention as organic semiconducting materials for use in various electronic and optoelectronic devices. Such oligomers have been synthesized by the use of Wittig reactions on appropriate substrates <2005T3045>. The phosphonate reagents 177 based on EDOT were prepared as shown in Equation (81). Twofold Wittig–Horner olefination with dialdehydes led to the required oligomers. An example is given in Equation (82).
ð81Þ
ð82Þ
Several (E,E,E)-39-styrylbis (thienylvinyl) thiophenes 179 have been prepared for eventual polymerization <2006T2190>. The synthesis makes extensive use of the Wittig reaction. The protected trialdehyde 178 was made by lithiation of 2,5-dibromothiophene-3-carbaldehyde followed by DMF formylation. Two subsequent Wittig reactions lead to the desired monomers 179.
Thiophenes and their Benzo Derivatives: Reactivity
2-Acetyl-5-bromothiophene has been converted to 2-acetamido-5-bromothiophene in 37% yield by the Beckmann rearrangement of its oxime <2006S1295>. Treatment of 2-acetyl-5-bromothiophene with excess methylidenetriphenylphosphorane has yielded some unexpected results <2000T7573>. The major product (46%) was the thienofuran 180 along with the phosphorane 181 (22%). The suggested mechanism for the formation of these two products involves initial nucleophilic displacement of the bromine, followed by addition of a second molecule of the ylide to the conjugated double bond of the 2-acetylthiophene unit (Scheme 46).
Scheme 46
With a stabilized ylide, 2-acetyl-5-bromothiophene yields about 25% of the normal Wittig products as a mixture of (E)- and (Z)-isomers. The phosphonium salt 182 is the other product (32% yield) of the reaction (Scheme 47). Guaiazulene reacts with thiophene 2-carbaldehyde in methanol in the presence of hexafluorophosphoric acid to give the stabilized carbenium ion 183 in 98% yield <2005T10349>. Reduction of this with zinc powder gives a mixture of stereoisomeric dimers (Equation 83).
803
804
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 47
ð83Þ
The newly developed ruthenium catalyst 184, having 2,2-bis(diphenyl-phosphanyl)-1,1-binaphthyl (BINAP) and 2-picolylamine as ligands, effects asymmetric reduction of t-butyl (2-thienyl) ketone under mild conditions with very high enantioselectivity <2005JA8288>. The (S)-enantiomer of the complex leads to the (R)-alcohol with 98% ee (Equation 84).
ð84Þ
Hexamethyldisilathiane 185 is a valuable reagent for the thionation of carbonyl compounds. It can also reduce azido groups to amines. These two properties have been combined to convert ortho-azidothiophene carbaldehydes to stable ortho-aminothiophene thioaldehydes (Equations 85–88) <1996S1185>.
ð85Þ
Thiophenes and their Benzo Derivatives: Reactivity
ð86Þ
ð87Þ
ð88Þ
3.10.4.2 N-Linked Substituents 3.10.4.2.1
Nitro compounds
The ring opening of 3,4-dinitrothiophene on treatment with primary and secondary amines has been mentioned in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. This results in the formation of the bis(nitroenamine) 186 with the concomitant extrusion of sulfur as H2S. It has also been reported that secondary aliphatic amines react with 2-nitrothiophene to form the nitrodienamines 187 <1984CHEC(4)741, 1997HCA2329>. Subsequently, a few other similar ring-opening reactions of nitrothiophenes and nitrobenzo[b]thiophenes have been reported. 3-Nitrothiophene has also been shown to undergo a facile ring opening on treatment with primary and secondary aliphatic amines in the presence of Agþ. Subsequent methylation led to 1-amino-4-methylthio-2-nitro-1,3-butadienes 188 (Scheme 48). The structure of diene 188 and the configuration about the double bonds (Z,Z) have been established by NMR spectroscopy and X-ray crystallography <1997T8531>. Lead tetraacetate (LTA) oxidation of 188 gave the nitropyrrole 189 and the acetoxylated product 190 in 14% and 51% yields, respectively.
Scheme 48
805
806
Thiophenes and their Benzo Derivatives: Reactivity
The scope of the above Agþ-mediated ring opening of 3-nitrothiophene has been extended to 3-nitrobenzo[b]thiophene <1997T8531>. Nitroenamines 191 have been obtained after methylation (Equation 89).
ð89Þ
In contrast, reaction of 2-nitrobenzo[b]thiophene with n-butylamine under the same conditions did not lead to any ring-opened product. Instead, the substrate underwent an oxidative nucleophilic substitution reaction. Reaction conditions have been systematically varied in order to maximize the yield of the ring-opened products from 3-nitrothiophene and 3-nitrobenzo[b]thiophene <2001T8159>. The scope of the reaction has been enlarged to include 2-substituted-4-nitrothiophenes as substrates (Equation 90). Yields range from 50% to 80%.
ð90Þ
The ring opening of 3,4-dinitrothiophene has been extended to 3-nitro-4-(phenylsulfonyl)thiophene. The attack by pyrrolidine in the presence of Agþ is chemoselective, taking place only at C-2 (Equation 91) <2003JOC5254>.
ð91Þ
The substituted nitrobutadienes obtained from all the above ring-opening reactions have lent themselves to a plethora of useful transformations <1996T3313, 1999EJO431, 2000EJO903, 2002ARK142, 2002EJO1284, 2004T4967, 2005JOC8734>. It is beyond the scope of the present chapter to describe these in detail. A few unexpected reactions have also been encountered during the ring-opening studies. As mentioned earlier, treatment of 2-nitrobenzo[b]thiophene with aliphatic primary amines in the presence of AgNO3 does not give the ringopened product; what is obtained in low yield is the result of an oxidative nucleophilic substitution. The yield of the resultant 3-amino-2-nitrobenzo[b]thiophenes could be improved by using ceric ammonium nitrate as the oxidant instead of AgNO3 <1997T8531>. The initial step in this reaction is the reversible addition of the amine at the electron-deficient carbon to form the H-adduct, which derives some stabilization from intramolecular hydrogen bonding with the NO2. The second step involves the oxidation of the H-adduct to yield the 3-amino-2-nitrobenzo[b]thiophene (Scheme 49).
Scheme 49
Thiophenes and their Benzo Derivatives: Reactivity
Treatment of 3,4-dinitrothiophene with an aryl Grignard reagent leads to an unexpected product in about 30% yield. One of the NO2 groups is reduced to an amine; this is accompanied by the ipso-substitution of a hydrogen atom by an ortho-phenolic unit <2004EJO3566>. The suggested mechanism involves initially the reduction of NO2 to NO by the Grignard reagent, possibly via a radical pathway. The subsequent stages are shown in Scheme 50.
Scheme 50
Photosubstitution of the nitro group in 2-nitrothiophene has been reported earlier <1996CHEC-II(2)491>. In that example, photolysis of 2-nitrothiophene in the presence of indene in acetonitrile had given an excellent yield of 192, while 2-iodo-5-nitrothiophene gave a mixture of 192 and 193. However, if styrene were substituted for indene as the substrate, the reaction with 2-nitrothiophene took a completely different pathway, leading to 194 (Equation 92) <1996T14253>. The mechanism could involve an intermolecular electron transfer followed by cycloaddition of the nitro group to the alkene, rearrangement, and a final oxidation. If 1,1-diphenylethene were used instead of styrene, the major product was benzophenone with about 10% of 195, which is the product of substitution of the nitro group.
ð92Þ
3.10.4.2.2
Amines and derivatives
The properties of aminothiophenes have been summarized earlier <1984CHEC(4)741, 1996CHEC-II(2)491>. Therefore only significant new results are reported below.
807
808
Thiophenes and their Benzo Derivatives: Reactivity
The tautomerism of aminothiophenes has been discussed in a comprehensive review of the tautomerism of heterocycles <2000AHC(76)85>. 3-Methoxy-2-methylaminothiophene exists as a mixture of the amino (196a) and the imino (196b) forms in solution. In CCl4 the ratio of 196a to 196b is 1:7. More polar solvents favor the imino form.
Potentiometric measurements indicate that in water–DMSO the 3-aminothiophenes 197 undergo protonation exclusively at the nitrogen with dilute acid. But on treatment with the superelectrophile 4,6-dinitrobenzofuroxan (DNBF) they react as carbon nucleophiles giving rise directly to the corresponding C-adducts. The 3-aminothiophenes are thus shown to possess strong enaminic character <1998CJC937>.
The synthesis of 3,4-diaminothiophene has been standardized and optimum conditions established for its condensation with -diones to produce thieno[3,4-b]pyrazines <2002JOC9073>. Selective monocarbamoylation of 3,4-diaminothiophene has given access to several 2-alkyl-3,4-diaminothiophenes <1997T10331>. Acid-catalyzed reductive alkylation of the monocarbamate by treatment with an aldehyde and selenophenol in the presence of p-toluenesulfonic acid gave the 2-alkylthiophene; the carbamate could then be cleaved by means of HBr to give the diamine (Scheme 51).
Scheme 51
Conditions have been standardized for the conversion of the o-aminoesters 198 and 199 into the corresponding isatoic anhydride analogs 200 and 201. This involves microwave heating conditions to hydrolyze the esters and subsequent reaction with phosgene. These anhydrides react readily with nucleophiles at the carbonyl group attached to the nitrogen (Scheme 52). Similar results have been obtained with other thiophene derivatives bearing substituents at C-4 or C-5 <1998T10789, 2003T10051>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 52
3.10.4.2.3
Azides and nitrenes
The thermolysis of azidothiophenes and azidobenzo[b]thiophenes has been investigated in detail <1993J(P2)1129, 1995J(P1)613>. As mentioned in CHEC-II(1996), it has been suggested that the unimolecular decomposition (with extrusion of N2) and ring opening in the case of 2-azidobenzo[b]thiophene could occur in a concerted manner (Equation 93). GC MS analysis of the thermolysis products of 2-azidothiophene suggests the presence of a m-dithiin which could arise as shown in Equation (94).
ð93Þ
ð94Þ
This study has been extended to the thermolysis of 2-azido-5-methylthiophene and 2-azido-5-(trimethylsilyl)thiophene. The former underwent total decomposition at 20 C within a few months to give the 2,5-dihydrothiophene 202. The suggested mechanism for this involves the formation of an ene-thione as before, cyclodimerization, and sulfur extrusion (Scheme 53).
Scheme 53
809
810
Thiophenes and their Benzo Derivatives: Reactivity
In contrast to the above examples, thermolysis of 3-azidothiophene seems to proceed through a nitrene intermediate, as shown by the product distribution (Equation 95).
ð95Þ
The azidothiophenes underwent the expected 1,3-dipolar cycloaddition with (trimethylsilyl)acetylene.
3.10.4.3 O-Linked Substituents The synthesis of vinylenedioxythiophene 203, in which the CH2–CH2 bridge of EDOT (see Section 3.10.2.3.2) has been replaced by –CHTCH–, has been reported recently <2006CC275>. The three-step synthesis involves transetherification of 3,4-dimethoxythiophene in the first step and a ring-forming olefin metathesis in the last (Scheme 54).
Scheme 54
Transetherification had earlier been employed to prepare thieno[3,4-b]-1,4-oxathiane 204 from 3,4-dimethoxythiophene <2002OL607>. The difference in the reactivity of the 2- and 5- positions in 204 has been studied. Both monobromination and monoformylation gave the regioisomer substituted at the 5-position as the major product (Scheme 55). DNBF 205 is a powerful electrophile – even more powerful than the proton or p-nitrobenzenediazonium cation. The reaction of 3-methoxythiophene with DNBF has been investigated <1997J(P2)2667>. The reaction leads to the formation of the formal product of SEAr substitution 206 in quantitative yield (Equation 96). The product could be isolated as a crystalline sodium salt. The kinetic data from this reaction provide strong support to the view that 3-methoxythiophene exhibits behavior characteristic of a vinyl ether.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 55
ð96Þ
The reaction of 2-(trimethylsilyloxy)thiophene with carbon nucleophiles has been discussed in CHEC-II(1996) <1996CHEC-II(2)491>. Several recent publications have reported the isolation of the initial aldol from the reaction of 2-(trimethylsilyloxy)thiophene with aldehydes. The reaction and its synthetic applications have been reviewed several times <1995S607, 1999SL1333, 2000CSR109>. The 2-silyloxythiophene 207 was prepared from 2,5-dihydrothiophene-2-one by treatment with t-butyldimethylsilyl triflate (TBDMS-OTf) <1995TL1941> in dichloromethane in the presence of 2,6-lutidine (Equation 97).
ð97Þ
811
812
Thiophenes and their Benzo Derivatives: Reactivity
On reaction with D-glyceraldehyde acetonide in the presence of a Lewis acid at 90 C, the silyloxythiophene gave the 4,5-threo-5,6-erythro-isomer 208 (d.s. >95%) along with a small amount of the other diastereomer. This reaction has been used for the synthesis of the thio analog 209 of the natural product muricatacin (Scheme 56) <1997JOC4513>.
Scheme 56
The asymmetric version of the vinylogous aldol addition has been further exploited for the synthesis of several pyrimidine nucleoside analogs (Scheme 57) <1995TL1941>.
Scheme 57
Cyclic oxonium compounds generated from hemiacetals by a Lewis acid react with 2-silyloxythiophene to produce useful intermediates via C–C bond formation (Scheme 58). This reaction has been extensively used to prepare a large number of synthetic analogs of acetogenins, which are effective antitumor agents (Scheme 59) <2000CSR109>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 58
Scheme 59
3.10.4.4 Halo Groups 3.10.4.4.1
Nucleophilic displacement
Nucleophilic displacement of halo groups both from activated thiophenes and unactivated ones has been extensively covered in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Spinelli and his group have continued their in-depth study of the kinetics and mechanism of such displacements. Only recent results are mentioned briefly here. The application of the Hammett-type equation to SNAr reactions of thiophene compounds is continuing. Data for the reaction of 3-nitro-2-p-nitrophenoxy-5-X-thiophenes (X ¼ H, Br, CONH2, CO2Me, COMe, SO2Me, CN, NO2) with various substituted anilines have been collected and the thiophene -values calculated <2001JCM266>. The reactions of some 2-L-5-nitro-3-X-thiophenes with primary and secondary amines in methanol and in benzene have been investigated <2002J(P2)965, 2002J(P2)971>. The results show that it is possible to establish a set of ortho -constants that account well for the electronic effects of 3-X substituents, and to obtain excellent linear free energy ortho-correlations. Detailed information about various aspects of the base catalysis in SNAr reactions of 3-nitro-2-phenoxy-5-X-thiophenes with amines has been obtained in a kinetic study <1998J(P2)325>. Secondary steric effects could become significant in aromatic nucleophilic substitution in activated halogenobenzenes. This can be ascribed to steric inhibition of resonance. In contrast, secondary steric effects are not important in SNAr reactions of thiophene derivatives; this is due to the geometry of five-membered ring derivatives, which strongly lowers the steric interactions between the substituents on the thiophene ring. This has been reconfirmed by kinetic data in methanol on SNAr reactions of the two pairs of substrates 210 and 211 with different nucleophiles (piperidine and sodium benzenethiolate) <1997J(P2)309>.
813
814
Thiophenes and their Benzo Derivatives: Reactivity
An unexpected rearrangement has been encountered during studies on the reactivity of 3-bromo-2-nitrobenzo[b]thiophene with nucleophiles <1995J(P1)1243, 1997JOC4921, 2001T8903>. The reaction conditions are rather critical. The rearrangement was found to occur only with weak nucleophiles (such as anilines) in the presence of nonnucleophilic bases (such as Et3N or K2CO3) in refluxing DMF. Under these conditions, the reaction gives rise to a mixture of the expected product 213 and the rearrangement product 214 in good overall yields. The ratio of 213 to 214 varies from 85:15 to 66:34. The mechanism of this rearrangement has been investigated. The migration of the nitro group has been explained by postulating the formation of a three-membered intermediate 212 (Scheme 60).
Scheme 60
3.10.4.4.2
Halogen–metal exchange
The difficulty of making Grignard reagents from 3-bromothiophene has been commented on earlier <1984CHEC(4)741>. It has now been shown that 3-thienylzinc- and 3-thienylmagnesium iodides can be prepared easily at room temperature by the oxidative addition of activated zinc and magnesium to 3-iodothiophene <1995JOC6658, 1997JOC6921>. The regiostability of the 3-thienyl organometallic reagents was established by reacting them with electrophiles and checking the identity of the products (Scheme 61). The ‘active’ metals used in this process are prepared through the reduction of ZnCl2 and MgCl2 by lithium using naphthalene as the electron carrier.
Scheme 61
Thiophenes and their Benzo Derivatives: Reactivity
A similar procedure yielded the manganese derivatives from 3-bromothiophene and 3,4-dibromothiophene <1997TL993, 1997JOC6921>. Starting from 3,4-dibromothiophene, unsymmetrically substituted thiophenes could be prepared through a stepwise process.
3.10.4.4.3
Generation and reactivity of thienyl radicals
The photolysis of 2-iodothiophene in the presence of benzene to generate 2-phenylthiophene has been mentioned earlier <1984CHEC(4)741, 1996CHEC-II(2)491>. Such photochemical arylation is particularly facile if the thiophene ring bears an EWG (Equations 98–100) <2000J(P1)3513, 1996CHEC-II(2)491>.
ð98Þ
ð99Þ
ð100Þ
The reaction has been successfully extended to 2,3-diiodo-5-nitrothiophene (Scheme 62). However, irradiation of 2,4-diiodo-5-nitrothiophene in the presence of benzene gave a mixture of the expected product and a rearranged one (Equation 101).
Scheme 62
ð101Þ
The mechanism of the photoarylation has been investigated <1995JPC5365>. The homolytic cleavage of the C–I bond probably occurs, not from an n,p* - but a higher excited state, perhaps ,* -triplet state, localized mainly on C–I bond.
815
816
Thiophenes and their Benzo Derivatives: Reactivity
The reaction of such photogenerated thienyl redicals with alkenes has given mixed results. Irradiation of 2-iodothiophenes having an EWG at the 5-position in the presence of electron-poor alkenes gives a mixture of two types of products; the major one is the adduct 215 and the minor one the alkene 216 (Equation 102) <2000EJO1653>.
ð102Þ
With arylalkenes, only the coupled alkenes were obtained as (E/Z)-mixtures (Equation 103). If a CH2OAc group was present at the other end of the arylalkene, the reaction took a totally different course, leading to an arylation (Equation 104). These results have been interpreted in terms of the generation of an electrophilic radical on homolysis of the C–I bond.
ð103Þ
ð104Þ
3.10.4.4.4
(Diacetoxyiodo)thiophenes
Both 2-(diacetoxyiodo)- and 3-(diacetoxyiodo)thiophene have been prepared. Their reactivity as oxidizing agents is similar to that of (diacetoxyiodo)benzene <2000JOC8391>.
3.10.4.5 Si-Linked Substituents An efficient strategy has been developed for synthesizing unsymmetrically 3,4-disubstituted thiophenes <1997JOC1940, 1997LA459>. This utilizes 3,4-bis(trimethylsilyl)thiophene 217 as the starting material. Crucial to this strategy was the development of a method for the synthesis of 217 using a cycloaddition/cycloreversion process (Equation 105). Treatment of 3,4-bis(trimethylsilyl)thiophene 217 with iodine and silver trifluoroacetate in THF at 78 C resulted in mono-ipso-iodination to give 218. This is now set up for a host of cross-coupling reactions (see Section 3.10.2.11). The second trimethylsilyl group could again be replaced by iodine and a further crosscoupling reaction carried out to provide unsymmetrically substituted thiophenes. A few examples are given in Scheme 63.
ð105Þ
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 63
The alkynylthiophenes 219 could be converted to the boroxines 220 through the following sequence: hydrogenation to the alkylthiophenes, treatment with BCl3, and hydrolysis (Scheme 64).
Scheme 64
817
818
Thiophenes and their Benzo Derivatives: Reactivity
The boroxines could then be subjected to Suzuki coupling with aryl, vinyl, or benzyl halides. Suzuki coupling with tri-n-butylstannyl chloride also gave the tri-n-butylstannyl-substituted thiophenes 221. These can form the starting materials for further transformations. The carbonylative coupling with halides resulted in the formation of ketones; tin–lithium exchange followed by reaction with electrophiles led to a host of other useful products (Scheme 65).
Scheme 65
Fluoride activation of Si–C bonds toward electrophiles has recently been exploited to synthesise alternating thiophene–perfluoroarene copolymers without using transition metal catalysis. This has the advantage of leading to products that are devoid of even traces of metal residues <2006JA2536>. Here the electrophiles are perfluoroarenes (pF); the potential nucleophilic sites are the 2- and 5-positions of 3,4-dibutoxy-2,5-bis(trimethylsilyl)thiophene. The reaction is initiated with catalytic fluoride ion, which is regenerated with each C–C bond formed (Equation 106).
ð106Þ
Denmark and Baird have developed organosilanols as a new class of donors in cross-coupling reactions. The Pdcatalyzed coupling with suitable haloarenes can be initiated either by fluoride or by bases. The advantage is that silanols are stable and can be stored as the sodium salts. Conditions have been optimized for such cross-coupling reactions using 2-thienylsilanols and iodo- or even bromoarenes (Equations 107 and 108) <2006OL793>.
ð107Þ
ð108Þ
Hiyama has used the ingenious strategy of intramolecular activation to facilitate the cross-coupling of readily accessible and stable silanes with aryl iodides (Equation 109) <2005JA6952>. The thienylsilane 223 could be reacted with ethyl 4-iodobenzoate in the presence of PdCl2 and the iminophosphine ligand 224 to give the product in 93% yield.
Thiophenes and their Benzo Derivatives: Reactivity
ð109Þ
3.10.4.6 Metallo Groups 3.10.4.6.1
Metal–metal exchange
As mentioned in Section 3.10.2.6, lithium derivatives of thiophenes cannot be directly used for transition metalassisted cross-coupling reactions. The strategy usually adopted is to first exchange the lithium for another metal, which can then be used for coupling reactions. This has been discussed in CHEC-II(1996) <1996CHEC-II(2)491>. A recent example of the application of this strategy is given below <2005JA9710>. 5-Nitro-[2,29:59,20]terthiophene has been prepared by palladium-catalyzed Negishi cross-coupling between 2-iodo5-nitrothiophene and the organozinc derivative of bithiophene. The latter was obtained from the corresponding lithio derivative (Scheme 66).
Scheme 66
The cyanocuprates of thiophene have been discussed earlier <1996CHEC-II(2)491>. An attempt has been made to use negative ion electrospray ionization mass spectrometry for obtaining information on the solution composition of organocuprates such as 225 and 226 in THF <1999OM1571>.
819
820
Thiophenes and their Benzo Derivatives: Reactivity
3.10.4.6.2
Formation of C–C bonds
The use of lithiated thiophenes for the introduction of substituents on the ring through C–C bond formation is now a standard tool in organic synthesis. This has been covered exhaustively in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Further elaboration of this topic is therefore not necessary.
3.10.4.6.3
Ni- and Pd-catalyzed cross-coupling reactions
This topic is exhaustively dealt with in Section 3.10.2.11.
3.10.4.6.4
Formation of C–halogen bonds
Several 3-aryl-2-fluorobenzo[b]thiophenes have been prepared by fluorination of the 2-lithio derivatives using the electrophilic fluorinating reagent N-fluorobenzenesulfonimide (Equation 110) <2005SL247>. The yields are fair to excellent.
ð110Þ
Iodination of thiophene zincates and thiophene magnesiates has been mentioned in Section 3.10.2.6.
3.10.5 Reactivity of Substituents Attached to the Thiophene Sulfur Atom It has been briefly mentioned in CHEC-II(1996) <1996CHEC-II(2)491> that S-alkylbenzo[b]thiophenium ions react with nucleophiles by alkylating them. This concept has now been used in developing several dibenzothiophene-based electrophilic trifluoromethylating agents with tunable alkylating power <1996CRV1757, 1995AHC(64)323>. S-Trifluoromethyldibenzothiophenium salts 229 can be prepared by fluorination of the sulfides 227 with 10% F2/N2 in the presence of triflic acid, or by treatment of the corresponding sulfoxides 228 with triflic anhydride (Scheme 67). The yields are good. The unsubstituted S-trifluoromethyldibenzothiophenium triflate 229a could be mononitrated by means of nitronium triflate in MeNO2 as solvent. Using an excess of the nitronium triflate in the absence of MeNO2 gave the dinitro derivative 230 in high yield. Sulfonation of 229a could be achieved by means of fuming sulfuric acid; the resulting sulfonate could be nitrated to the nitrosulfonate (Scheme 68). The S-trifluoromethyldibenzothiophenium salts are stable solids. Thermolysis leads to dibenzothiophene and trifluoromethyl triflate. Alkaline hydrolysis leads to the S-oxide (Equation 111).
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 67
Scheme 68
ð111Þ
A wide range of nucleophilic substrates could be trifluoromethylated with such S-trifluoromethyldibenzothiophenium triflates. The trifluoromethylating ability increases in the order 229b < 229a < 230. If the nucleophile is very reactive, the preferred agent for trifluoromethylation is the dimethyl derivative 229b, which is not very powerful. Less reactive substrates were trifluoromethylated in reasonably good yields by the more powerful dinitro salt 230. The unsubstituted salt 229a is intermediate in its trifluoromethylating power. Carbanions, enamines, enol trimethylsilyl ethers, aniline, phenol, and pyrrole have all been successfully trifluoromethylated at their respective nucleophilic carbon atoms (Equations 112–117).
821
822
Thiophenes and their Benzo Derivatives: Reactivity
ð112Þ
ð113Þ
ð114Þ
ð115Þ
ð116Þ
ð117Þ
Trifluoromethylation of enolates could be achieved by complexing the enolate with boron Lewis acids (Equation 118). The best boron Lewis acid for this purpose was 2-phenyl-1,3,2-benzodioxaborole 231. For enantioselective trifluoromethylation, the optically active boron compound 232 was used (Equation 119).
ð118Þ
Thiophenes and their Benzo Derivatives: Reactivity
ð119Þ
Perfluoroalkylations of nucleophiles could similarly be achieved by using S-perfluoroalkyldibenzothiophenium salts.
3.10.6 Reactivity of Transition Metal Complexes of Thiophene 3.10.6.1 General Survey The removal of the various organosulfur compounds present in fossil fuels over heterogeneous catalysts is known as hydrodesulfurization (HDS). Molybdenum and tungsten sulfides are essential components of such heterogeneous catalysts; but it is also necessary to include various late transition metals as promoters, especially to achieve the desulfurization of thiophene, benzothiophene, and dibenzothiophene. Modeling studies based on homogeneous catalysis have contributed a great deal to understanding the mechanism of HDS. The catalysts were several transition metal complexes. During such studies, several other reactions of thiophenes in organotransition metal complexes were discovered. These have led to the utilization of specific reactions of coordinated thiophenes for the synthesis of organosulfur compounds that are difficult to prepare by other methods. Four types of coordination of thiophenes to metals are known (Figure 2). Coordination can occur through the sulfur alone [1(S)], through one carbon–carbon double bond (2), through two C–C double bonds involving four atoms (4), or through all five atoms of the ring (5). Benzo[b]thiophenes can exhibit 1(S)- or 2-coordination as with the thiophenes, 4-coordination through the four carbon atoms (C4–C7) of the benzene ring, or 6-coordination through all six carbon atoms of the benzene ring. Dibenzothiophene can take part in 1-(S), 4-, or 6-coordination as above.
Figure 2
In the 1-(S)-coordinated thiophenes, the sulfur appears to be sp3-hybridized; the metal does not lie in the plane of the thiophene. They are all weakly coordinating compared to THT (a dialkyl sulfide type of molecule); consequently, such complexes can be isolated only in some special cases. The tendency to coordinate to metal ions in the 1-(S) mode generally increases in the order T* < BT* < DBT* . (As per the normal convention, the unstarred symbols T, BT, and DBT refer to the unsubstituted heterocycles thiophene, benzo[b]thiophene, and dibenzo[b,d]thiophene, respectively, while a star indicates the inclusion of substituted thiophenes as well. Cp and Cp* refer to the 5- bound C5H5 and C5Me5, respectively.) Several excellent reviews are available on the reactivity of organotransition metal complexes of thiophenes: <2001OM1259, 2000CCR63, 1998ACR109>. In addition, Sadimenko has provided a compendium of all the known syntheses and reactions of the organometallic derivatives of thiophene and benzo[b] thiophene <2001AHC(78)1>. In the following sections, the reactivity of the transition metal complexes of thiophenes has been classified from an organic chemist’s perspective.
3.10.6.2 Metal Insertion into the C–S Bond: C–S Bond Activation The insertion of a metal atom into the C–S bond might constitute the first stage in the ultimate desulfurization of thiophene derivatives. It is therefore of great interest that several reactions have been discovered from which such metallothiacycles could be isolated.
823
824
Thiophenes and their Benzo Derivatives: Reactivity
Reductive elimination of benzene from Cp* (Me3P)Rh(Ph)(H) leads to the formation of the reactive 16-electron intermediate Cp* (Me3P)Rh. In the presence of thiophene, this gives the C–S insertion product 234. The mechanism of this reaction has been elucidated <2001OM1259> (Scheme 69). Initial 1(S)-coordination gives rise to 233, which then undergoes insertion to form 234. The 2-complex 235, which is the minor initial product, undergoes reversible C–H oxidative addition to give the 2-rhodium-substituted thiophene 236. But 235 itself is irreversibly transformed to 233, and hence ultimately only the rhodium-inserted product is isolated <2001OM1259>. The mechanism emphasizes the importance of 1-coordination mode to the C–S bond activation of thiophene. Theoretical calculations appear to support this <1998OM65>.
Scheme 69
Benzo[b]thiophene and dibenzo[b,d]thiophene also undergo a similar metal insertion on treatment with Cp* (Me3P)Rh(Ph)(H). Structures of many of these products have been determined by X-ray crystallography <2001OM1259>. The rhodium in complex 234 has a formal 18-electron count and cannot therefore participate in p-bonding with electrons on the sulfur, which might lead to delocalization in the six-membered ring. Similarly, a ferrathiacycle 237 is formed when the Fe(DMPE)2 fragment generated by photolysis of cisFe(DMPE)2(H)2 reacts with thiophenes (Equation 120). In this too, there is no delocalization as shown by the C–C bond lengths <2001OM1259>.
ð120Þ
Thiophenes and their Benzo Derivatives: Reactivity
The platinum-inserted product 238 is obtained when Pt(PEt3)3 reacts with benzo[b]thiophene. Similar products are obtained from thiophene and dibenzothiophene. The platinathiacycle 238 is nonplanar, and hence not aromatic <2001OM1259>. p-Coordination of benzo[b]thiophene, dibenzothiophene, and 2,5-dimethylthiophene activates the C–S bonds toward metal insertion. Thus Pt(PPh3)3 fails to react with 2,5-dimethylthiophene. But if the latter is 5-coordinated with manganese tricarbonyl, the reaction takes place at room temperature to give 239 <2001OM1259>.
When 2,5-dimethylthiophene reacts with Cp* IrCl2 and AgBF4 in acetone, the dicationic 5-iridium complex 240 is formed in high yield as its fluoroborate. Two-electron reduction of this with cobaltocene leads to the 4-complex 241 and the ring-inserted product 242. The former can be isomerized to the iridium-inserted 242 by basic alumina or Et3N. The bond lengths in the six-membered ring of 242, as revealed by X-ray crystallography, suggest that the molecule is best represented as a hybrid of the two resonance forms (A) and (B). In 242A, the Ir-atom is a 16-electron center; there could be p-donation from S to Ir which would then make the Ir an 18-electron center. The NMR data also support a delocalized p-system in the six-membered ring <2000CCR63>.
The monocationic 5-thiophene manganesecarbonyl complex 243 on reduction with 1 equiv of cobaltocene under a carbon monoxide atmosphere at room temperature leads to the product 244 which is still 5-coordinated to the Mn(CO)3 fragment, while the second manganese atom inserted in the ring is above the C4S plane <2001OM1259>. A similar reduction of benzo[b]thiophene gives 245. If there is a methyl or ethyl at position 7 of the benzo[b]thiophene, the product rearranges further as shown in Scheme 70 <2001OM1259>.
825
826
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 70
3.10.6.3 Hydrogenolysis of Thiophenes to Thiols Hydrogenolysis refers to the transformation of a thiophenic substrate into the corresponding thiol. Catalytic hydrogenolysis of thiophenes, benzo[b]thiophene, and dibenzothiophene can be brought about with the help of the 16-electron species [(triphos)MH] (M ¼ Rh or Ir; triphos ¼ MeC (CH2PPh2)3). These are generated in situ by thermolysis of the appropriate precursors. The rhodium complex 246 effectively catalyzes such hydrogenolyses. The required experimental conditions are rather drastic (Scheme 71) <1998ACR109>.
Scheme 71
In a similar manner, the 16-electron fragment [(triphos)IrH], generated thermally by reductive elimination of ethane from (triphos)Ir(H)2Et, is capable of cleaving dibenzothiophene in THF to give the C–S insertion product 247. This product is hydrogenated (100 C, 5 atm of H2) to the biphenyl derivative 248; the latter upon hydrogenation at 170 C (30 atm of H2) is converted to biphenyl, H2S, and 2-phenylthiophenol (Scheme 72) <1995OM2342, 1995OM4850>. This is thus a close model for the HDS process.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 72
3.10.6.4 Catalytic Hydrogenation of the Thiophene Ring Of the three possible substrates, thiophene, benzo[b]thiophene, and dibenzo[b,d]thiophene, benzo[b]thiophene is the most easily hydrogenated to the dihydro derivative; this is ascribable to the more pronounced ‘olefinic’ character of the C(2)–C(3) double bond in benzo[b]thiophene as compared to that in thiophene. There is no example in the literature of the hydrogenation of dibenzothiophene either to the tetrahydro or the hexahydro stage. The hydrogenation of benzo[b]thiophene is catalyzed by transition metals such as Ru, Os, Rh, and Ir. An excellent overview of homogeneous catalytic hydrogenation of thiophenic substrates has been presented recently <2004JOM (689)4277>. The catalysis cycle comprises the following steps: oxidative addition of H2 to the metal; coordination of the benzothiophene in the 2-mode; hydride migration; and, finally, elimination of dihydrobenzo[b]thiophene by reductive coupling of the hydride and dihydrobenzothienyl ligands (Scheme 73). Based on this, various ruthenium and rhodium complexes have been developed, which exibit good catalytic activity.
Scheme 73
One of the best catalysts developed so far is the Ru(II) complex [(triphos) RuH]þ, obtained by hydrogenation of the precursor [Ru(MeCN)3(triphos)](SO3CF3)2. This shows a reasonable turnover frequency of about 2000, but a serious drawback of this system is the deactivation of the catalyst in solvents containing even traces of water.
827
828
Thiophenes and their Benzo Derivatives: Reactivity
Subsequently, water-soluble catalysts have been developed for use in aqueous biphasic systems. One such catalyst precursor is RuHCl(TPPTS)2(L)2 (where TPPTS ¼ triphenylphosphine trisulfonate and L ¼ aniline or a similar base). The conditions required for the hydrogenation of benzo[b]thiophene with this catalyst are rather harsh: 130–170 C and 70–110 bar H2 <2004JOM(689)4277>. The conversion of thiophene to THT, via 2,3-dihydrothiophene, is much more difficult. A major difference is that after the first hydride migration a thioallyl ligand is formed (Scheme 74). The poor catalytic activity has been attributed to the fact that THT is a good -donor and is not easily displaced by the thiophene; so it traps all the available catalytically active species as the bis-THT complex <1998ACR109>.
Scheme 74
3.10.6.5 Transition Metal-Mediated C–H Activation Catalytic transformations involving the C–H bonds of thiophene are rare, but recently there has been a report on the catalytic addition of the C(2)–H bond of thiophene across ethylene to form 2-ethylthiophene <2004OM5514>. Reaction of the ruthenium complex TpRu(CO)(NCMe)(Me) (where Tp ¼ hydrido tris(pyrazolyl)borate) with thiophene produces the 2-thienyl complex 249 and methane. This complex catalyzes the formation of 2-ethylthiophene from a solution of thiophene and ethylene (Equation 121). The mechanism of this reaction has been explored.
ð121Þ
3.10.6.6 Nucleophilic Attack at C-2 and Cleavage of the Thiophene Ring Cationic 5-complexes of thiophene may react with nucleophiles by undergoing ring scission. Thus the ruthenium complex 250 reacts with various nucleophiles to give the ring-opened butadiene thiolate complexes 251. The mechanism presumably involves initial attack at C-2 to give a thioallyl intermediate, which then undergoes C–S cleavage (Scheme 75) <2001OM1259>.
Scheme 75
Thiophenes and their Benzo Derivatives: Reactivity
Similarly, the dicationic iridium complex 240 reacts with malonate as in Scheme 76 <2000CCR63>.
Scheme 76
3.10.6.7 Nucleophilic Attack at Sulfur The thiophene manganesecarbonyl complex 243 is attacked at the sulfur atom by carbanion nucleophiles (Equation 122) <2001OM1259>.
ð122Þ
The iridium complex 240 reacts with 2 equiv of tetra-n-butylammonium hydroxide to give the sulfoxide 252 and the methyl ketone 253 in 23% and 37% yields, respectively <2000CCR63>. The mechanism shown in Scheme 77 has been proposed.
Scheme 77
829
830
Thiophenes and their Benzo Derivatives: Reactivity
3.10.6.8 Nucleophilic Attack at Benzenoid Carbon in Benzo[b]thiophene Complexes The 6-bound benzo[b]thiophene and dibenzothiophene complexes of iridium undergo reduction to the corresponding 4-complexes by hydride; reaction with 2 mol of ‘Red-Al’ results in addition of two H to give the cyclohexadiene complexes (Scheme 78) <2000CCR63>.
Scheme 78
3.10.6.9 Nucleophilic Attack on Hydrogen Attached to Carbon: Deprotonation Neutral 5-thiophene complexes undergo deprotonation by strong bases. The chromiumtricarbonyl complex of thiophene undergoes metalation with n-butyllithium. Treatment with 1 mol n-BuLi results in the removal of one of the -protons. Reaction with excess n-BuLi results in deprotonation at both the -positions of the thiophene. Subsequent quenching with D2O gives the 2,5-dideuterated complex. The lithiated derivatives can be reacted with other electrophiles such as Me3SiCl and PhCHO. If both the -positions are blocked in the thiophene, lithiation can take place at the -position. By iteration, the remaining -H can also be replaced (Scheme 79) <2001AHC(78)1>.
Scheme 79
Reaction of the 2-lithio derivative of the tricarbonylchromium complex of thiophene with Mn(CO)5X (X ¼ Cl, Br) yields the ,p-dicoordinated complex, which inserts carbon monoxide to form 254 (Scheme 80) <2001AHC(78)1>. Lithiation of the 6-chromiumtricarbonyl complex of benzo[b]thiophene occurs at C-2; with excess butyllithium the 2,7-dilithiated derivative results <2001AHC(78)1>.
Thiophenes and their Benzo Derivatives: Reactivity
Scheme 80
An interesting migration of the metal takes place when the 1(S)-thiophene complex 255 is treated with a base. Deprotonation at C-2 is followed by migration of the metal from sulfur to the adjacent carbon. On further treatment with triflic acid, reprotonation takes place at C-3 in this system (Scheme 81) <2001OM1259>.
Scheme 81
Benzo[b]thiophene behaves similarly. If the 2,5-positions in 255 are blocked by methyl groups, deprotonation followed by metal migration leads to the formation of a Re–C bond at C-3 of the thiophene.
3.10.6.10 Electrophilic Attack on Metal Complexes of Thiophene Normal electrophilic attack on thiophenes takes place mainly at the 2-position, with 3-substitution being a minor pathway. The initial products of electrophilic addition are 2H- or 3H-thiophenium species which are unstable and undergo rapid deprotonation to give 2- or 3-substituted thiophenes <1984CHEC(4)741>. Further, reactions of thiophenes with electrophiles are often accompanied by polymerization or multiple attacks by the electrophile. It was expected that complexation of the thiophene substrate with suitable metal derivatives might stabilize the thiophenium intermediates and lead to a more controlled electrophilic attack. Greater selectivity might result from this <1999OM2988>.
3.10.6.10.1 2
Electrophilic attack on 2-complexes
-Coordination results in greater localization of the p-bond in the uncoordinated portion of the thiophene ring. This partial dearomatization would be expected to result in increased reactivity toward electrophiles. A final oxidative removal of the complexing metal may thus lead to a new general strategy for the preparation of substituted thiophenes. The electron-rich pentammineosmium(II) moiety was the first to give positive results using this concept <1999OM2988>.
831
832
Thiophenes and their Benzo Derivatives: Reactivity
3.10.6.10.1(i) Protonation The 2-thiophene complex of pentammineosmium, on protonation with triflic acid gave the 2-coordinated 2Hthiophenium complex in high yield (Scheme 82). With the benzo[b]thiophene complex, however, protonation occurred on the sulfur on reacting with excess triflic acid.
Scheme 82
3.10.6.10.1(ii) Alkylation and acylation The 2-osmium complexes of -unsubstituted thiophenes undergo Lewis acid-promoted addition with acetals at C-2 to give the thiophenium complexes in good yields <1999OM2988>. These can be deprotonated to give the 2-substituted thiophene complexes. The electrophile attacks the substrate on the exo-face (Scheme 83).
Scheme 83
Surprisingly, acylation of the complex with acid anhydrides leads to 3-substitution. Thus the 3-acetylthiophene complex is obtained in 93% yield. Several novel thiafulvenium complexes have been prepared from the above products <1999OM2988>. Alkylation of the thiophene 2-osmium complex with hard electrophiles such as MeOTf or Et3Oþ takes place at the sulfur atom <2001OM1259>. The high cost associated with the use of stoichiometric quantities of osmium has limited the general use of this strategy. It is interesting that a new molybdenum 2-thiophene complex has now been developed <2003JA2024>. Its usefulness for further reactions has not yet been demonstrated.
3.10.6.10.2 4
Electrophilic attack on 4-complexes
-Thiophene complexes are synthesized by two-electron reduction of 5-thiophene dicationic complexes. They are thus relatively electron rich and tend to react with electrophiles.
Thiophenes and their Benzo Derivatives: Reactivity
3.10.6.10.2(i) Protonation The 4-ruthenium complex 256 is protonated by the weak acid (NH4)PF6 to give a thioallyl complex (Scheme 84) <2001OM1259>. Using (ND4)PF6, it has been shown that the protonation occurs stereospecifically on the endo-side of the ring; this suggests that the initial protonation takes place on the metal. The weak C–S bond in the thioallyl complex then cleaves to give the butadienethiolate 257. The same product is also obtained by the reaction of the 5-complex with hydride (see Scheme 75; Nuc ¼ H).
Scheme 84
3.10.6.10.2(ii) Attack at sulfur The iridium–4-thiophene complex 240 reacts with various electrophiles at the sulfur atom (Scheme 85) <2000CCR63>.
Scheme 85
3.10.6.10.3
Electrophilic attack on metallathiacycles leading to conjugated thioaldehydes and thioketones
[(triphos)RhH], generated from the rhodium complex 246 (Scheme 71), reacts with thiophene or its monosubstituted derivatives to form the 3-S,C,C-butadienethiolate complex 258 <1997SL643>. These butadienethiolate complexes readily react with electrophiles either at C-2 or at sulfur. Reaction with methyl iodide gives the S-methylated compound 259, while triphenylcarbenium ion attacks C-2 (or C-5 if there is a substituent on C-2) to yield the 4-coordinated pentenethial complex 260. Carbonylation of 260 (R1 ¼ R2 ¼ H) with CO gives the thioaldehyde 261. A similar series of reactions on benzo[b]thiophene leads to 262. Several analogs of such rare conjugated thiocarbonyl compounds have been reported.
833
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Thiophenes and their Benzo Derivatives: Reactivity
3.10.7 Further Developments In this section the bold section numbers refer to the main text. 3.10.2.1.3 Several new dithienylethenes carrying novel substituents on the thiophenes have been reported. The photochromic property of the system containing organo-boron substituents could be modulated by a fluoride ion <2006OL3911>. Dithienylethene derivatives having hexaethylene glycol side-chains exhibit photochromism and self-assembly in aqueous solution <2006JOC7499>. Another dithienylethene system investigated, has a naphthopyran attached to one of the thiophene rings; this hybrid system can give rise to eight different isomers <2006OL4931>. Conditions have been optimized for the scandium triflate catalyzed Nazarov cyclization of thiophene substrates in the presence of LiClO4 <2006OL5661>. 3.10.2.1.4 The matrix photolysis of 2,5-diiodothiophene, a possible precursor of 2,5-didehydrothiophene has been investigated <2006JOC9602>. 3.10.2.2 A remarkable room temperature oxidative homocoupling of bromothiophenes has been described <2006JA10930>. Treatment of 2-bromothiophene with AgNO3/KF in the presence of PdCl2 (PhCN)2 leads to 5,59-dibromo-2,29-bithiophene in 52% yield. The tolerance of the C–Br bond to the Pd-catalyzed homocoupling permits further elaboration to specific oligothiophenes by means of cross-coupling reactions. 3.10.2.2.1 The stable radical cation of terthiophene end-capped by bicyclo [2.2.2] octene units has been generated by oneelectron oxidation, and its crystal structure determined <2006JA14470>. Dimerization of several one-end-blocked 1,3-dithienylbenzo[c]thiophenes by chemical oxidation has been reported <2007TL779>.
Thiophenes and their Benzo Derivatives: Reactivity
3.10.2.6 Lithiation of 3-methylthiophene with lithium 2,2,6,6-tetramethylpiperidide is reported to be highly selective, giving the 5-lithio derivative <2007JOC1031>. 3.10.2.7 Aryl radicals generated by the action of tributyltin hydride on aryl iodides in the presence of benzeneselenol add to thiophene mainly at position 2. The product is a mixture of the 2,5- and 2,3-dihydro-2-arylthiophenes <2006T7824>. 3.10.2.7.6 Reductive desulfurization of a fused thiophene has been used to synthesize 7(S)-ethyl-8(S)-indolizidinol <2007TL697>. 3.10.2.8.1 Benzo[b]thiophene participates in intramolecular dipolar cycloaddition with an in situ generated carbonyl ylide; the reaction fails with the corresponding thiophene <2006JA10589>. 3.10.2.11.2 Pd(0)-catalyzed regioselective Suzuki cross-coupling reactions of tetrabromothiophene have been described <2007TL845>. This has enabled the preparation of tetraarylthiophenes containing two different types of aryl groups. A new Pd-catalyzed decarboxylative cross-coupling has been reported <2006JA11350>. Treatment of 3-methylthiophene 2-carboxylic acid with bromobenzene in the presence of Pd(PBut3)2 and tetrabutylammonium chloride hydrate in DMF gave 3-methyl-2-phenylthiophene in 63% yield. Pd-catalyzed 2,3-diarylation of ,-disubstituted 3-thiophenemethanols by reaction with aryl bromides occurs through the cleavage of the C(3)–C and C(2)–H bonds of the substrate <2006JOC8309>. The direct rhodium-catalyzed C–H arylation of thiophenes has been reported; yields range from 50% to 94% <2006JA11748>. Direct C–H arylation has been used in combination with ortho-alkylation to create polycyclic thiophenes in a one-pot reaction <2006OL4827>. The Pd-catalyzed tandem alkylation/Heck reaction of 3-iodothiophene in the presence of norbornene leads to a variety of di- and tri-substituted thiophenes in a one-pot reaction <2006OL3939>. 3.10.3 Bis(2,29-biphenylylene)sulfuranyl bis(tetrafluoroborate), a stable organo-sulfuranyl dication that contains only carbon ligands has been synthesized from the corresponding sulfurane <1996CHEC-II(2)527>. The dication reacts with MeLi or PhLi to give the corresponding bis (2,29-biphenylylene) di C-substituted persulfuranes as stable solids. These persulfuranes contain only carbon ligands <2006JA6778>. Tetrahydrothiophene functions as a catalyst in an annulation reaction leading to chromenes. It is postulated that a sulfonium ylide is formed initially which then adds intramolecularly to an acrylate <2006OL3853>. Diels–Alder cycloadditions of thiophene-1,1-dioxides with cyclopentadiene can take place either in the (2þ4) or (4þ2) mode depending on whether the thiophene dioxide has two or one electron-withdrawing substituents <2006T4139>. 1,3-Dipolar cycloaddition of benzo[b]thiophene 1,1-dioxide with azomethine ylides has been reported <2006TL5139>. 2,3-Dihydrobenzo[b]thiophene-2-one is considerably more acidic (pKa ¼ 8.82) than the corresponding benzofuran derivative; this reflects the greater aromatic stabilization of the conjugate base of the former <2006JOC8203>. 3.10.4.1 3-Methylthiophenylphosphonium salts form symmetric ethenyldithiophenes in MeCN in the presence of a strong base through a homocoupling reaction <2006OL4085>. Tris(2,29bithiophene-5-yl)methane reacts with atmospheric oxygen to generate a stable radical; the radical resides on the central carbon <2007TL281>. Me2Zn adds to thiophene-3-carbaldehyde and benzo[b]thiophene-3-carbaldehyde in the presence of the commercially available chiral metal complex ClCr(salen) to give the product alcohols in >95% enantiomeric excess <2006JA4940>. 3.10.4.2.2 Several push–pull systems based on thiophene oligomers bearing amino donors and cyanovinyl acceptors have been studied. They generate stable species both upon oxidation and reduction <2006JOC7509>.
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3.10.4.6 Silole rings have been constructed by treating 3,39-dibromo-2,29-bithienyl with BuLi and reacting the dilithio derivative so obtained with a dialkyldichlorosilane <2006JA9034>. The aryl–aryl bond formation by electron-transfer oxidation of Lipshutz cuprates has been utilized for the construction of macrocycles involving thiophene rings <2006JOC6110>.
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839
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Thiophenes and their Benzo Derivatives: Reactivity
Biographical Sketch
Dr. S. Rajappa (b. 1934) obtained his Ph.D. degree in chemistry from the Madras University in 1958. After a short stint as lecturer at the IIT, Madras, he proceeded to the USA to gain postdoctoral experience, first at the Florida State University and then at Harvard (Prof. R. B. Woodward). In 1964, he returned to India to join the CIBA Research Centre in Bombay, where he continued for nearly 22 years. He was promoted to manager, and head of the Synthetic Chemistry Division in 1984. In 1987, he moved to the National Chemical Laboratory, Pune, as the head of the Division of Organic Synthesis. His responsibilities included interaction with industry, initiating research projects of potential value to the industry, and guiding students for their Ph.D. degrees. Dr. Rajappa formally retired from this position in 1994, but continued his research at NCL as emeritus scientist for five more years. His deep concern at the continuing environmental degradation has led him to give seminars to industrial R&D groups on modern developments in catalysis aimed at bringing about the same chemical transformations with greater efficiency and hence less pollution. Of late, he has been addressing students, both at the graduate and postgraduate level, on ‘Ethics in Science’. Dr. Rajappa is a Fellow of the Indian Academy of Sciences and the Indian National Science Academy. He has nearly 150 publications to his credit. His association with industries as a consultant is still continuing.
Dr. Abdul Rakeeb Deshmukh (b. 1951) obtained his M.Sc. degree in organic chemistry from the Department of Chemistry, Pune University (1975). After spending a short period in an industry, he joined National Chemical Laboratory (NCL), Pune, and completed his Ph.D. degree (1984) from Pune University. Since then, he has been working as a scientist at NCL. He spent about a year at Southern Methodist University, Dallas, TX, USA, as a postdoctoral fellow (1991–92). He has published 78 research papers and filed 32 patents. His research interests include synthesis of drugs and drug intermediates, asymmetric synthesis, and synthesis of -lactams, and their applications as synthons in the synthesis of biologically useful compounds.
841
3.11 Thiophenes and their Benzo Derivatives: Synthesis O. Sato and J. Nakayama Saitama University, Saitama, Japan ª 2008 Elsevier Ltd. All rights reserved. 3.11.1
Introduction
844
3.11.2
Ring Synthesis by Formation of One Bond
845
3.11.2.1
Formation of a Bond Adjacent to the Sulfur Atom
3.11.2.1.1 3.11.2.1.2 3.11.2.1.3 3.11.2.1.4 3.11.2.1.5 3.11.2.1.6
3.11.2.2
Formation of a Bond to the Sulfur Atom
3.11.2.2.1 3.11.2.2.2 3.11.2.2.3
3.11.2.3
3.11.3.1
Intramolecular condensation of an active methylene with a carbonyl group and related groups Intramolecular addition of an active methylene carbon atom to nitrile group and related groups Miscellaneous cyclization
Formation of a Bond to the Sulfur Atom
3.11.2.3.1 3.11.2.3.2 3.11.2.3.3 3.11.2.3.4 3.11.2.3.5 3.11.2.3.6
3.11.3
Processes involving nucleophilic addition of thiol, thiolate, and dithiocarboxylate to sp2 and sp carbons Processes involving electrophilic attack of sulfenium and sulfonium ions and the equivalents on unsaturated carbon–carbon bonds Processes involving addition of thiyl radicals to unsaturated carbon–carbon bonds Processes involving attack of vinyl or aryl radicals on sulfur Processes involving attack of carbenium and related ions and carbene on sulfur Thio-Claisen rearrangement and related electrocyclization
Intramolecular reductive coupling of diketo sulfides (3-thiapenetane-l,5-diones) Intramolecular Friedel–Crafts or Wittig–Horner reaction Cycloaromatization of diallenyl, allenyl ethynyl, diethynyl, divinyl, and related sulfides Cyclization of vinyl and aryl radical intermediates Intramolecular [4þ2] cycloaddition Miscellaneous cyclization
Ring Synthesis by Formation of Two Bonds Sulfuration of a Four-Carbon Unit with a Sulfur Reagent
3.11.3.1.1 3.11.3.1.2 3.11.3.1.3 3.11.3.1.4
Sulfuration of alkanes, alkenes, and alkynes Gewald synthesis and related syntheses Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis) Miscellaneous cyclizations
845 845 851 853 855 855 858
860 860 868 871
876 876 876 879 882 883 884
886 886 886 891 894 896
3.11.3.2
Combination of a C–C–C–S Unit with a One-Carbon Unit
897
3.11.3.3
Combination of a C–C–S Unit with a C–C Unit
900
3.11.3.4
Combination of a C–S–C Unit with a C–C Unit
901
3.11.3.4.1 3.11.3.4.2
3.11.3.5
Hinsberg synthesis and related syntheses 1,3-Dipolar cycloaddition
901 902
Combination of a C–S Unit with a C–C–C Unit
903
3.11.4
Ring Synthesis by Formation of Three Bonds
904
3.11.5
Ring Synthesis from Other Heterocyclic Compounds
904
3.11.5.1
From Three- and Four-Membered Heterocyclic Compounds
904
3.11.5.2
From Five-Membered Heterocyclic Compounds
905
3.11.5.2.1 3.11.5.2.2 3.11.5.2.3
From furans and related compounds From tetra- and dihydrothiophenes and related compounds From sulfur- and nitrogen-containing five-membered heterocyclic compounds
843
905 906 907
844
Thiophenes and their Benzo Derivatives: Synthesis
3.11.5.3
From Six-Membered Heterocyclic Compounds
3.11.5.3.1 3.11.5.3.2
3.11.6 3.11.6.1
Extrusion of sulfur or sulfur monooxide from 1,2- and 1,4-dithiins Ring contraction of other sulfur-containing six-membered heterocyclic compounds
Benzo[b]thiophenes by Annelation of Thiophenes
909 909 911
912
[2þ4] Cycloaddition of Thiophene-2,3-Quinodimethanes (2,3-Dimethylene-2,3dihydrothiophenes) and Related Compounds
912
3.11.6.2
Acid-Promoted Cyclizations
912
3.11.6.3
Photocyclization of 1-Aryl-2-(thienyl)ethylenes and the Related Compounds
913
3.11.6.4
Transition Metal-Mediated Cyclizations
915
3.11.6.5
Diels–Alder Reactions of Vinylthiophenes and Related Compounds
917
Miscellaneous Cyclizations
919
3.11.6.6 3.11.7
Benzo[c]thiophenes by Annelation of Thiophenes
921
3.11.8
Further Developments
922
References
922
3.11.1 Introduction This chapter deals with the advances in the synthetic methods of thiophenes and their benzo derivatives. The references cover the literature of the period 1995–2006. Stress has been laid on the practical or newly developed syntheses and syntheses of structurally interesting compounds, although efforts have been made to cover the literature published in that period as extensively as possible. A number of new synthetic methods have been developed after publication of CHEC-II(1996), and also excellent reviews have appeared <1996PHC(8)82, 1997PHC(9)77, 1998PHC(10)87, 1999PHC(11)102, 2000PHC(12)92, 2001PHC(13)87, 2002PHC(14)90, 2003PHC(15)116, 2004PHC(16)98, 2005PHC(17)84, 2006PHC(18)126>. This is partially due to the increasing need for thiophene derivatives as the starting materials for constructing a variety of molecular devices in addition to the need in the field of pharmaceuticals and agrochemicals. For synthetic studies on thiophenes in the period before 1994, readers are recommended to consult CHEC(1984) <1984CHEC(4)863> and CHEC-II(1996) <1996CHEC-II(2)607>). These are covered in 72 pages in CHEC(1984) (Volume 4, Chapter 3.15) and in 72 pages in CHEC-II(1996) (Volume 3, Chapter 2.11). The present chapter is intended to update the previous work concentrating on new synthesis, reactions, and concepts. Sulfur exists in many forms in organic compounds: thiols (thiolates), sulfides, disulfides, sulfonium salts, sulfoxides, sulfones, and sulfonic acids and their esters are representative compounds containing sulfur. There also exist sulfurcontaining transient intermediates such as thiyl radicals and sulfenium ions in addition to rather labile species such as sulfonium ylides and sulfuranes. All of these compounds serve as starting materials for the construction of the thiophene ring. In addition, there are many inorganic compounds that serve as the sulfur source for constructing a thiophene nucleus. Elemental sulfur, hydrogen sulfide, metal sulfides, phosphorus pentasulfide, Lawesson’s reagent, sulfur mono- and dichlorides, and thionyl chloride are the representative sulfur sources of thiophene synthesis. This makes possible a plethora of combinations that can lead to the formation of the thiophene ring. Therefore, the synthetic methods of thiophenes are much more complex and abundant in numbers than those of other fivemembered hetarenes such as furans and pyrroles. As in the case of CHEC(1984), the synthetic methods are described in order of bond formation, beginning with the formation of one bond, between sulfur and C-2 of thiophene, and proceeding around the ring, then two bonds, etc. However, the classification of the synthetic methods is often difficult because of the intricate plot of the synthesis. In this chapter, the synthetic methods are classed, in many cases, according to the final reaction leading to the thiophene nucleus but not the starting materials since this permits a more clear-cut classification, as in the same way of CHECII(1996). Thiophene syntheses using other heterocyclic compounds as the starting material are treated in independent sections. Also treated in independent sections are the benzo[b]- and benzo[c]-thiophene syntheses by annelation of thiophenes. In order to aid the quick understanding of the reader, most synthetic methods are shown by chemical equations, and the yields and reaction conditions are also given in as much detail as possible.
Thiophenes and their Benzo Derivatives: Synthesis
3.11.2 Ring Synthesis by Formation of One Bond 3.11.2.1 Formation of a Bond Adjacent to the Sulfur Atom According to the classification mentioned above, the thiophene ring synthesis by forming one carbon–sulfur bond adjacent to sulfur is described first (Equation 1).
ð1Þ
This approach to the thiophene ring seems most direct and involves: (1) intramolecular nucleophilic addition of thiol, thiolate, and dithiocarboxylate sulfurs and, in a rare case, sulfide sulfur to sp2 and sp carbons; (2) electrophilic attack of sulfenium and sulfonium ions and their equivalents on unsaturated carbon–carbon bonds; (3) addition of thiyl radicals to unsaturated carbon–carbon bonds; (4) addition of vinyl and aryl radicals to the sulfur atom of sulfides; and (5) electrophilic attack of a carbocation on the sulfur atom of sulfides.
3.11.2.1.1
Processes involving nucleophilic addition of thiol, thiolate, and dithiocarboxylate to sp2 and sp carbons
Intramolecular addition of thiols 2 derived from the acetates 1 affords thieno[3,4-c]cepham sulfones 3 having properties as a human leukocyte inhibitor (Scheme 1) <1995BML691>.
Scheme 1
Titanium(IV) benzylidenes (Schlock carbenes) 4 react with resin-bound esters 5 to generate the resin-bound enol ethers 6. Treatment of the enol ethers with a mixture of trifluoroacetic acid (TFA) and trifluoroacetic anhydride (TFAA) leads to cleavage from the resin, removal of the ButMe2Si group, and subsequent cyclization to give the benzothiophenes 7 (Scheme 2) <2004JOC6145>.
Scheme 2
The condensation of -mercaptoacetaldehyde with sulfones 8 affords 2-aminothiophenes 9 (Scheme 3) <2001BMC1123>. 2-Aminothiophene 10 <1998JHC933> and bis(2-amino-3-thienyl)sulfone 11 <1998JHC927> have been synthesized by use of this method.
845
846
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 3
Lithiation of propargyl amine 12 and treatment with methyl isothiocyanate afford the thiolate 13, which cyclizes in the presence of KOBut and is methylated by iodomethane to produce 2,5-bis(N,N-dimethylamino)thiophene 14 (Scheme 4) <1997TL7241>. Similar reactions of 15 and 17 give the corresponding thiophenes 16 <1998EJO253> and 18 <1998TL2433>, respectively. 2-Aminothiophenes 20 are derived from the intermediate 19 <2001TL4687>.
Scheme 4
Thieno[2,3-b]quinolin-4(9)-ones 23 are synthesized by thermal [1,3]-sigmatropic rearrangement of alkyne 21 followed by cyclization of the intermediates 22 (Scheme 5) <2002S669>.
Scheme 5
Thiophenes and their Benzo Derivatives: Synthesis
The carbanion generated from the dinitrile 24 causes a Smiles-type nucleophilic rearrangement to produce new anions 25 and 26. The tandem intramolecular cyclization of the latter affords dihydrothiophene 27. Thieno[2,3b][1,6]naphthyridine 28 is derived from 27 in four steps (Scheme 6) <1995H(41)1307>.
Scheme 6
The cyclization of the Pummerer rearrangement product 30 derived from o-methylsulfinyl-difluorostyrene 29 leads to 2-fluorobenzo[b]thiophene 31 (Scheme 7) <1997CC1537>. Treatment of thiol 32 with NaH affords 2-fluoro-4,5-dihydrothiophene 33 by a 5-endo-trig cyclization <2000CC1887>.
Scheme 7
A base-induced ring opening of dithiolanes 34 and subsequent cyclization gives 5-vinylsulfanylthiophenes 35 (Scheme 8) <2004H(63)1281>.
Scheme 8
847
848
Thiophenes and their Benzo Derivatives: Synthesis
Treatment of unsaturated diketones 36 with sulfuration reagents affords a mixture of thiophenes 37 and 38, the ratio of which depends on the reagent used (Equation 2) <1998TL9191>.
ð2Þ
Triethylamine is converted into thienopentathiepin 39 and heptathiocane 40 by the unprecedented cascade reaction with S2Cl2 in the presence of DABCO. Oxidation of an N-ethyl group of Et3N by a complex of S2Cl2 with 1,4-diazabicyclo[2.2.2]octane (DABCO) (X–S–S–Cl) affords an enamine, which reacts with X–S–S–Cl to give a thioamide followed by elimination of X–SH. The condensation of this thioamide with the enamine followed by cyclization and oxidation affords the thiophene 39 (Scheme 9) <2003OL1939>.
Scheme 9
Treatment of compounds 41 with -nitrostyrenes in the presence of piperidine affords tetrahydrothiophenes 43. Michael addition of 41 to nitrostyrenes produces adducts 42. Intramolecular cyclization of 42 with loss of H2O leads to 43 (Scheme 10) <2006M219>.
Scheme 10
Thiophenes and their Benzo Derivatives: Synthesis
Bis-allenyl thiosulfonate 44, when heated, affords a mixture of thienooxathiine-3-oxide 47, thienothiophene-2,2dioxide 48, and thiophene 49. [3,3]-Sigmatropic rearrangement of 44 generates intermediate 45, which undergoes cyclization, and subsequent [2,3]-sigmatropic rearrangement (path A) or [1,3]-sulfinate migration (path B) produces 47 or 48, respectively. On the other hand, extrusion of SO2 from 45 generates the carbene 46, which undergoes cyclization to give 49 (path C). Cyclization through path C belongs to the category of Section 3.11.2.1.5 (Scheme 11) <2002TL9615>.
Scheme 11
Sulfuration of 2,3-diaroylbicyclo[2.2.1]hepta-5-enes 50 using B2S3, which is generated in situ by reaction of BCl3 with bis-trialkyltin sulfide or with bis-trimethylsilyl sulfide, produces enthiols 51 and 52. Their cyclizations followed by [3,4] and [3,5] rearrangements afford dihydrothiophene 53 and thiophene 54, respectively (Scheme 12) <1997TL799>.
Scheme 12
849
850
Thiophenes and their Benzo Derivatives: Synthesis
Compounds 55 are subjected to cleavage of the xanthate part by H2NCH2CH2NH2 and acid-catalyzed cyclization, which provide dihydrothiophenes 56 (Scheme 13) <2005TL8053>.
Scheme 13
Treatment of 2-(1,2-dibromoethenyl)quinoxalines 57 with Na2CS3 affords thieno[2,3-b]quinoxalines 59. Addition of the thiocarbonate to the side chain generates 58. Intramolecular cyclization of 58 with loss of CS2 and NaBr leads to 59 (Scheme 14) <2001J(P1)154>. Azulenothiophenes 61 are prepared from azulene derivatives 60 by the reaction with thioacetamide (Scheme 15) <2002H(58)405>. Similar reactions of furyl ketones 62 afford thieno[3,4-b]furans 63 <1998JHC71>.
Scheme 14
Scheme 15
Thiophenes and their Benzo Derivatives: Synthesis
Reaction of o-halo pyridines 64 with CS2 followed by quenching with MeI affords thienopyridines 65. The yield of 65 is improved by using the corresponding N-oxide 66 as the starting material, followed by deoxygenetion with PBr3 (Scheme 16) <1997S949>. The industrial synthesis of 3-methylthiophene by the reaction of 2-methylbutanol with CS2 in the presence of a Cr catalyst has been reported <1998CC2541>.
Scheme 16
3.11.2.1.2
Processes involving electrophilic attack of sulfenium and sulfonium ions and the equivalents on unsaturated carbon–carbon bonds
In all of the examples given above, the sulfur atom acted as a nucleophile. In contrast, there are a number of cases where electron-deficient sulfur species such as sulfenyl ion and its equivalent (e.g., disulfide/Lewis acid complex, sulfenic acid, and sulfenyl halide), sulfonium ion, sulfine, etc., serve as an electrophile. Conjugated vinyl sulfines 68, produced by treatment of the allene 67 with an alkyllithium and then with sulfur dioxide, undergo cycloaromatization to give thiophenes 69 in one pot (Scheme 17) <1995RTC51>.
Scheme 17
Cyclization of the acid 70 to condensed thiophene 71 is performed with thionyl chloride in the presence of a catalytic amount of pyridine <1998SC2191>. Preparation of 3-chloro[1]benzothiophene-2-carbonylchloride 72 <2001H(55)741> from trans-cinnamic acid and benzothienothiophene 73 <1995JHC659> from benzo[b]thiophene-2-acrylic acid has been reported. A similar reaction of dicarboxylic acid 74 (R ¼ OH) affords a mixture of thiophenes 75 and 76 together with the dicarbonyl chloride 74 (R ¼ Cl) <2001SC2997>.
851
852
Thiophenes and their Benzo Derivatives: Synthesis
Condensation of S,N-acetals 77 with 1,3-dicarbonyl compounds in the presence of mercury acetate leads to thiophenes 80. Mercury complexes 78 derived from 77 react with 1,3-dicarbonyl compounds to generate intermediates 79, which undergo cyclization and subsequent hydrolysis-deacylation to afford 80 <1998JOC6086, 2000JOC3690, 2000JHC363>. Thiophenes 82 <2002OL873, 2004JOC4867> are also prepared by reaction of 77 with 2-diazo-3-trimethylsilyloxy-3-butenoate 81 (Scheme 18).
Scheme 18
Dihydrobenzothiophene 84 is prepared from anisole derivative 83 via intramolecular cyclization using phenyliodin(III) bis(trifluoroacetate) and BF3?Et2O followed by treatment with aq MeNH2 (Scheme 19) <1999CC143>.
Scheme 19
Oxidative cyclization of -aryl--mercaptoacrylic acids 85 in the presence of iodine under microwave (MW) irradiation affords the corresponding benzothiophenes 86 (Equation 3) <2004TL9645>.
Thiophenes and their Benzo Derivatives: Synthesis
ð3Þ
Treatment of 1,3-benzoxathiole derivatives 87 with benzaldehydes in the presence of piperidine/acetic acid gives thioaurone derivatives 88. This reaction probably involves an oxidation step. These are also synthesized by the reaction of disulfide 89 with aldehydes (Equation 4) <2005T8648>.
ð4Þ
3.11.2.1.3
Processes involving addition of thiyl radicals to unsaturated carbon–carbon bonds
There are also cases where addition of thiyl radicals to unsaturated carbon–carbon bonds is the crucial step for thiophene ring formation. Flash vacuum pyrolysis (FVP) of the phosphorus ylide 90 affords initially the alkyne 91, which produces thiyl radical with loss of methyl radical. Cyclization of the resulting radical affords thienothiophene 92 as the final product with loss of one more methyl radical (Scheme 20) <1995SL53>. FVP of ylide 93 results in a multistep cascade reaction leading to 7-(2-benzothienyl)benzofuran 94 (Scheme 21) <2001SL228>.
Scheme 20
853
854
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 21
Ultraviolet (UV) irradiation of chiral thiol 95 in the presence of 2,29-azobisisobutyronitrile (AIBN) gives tetrahydrothiophene 96 without epimerization <2000OL3757>.
Irradiation of compound 97 with SO2 in the presence of PhSSPh affords tetrahydrothiophene 1,1-dioxide 99 via 5-exo-cyclization of intermediary sulfonyl radical 98 (Scheme 22) <2005JOC10854>.
Scheme 22
Thiophenes and their Benzo Derivatives: Synthesis
3.11.2.1.4
Processes involving attack of vinyl or aryl radicals on sulfur
Treatment of the ketenethioacetals 100 with Bu3SnH under radical forming conditions (AIBN, PhH, reflux) directly affords benzothiophene 101. The reaction involves a radical centered tandem cyclization–fragmentation sequence (Scheme 23) <1995TL2861>.
Scheme 23
3.11.2.1.5
Processes involving attack of carbenium and related ions and carbene on sulfur
Iodine-mediated cyclization of benzyl o-ethynylaryl sulfide 102 gives 3-iodobenzo[b]thiophene 103. The iodide 103 can be converted into a novel tubulin binding agent 104 by Pd-mediated coupling (Scheme 24) <2001OL651>. Similar cyclization of 105, 107, and 109 affords dihydrothiophene 106 <2001BML2341>, benzothiophenes 108 <2001TL6011, 2002JOC1905, 2005JOC9985>, and benzodithiophene 110 <2005TL8153>, respectively.
Scheme 24
855
856
Thiophenes and their Benzo Derivatives: Synthesis
Pd-catalyzed cycloisomerization of (Z)-2-en-4-yne-1-thiols 111 gives substituted thiophenes 112. The mechanism involves electrophilic activation of the alkyne moiety by Pd(II) followed by intramolecular cyclization, protonolysis, and aromatization (Scheme 25) <2000OL351>. 5-Endo cyclization of alkynyl thiols 113 using a Mo, W, or Cr catalyst affords dihydrothiophene 114 <2000S970>.
Scheme 25
Au-catalyzed cyclization of alkoxyalkyl o-ethynylphenyl sulfides 115 affords benzothiophenes 117. The reaction involves Au-mediated intramolecular cyclization and subsequent migration of alkoxyalkyl group of the resulting 116 (Scheme 26) <2006AGE4473>.
Scheme 26
Condensation of benzotriazoles 118 with phenyl isothiocyanate followed by heterocyclization in the presence of ZnBr2 gives 2-aminothiophenes 119 (Scheme 27) <2001JOC2850>.
Scheme 27
Thiophenes and their Benzo Derivatives: Synthesis
Substituted thiophenes 121 are prepared from 1-alkynyl-2,3-epithioalcohols 120 with Hg2þ catalyst and dilute sulfuric acid (Scheme 28) <1997TL7785>.
Scheme 28
,-Epoxycarbonyl compounds 122 are converted to corresponding thiophenes 123 by treatment with Lawesson’s reagent in the presence of p-TsOH (Scheme 29) <1995SC2647>.
Scheme 29
Reaction of 2-[bis(methylthio)methylene]cyclohexanone 124 with lithium hexamethyldisilazide (LHMDS) and ethyl bromoacetate generates intermediate 125, which gives thiophene 126 and furan derivatives 127 (Scheme 30) <1997JOC1599>.
Scheme 30
The reaction of thiol 128 with tert-butyllithium affords two isomeric thiophenes 130 and 131. The latter is probably produced through rearrangement of the carbenoids 129 (Scheme 31) <1995JOC5588>.
Scheme 31
857
858
Thiophenes and their Benzo Derivatives: Synthesis
Rh-catalyzed decomposition of diazoketone 132 in the presence of benzaldehyde and Ti(OPri)3Cl affords ringtransformed thiophene 134 and ring-enlarged enone 135. Both products are formed by the condensation of intermediary bicyclosulfonium ylide 133 with the aldehyde (Scheme 32) <2004JOC2899>.
Scheme 32
3.11.2.1.6
Thio-Claisen rearrangement and related electrocyclization
If we consider the intermediate of the thio-Claisen rearrangement, it is reasonable that the ring synthesis via thio-Claisen rearrangement is treated in this section. Thermal isomerization of 136 in the presence of PPh3 gives thienodithiolethione 138 via cyclization of an allenic intermediate 137 (Scheme 33) <1997T11627>. Thieno[2,3-b]thiochromen-4-ones 140 are synthesized by TsOH-catalyzed reaction of 139 <2002SC1271>. Treatment of thioacylmorpholines with propargyl bromide generates the intermediates 141, which on heating give 2-morpholinothiophenes 142 <2003TL6253>.
Scheme 33
Thiophenes and their Benzo Derivatives: Synthesis
Sulfoxides 143 are heated in refluxing CCl4 to give monothio-hemiacetals 144. Compounds 144 afford dihydrothienoquinolinones 145 when dissolved in MeOH. The formation of 144 from 143 is explained by [2,3], [3,3] sigmatropic rearrangements followed by cyclization (Scheme 34) <1998T11603>. Closely related compounds 146 <2002T10309>, 147 <1999T1449>, 148 <2002TL2123>, 149 <2002T10047>, and 150 <2004SC2159> are also synthesized by using this method. The reaction of 151 with m-chloroperbenzoic acid (MCPBA) affords the thiophenes 152 <2002T4551>.
Scheme 34
Treatment of thione 153 with diphenyldiazomethane generates dithiazole 154, which is followed by electrocyclization to afford benzo[b]thiophene 155 (Scheme 35) <1997J(P1)3345>.
Scheme 35
859
860
Thiophenes and their Benzo Derivatives: Synthesis
3.11.2.2 Formation of a Bond to the Sulfur Atom The thiophene ring synthesis by forming a carbon–carbon bond to sulfur atom is defined by Equation (5). Several new syntheses that belong to this category have been developed. However, many syntheses reported since the early 1980s are applications or modifications of the traditional methods, though many of them are practical. The most frequently encountered method involves the intramolecular condensation between a carbonyl group with an -carbon atom adjacent to the sulfur and activated by an electron-withdrawing group. Intramolecular addition of the -carbanion adjacent to the sulfur to a cyano group is also used conveniently for the preparation of 3-aminothiophenes. ð5Þ
3.11.2.2.1
Intramolecular condensation of an active methylene with a carbonyl group and related groups
One of the most common strategies for the preparation of thiophenes involves the intramolecular condensation of -thioglycolates onto adjacent calbonyls (Knoevenagel synthesis). A nucleophilic aromatic substitution of tosylate 156 with methyl thioglycolate gives the precursor 157, which affords naturally occurring anthrathiophene 158 by treatment with sodium methoxide (Scheme 36) <2000OL2351>. Similar reactions of 159, 161, 163, 165, 167, 169, 171, and 173 with ethyl (or methyl) thioglyclate give the corresponding thiophenes 160 <1997SC2143, 1999CPB1221>, 162 <2000TL4973>, 164 <1997J(P1)3465>, 166 <1998CPB279>, 168 <2001T7213>, 170 <1997TL183>, 172 <1997BML3101, 2006BML5057>, and 174 <2000S1078>, respectively. Thienomorphinam 176 <1999OL513> is prepared from 175. Synthesis of thienoindole 177 <2004EJO2589>, tetrahydro-thienopyridine 178 <2002BML2549>, thienopyridines 179 <2002JOC943>, and thienopyrazole 180 <2005JHC1305> is reported.
Scheme 36
Thiophenes and their Benzo Derivatives: Synthesis
Tetrasubstituted thiophenes 182 <2002TL257> and 184 <1997T161> are synthesized by cyclization of 181 and 183, respectively. Similar transformations of 185 to 186 have been reported <1995JFC(70)121>.
Treatment of the disulfide 187 with tributylphosphine produces the thiol 188, which is alkylated with ethyl bromo-[2-14C]acetate and subsequent cyclization of the resulting product by NaOEt gives 14C-labeled thieno[4,3,2ef ][3]benzazepine 189 (Scheme 37) <1996H(43)1189>. The preparations of 2-substituted benzo[b]thiophenes 191 from 190 have been reported <2000TL5415>. Condensation of -chlorodihydrobenzaldehyde 192 or 5-nitro-2chlorobenzaldehyde with sodium sulfide and ethyl chloroacetate gives dithiophene 193 <1996LA239> or benzo[b]thiophene 194 <2001JHC1025>, respectively.
861
862
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 37
Solid-phase synthesis of the substituted thiophenes 197 has been reported. Intermediates 196, derived from resinbound ester 195, react with -bromo ketones, and treatment of the resulting products with NaOMe affords the thiophenes 197 (Scheme 38) <2003T4851>.
Scheme 38
Thiophenes and their Benzo Derivatives: Synthesis
Reaction of 2,3-dibromo-1,4-diketone with 2 molar equiv of thioamide affords bithiophene 198 (Equation 6) <2002CL896>.
ð6Þ
Bimetallated compound 199, derived from thioanisole, reacts with 2 molar equiv of methyl chlorocarbonate to give the diester 200, which is converted into benzothiophene 201 (Scheme 39) <2002T4529>.
Scheme 39
Treatment of thiasalicylate with o-fluoro--bromoacetophenones in the presence of Cs2CO3 affords 5-oxa-11thiabenzo[b]fluoren-10-ones 204. The reaction involves formation and cyclization of intermediates 202, and subsequent intramolecular ipso-fluorosubstitution of 203 (Scheme 40) <2001TL8429>.
Scheme 40
Reaction of the compounds 205 with lithium diisopropylamide (LDA) gives cyclized intermediates 206, which are treated with a low-valence titanium reagent to afford the corresponding benzothiophenes 207 (Scheme 41) <2002CHE156>. Treatment of the intermediate 208 with LDA affords pyrazolothienopyridines 209 <2002BML9>. 2-Arylthiophenes 210 <2003TL6665> and 2,5-diarylthiophene 211 <2006BML1350> have also been synthesized.
863
864
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 41
Condensation of -alkyl--phenylthio-,-unsaturated carbonyl compounds 213, prepared from 3-methoxy-1phenylthio-1-propyne 212, with methyl thioglycolate readily affords a number of 2,3,5-trisubstituted thiophenes 214 (Scheme 42) <1995H(41)13>. Similar reactions of 215, 217, and 219 with ethyl (or methyl) thioglycolate give the thiophenes 216 <1997TL1049>, 218 <1997JOC1599>, and 220 <1997S461>, respectively. Conjugate addition onto acetylenic ketones 221 gives the corresponding thiophenes 222 <1997HCA531>. Synthesis of thiophene derivatives 223, which are precursors of dimethylene thiophene 224 <1995SC3435>, is reported as an application of this method.
Scheme 42
Thiophenes and their Benzo Derivatives: Synthesis
Conjugated addition of 2-(mercaptomethyl)benzimidazole 225 onto N-succinimidyl phenylpropiolate 226 followed by cyclization gives 2-(2-thienyl)benzimidazole 227 (Equation 7) <1997SC2041>.
ð7Þ
Benzo[b]thienoquinones 230 are synthesized by the reaction of 2-acyl-1,4-benzoquinones with thioglycolic acid esters followed by protection of 228 with 1-trimethylsilylimidazole and oxidation of 229 with ceric ammonium nitrate (CAN) (Scheme 43) <2001H(55)2423>. Similar reaction of 4,7-dioxo-dihydrobenzothiophenes 231 affords 4,7dioxo-dihydrobenzodithiophenes 232 <2003H(60)1689>. Synthesis of thiophenes 233 <2005H(65)2973> and 234 <2006H(68)1709> has also been reported.
Scheme 43
Reaction of 2-fluoroalkylchromones 235 with -thioglycolates gives dihydrothienocoumarin derivatives 237. Conjugate addition of the thiols onto 235 forms the tricyclic intermediates 236, which undergo a reductive ring opening and subsequent intramolecular lactonization to afford the final products 237 (Scheme 44) <2001TL5117, 2001TL5121, 2003T2625>.
865
866
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 44
-Formyl esters 238 react with thioglycolic acid in acidic methanol to give triester derivatives 239 and sulfides 240. The base-catalyzed intramolecular cyclization of the triester 239 affords 2,3,4-trisubstituted thiophenes 241 (Scheme 45) <1996H(43)775>.
Scheme 45
Condensation of CS2 with 1,3-cyclohexanediones 242 under basic conditions forms dithioketene anions, treatment of which with active methylene compounds and then with methyl iodide leads to thiophene derivatives 243 (Scheme 46) <1995SC2449, 1996LA239>. Similar transformations of 244, 246, and 248 to 245 <2000SC1695>, 247 <2001JHC1167>, and 249 <2005T3507>, respectively, have been reported.
Scheme 46
Thiophenes and their Benzo Derivatives: Synthesis
Treatment of 250 with CS2 in the presence of KOH generates intermediary adducts 251, which afford tetrasubstituted thiophenes 252 by addition of 2 molar equiv of R1R2CHBr (Scheme 47) <1995M601>.
Scheme 47
3-(1-Pyridino)thiophene-2-thiolates 255 are synthesized by the reaction of pyridinium chlorides 253, CS2, and phenacyl bromides in the presence of Et3N via a cyclization of intermediates 254 (Scheme 48) <2003CPB75>.
Scheme 48
Condensation of -diketones with phenyl isocyanate followed by alkylation and cyclization gives 2-aminothiophenes 256 (Scheme 49) <2001SL1731, 2002TL257, 2003T1557>. Treatment of 2-[(carboxymethyl)mercapto]benzoic acid 257 with Vilsmeier reagent (DMF/POCl3) gives 3-chlorobenzo[b]thiophene-2-carboxaldehyde 258 (Scheme 50) <1996JOC6523>.
867
868
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 49
Scheme 50
3.11.2.2.2
Intramolecular addition of an active methylene carbon atom to nitrile group and related groups
The condensation of thioglycolates or -thioketones onto nitriles can be employed to produce 3-aminothiophenes (Thorpe–Ziegler synthesis). This method is utilized to synthesize 2-(methylthio)thiophenes 260 <1997H(45)493> from 259, 3-aminothiophenes 261 <1999JHC423>, 2,4-diaminothiophenes 263 <1997JOC6096> from 262, and 4-sulfonylthiophenes 264 <1999JHC659>. Synthesis of 3-aminobenzothiophenes 266 <2001TL8539>, 268 <2002CPB1215>, 270 <2002H(57)317>, 272 <1997JHC1163>, and dihydronaphthothiophene 274 <2002S1096> from 265, 267, 269, 271, and 273, respectively, is reported. 3-Aminothiophenes 276 <2001BML915>, 278 <2001BML2205>, and 280 <2001BML9> are prepared from 275, 277, and 279, respectively. Preparation of thieno[2,3-c]pyridazine 282 <1997H(45)1319> from 281, thienopyridothienopyridazine 284 <1997H(45)1733> from 283, thieno[2,3-d]pyrimidines 286 <1995LA1703> from 285, and thieno[3,2-c]pyran-4-ones 288 <1997BML3101> from 287 is reported. Thieno[2,3-b]thiophenes 290 <2001JHC1167> and dithienopyridine (or dithienopyrimidine) 292 <2004T275> are synthesized from 289 and 291, respectively. Treatment of halosubstituted acrylonitriles 293 with ethyl mercaptopyruvate affords the corresponding thiophenes 294 <2005JHC661>.
Thiophenes and their Benzo Derivatives: Synthesis
2-Pyridyl sulfides 295 containing a fluorine atom at the side chain derived from 2-thioxopyridine undergo a basecatalyzed cyclization to give 3-amino-2-fluorothieno[2,3-b]pyridines 296 (Equation 8) <1995JOC7654>.
ð8Þ
Thieno[2,3-d]pyrimidines 298 <1998H(48)1157> are synthesized by the reaction of thioxopyrimidines 297 with halomethyl reagents such as chloroethyl acetate, chloroacetonitrile, and chloroacetone, etc. Similar reactions with thioxopyridines 299 give the corresponding thiophenes 300 <1995JHC819>, 301 <1997JHC729, 2004CHE377>, 302 <2002SC3493>, and 303 <1996JHC431>. Synthesis, properties, and biological activity of thienopyridines have been reviewed <2005RCB864>.
869
870
Thiophenes and their Benzo Derivatives: Synthesis
The condensation of active methylene compounds such as malononitrile, ethyl cyanoacetate, etc., with phenyl isocyanate followed by alkylation and cyclization gives 3-aminothiophenes 304 (Scheme 51) <2003T1557>. Dihydrothienopyrimidine-4(1H)ones 306 are prepared by the reaction of 305 with -halo ketones <2006HAC104>.
Scheme 51
A nucleophilic aromatic substitution of imine 307 with methyl thioglycolate gives the intermediates 308, which undergo intramolecular cyclization and subsequent aromatization to give benzothiophenes 309 (Scheme 52) <2001HCO283>. Vinamidinium salts 310 react with methyl thioglycolate to give 2,4-substituted thiophenes 311 <2005TL1319>. Reaction of thioacrylamides 312 with acceptor-substituted halomethyl compounds generates iminium salts 313 which undergo intramolecular cyclization to give the corresponding thiophenes 314 (Scheme 53) <2000EJO1327, 2000EJO3273, 2000J(P1)4316, 2004S1633, 2005BMC1275>. Bis(2-amino-5-thienyl)ketones 315 can be prepared by use of this method (Equation 9) <2001AGE3008, 2002T2137>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 52
Scheme 53
ð9Þ
3.11.2.2.3
Miscellaneous cyclization
Photochemical reaction of disulfide 316 with isonitriles 318 affords benzothienoquinoxalines 321. Irradiation of 316 generates thiyl radical 317, which reacts with 318 to form the imidoyl radicals 319. Tandem cyclization of 319 onto CN group and the resulting iminyls 320 onto the aromatic ring lead to 321 <1998T5587>. The reaction of diazonium salts 322 with isothiocyanates 323 affords isomeric phenylbenzothienoquinolines 324 and 325 <2000JOC8669> (Scheme 54).
871
872
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 54
Intramolecular radical 5-exo-cyclization of -thioacrylate-thiocarbonate 326 using Bu3SnH/AIBN affords a diastereomeric mixture of thiabicyclononane derivatives 327 (Scheme 55) <2000T3425>. Similar stereoselective cyclization of 328 to 329 has been reported <2005T9273>.
Scheme 55
Aroyl ketene N,S-acetals 330 undergo deprotonation in the presence of LDA to generate stabilized carbanion 331 which undergoes a cyclization to afford the corresponding 2-amino-4-aryl thiophenes 332 (Scheme 56) <1996SC4157>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 56
Side-chain deprotonation of the methylthio group of 333 by LDA followed by an intramolecular cyclization gives thioindoxyls 334 <2002SL325, 2003T4767>. Subsequent treatment of 334 with LDA and aldehydes affords thioaurones 335 <2003SL1479, 2005T9007>. The reaction of 334 with LDA and crotonaldehyde gives benzothienopyran 336 via conjugate addition and ring closure of the intermediates (Scheme 57) <2003SL1479>.
Scheme 57
Treatment of eight-membered ring compounds 337 and 339 with ButLi affords isomeric trithienothiophenes 338 and 340, respectively <2004OL3437>.
873
874
Thiophenes and their Benzo Derivatives: Synthesis
Side-chain deprotonation of the thiomethylsilyl group of 341 by LDA followed by an intramolecular cyclization gives thienopyridines 343. The reaction probably involves a [1,3]-silyl sift of the intermediates 342 (Scheme 58) <2004H(63)2199>.
Scheme 58
Treatment of the N,N-diethylthiocarbamate 344 with LDA and then with aldehydes affords (Z)-3-(alkyliden-1-yl)3H-benzo[b]thiophen-1-ones 345 as major products along with minor amounts of the (E)-isomers 346 <2004H(63)1813>.
Treatment of alkynyl sulfides 347 with KOBut gives 2,3-dihydrothiophenes 351. The reaction might involve 5-enddig cyclization of intermediates 348, 349, and/or 350 (Scheme 59) <2000TL5637>.
Scheme 59
Thiophenes and their Benzo Derivatives: Synthesis
Thermal reaction of allenes 352 and 354 affords phenyl substituted thiophenes 353 and 355, respectively, together with other cyclic and acyclic compounds (Scheme 60) <1997TL8529>.
Scheme 60
FVP of the Meldrum’s acid derivatives 356 at 600 C (103 torr) gives 3-hydroxythiophenes 357. A mechanism involving ketenes as the intermediates has been proposed for this conversion (Scheme 61) <1995J(P1)1209>.
Scheme 61
Treatment of diphenyl thioacetals 358 with the low-valent titanium Cp2Ti[P(OEt)3]2 produces 2,3-dihydrothiophenes 360 together with 2-alkylidenetetrahydrothiophenes 361. The formers are formed by intramolecular olefination of the titanium–carbene intermediates 359 (Scheme 62) <1999SL1029>.
Scheme 62
875
876
Thiophenes and their Benzo Derivatives: Synthesis
Reaction of diazolactones 362 with Rh2(OAc)4 as a catalyst proceeds through diastereoselective 1,5-carbenoid C–H insertion to afford the thienofuranones 363 <2004CC1772>.
3.11.2.3 Formation of a Bond to the Sulfur Atom The thiophene ring synthesis by forming a carbon–carbon bond to sulfur atom is described (Equation 10). Several new syntheses that belong to this category have been developed.
ð10Þ
3.11.2.3.1
Intramolecular reductive coupling of diketo sulfides (3-thiapenetane-l,5-diones)
A practical thiophene synthesis, the Nakayama procedure, which involves an intramolecular pinacol coupling of diketo sulfides (3-thiapentane-l,5-diones) 364, has been reported. Treatment of 364 with a low-valent titanium reagent, prepared from TiCl4 and Zn powder, provides cis-thiolanediols 365. p-TsOH-catalyzed dehydration of 365 works cleanly to give the corresponding thiophenes 366 in high yields. This reaction has been utilized to prepare a variety of sterically congested 3,4-disubstituted thiophenes (Scheme 63) <1998JOC4912>.
Scheme 63
3.11.2.3.2
Intramolecular Friedel–Crafts or Wittig–Horner reaction
A proton-mediated aryl migration was observed during the attempted preparation of 3-arylbenzothiophene. The cyclization of 367 by polyphosphoric acid (PPA) gives only the rearranged 2-arylbenzothiophenes 368 and 369. In contrast, the rearrangement is avoided by use of BF3?Et2O-mediated cyclization, which affords the nonrearranged products 370 and 371 (Scheme 64) <1999TL2909>. Acid-catalyzed cyclization of pyrimidine derivatives 372 with TsOH gives thienopyrimidines 373 <1996H(43)349>. Treatment of ketones 374 with P2O5 affords benzo[b]thiophenes 375 <1998JCM172>. Ketones 376, 378, 380, 382, and acetals 384 and 386 undergo acid-catalyzed cyclizations with PPA to afford benzo[b]thiophenes 377 <1998J(P1)1059>, 379 <2002T1709>, 381 <2002JHC1177>, naphtho[b]thiophene 383 <2001S2327>, and benzo[b]thiophene 385 <2001JHC1025>, and 387 <1998SC3479>, respectively.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 64
877
878
Thiophenes and their Benzo Derivatives: Synthesis
A one-pot reaction of benzenethiols 388 with -halo ketones using acid- and base-supported reagent system Na2CO3/SiO2-PPA/SiO2 yields thiophenes 389 (Equation 11) <2005SL2739>.
ð11Þ
Treatment of 7-mercaptocoumarin 390 with MeSO3H affords 2H-thieno[2,3-h]-1-benzopyran-2-one 391. In contrast, isomeric benzopyran-2-one 392 is prepared from 390 under basic conditions (Scheme 65) <1998JHC847>.
Scheme 65
Lewis acid-catalyzed cyclization of carbonyl compounds 393 or 395 with AlCl3 gives benzothiophene 394 <2001HCO271> or thioindoxyl 396 <2001JOC2966>, respectively. ZnCl2-mediated cyclization of 397 affords thienothiophene 398 <2001J(P1)2483>.
Intramolecular Wittig–Horner reaction of the compounds 399, which are prepared by the condensation of 2-mercapto-2-arylethanols with a vinyl phosphonate followed by oxidation, gives dihydrothiophenes 400 <1996JHC687>.
Thiophenes and their Benzo Derivatives: Synthesis
3.11.2.3.3
Cycloaromatization of diallenyl, allenyl ethynyl, diethynyl, divinyl, and related sulfides
Reaction of alkynol 401 with sulfur dichloride leads to alkynyl sulfinyl ester 402, which, when heated, rearranges to bisallenyl sulfone 403. Pyrolysis of 403 yields thiophene 1,1-dioxide 404 (Scheme 66) <1996LA171>. The reaction of bis-propargylic derivatives 405 with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) leads to dihydrobenzothiophenes 407 via a tandem cyclization of the intermediates 406 (Scheme 67) <2000TL2675, 2005JOC10166>.
Scheme 66
Scheme 67
Irradiation of diethynyl sulfide 408 at 300 nm in hexane in the presence of 1,4-cyclohexadiene gives 3,4diphenylthiophene 409 (photo-Bergman cyclization). The authors describe this as being the first five-membered ring cycloaromatization reaction. The low yield of the thiophene 409 is due to the production of many side products (Scheme 68) <2003OL2195>. Naphthothiophene 411 and dinaphthothiophene 413 can be prepared from 410 and 412, respectively, by use of this method <2004T7191>.
Scheme 68
879
880
Thiophenes and their Benzo Derivatives: Synthesis
Reaction of 1,6-diynes 414 and 415 with PdI2, CO, and O2 in methanol followed by treatment with Et3N affords bi- and terthiophenes 416 and 417, respectively <1999T485>. 2,5-Dihydrothiophene 1,1-dioxide 419 is synthesized by Ru-catalyzed hydrative cyclization of diyne 418 (Equation 12) <2005OL2097>.
ð12Þ
An enantioselective photocyclization method has been reported. Irradiation of 1:1 complexes of thiaketones 420 with chiral diols 421 results in photocyclization to afford dihydrobenzothiophenes 422 with moderate to good enantioselectivity (Equation 13) <1996JA11315>.
ð13Þ
Intramolecular Pd-catalyzed cross-coupling of bromothiophene derivatives 423 and 425 gives dithienothiophenes 424 and 426, respectively (Equation 14) <1997TL4581>. Synthesis of benzonaphthothiophene-6,11-diones 428 by Pd(OAc)2-mediated cyclization of 427 has been reported <2005H(65)1205>.
ð14Þ
Thiophenes and their Benzo Derivatives: Synthesis
Treatment of the aryl bromide 429 with ButLi generates a dilithiated compound that undergoes oxidative intramolecular cyclization with CuCl2 to afford fused thiophene 430 (Scheme 69) <2004OL4179>. Similar syntheses of pentathionoacene 432 <2005JA13281> from 431 and heptathionoacene 434 <2005JA10502> from 433 have been reported.
Scheme 69
Chiral biphenyl-2,29-sulfone-3,39bisfenchol 436 is synthesized by cyclization of diphenylsulfone with BuLi and subsequent addition of ()-fenchone 435 (Scheme 70) <2005T10449>.
Scheme 70
Treatment of cyclopropanethiones 437 with triphenylphosphine results in dimerization to form cyclopropenes 438, which isomerize to carbenes 439. The intramolecular coupling of the carbene 439 (R1 ¼ Ph) affords thieno[3,2b]thiophene 441, whereas the carbenes 439 (R1 ¼ Ph, 2-thienyl, R2 ¼ SBut) isomerize to bis(allene)s 440, whose
881
882
Thiophenes and their Benzo Derivatives: Synthesis
cyclization produces thieno[3,4-c]thiophenes 442 as the final products. Cyclization to the former compound belongs to the category of Section 3.11.2.2.3 (Scheme 71) <1996CL421, 1998JOC163>.
Scheme 71
3.11.2.3.4
Cyclization of vinyl and aryl radical intermediates
Acyclic !-yne sulfides 443 react with tributyltin hydride in the presence of AIBN to produce 4,5-dihydrothiophenes 444 through free-radical 5-endo-trig cyclization (Scheme 72) <1997JOC8630>.
Scheme 72
Reaction of 2-bromoaryl allyl sulfides 445 with tributyltin hydride in the presence of AIBN gives dihydrobenzothiophenes 446 via intramolecular free-radical 5-endo-trig cyclization. In the case of 445 (R ¼ Me), rearranged product 447 is also formed (Scheme 73) <1998JOC3318>. Similar synthesis of 449 <1998JOC4645> from 448 has been reported.
Scheme 73
Thiophenes and their Benzo Derivatives: Synthesis
A series of 2,3-dihydrobenzothiophenes 451 have been synthesized by Ni-catalyzed electrochemical cyclization of allyl 2-haloaryl sulfides 450 (Equation 15) <2004SC3343>.
ð15Þ
The diazonium salt 453, derived from aminoisoquinoline 452, undergoes thermal cyclization to afford 6-thiaellipticine 454 and 3H-pyrazolo[3,4-h]isoquinoline 455. Formation of 454 may involve the cyclization of an aryl radical intermediate (Scheme 74) <1996CC2711>. Isomerically pure 4,6-dimethyldibenzothiophene 457 <1996T3953> and benzothiophene 459 <2005T8711> can be synthesized from the diazonium salts 456 and 458, respectively.
Scheme 74
3.11.2.3.5
Intramolecular [4þ2] cycloaddition
Acetylenic ester 460, when heated, undergoes an intramolecular Diels–Alder reaction to produce tricyclic compound 461. Further Diels–Alder reaction of 461 with tetrazine 462 generates the intermediate 463, which affords the dihydrothiophene 464 (Scheme 75) <1995AJC593>.
883
884
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 75
3.11.2.3.6
Miscellaneous cyclization
Compound 466, derived from 1,3-cyclohexanedione 465, cyclizes by treatment with PPA to afford thiophene 467 (Scheme 76) <1996CC177>.
Scheme 76
Treatment of thioacylmorpholines with -bromo ketones affords the substituted thiophenes 469. The reaction involves S-alkylation of thioacylmorpholines and subsequent cyclization of the intermediates 468 (Scheme 77) <2004T6085>.
Scheme 77
Reaction of 3-mercapto-2-butanone with 3-methoxyacrylate in the presence of NaOMe gives tetrahydrothiophene 471 via intramolecular cyclization of the intermediate 470. Compound 471 is converted into thiophene 472 by treatment with HCl (Scheme 78) <2001JOC2493>. Its cost-effective and scaleable synthesis is also reported <2002OPD357>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 78
Reaction of 2 equiv of acrolein with 1 equiv of 1,4-dithiane-2,5-diol 473 gives dihydrothiophene-3-carboxaldehyde 474 (Scheme 79) <2001SC1527>.
Scheme 79
Treatment of diketones 475 with Lawesson’s reagent (LR) affords dithienothiophenes 476 (Equation 16) <2004TL3405>.
ð16Þ
Either intramolecular nitrile oxide cycloadditions (INOC) or intramolecular silylnitroate cycloadditions (ISOC) of -nitrosulfides 477 gives isomeric thieno[3,4-c]isoxazolines 478 and 479 (Equation 17) <1997SC1865>.
ð17Þ
1,3-Dithioles 480 undergo cycloaddition with alkynes, and subsequent rearrangement with loss of Cl2 gives 7Hthieno[2,3-c]thiopyran-7-thiones 481 and 4H-thieno[3,2-c]thiopyran-4-thiones 482 as an isomeric mixture (Scheme 80) <2005OL791>.
885
886
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 80
3.11.3 Ring Synthesis by Formation of Two Bonds Thiophene rings might be constructed from the following sets of two components with formation of two new bonds: (1) C–C–C–C þ S; (2) C–C–C–S þ C; (3) C–C–S þ C–C; (4) C–S–C þ C–C; (5) C–C–C þ C–S.
3.11.3.1 Sulfuration of a Four-Carbon Unit with a Sulfur Reagent Reaction of a four-carbon unit with sulfur sources such as hydrogen sulfide, carbon disulfide, and elemental sulfur is one of the traditional thiophene syntheses that belong to this category (Equation 18). A wide variety of hydrocarbons, for example, alkanes, alkenes, dienes, alkynes, and diynes, serve as four-carbon units. Another practical method is the sulfuration of 1,4-dicarbonyl compounds (Paal synthesis). The method has become very popular with development of sulfuration reagents such as Lawesson’s reagent. The reaction of ,-unsaturated nitriles with elemental sulfur in basic media, Gewald synthesis, is also useful for the preparation of 2-aminothiophenes which are important compounds in dyestuff and pharmaceutical industries.
ð18Þ
3.11.3.1.1
Sulfuration of alkanes, alkenes, and alkynes
Addition of Na2S, NaHS, H2S, etc., as a sulfur source to 1,3-diynes has been proved to be an access to interesting thiophene derivatives. Treatment of dicyclopropyldiacetylene 483 with Na2S under strongly basic conditions gives 2,5-disubstituted thiophene 484. Extension of the reaction to ‘exploding’ [n]rotanes affords the corresponding macrocycles 485 (Equation 19) <1995AGE781>. Saccaride analogue 487 <1995HCA177>, tetra(2-thienyl)methane 489 <2002TL3049>, and bis(diazo) compound 491 <2005OBC431> have been prepared from diynes 486, 488, and 490, respectively, using this methodology.
Thiophenes and their Benzo Derivatives: Synthesis
ð19Þ
Biphenyl 492 substituted by electron-donating groups reacts with sulfur dichloride to give dibenzothiophene 493 (Equation 20) <1995NJC65>. Similar reaction of 2,3-dimethoxy-1,3-butadiene affords 3,4-dimethoxythiophene 494 ˚ <2004TL6049>. Dienol silyl ethers 495 and elemental sulfur, when heated in the presence of molecular sieve (4 A), provide 3-siloxythiophenes 496 <2006T537>.
ð20Þ
The reaction of either titanocene 497 or zirconocene 499 with S2Cl2 gives the same 2,4-bis(ethynyl)thiophene 498 (Scheme 81) <1997CCC331>. Similar reaction of zirconocene derivatives 500, 502, and 504 yields phenylene– thiophene oligomer 501 <2000AGE2870>, C2-symmetric thiophene 503 <2002TL3313>, and phenyl bridged macrocycle 505 <2003JOM(666)15>, respectively. Treatment of zirconocene intermediates 506 with SO2 affords thiophene-1-oxides 507 <1999JA9744>.
887
888
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 81
Treatment of 3,39-bis(phenylethynyl)-2,29-bithiophenes 508 with Wilkinson’s catalyst yields the cyclic rhodium complexes 509 which react with elemental sulfur to give benzotrithiophenes 510 (Scheme 82) <1997S1027, 1997HCA111>. Reaction of di(benzothienyl) 511 with ethoxycarbonylsulfenyl chloride in the presence of TiCl4 affords bis(benzothieno)thiophene 512. The reaction with BuLi-TMEDA-elemental sulfur also gives the same thiophene 512 instead of 1,2-dithiin 513 (Scheme 83) <1997T7509>. Treatment of 1,4-dibromobenzene derivatives 514 with ButLi and elemental sulfur affords benzodithiophenes 515 <2004JA5084, 2005JOC10569>. Dithieno-fused 1,2dithiins 517 are prepared from bis(bromoaryl)diacetylenes 516 by similar reaction <2005OL5301>. Synthesis of fused thiophene 519 <2002CC1192, 2005SL187> or tetrasubstituted thiophenes 521 <2002TL3533> by the reaction of 518 with S8 or of 520 with CS2 has been reported. Dithienothiophene 523 <2002TL1553>, thia[5]helicene 525 <2004SL177>, and thia[7]helicene 527 <2000AGE4481, 2004JA15211> are prepared by dilithiation of dibromobithiophene 522 and dithienothiophene derivatives 524 and 526 followed by sulfuration with (PhSO2)2S. Asymmetric synthesis of thia[11]hericene 528 <2005JA13806> is also reported.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 82
Scheme 83
889
890
Thiophenes and their Benzo Derivatives: Synthesis
Dinaphthothiophene 530 is synthesized by the Newman–Kwait rearrangement of dithiocarbamoyl derivative 529 <2005S1109>.
Thermal decomposition of each thiirane-1-oxide 531 <1997JOC8366> and trisulfide 2-oxide 533 <2001OL3565> delivers sulfur monoxide to 1,3-dienes giving 2,5-dihydrothiophene-1-oxides 532 (Scheme 84).
Scheme 84
Thiophenes and their Benzo Derivatives: Synthesis
Stereoselective cheletropic addition of SO2 to vinylallene 534 gives the cyclic 1,1-dioxide 535 (Equation 21) <2005OL1565>.
ð21Þ
1,6-Methano[10]annuleno[3,4-c]thiophene 537 is synthesized by the reaction of bis(cyanomethyl) derivative 536 with SOCl2 in the presence of Et3N (Equation 22) <2005TL7311>.
ð22Þ
Reaction of aluminacyclopentanes 538, derived from 2 molar equiv of alkenes and Et3Al in the presence of Cp2ZrCl2 catalyst, with SOCl2 affords the corresponding tetrahydrothiophenes 539 (Scheme 85) <2004T1281>.
Scheme 85
Cyclic bis-thionocarbonate 540, derived from 1-O-Bn-D-arabinose, reacts with Na2S and then with Ac2O to give thioanhydro-D-arabinose 541 (Equation 23) <2004TL4365>.
ð23Þ
3.11.3.1.2
Gewald synthesis and related syntheses
The reaction of ,-unsaturated nitriles with elemental sulfur in basic media, Gewald synthesis, provides a most convenient route to 2-aminothiophenes, many of which are a useful class of compounds as intermediates in the preparation of dyestuffs and pharmaceuticals. This method is reviewed <1999JHC333>. Reaction of 4-methyl-2-pentanone with methyl or ethyl cyanoacetate and sulfur in the presence of morpholine as a base gives three aminothiophenes 542, 543, and 544 (Scheme 86) <1996M297>.
891
892
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 86
The reaction of 2-aminoprop-1-ene 1,1,3-tricarbonitrile 545 with acetylacetone or cyclohexanone in the presence of elemental sulfur affords thieno[2,3-b]pyridine 546 or tetrahydrobenzo[b]thiophene 547, respectively (Scheme 87) <1996JCM356>. 2-Aminothiophenes 548 <1999TL5471> and 549 <2001J(P1)144> are prepared from carbonyl compounds, cyanoacetates, and elemental sulfur. Condensation of -keto ester (or diketone), 3-aminocrotononitrile, and elemental sulfur affords 2-cyanothiophenes 550 <1999JCM536>. Tetrasubstituted thiophenes 551 <2000HAC94>, 552 <2000TL1597>, and 553 <2002BMC3113>, fused thiophenes 554 <2005BML1401>, 555 <2002BML1607, 2002BML1897, 2003HAC459, 2006BMC2358>, and 556 <2006HCO187> are also synthesized by use of this method. The Gewald synthesis of 2-aminothiophenes 557 in ionic liquids has been reported (Equation 24) <2004SC3801>.
Scheme 87
Thiophenes and their Benzo Derivatives: Synthesis
ð24Þ
Reaction of ketones with cyanoacetic acid derivatives and sulfur under MW irradiation gives tetrasubstituted thiophenes 558 (Equation 25) <2005SC1351>.
ð25Þ
The Gewald synthesis can be performed on a solid support. Treatment of resin-bound nitrile 559 with carbonyl compounds and sulfur gives resin-bound aminothiophenes 560. Acylation and removal of the resin provide thiophenes 561 (Scheme 88) <2001TL7181>. The same resin-bound nitrile 559 reacts under MW irradiation to give 560 <2004S3055>. MW-assisted synthesis of 2-N-acylthiophenes 563 from 562 on a solid support has also been reported <2003SL63>.
Scheme 88
Synthesis of 2-aminothiophenes 564 by using calcined Mg–Al (Mg:Al ¼ 4:1) hydrotalcite (HT) as a heterogeneous base catalyst has been reported (Equation 26) <2001SC3113>.
ð26Þ
893
894
Thiophenes and their Benzo Derivatives: Synthesis
3.11.3.1.3
Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis)
Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis) provides one of the most widely used methods for the preparation of thiophenes. P2S5 (P4S10), combination of hydrogen sulfide and an acid catalyst, Lawesson’s reagent, bis(trialkyltin) sulfides, and hexamethyldisilathiane are the sulfuration reagents used most commonly. Treatment of 1,4-dicarbonyl compounds 565 with P2S5 leads to mercaptothienoindoles 566 <1998JOC2909>. The role of red phosphorus in the synthesis of 3-aryl thiophene 568 from disodium 2-arylsuccinate 567 using P4S10 has been discussed (Scheme 89) <1995SC235>.
Scheme 89
The use of LR as the sulfurating agent has become very popular and a large number of interesting thiophene syntheses using this reagent have been developed. For example, treatment of diketones 569 with the reagent affords 1,3-dithienylisothianaphthenes 570 <1997JOC1473, 2000CC939>. 3-Cyanopropylthiophene 571 <2000JMC107> and bis(2-furyl)-2,5-thiophene 572 are also synthesized <1998JOC5324>. Ketoaldehydes 573 affords 2,4-disubstituted thiophenes 574 <1997H(45)2425>. Treatment of ketoamides and ketoesters 575 with LR gives bithiophenes 576 <2001H(55)1487>. 2,5-Disubstituted thiophenes 577 <2001JOC7283, 2001JMC3068>, fused thiophene 578 <2002BML1675>, 4H-indenothiophene-4-one 579 <2006JHC629>, 2,3-dihydro-2-thioxothieno[2,3-d]thiazoles 580 <2001S413>, and diferrocenylbenzothiophene 581 <2006TL2887> have also been prepared. Reaction of ketoamides 582 with LR affords pyrroles 583 and/or thiophenes 584 <2005S199>. 2,6-Bis(2-thienyl)pyridine 586 <1997T11529> and mixed copolymer oligothiophene 588 <1998JA2798> have also been synthesized by sulfuration of tetraketones 585 and 587, respectively. Synthesis of oligo(thiophene)s has been reviewed <2006SL1793>.
Thiophenes and their Benzo Derivatives: Synthesis
LR-mediated cyclization of 1,4-carbonyl compounds 589 under MW irradiation affords the corresponding thiophenes 590 (Equation 27) <2001JOC7925>. 2,3,5-Trisubstituted thiophenes 592 are prepared from 591 in a similar way <2005EJO5277>.
ð27Þ
A one-pot synthesis of 2,5-disubstituted thiophenes 595 from 3,5-dihydro-1,2-dioxines 593 has been reported. The reaction proceeds by a Kornblum–de la Mare rearrangement to 1,4-diketones 594 followed by sulfuration with LR (Scheme 90) <2002TL3199>.
Scheme 90
LR-mediated cyclization of 1,4-carbonyl compounds 596 in the presence of Bi(OTf)3 in ionic liquids affords the corresponding thiophenes 597 (Equation 28) <2004TL5873>.
895
896
Thiophenes and their Benzo Derivatives: Synthesis
ð28Þ
Sulfuration of dithiophene-1,4-diketone 598 using Steliou’s reagent [(Bu3Sn)2S, BCl3] or Lawesson’s reagent affords -terthiophene 599 (Equation 29) <1998BML2695>.
ð29Þ
The sulfuration of diketones 600 with hexamethyldisilathiane under cobalt(II) chloride catalysis gives the disilylated thiophenes 601 along with minor amounts of the corresponding furans 602 (Equation 30) <2004TL87>.
ð30Þ
3.11.3.1.4
Miscellaneous cyclizations
2-Chloro-3-(-cyano--carbethoxy)methyl-1,4-naphthoquinone 603 is cyclized by using Na2S to yield the corresponding thiophene 604 <1999JHC15>. Treatment of the 3-bromopropene 605 with NaSH affords tetrasubstituted thiophene 606 <2005SC2251>.
3,4-Bridged 1,6,6a4-trithiapentalenes 608 are synthesized by the reaction of keto dienamines 607 with P2S5 or LR (Equation 31) <2001SL1129>.
ð31Þ
Treatment of amidine derivative 609 with elemental sulfur in the presence of piperidine gives fused thiophene 611 via cyclization of the intermediate 610 (Scheme 91) <1998JCM294>. Saccaride-substituted thiophenes 613 <2005CAR547> and 2,2-dioxo-1H-thieno[3,4-c][1,2]thiazines 615 <1998JHC1449> are synthesized by the reaction of saccharide derivative 612 and 1,1-dioxo-1,2-thiazines 614 with sulfur in the presence of Et3N.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 91
3.11.3.2 Combination of a C–C–C–S Unit with a One-Carbon Unit Reactions of a C–C–C–S unit with a one-carbon unit belong to this category (Equation 32). ð32Þ Oxoketene dithioacetal 616 undergoes conjugate addition with BnCuMgCl to afford vinylogous thiolester 617. Cyclization of 617 under Simmons–Smith reaction conditions affords 2,4-disubstituted thiophene 619 via cyclization of the intermediate ylide 618 (Scheme 92) <1995TL1925>. Similar reactions of 620 and 622 give 2-(methylthio)thiophene 621 <2003T2631> and acenaphthothiophene 623 <2005EJO2045>, respectively.
Scheme 92
Sulfonium ylides, generated from sulfonium bromides 625, react with arylidenecyanothio-acetamides 624 providing 4,5-dihydrothiophenes 627 via a cyclization of the intermediates 626 (Scheme 93) <1997S623>. Similar cyclizations of 628 or 629 afford the dihydrothiophenes 630 <2001SC1647>.
897
898
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 93
Reaction of ketene S,S-acetals 631 with lithiotrimethylsilyldiazomethane generates alkylidenecarbene intermediates 633 through the diazo alkoxides 632. The carbene undergoes an intramolecular cyclization and subsequent elimination to afford 2-(alkylthio)thiophenes 634 (Scheme 94) <2002H(57)1313>.
Scheme 94
Treatment of thioketone 635 with -diazo carbonyl compounds in the presence of Rh2(OAc)4 gives 3-aminothiophenes 637. Condensation of the ketene acetal with carbenoids, derived from diazo compounds, produces the intermediates 636, which undergo an intramolecular cyclization and subsequent aromatization to afford 637 (Scheme 95) <2002J(P1)2414, 2002OL873>. Reaction of heteroaromatic thioketones 638 with the carbenoids, generated from phenyliodonium bis(phenylsulfonyl)methane or bis(arylsulfonyl)diazomethanes in the presence of a copper acetylacetonate catalyst, affords heterocycle-fused [c]thiophenes 639. The reaction involves ring closure of the intermediary thiocarbonyl ylides and elimination of a sulfenic acid (Equation 33) <1995S87>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 95
ð33Þ
Cyclization of alkenylthioimidoyl radical 640, generated by the reaction of a thiyl radical with ButNC, affords several dihydrothiophene-2-ylideneamines 641–645 together with six-membered and acyclic compounds 646 and 647 (Scheme 96) <2004JOC2056>.
Scheme 96
899
900
Thiophenes and their Benzo Derivatives: Synthesis
3.11.3.3 Combination of a C–C–S Unit with a C–C Unit Ring synthesis by a [3þ2]-type cycloaddition belongs to this class (Equation 34). Several interesting syntheses that belong to this category have been developed. ð34Þ O-Acyl derivatives of thiohydroxamic esters (Barton esters) 648 react with benzynes to give benzo[4,5]thieno[2,3b]pyridines 649 (Equation 35) <2002JOC3409>.
ð35Þ
Cycloaddition of ethylthiocolchicine 650 with 2 molar equiv of cyclooctyne affords thiophene-annelated homobarrelenones 651 and 652. The authors propose a reaction sequence including a consecutive [4þ2]/[3þ2] cycloaddition (Equation 36) <1998EJO2451>.
ð36Þ Cycloaddition between 1,4-naphthoquinone and thiazolidines gives dihydrothieno[2,3-b]naphtha-4,9-diones 653 (Scheme 97) <2001TL5755>.
Scheme 97
Reaction of diazonium salt 654 with alkynes in the presence of FeSO4 or TiCl3 gives 2-arylbenzothiophenes 655 in a single step. The reaction process involves aryl radical addition to the alkyne and cyclization followed by demethylation <2000S970>.
Thiophenes and their Benzo Derivatives: Synthesis
3.11.3.4 Combination of a C–S–C Unit with a C–C Unit Hinsberg synthesis and 1,3-dipolar cycloaddition of thiocarbonyl ylides with dipolarophiles are typical thiophene syntheses in this class (Equation 37). ð37Þ
3.11.3.4.1
Hinsberg synthesis and related syntheses
-Dicarbonyl compounds condense with thioglycolic acid esters in the presence of sodium alkoxide to give thiophene-2,5-dicarboxylic acid derivatives (Hinsberg thiophene synthesis). For example, treatment of diester 656 with diethyl oxalate gives the disodium salt 657, which is methylated by Me2SO4 to afford tetrasubstituted thiophene 658 (Scheme 98) <2004T10671>. Norbornadiene-fused thiophene 660 <1999BCJ1597>, cyclobutane-substituted 2,5diacylthiophenes 662 <2004HAC26>, amide-substituted thiophenes 664 <2005HAC503>, and [n]thiophenophane1,n-diones 666 <2006JOC6516> have been prepared from dicarbonyl compounds 659, 661, 663, and 665, respectively.
Scheme 98
Wittg reaction of a bis-ylide with acenaphthenequinone 667 or dione 669 affords fused thiophene 668 <1997PS419> or 670 <1999BCJ1597>, respectively (Equation 38).
ð38Þ
901
902
Thiophenes and their Benzo Derivatives: Synthesis
3.11.3.4.2
1,3-Dipolar cycloaddition
Thiocarbonyl ylide 672, generated by 1,4-sigmatropic rearrangement of thioester derivative 671, undergoes a 1,3dipolar cycloaddition with 1-diethylaminoprop-1-yne to give 3-(N,N-diethylamino)-4-methyl-2,5-diphenylthiophenes 674. The regioisomer 675 was also produced, probably by reaction of a thiirane intermediate 673 with the alkyne (Scheme 99) <2002H(57)1989>.
Scheme 99
3,4-Bis(trimethylsilyl)dihydrothiophene 678 is synthesized by a 1,3-dipolar addition of ylide 677, derived from sulfoxide 676, with bis(trimethylsilyl)acetylene (Scheme 100) <1997JOC1940>. Cycloaddition of C60 with this ylide gives tetrahydrothiophene-C60 679 <2001T1737>.
Scheme 100
S-Methyl ylide 681, produced by thermal N2 extrusion of dihydrothiadiazole 680, undergoes 1,3-dipolar cycloaddition with alkynes to give dihydrothiophenes 682 (Scheme 101) <2002HCA451>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 101
Tetrahydrothiophenes 685 are synthesized by 1,3-dipolar cycloaddition of ylides 684, produced from dithioesters 683 and CH2N2, with maleic anhydride or N-phenylmaleimide (Scheme 102) <2005HCA2582>.
Scheme 102
3.11.3.5 Combination of a C–S Unit with a C–C–C Unit Reactions of a C–S unit with a C–C–C unit belong to this category (Equation 39). Several new syntheses have been developed. ð39Þ Treatment of naphtho[b]cyclopropene 686 with dimethyltrithiocarbonate and with 1,3-dithiole-2-thiones affords 1,3-dihydrobenzo[2,3-c]thiophenes 687 and 688, respectively. This reaction involves a [2pþ2]-type cycloaddition process (Scheme 103) <2004H(62)773>.
Scheme 103
903
904
Thiophenes and their Benzo Derivatives: Synthesis
Synthesis of thiophene derivatives 692 using cyclopropenyl cation 689 is reported. The reaction involves ring opening of 689 by dithiocarbamates (R ¼ NMe2, N(Me)Ph), dithocarbonate (R ¼ OEt) or xanthate (R ¼ SPri), which gives allylcarbenes 690. An intramolecular cyclization of 690 gives thiiranes 691, which then extrudes sulfur to give thiophene 692 (Scheme 104) <1996S1193>.
Scheme 104
3.11.4 Ring Synthesis by Formation of Three Bonds It is theoretically possible to construct a thiophene ring by combining the following units with three bonds: (1) C–C–S þ C þ C, (2) C–S–C þ C þ C, (3) C–C–C þ C þ S, (4) C–C þ C–C þ S, and (5) C–C þ C–S þ C. Among these, only combination (4) (two two-carbon units þ sulfur source) can provide practical synthetic methods for thiophenes (Equation 40). ð40Þ Treatment of acenaphthene derivative 693 with elemental sulfur produces an isomeric mixture of dicyclopentathienodiphenalenes 694, 695, and 696 (Equation 41) <2004AGE6474>.
ð41Þ
3.11.5 Ring Synthesis from Other Heterocyclic Compounds Many thiophenes are prepared by processes involving a ring transformation, that is, conversion of other heterocyclic compounds to thiophenes. Several syntheses of this type have already been described; however, there are still many syntheses that should be independently treated here.
3.11.5.1 From Three- and Four-Membered Heterocyclic Compounds Heating of 2H-1-benzothiete 697 and a diazo compound in the presence of Rh2(OAc)4 as a catalyst yields 2,3-dihydrobenzo[b]thiophene 700, which is oxidized to afford thiophene 701. The mechanism probably involves the initial formation of thiirane 698 or cyclopropane 699 followed by its ring enlargement with a [1.3] shift (Scheme 105) <1995TL6047>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 105
The thiiranes 703, derived from thermolysis of thiosulfinic S-esters 702, are converted to thiophenes 704 by treatment with TsOH. Acid-promoted ring expansion and successive dehydration explains the formation of 704 (Scheme 106) <1995JCM86>.
Scheme 106
3.11.5.2 From Five-Membered Heterocyclic Compounds 3.11.5.2.1
From furans and related compounds
Trithia-[3]-peristylane 706, a novel C3v symmetric thiabowl, can be synthesized by the reaction of cyclic acetal 705 with LR. The acetal is derived by ozonolysis and subsequent acetalization of bullubalene (Scheme 107) <2004OL1617>.
Scheme 107
1,3-Diaryl benzo[c]thiophenes 708 are synthesized via a ring opening of lactones 707 followed by sulfuration using LR (Equation 42) <2005TL4225>.
ð42Þ
905
906
Thiophenes and their Benzo Derivatives: Synthesis
3.11.5.2.2
From tetra- and dihydrothiophenes and related compounds
Although conversions of tetrahydrothiophenes (thiolanes), dihydrothiophenes (sulfolenes), thiophenones, and related compounds to the corresponding thiophenes do not involve a process of ring transformation, they are important in the synthesis of thiophenes. Benzo[c]thiophene 710 is prepared by the dehydration of sulfoxide 709 with KOBut as a variant method of the Pummerer reaction. Irradiation of 710 affords 711 as a first example of Dewar benzo[c]thiophene (Scheme 108) <1995TL3177>. Reaction of dinitrile 712 with thionyl chloride in the presence of Et3N yields thieno[3,4-c]thiophene 714 via Pummerer dehydration of the intermediate 713 <2000TL8843, 2002JOC2453>.
Scheme 108
3-Oxotetrahydrothiophenes 715 are converted into 3-aminothiophenes 716 by heating with hydroxylamine hydrochloride in a polar solvent (Equation 43) <2002SC2565>.
ð43Þ
Reduction of enone 717 with diisobutylaluminium hydride (DIBAL) or thioindoxyls 719 with NaBH4 followed by spontaneous dehydration gives the thiophene 718 <2002TL8485> or benzothiophenes 720 <2002SL325, 2003T4767>, respectively.
Thiaurones 721, when heated, undergo electrocyclization and subsequent [1,3]-hydrogen shift to give benzothienopyrans 722 (Scheme 109) <2003SL1479>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 109
3.11.5.2.3
From sulfur- and nitrogen-containing five-membered heterocyclic compounds
Photocyclization of 1,3-dithiole-2-ones 723 affords thieno[3,2-c]dithiins 725. The reaction probably involves cyclization of the intermediate dithiones 724 (Scheme 110) <2001OL3573, 2003JOC7115>.
Scheme 110
Acid treatment or photolysis of the cycloadduct 728, derived from the reaction of meso-ionic dithiolium-4-olate 726 with triphenylphosphinine 727, affords tetraphenylthiophene 729 (Scheme 111) <1995H(40)311>.
Scheme 111
3,4-Disubstituted thiophenes 731 can be synthesized by an intermolecular cycloaddition–cycloreversion procedure between substituted acetylenes and 4-substituted thiazoles 730 (Scheme 112) <1996CC339>. 1,3-Thiazolium-4olates 732 react with dimethyl acetylenedicarboxylate (DMAD) to produce either thiophenes 733 or pyridones 734, depending on the substituent on the nitrogen atom (Scheme 113) <2000T1247>. Reaction of 732 with chiral 1,2diaza-1,3-butadienes 735 affords a diastereomeric mixture of 4,5-dihydrothiophenes 738 and 739 via a ring opening of the adducts 736 and 737, respectively (Scheme 114) <2000JOC5089>.
907
908
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 112
Scheme 113
Scheme 114
Thiophenes and their Benzo Derivatives: Synthesis
Compound 740, when heated, undergoes S,N-carbonyl migration and subsequent cyclization to afford thiolactone 741 (Scheme 115) <2004CEJ6102>.
Scheme 115
3.11.5.3 From Six-Membered Heterocyclic Compounds 3.11.5.3.1
Extrusion of sulfur or sulfur monooxide from 1,2- and 1,4-dithiins
Formation of thiophenes by extrusion of sulfur has been observed for a number of substituted 1,2- and 1,4-dithiins. Particularly, sulfur extrusion of the latter compounds is often useful for thiophene synthesis. Their synthesis and chemistry have been reported <2000JA5052>. Treatment of diketone (R ¼ 4-MeOC6H4) 742 with LR leads to thiophene 744 (R ¼ 4-MeOC6H4) through the intermediary 1,4-dithiin 743; in the case of R being Ph or 4-NO2C6H4, 1,4-dithiin 743 is obtainable (Scheme 116) <1996TL2821>. Photochemical rearrangement of 1,2-dithiins 745 produces episulfides 746, which undergo sulfur extrusion or heterolytic ring opening to lead to thiophenes 747 or thiophene-3-thiols 748 (Scheme 117) <1998EJO2365>.
Scheme 116
Scheme 117
909
910
Thiophenes and their Benzo Derivatives: Synthesis
Benzothieno-1,2-dithiin 749 produces benzothienothiophene 750 by exposure to daylight, while such sulfur extrusion of dithieno anellated dithiins 751 is performed only by means of copper bronze at high temperature to yield dithienothiophenes 752 <1997T7509>.
1,2-Dithiete 753, when heated, undergoes cycloaddition through its tautomeric dithione 754 to produce 1,4-dithiin 755 which gives the thiophene 756 by extrusion of sulfur. Heating 753 with alkynes affords the thiophenes 757 (Scheme 118) <1999JOC8489>. 2,3,4,5-Tetra(2-chlorotetrafluoroethyl)thiophene 758 can be prepared in a similar way. Irradiation of 758 produces the Dewar thiophene 759 <2000JFC(102)323>.
Scheme 118
Treatment of compound 760 with Pt(COD)2 affords platinum complex 761, which produces 762 when heated (Scheme 119) <2004JOM(689)65>. Heating 1,2-dithiin 763 with Cu affords dithienothiophene 764 <2005OL5301>.
Scheme 119
Thiophenes and their Benzo Derivatives: Synthesis
Tetrathienylthiophene 767 is prepared by the oxidation of 1,4-dithiin 766, derived by photodimerization of thienyl[1,3]dithiol-2-one 765 (Scheme 120) <2003JOC7115>.
Scheme 120
3.11.5.3.2
Ring contraction of other sulfur-containing six-membered heterocyclic compounds
2-Thiono-1,3-dithiole-4,5-dicarboxylate 768 and DMAD undergo a 1,3-dipolar cycloaddition to produce a short-lived ylide intermediate 769. The reaction of 769 with DMAD under conditions without solvent affords a spiro-1,3dithiole 770, which undergoes thermal rearrangement to give the thiophene 771 (Scheme 121) <2000HAC434>.
Scheme 121
Reaction of dihydrothiopyranes 772 with N-iodosuccinimide in the presence of carboxylic acids results in the stereospecific formation of iodothiolanes 774 via the intermediates 773 (Scheme 122) <2004EJO74>.
911
912
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 122
3.11.6 Benzo[b]thiophenes by Annelation of Thiophenes 3.11.6.1 [2þ4] Cycloaddition of Thiophene-2,3-Quinodimethanes (2,3-Dimethylene-2,3dihydrothiophenes) and Related Compounds Thieno[2,3-c]furan behaves as a thiophene-2,3-quinodimethane equivalent. Diels–Alder reaction of furan 775 with N-phenylmaleimide or maleic anhydride followed by acid-catalyzed dehydration affords benzo[b]thiophenes 776 (Scheme 123) <1996JOC6166>.
Scheme 123
3.11.6.2 Acid-Promoted Cyclizations Treatment of bis-alkyne 777 with TFA gives pentacyclic thiophenes 778 and 779. The latter is formed by aryl migration of the former (Equation 44) <1997JA4578>.
ð44Þ
Thiophenes and their Benzo Derivatives: Synthesis
Cyclohepta[a]benzothieno[c]naththalenium ion 781 <1997H(45)467> and cyclohepta[e]-thieno[g]benzodithiophenylium ion 783 <2005H(65)2791> are synthesized by an intramolecular Friedel–Crafts type reaction of 780 and 782 with triphenylmethyl tetrafluoroborate in a one-pot reaction. BF3-mediated cyclization of (thienyl)oxobutanal 784 in methanol gives 7-methoxybenzo[b]thiophene 785 <1997J(P1)2683>. Thienobisbenzo-thiophene 787 is prepared from dialdehyde 786 with Amberlyst-15 as catalyst <2004JOC2197, 2005JOC4502>. The cyclization of ketones 788 by TsOH affords benzo[b]thiophenes 789 <2000T8153>. Similar cyclization of epoxide 790 with BF3 or 792 with MeSO3H affords benzonaphthothiophene 791 <2000JOC3883> or phenanthrothiophenes 793 <2005JHC1345>, respectively. A domino cationic cyclization of cyclopropyl ketone 794 with PPA leads to the corresponding indeno[4,5-b]thiophene 795 <2002JOC4916>.
3.11.6.3 Photocyclization of 1-Aryl-2-(thienyl)ethylenes and the Related Compounds 1-Aryl-2-thienylethylenes undergo an oxidative photocyclization to give benzoannelated thiophenes. For example, irradiation of trans-1-(3-pyridyl)-2-(3-thienyl)ethene 796 leads to a mixture of thienoquinoline 797 and thienoisoquinoline 798. The use of the cis-isomer is not necessarily required because the trans-isomer isomerizes to the cis on irradiation. In most cases, the irradiation is carried out in the presence of oxidant to give the fully conjugated compounds (Equation 45) <1995S1131>. Photocyclization of 799 affords a regioisomeric mixture of [7]heterohelicines 800–802 together with 4-phenyl-substituted compound 803 <1997CL501>. Naphtho[2,3-g]thiopheno[3,2-e]benzo[b]thiophene 805 <1999S1303>, benzodithiophene 807 <2002BCJ1795>, benzotrithiophene 809 <2004OL273>, and tetrathia[7]helicenes 811 <2005SL1137> are synthesized by the irradiation of 804, 806, 808, and 810, respectively.
913
914
Thiophenes and their Benzo Derivatives: Synthesis
ð45Þ
Photocyclization of 2-(1-naphthyl)-3-(2-thienyl)propenoic acid 812 in the presence of iodine affords phenanthrothiophenes 813 and 814 together with naphthothienobenzopyran 815 <1996JHC1017>. Photolysis of 2-([1]benzothienyl)-3-arylpropenoic acids 816 gives a mixture of benzonaphthothiophenes 817, benzonaphthothiopyran-6ones 818, and benzonaphthopyran-6-ones 819 <1996JHC1319>.
Thiophenes and their Benzo Derivatives: Synthesis
Irradiation of thiophene 820 in hydrated CH2Cl2 gives benzothiophene 823. The reaction involves [1,9] hydrogen shift of 821, ring opening, and hydrolysis. For the reaction in dry benzene, 822 is obtainable without hydrolysis <1999OL1039>. Irradiation of thiophene 820 (R ¼ Me) in the presence of HCl gives the tricyclic compound 824 <2000JA8575> (Scheme 124).
Scheme 124
3.11.6.4 Transition Metal-Mediated Cyclizations Ruthenium vinylidene 826 derived from terminal alkyne 825 with RuCl2( p-cymene)PPh3 undergoes 6p-electrocyclization to afford benzothiophene 827 (Scheme 125) <1996JA11319>. Pt-catalyzed double cyclization of diynes 828 gives polycyclic benzodithiophenes 829 <2005TL8153>.
Scheme 125
915
916
Thiophenes and their Benzo Derivatives: Synthesis
Treatment of 2-iodothiophene 830 with 2 molar equiv of diethyl acetylenedicarboxylate in the presence of Pd catalyst affords tetrasubstituted benzothiophene 834. Syn-addition of intermediate 831, generated by oxidative addition of 830 to Pd(0), to the acetylene gives vinylpalladium 832. Cyclization of 832 to 833 and its subsequent reaction with the acetylene affords the final product 834 (Scheme 126) <2003JOC6836>. Intramolecular electrocyclization of the intermediate 837, produced by the reaction of the propargyl methyl carbonate 835 with 2-thiophene boric acid 836 in the presense of Pd catalyst, affords benzothiophene 838 (Scheme 127) <2004CEJ5338>.
Scheme 126
Scheme 127
Benzodithiophenes 840 are synthesized by In-catalyzed annulation of 2,29-bithiophenes 839 with methyl propargyl ether (Scheme 128) <2005AGE1336>.
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 128
3.11.6.5 Diels–Alder Reactions of Vinylthiophenes and Related Compounds 2-Vinyl- and 3-vinyl-thiophenes behave as a diene on reaction with dienophiles to give six-membered ring-fused thiophenes. Cycloaddition of the cyclobutene 842 with 841 or with 844 followed by aromatization gives benzo[b]thiophene-fused benzocyclobutenedione 843 or 845, respectively (Scheme 129) <1996J(P1)497>. Heterohelicene 847 is synthesized by the reaction of 846 with 1,4-benzoquinone <2001JA11899>.
Scheme 129
The high-pressure cycloaddition of 2-vinylbenzothiophene 848 with 3-nitro-2-cyclohexen-1-one gives adduct 849, which is treated with 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) to afford benzothiophene 850. The reaction with indenone affords the thiophene 852 via oxidation of 851 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 130) <2001T4959>. Diels–Alder reaction of vinylthiophenes 853 with acetylenes having electron-withdrawing group(s) affords benzo[b]thiophenes 855 by loss of ethylene from the intermediates 854 (Scheme 131) <1998SC2531>.
917
918
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 130
Scheme 131
4-Substituted 3-bromobenzoic acids 856 react with 3-thienylacetonitrile under aryne-forming conditions, where lithium diisopropylamide (LDA) is used as the base, to give the corresponding thiophenes 857 by stepwise [2þ4] cycloaddition (Scheme 132) <1998J(P1)1461>.
Scheme 132
Thiophenes and their Benzo Derivatives: Synthesis
3.11.6.6 Miscellaneous Cyclizations Condensation of 2 molar equiv of dialdehyde 858 with 1,4-cyclohexanedione under alkaline conditions affords a mixture of the heterocyclic systems 859 and 860 <2004OL3325>.
An intramolecular double Horner–Wittig reaction of dialdehyde 861 using NaOMe as base provides the naphthodithiophene 862 <2002BCJ1795>.
Electrocyclization of benzothiophenes 863 affords intermediary adducts 864, which eliminate carbamic acid to give dibenzothiophenes 865 (Scheme 133) <1999CC541>.
Scheme 133
The thermally generated imminium salts 866 and 868 undergo intramolecular cyclization followed by aromatization. The former affords 5-methylthieno[3,2-b]carbazole 867 and the latter gives the [2,3-b] isomer 869 (Scheme 134) <1995JOC3707>. The thermally induced electrocyclization of enamines 870 affords benzo[b]thiophenes 871 or pyrrothienoazepine 872 <1997JOC7744>. FeCl3-mediated oxidative cyclization of bis(thienyl) substituted compound 873 affords – coupled product 874 (Equation 46) <2002JA7762>: – coupled compound 876 can be prepared from 875 <2006TL1551>.
919
920
Thiophenes and their Benzo Derivatives: Synthesis
Scheme 134
ð46Þ
Thiophenes and their Benzo Derivatives: Synthesis
FVP of alkynyl-substituted and chlorovinyl-substituted thiophenes 877 affords the corresponding naphtho[b]thiophenes 878 <1999TL2789>. The bowl-shaped heteroaromatic thiophene 880 is prepared from an isomeric mixture of 879 by the FVP method <1999CC1859>.
Reaction of aldehydes 881 with alkenes in the presence of IPy2BF4 gives benzothiophenes 883. The reaction involves addition of the alkenes to intermediates 882, ring opening, and loss of HI (Scheme 135) <2006CEJ5790>.
Scheme 135
3.11.7 Benzo[c]thiophenes by Annelation of Thiophenes Thermal electrocyclization of benzothiophene 884 affords the dihydrothiophenes 885 (Scheme 136) <1999CC541>.
Scheme 136
FVP of alkynyl-substituted and chlorovinyl-substituted thiophenes 886 affords the naphtho[c]thiophene 887 <1999TL2789>.
921
922
Thiophenes and their Benzo Derivatives: Synthesis
3.11.8 Further Developments Further development have been reviewed in 31 recent studies <2006BMC6827, 2006EJM925, 2006JOC8006, 2006PS2051, 2006RCB2081, 2006SC3319, 2006T11513, 2007BCJ763, 2007BMC3832, 2007BML3905, 2007CEJ548, 2007CL578, 2007CM1070, 2007CM3018, 2007H(72)697, 2007HAC239, 2007HAC294, 2007HAC450, 2007JA2224, 2007JHC63, 2007JOC442, 2007JOC1729, 2007JOC5368, 2007OL829, 2007OL1005, 2007OL1729, 2007PS551, 2007PS667, 2007PS2193, 2007TL779, 2007TL3535>.
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925
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Thiophenes and their Benzo Derivatives: Synthesis
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Thiophenes and their Benzo Derivatives: Synthesis
2003T2625 2003T2631 2003T4767 2003T4851 2003TL6253 2003TL6665 2004AGE6474 2004CC1772 2004CEJ5338 2004CEJ6102 2004CHE377 2004EJO74 2004EJO2589 2004H(62)773 2004H(63)1281 2004H(63)1813 2004H(63)2199 2004HAC26 2004JA5084 2004JA15211 2004JOC2056 2004JOC2197 2004JOC2899 2004JOC4867 2004JOC6145 2004JOM(689)65 2004OL273 2004OL1617 2004OL3325 2004OL3437 2004OL4179 2004PHC(16)98 2004S1633 2004S3055 2004SC2159 2004SC3343 2004SC3801 2004SL177 2004T275 2004T1281 2004T6085 2004T7191 2004T10671 2004TL87 2004TL3405 2004TL4365 2004TL5873 2004TL6049 2004TL9645 2005AGE1336 2005BMC1275 2005BML1401
2005CAR547 2005EJO2045 2005EJO5277 2005H(65)1205 2005H(65)2791 2005H(65)2973 2005HAC503 2005HCA2582 2005JA10502 2005JA13281
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Thiophenes and their Benzo Derivatives: Synthesis
2005JA13806 2005JHC661 2005JHC1305 2005JHC1345 2005JOC4502 2005JOC9985 2005JOC10166 2005JOC10569 2005JOC10854 2005OBC431 2005OL791 2005OL1565 2005OL2097 2005OL5301 2005PHC(17)84 2005RCB864 2005S199 2005S1109 2005SC1351 2005SC2251 2005SL187 2005SL1137 2005SL2739 2005T3507 2005T8648 2005T8711 2005T9007 2005T9273 2005T10449 2005TL1319 2005TL4225 2005TL7311 2005TL8053 2005TL8153 2006AGE4473 2006BMC2358 2006BMC6827 2006BML1350 2006BML5057
2006CEJ5790 2006EJM925 2006H(68)1709 2006HAC104 2006HCO187 2006JHC629 2006JOC6516 2006JOC8006 2006M219 2006PHC(18)126 2006PS2051 2006RCB2081 2006SC3319 2006SL1793 2006T537 2006T11513 2006TL1551 2006TL2887 2007BCJ763 2007BMC3832 2007BML3905
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Morikawa, and H. Konishi, Heterocycles, 2006, 68, 1709. M. V. Vovk, V. A. Sukach, V. V. Pyrozhenko, and A. V. Bol’but, Heteroatom Chem., 2006, 17, 104. Vijayakumari, and Shivaraj,, Heterocycl. Commun., 2006, 12, 187. L. W. Castle and T. A. Elmaaty, J. Heterocycl. Chem., 2006, 43, 629. Y. Miyahara, J. Org. Chem., 2006, 71, 6516. Y. Li, F. S. Liang, X. H. Bi, and Q. Liu, J. Org. Chem., 2006, 71, 8006. K. Bogdanowicz-Szwed, R. Gil, and P. Serda, Monatsh. Chem., 2006, 137, 219. T. Janosik and J. Bergman; in ‘Progress in Heterocyclic Chemistry’, G. W. Gribble and J. A. Joule, Eds.; Pergamon, New York, 2006, vol. 18, p. 126. W. W. Wardakhan, Phosphorus Sulfur and Related Elements, 2006, 181, 2051. L. S. Konstantinova, S. A. Amelichev, and O. A. Rakitin, Russ. Chem. Bull., 2006, 55, 2081. C.-K. Ryu, I. H. Choi, and R. E. Park, Synth. Commun., 2006, 36, 3319. N. Franz, G. Kreutzer, and H.-A. Klok, Synlett, 2006, 1793. Y. Kasano, A. Okada, D. Hiratsuka, Y. Oderaotoshi, S. Minakata, and M. Komatsu, Tetrahedron, 2006, 62, 537. M. C. Willis, D. Taylor, and A. T. Gillmore, Tetrahedron, 2006, 62, 11513. J. Pei, W.-Y. Zhang, J. Mao, and X.-H. Zhou, Tetrahedron Lett., 2006, 47, 1551. S. Ogawa, K. Kikuta, H. Muraoka, F. Saito, and R. Sato, Tetrahedron Lett., 2006, 47, 2887. K. Kobayashi, S. Fujita, M. Hase, O. Morikawa, and H. Konishi, Bull. Chem. Soc. Jpn., 2007, 80, 763. M. A. A. Radwan, E. A. Ragab, N. M. Sabry, and S. M. El-Shenawy, Bioorg. Med. Chem., 2007, 15, 3832. S. Louise-May, W. Yang, X. Nie, D. Liu, M. S. Deshpande, A. S. Phadke, M. Huang, and A. Agarwal, Bioorg. Med. Chem. Lett., 2007, 17, 3905.
Thiophenes and their Benzo Derivatives: Synthesis
2007CEJ548 2007CL578 2007CM1070 2007CM3018 2007H(72)697 2007HAC239 2007HAC294 2007HAC450 2007JA2224 2007JHC63 2007JOC442 2007JOC1729 2007JOC5368 2007OL829 2007OL1005 2007OL1729 2007PS551 2007PS667 2007PS2193 2007TL779 2007TL3535
T. Okamoto, K. Kudoh, A. Wakamiya, and S. Yamaguchi, Chem. –Eur. J., 2007, 13, 548. K. Takimiya, Y. Kunugi, and T. Otsubo, Chem. Lett., 2007, 36, 578. S. Ellinger, U. Ziener, U. Thewalt, K. Landfester, and M. Moller, Chem. Mater., 2007, 19, 1070. F. Valiyev, W.-S. Hu, H.-Y. Chen, M.-Y. Kuo MY, I. Chao, and Y.-T. Tao, Chem. Mater., 2007, 19, 3018. R. Nagase, H. Gotoh, M. Katayama, N. Manta, and Y. Tanabe, Heterocycles, 2007, 72, 697. A. Alam, H. Ohta, T. Yamamoto, S. Ogawa, and R. Sato, Heteroatom Chem., 2007, 18, 239. K. M. Dawood, A. M. Farag, and H. A. Abdel-Aziz, Heteroatom Chem., 2007, 18, 294. M. Iyoda, Heteroatom Chem., 2007, 18, 450. T. Yamamoto and K. Takimiya, J. Am. Chem. Soc., 2007, 129, 2224. F. M. Abdelrazek, S. A. Ghozlan, and F. A. Michael, J. Heterocycl. Chem., 2007, 44, 63. M. He and F. Zhang, J. Org. Chem., 2007, 72, 442. L. A. Carpino, A. A. Abdel-Maksoud, D. Ionescu, E. M. E. Mansour, and M. A. Zewail, J. Org. Chem., 2007, 72, 1729. D. A. Androsov and D. C. Neckers, J. Org. Chem., 2007, 72, 5368. N. Negishi, Y. Ie, M. Taniguchi, T. Kawai, H. Tada, T. Kaneda, and Y. Aso, Org. Lett., 2007, 9, 829. L. San Miguel, W. W. Porter, and A. J. Matzger, Org. Lett., 2007, 9, 1005. S. Sasaki, K. Adachi, and M. Yoshifuji, Org. Lett., 2007, 9, 1729. N. R. Mohamed, M. M. A. Halim, W. A. Gad, and M. F. Zaid, Phosphorus Sulfur and Related Elements, 2007, 182, 551. K. C. Majumdar, N. Pal, and S. K. Samanta, Phosphorus Sulfur and Related Elements, 2007, 182, 667. S. E. Zayed, Phosphorus Sulfur and Related Elements, 2007, 182, 2193. A. K. Mohanakrishnan, P. Amaladass, and J. A. Clement, Tetrahedron Lett., 2007, 48, 779. A. Traversone and W. K.-D. Brill, Tetrahedron Lett., 2007, 48, 3535.
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Biographical Sketch
Dr. Ohki Sato was born in Sendai, Japan in 1967 and studied chemistry at Tohoku University from 1985 until 1994. He received his PhD degree in 1994 from Tohoku University and has been an assistant professor at Saitama University since 1994. His current research interests are syntheses, reactions, structures, and properties of novel aromatic compounds.
Juzo Nakayama is a professor of the department of chemistry at Saitama University and the vice president for research work of the same University. He received an award from the Society of Synthetic Organic Chemistry, Japan and the International Council on Main Group Chemistry for Excellence in Main Group Chemistry (ICMGC Award). His research interests include the chemistry of a range of sulfur-containing heterocycles (dithiiranes, thiirenes, dithietes, thiophenes, etc.), and sulfur-containing inner salts.
3.12 Thiophenes and their Benzo Derivatives: Applications J. Schatz, T. Brendgen, and D. Schu¨hle University of Ulm, Ulm, Germany ª 2008 Elsevier Ltd. All rights reserved. 3.12.1
Introduction
932
3.12.2
Naturally Occurring Thiophenes and Medicinal Applications
932
3.12.2.1
Naturally Occurring Thiophenes
932
3.12.2.2
Medicinal Applications
933
3.12.2.2.1 3.12.2.2.2
Introduction Analgesics
933 934
3.12.2.3
Anti-Inflammatory Agents
3.12.2.4
Antibacterial Agents
935
3.12.2.5
HIV and Anti-Tumor Agents
936
3.12.2.6
Binding to Selected Biological Substrates and Antagonists
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3.12.2.7
Further Medicinal Applications
938
3.12.3
935
Thiophenes as Intermediates
939
3.12.3.1
Introduction
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3.12.3.2
Photochemical Isomerism
939
3.12.3.3
Electrocyclic Additions
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3.12.3.3.1 3.12.3.3.2 3.12.3.3.3 3.12.3.3.4
3.12.3.4 3.12.3.5 3.12.4
[2þ1] Cycloadditions [2þ2] Cycloadditions [2þ4] Cycloadditions [4þ2] Cycloadditions
941 941 942 943
Transformation to Nonthiophene Derivatives Hydrodesulfurization
943 944
Electrochemical Applications
944
3.12.4.1
Introduction
944
3.12.4.2
Photovoltaic and (Semi)conducting Materials
944
3.12.4.2.1 3.12.4.2.2
3.12.5 3.12.5.1 3.12.5.2
Polymers based on thiophenes Oligomers based on thiophenes
944 947
Optical Applications
952
Donor/Acceptor-Substituted Dyes
952
Photochromic Dyes
953
3.12.6
Cyclophanes, Macrocycles, and Supramolecular Applications
956
3.12.7
Organometallic and Coordination Chemistry
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3.12.7.1 3.12.7.2 3.12.8
Metals Bound to Sulfur 1
963
5
Metals Bound – to Thiophenes
963
Further Developments
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3.12.8.1
Medical Applications
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3.12.8.2
Electrochemical and Optical Applications
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References
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Thiophenes and their Benzo Derivatives: Applications
3.12.1 Introduction The applications of thiophenes and benzothiophene derivatives were covered in the second edition of CHECII(1996) <1996CHEC-II(2)679>. For this edition, which covers the literature for the period 1996–2007, all general statements made in CHEC-II(1996) are applicable also today. Owing to the very rich chemical literature on thiophenes and their applications, the focus in this section has been directed to opto-electronic uses of thiophenes. All other areas are covered basically in the same order as in CHEC-II(1996) extending the applications reported there. Here, it is intended to give only selected examples and not a full coverage which enables the reader to gain quick access to the topic of interest.
3.12.2 Naturally Occurring Thiophenes and Medicinal Applications 3.12.2.1 Naturally Occurring Thiophenes Many sulfur-containing organic compounds can be isolated from natural sources such as crude oil, petroleum, gas condensates, and coals <2004MI1>. By chromatographic methods <1999MI58> various polycyclic aromatic sulfur heterocycles (PASHs) (1–7) have been identified from standard samples of coal tar, petroleum crude oil and decant oil.
A multidimensional chromatographic method was reported for the separation of thia-arenes and polycyclic aromatic hydrocarbons (PAHs) derived from coal tar, air particulate material, sediments, and biological samples. A thia-arene-rich fraction, prepared using a combination of alumina chromatography and palladium chloride/silica gel chromatography, was further separated using normal phase high-performance liquid chromatography (HPLC) to isolate fractions containing thia-arenes with molecular masses ranging from 184 to 284 amu <2000MI15>. Besides free lipids, sulfur-bound lipids are present in sedimentary organic matter deposited under natural sulfurization conditions in the Lorca Basin, Murcia, Spain. The high abundance of phytane (2,3-dimethyl-5-(2,6,10-trimethylundecyl)thiophene), mid-chain C-20 isoprenoid thiophenes and bithiophenes indicates that the organic matter in all these samples was deposited under hypersaline conditions <1997MI605>. Furthermore, solvent extraction of samples from immature oil shales from tertiary lacustrine basins, Ribesalbes and Campins (southern European rift system) deposited under reducing conditions, allowed the identification of S-containing hopanoids and novel highly branched isoprenoids (HBIs). They are present as thiophenes, thiolanes, and thiolane sulfoxides. 17,21(H)-, 17,21(H)- and 17,21(H)-thienyl- and methylthienylhopanes have been found <1997MI41>. The phytochemical investigations of Blumea obliqua afforded bithiophenes 8–10 and 59-methyl-[5-(3-hydroxy-4isovaleroxy-1-butynyl)]-2,29-bithiophene 11 as a new natural product <1996P733>.
Thiophenes and their Benzo Derivatives: Applications
Tagetes is a very rich source of naturally occurring thiophene derivatives. Various bithiophenes, for example, 12–14 or terthienyl 15, have been identified from Tagetes patula L. (Asteraceae) by GLC-MS analysis <2002ZNC63>.
To study the biosynthesis of thiophenes in Tagetes, 35S-labeled thiophene derivatives have been prepared by in vitro culture of Tagetes sp. A. Different sources of isotopic sulfur were tested and the best results were achieved with Na235SO4. The resulting bithiophenes such as alkyne 12 are derived from triceapentaynene obtained from oleic acid <1995MI807, 1996JRN455, 1997MI175>. Four new natural products, namely 5,50-dichloro--terthiophene, 5-chloro--terthiophene, 5-acetyl--terthiophene, and 5-carboxyl bithiophene, together with seven known thiophenes were isolated and purified from ethanol extract of roots of Echinops grijisii Hance <2002MI175>.
3.12.2.2 Medicinal Applications 3.12.2.2.1
Introduction
In pharmaceutical applications thiophene is often used as a substitute for a phenyl or an other heteroaromatic moiety. Hence, it is not surprising that thiophene derivatives do play an important role in pharmaceutical and medicinal applications and drug discovery <2006MI187, 2005MI723, 2001CHE141>. This importance already highlighted in CHEC(1984) <1984CHECI(4)863> and CHEC-II(1996) <1996CHECII(2)679> is still valid up to now. A short survey in the Merck Index and the Ashgate Drug Database identified up to 135 relevant drugs based on the thiophene skeleton in 2006 (about 1–2% of all drugs available on the market). A thiophene derivative was the second best selling drug on the market (US$6.4 billions) in the 12-month period ending June 2006: clopidogrel, marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. It is a potent oral antiplatelet agent often used in the treatment of coronary artery disease, peripheral vascular disease, and cerebrovascular disease <2006MI17>. Clopidogrel mainly replaced ticlopidine which has been reported to increase the risk of thrombotic thrombocytopenic purpura (TTP) and neutropenia.
Together with clopidogrel, various other thiophenes are currently used as medicinal drugs. In the following, only a few derivatives are highlighted.
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Thiophenes and their Benzo Derivatives: Applications
Dorzolamide <2006MI850> is a carbonic anhydrase inhibitor which is used to lower increased intraocular pressure in open-angle glaucoma and ocular hypertension. Duloxetine hydrochloride and closely related derivatives are antidepressants which inhibit the serotonin/noradrenaline uptake <2006MI30, 2004MI773, 2004BML5395, 2003BML4477>. Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. The drug acts on the renin–angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding of angiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilation. Second, it inhibits sympathetic norepinephrine production, which further reduces blood pressure. Olanzapine, already mentioned in CHEC-II(1996), has become one of the most commonly used atypical antipsychotics. Strontium ranelate <2005MI728> has emerged as a novel medication in the treatment of osteoporosis. It increases the synthesis of collagen and noncollagenic proteins in vivo.
Rivaroxaban (BAY 59-7939) <2005JME5900> is an oral anticoagulant currently under development. It acts by inhibiting the active form of coagulation factor Xa. Sitaxentan <2004JME1969, 2005MI985> is an orally active sulfonamide class endothelin-A receptor antagonist.
3.12.2.2.2
Analgesics
Sufentanil is a synthetic opioid analgesic drug, as outlined in CHEC-II(1996), and is approximately 5–10 times more potent than fentanyl. Sufentanil is marketed for use by specialist centers under different trade names. Other thiophene derivatives, such as the benzimidazol-thiophenes 16 and 17, exhibit analgesic activity that can be compared with morphine sulfate and acetylsalicylic acid <2005PS1841>.
Thiophenes and their Benzo Derivatives: Applications
In contrast, amides 18 exhibit only low analgesic (and antiinflammatory) activity <2005KFZ26>.
3.12.2.3 Anti-Inflammatory Agents Human chymase is a serine proteinase which appears to participate in various diseases, but it is unclear whether chymase plays major roles in physiological and pathophysiological functions in vivo. However, the novel human chymase inhibitor 19 <2003BML4085> exhibits reasonable antiinflammatory activity. Even simple thiophenes, such as alkyne 20 <2001TL7921> or the suprofen analog 21 <2004BML979>, are interesting candidates for nonsteroidal anti-inflammatory drugs.
3.12.2.4 Antibacterial Agents In times of multiresistant strains of bacteria, and similar threats, the quest for antibacterial, antifungal, and antimicrobial agents is still ongoing. Not surprisingly, many thiophene derivatives have been synthesized to be tested in this area. The derivatives 22 <2005FA727> exploit the -lactam antibiotic motif for antimicrobial activity; benzo[b]thiophenes such as the amides 23 <2004JIC694, 2004T11821, 2005PS601> or the thieno[2,3-b]pyridines 24 <2005PS1815> have also been tested in that respect.
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Thiophenes and their Benzo Derivatives: Applications
3.12.2.5 HIV and Anti-Tumor Agents In recent years, anticancer multidrug resistance has come into focus in medicinal research. Such drug resistance can be a major problem in the chemotherapy of cancer. Several ATP-dependent membrane proteins such as multidrug resistance protein 1 (MRP1) may be responsible for low accumulation levels of anticancer drugs in tumor cells <2005MI453>. Selective estrogen receptor modulators (SERMs) <2006AG4664> such as tamoxifen, raloxifene <2001MI459>, arzoxifene (LY353389) <2003JME1081>, or the arzoxifene analogue LY329146 <2003MI6516> can selectively modulate MRP1-mediated multidrug resistance and can therefore be used against breast cancer.
Thiophenes and their Benzo Derivatives: Applications
Raltitrexed <1998MI423> can be used in the treatment of advanced colorectal cancer. Substituted 2-thienyl-1,8naphthyridin-4-ones 25 <1999JME4081> exhibit cyctotoxicity and inhibit tubulin polymerization. Cyclopentathiophenes, for example, 26–29 <2002BMC2185>, have been successfully used against leukemia cell lines.
Compound 30 <2002JME1901>, an improved curacin A analogue, was found to have potent antiproliferative activity in human breast, prostate, and ovarian cancer. It can replace colchicin from tubulin and inhibits the GTP/ glutamate-induced polymerization of tubulin effectively. Pharmaceutical studies suggest that the oxime moiety in compound 30 may serve as a (Z)-alkene bioisostere.
Benzodithiophene 31 was synthesized as a potential new drug against HIV infection, exploiting the DNA damaging profile of this intercalating substance <2001SC2997>.
3.12.2.6 Binding to Selected Biological Substrates and Antagonists A plethora of thiophenes that were synthesized directly targeted toward a specific receptor or biological substrate can be found in the literature. Table 1 gives an impression of the flourishing structural diversity created for this purpose. Further thiophene derivatives have been designed for inhibition of IKK-2 <2005BML2870>, anthelmintic activity against Haemonchus conturtus <2004BML4037>, prostaglandin E2 production <2004BML2105>, targeting the NK-2 receptor <2002S1091>, urokinase inhibition <2002BML491>, serine protease factor Xa inhibition <2001BML1801,
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Thiophenes and their Benzo Derivatives: Applications
2003BML507>, NHE-1 inhibition <2005BML2998>, vitronectin receptor antagonists <2003BML503>, antiHTLV-1 activity <2002CPB1215>, and activation of the botulinum neurotoxin serotype A light chain metalloprotease <2006JA4176>.
Table 1 Selected thiophene derivatives targeted toward biological substrates Compound
Target
Reference
32 33 34 35 36 37 38
Antitubulin Neuronal nitric oxidase synthase Human glucagon receptor antagonist Allosteric enhancer at the human A1 receptor EP1 receptor antagonist Hepatitis C virus NS5B polymerase inhibitor Tumor necrosis factor- inhibitor
2000JOC8811, 2001BML2341 2003BML209 2005BML1401 2004EJM855 2005BML1155 2006BML100 2002BMC3113
3.12.2.7 Further Medicinal Applications Affinitychromic polythiophenes <2004SL380> such as derivatives 39 <2006JA14972> or 40 <2004JA4240> can be used in the direct visualization and optical detection of single-stranded DNA (ssDNA). Owing to multiple electrostatic interactions of ssDNA with the polyelectrolyte, a stable complex is formed in which the polythiophene adopts a planar, highly conjugated conformation resulting in a red shift in the UV/Vis absorption in the case of 39 or by fluorescence emission for 40.
Thiophenes and their Benzo Derivatives: Applications
Another interesting medicinal application is also based on chromophoric thiophenes. Various thiophene dyes coined Pittsburgh I–Pittsburgh VIII (PGH I–VIII) <2005MI125> were tested for their spectral properties in heart muscles. Using these long-wavelength voltage-sensitive dyes (VSDs) it is possible to measure membrane potential and gain insight into electrophysical properties of multicellular systems. For this purpose, open frog hearts were stained with fluorescent PGH I–VIII and the time-resolved action potentials of the muscles were measured by observing the spectral changes.
For potential pharmaceutical use many thiophene derivatives have been synthesized either by conventional (e.g., <2001J(P1)2483, 2002TL1829, 2004T6085>) or by parallel synthesis (e.g., <2005JCO253>). Often a precise application is still to be found.
3.12.3 Thiophenes as Intermediates 3.12.3.1 Introduction Thiophene is regarded as an electron-rich aromatic ring system similar to benzene. Therefore, the main reactivity, that is electrophilic substitution, is very similar to all comparable (hetero)aromatic rings. This is also true for addition reactions, for example, hydrogenation to tetrahydro derivatives. In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or N-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in.
3.12.3.2 Photochemical Isomerism Irradiation of 2-substituted thiophenes 41 gives the corresponding 3-substituted analogues. Several mechanisms have been proposed for this reaction; however, the pathway including Dewar thiophenes 42a/b is regarded as the most probable (Scheme 1) <2002JPH31>. This seems to be corroborated by a recent study of the walk rearrangement of perfluorotetramethyl Dewar thiophene exo-S-oxide <2007T2191>. When halogenated thiophenes are irradiated in benzene as a solvent, both arylation and dehalogenation reactions are observed (Scheme 2) <1997H(45)1775>. Irradiation of 5-iodo-2-cyanothiophene 44 gave the dehalogenated
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940
Thiophenes and their Benzo Derivatives: Applications
derivative 45 as the only product. A similar result was obtained with 5-chlorothiophene 2-carbaldehyde 46 as starting material and thiophene 2-carbaldehyde 47 was the sole product. In contrast, irradiation of 5-iodothiophene 2-carbaldehyde 48 gave arylation product 49. The different outcomes of arylation versus dehalogenation can be easily explained by simple PM3 calculation of Hf, that is, the energy difference between substrate and radical intermediate derived from cleavage of the C–X bond.
Scheme 1
Scheme 2
During the irradiation of 2,5-diiodothiophene 50 under matrix-isolation conditions <2006JOC9602> ethynylthioketene 52, formed via the bis-alkyne 51, could be identified by IR spectroscopy (Scheme 3).
Scheme 3
Photochemically induced ring closure may give rise to larger condensed heteroaromatic ring systems. For example, irradiation (>300 nm) of imine 53 for 6–8 h gave the tetracyclic product 54 in modest yield (30%) (Equation 1) <2006JOC7165>.
Thiophenes and their Benzo Derivatives: Applications
ð1Þ
Reversible ring closure/opening of photochromic systems is discussed in Section 3.12.3.3.
3.12.3.3 Electrocyclic Additions Owing to the less aromatic character of thiophene compared to benzene it can be involved in many electrocyclic reactions; for example, thiophene can react as a dienophilic 2p-component or as a diene (4p-component) in DielsAlder reactions. Furthermore, [2þ2] cycloadditions are possible using electron-deficient counterparts.
3.12.3.3.1
[2þ1] Cycloadditions
The carbene interconversion of thiabicyclopropylidene 55 was studied using computational methods <2001JA9418>. Scheme 4 summarizes one of the potential reaction pathways identified by high-level ab initio calculations. Carbene 57, formed by rearrangement of intermediate 56, could be trapped by thiophene itself giving rise to bicyclic product 58.
Scheme 4
3.12.3.3.2
[2þ2] Cycloadditions
Addition of dimethyl acetylenedicarboxylate (DMAD) to the benzothiophene 59 (Equation 2) followed by rearrangement results in an interesting formal [2þ2] cycloaddition leading to product 60 <2006BML3034>.
ð2Þ
The [2þ2] cycloaddition of benzyne 61 to substituted thiophenes (Equation 3) is a general method to trap such reactive intermediates. Usually, the adducts 62 are postulated; rearrangement and addition of a second equivalent of benzyne gives 1- and/or 2-substituted naphthyl sulfides 63 <2003JOC70, 2005JPO477>.
ð3Þ
941
942
Thiophenes and their Benzo Derivatives: Applications
3.12.3.3.3
[2þ4] Cycloadditions
Thiophenes can act as dienophiles in Diels–Alder reactions with electron-poor dienes such as hexachlorocyclopentadiene, tetrazines, or o-quinone monoimines. The masked o-benzoquinone 64 can undergo inverse electron demand cycloadditions with thiophene itself or simple derivatives such as 2-methyl-, 2-methoxy-, and 2,4dimethylthiophene (Scheme 5) <2001TL7851>. Depending on the substitution pattern on the thiophene skeleton, different cycloadducts can be observed. The basic thiophene skeleton gives rise to a bis-adduct 65. By blocking the second double bond with a methyl or methoxy group, a 1:1 adduct 66 or 67, respectively, is obtainable in moderate yield.
Scheme 5
2-Vinyl thiophenes, for example, 68, can be used as 4p-components in [4þ2] cycloaddition processes. Reaction with DMAD proceeds via a nonconcerted, zwitterionic reaction pathway to give a mixture of products including 69– 72 (Scheme 6) <2004TL2189>. It is reported that electron-poor 2- or 3-nitrothiophene can react as dienophiles with Danishefsky’s diene in normal electron demand Diels–Alder reactions <2004MI369>. The double bonds of the thiophene skeleton can be exploited as a 2-component in 1,3-dipolar cycloaddition reactions. The first examples of an intramolecular addition of nitrile imines 73 to give products 74 and 75 are shown in Scheme 7 <1998J(P1)4103>. Reactive nitrile imines 73 are formed by treatment of the corresponding hydrazonyl chloride with Ag2CO3 in dioxane. Mono adducts 74 can be isolated after 3–30 h reaction time in all cases studied, with yields increasing roughly with the increasing electron-accepting character of the substituent R on the aryl ring. For R ¼ H, Me, OMe, F, and Cl, bis-adducts 75a–e are formed in low yields. For R ¼ Cl, COMe, and NO2, bis-adducts in which the addition of the second nitrile imine occurs on the CTN double bond of 74 are formed as well (yields roughly 10%).
Thiophenes and their Benzo Derivatives: Applications
Scheme 6
Scheme 7
3.12.3.3.4
[4þ2] Cycloadditions
Thiophene itself is not very reactive in the standard Diels–Alder reaction. However, at elevated temperatures and under high-pressure clean reaction between thiophene and maleic anhydride, maleimides or acrylic dienophiles can be observed <2004AG2049>. Using solvent-free reaction conditions at 100 C and 0.8 GPa pressure, cycloadducts can be obtained in very good yields (90–100%). However, the endo/exo selectivity is approximately 50:50. A very elegant way to facilitate [4þ2] cycloadditions to thiophenes is the route via thiophene S-oxides (Equation 4) <2000H(52)1215 2000J(P1)2968, 2002JCM303, 2003JA8255, 2003NJC1377, 2003TL5159, 2005TL4165>, S,S-dioxides <2005RCB2182, 2005T10880, 2006T4139, 2006RCB712>, or S-phenyl thiophenium salts <2004H(64)199>. However, unexpected and complex products can be obtained by over-oxidation of the thiophene skeleton <2004T2433>.
ð4Þ
3.12.3.4 Transformation to Nonthiophene Derivatives 3-Nitro-, 3,4-dinitro-, or 3-nitro-4-(phenylsulfonyl)thiophene can be easily converted into open-chain 1,3-butadienes by nucleophilic ring opening (Scheme 8) <2001T9025, 2003JOC5254, 2005JOC8734>.
943
944
Thiophenes and their Benzo Derivatives: Applications
Scheme 8
3.12.3.5 Hydrodesulfurization A variety of hydrocarbons (and H2S) can be formed by the removal of sulfur over heterogeneous catalysts. This hydrodesulfurization (HDS) is an important process in industrial chemistry and various recent review articles deal with the scope, limitations, and mechanism of the HDS process <1997POL3073, 1998ACR109, 1999MI133, 2000MI203, 2002MI340, 2005AC143, 2006MI1110>. Good results can be achieved using soluble metal catalysts <1997POL3073>. Here, bimetallic nickel complexes <2000OM2114>, tungsten 2-thiophenes <2005OM1876>, other tungsten complexes <2001CC1506>, manganese <1997OM5688>, or iridium complexes <1997OM1912> serve as model compounds for a deeper understanding of industrial HDS processes in which Ni-, W-, and Mo-based heterogeneous catalysts are generally used <1999AC229, 1999AC189, 2003AC151, 2003JCT208, 2003CAL147, 2004JMO225, 2005EUP1508370, 2005MI755>.
3.12.4 Electrochemical Applications 3.12.4.1 Introduction Conducting and semiconducting organic molecules has been one of the most flourishing topics in the area of thiophene chemistry over the last decade. Since the discovery of conducting polyacetylenes in 1977 <1977CC578>, many tailormade organic compounds have found widespread interest as photoconducting materials, organic light emitting diodes (OLEDs), solar cells, and related applications. Here, thiophene has a considerable impact as a general building block of poly- and oligomeric materials for such applications. General aspects, basic principles, structure, and application of organic (semi)conducting materials have been reviewed in many excellent books and monographs and recent review articles <1997CRV173, 1999JMC1933, 2000JMC1, 2001AG1069, 2001ACR359, 2002AM99, 2004CM4436, 2005CC5378, 2005AM1581, 2005AM2281, 2005CRV1197, 2005CRV1491, 2005MI87, 2005MI389, 2005MI3167, 2006CRV5028>. Additionally, special literature surveys that are published regularly summarize the literature available for photovoltaic applications <2003MI353, 2004MI317, 2005MI725, 2006MI373>.
3.12.4.2 Photovoltaic and (Semi)conducting Materials 3.12.4.2.1
Polymers based on thiophenes
Pure polythiophene is neither soluble nor fusible and is therefore not useful for further processing. Side chains introduced on the polythiophene skeleton help to obtain organic materials that can be used in further processes <1999JMC1933>. When 3-substituted thiophenes are used in the polymerization process, three possible arrangements can be obtained: head-to-head (HH), head-to-tail (HT), and tail-to-tail (TT). The polymerization of thiophenes has been reviewed extensively <1998AM93, 2007PPO147>. Examples of polythiophenes can be found in Table 2 <1999JMC1933>, and in the extensive compilation in CHEC-II(1996) <1996CHEC-II(2)679>. Conjugated heterocyclic materials based on fused bithiophenes 76 have been thoroughly summarized <2005MI389> and are therefore not included here.
Thiophenes and their Benzo Derivatives: Applications
Table 2 Substituted polythiophenes
R1
R2
Reference
H
2000MM5481, 1999JMC1933
H
1999JMC2215
H H H H H H C8F17 H, Aryl H, CH3
CH2CH2COOH CH2COOH COOH B(OH)2 C8H17 C8H17, OC10H21 C8F17 Aryl OCH2CH2SO3Na O–CH2–CH2–O
2006JA5640 2004CC2222 2004CC2222 2004CC2222 2001EJO1249 2006JA8980 2006MM6092 2001CM634 1997CM2902 2000CM2996, 2005CC5378, 2005CC4187, 2003AG682
Mixed polymers containing thiophene moieties are of considerable interest for electrochemical applications because by this approach both physical and chemical properties can be fine-tuned in a very delicate fashion.
945
946
Thiophenes and their Benzo Derivatives: Applications
Thiophenes and their Benzo Derivatives: Applications
Phosphirene 93 <2006OM5176> has been proposed as a useful and novel conjugating spacer within polythiophenes. Model studies on the monomeric unit 90 show that all the important criteria for that purpose (conjugation, stability) are fulfilled.
3.12.4.2.2
Oligomers based on thiophenes
Oligomers containing thiophene units are of current interest due to their model character for polythiophenes and recent reviews are available <1999MI439, 2000JMC571, 2005CRV1197, 2006CRV5028, B-1998MI1, B-1999MI5>. Usually, oligothiophenes are better soluble, easier to characterize and to handle (e.g., further processing by stamping <2003MAC68>), and many functionalities can be incorporated in the same oligomeric unit. Thus, conducting materials with better or even novel properties compared to polythiophenes can be made and the theoretical description of the mechanism of conduction is somewhat easier <2003MI498, 2003IJQ350, 2006OL5243>. Additionally, supramolecular self-assembly can be exploited <2003AM2002, 2004CM4452, 2006JA5923, 2006JA4277, 2006MI1193, 2006CC3399>. However, these advantages have to be paid by a stepwise or convergent synthesis, which is sometimes tedious and lengthy. Here, usually aryl–aryl coupling reactions such as Suzuki, Stille, Negishi, Hijama, or Ullmann couplings are standard tools for the syntheses of oligomeric molecules. However, when using transition metal catalysts some effort has to be made by the synthetic chemist to remove trace amounts of precious metals which can strongly influence the conductivity of the materials obtained. Alternatively, thiophene ring-building reactions starting from suitably functionalized 1,4-diketones or 1,3-butadienes are often used in the preparation of oligomeric units . Conceptually, the easiest oligomeric thiophenes just consist of the basic thiophene skeleton. Usually, alkyl chains have to be attached to the backbone to improve the solubility of the material. By this approach quite long rods are available, for example, 16mers 94 <1998CC2743> and 95 <2004CL654>, and 17mer 96 <2004JA11796> or 98 <2000JA7042>, and the quest for the longest oligothiophene is still ongoing <2006CL942>.
Incorporation of other conjugated spacers, such as triple bonds in 97 <2002OL2533>, can extend the conjugation. Bridged oligothiophenes 99 have been synthesized as surfactants with an affinity for CdSe nanoparticles to prepare organic/inorganic polymer–nanocrystal hybrid materials <2003OL1879>. Linear fluorinated sexithiophenes, either fully fluorinated <2001JA4643> or with a C6F4 core <2005CC1465, 2005S1589>, have been synthesized.
947
Thiophenes and their Benzo Derivatives: Applications
Alternatives to linear arrangements are possible using dendrimers <2000CM1463, 2000JA7042, 2006OL2281> or trigonal 100 <2000J(P2)1976>, 101 <2007TL281, 2007CM443>, or hexogonal star-like molecules 102 <1999JRM2546>. Using a bisthieno-fused bicyclo[4.4.1]undecanone <2006JA13680> a stacked arrangement of oligothiophene strands is possible. A molecular cross consisting of b-linked pentathiophenes 103 can be used as a solution processable organic field effect transistor (OFET) <2006JA3914>. Even very big oligothiophenes can be made exploiting thiophene 104 <2006MI917> or bisthiophene 105 <2007AG1709> as core; generation G4 oligothiophene 105 consists of 90 thiophene units!
949
950
Thiophenes and their Benzo Derivatives: Applications
Furthermore, the oligomer approach enables different electroactive moieties to be brought together to improve performance, stability, and processability of the desired materials. Often fullerenes <2005SM(152)125, 2006JOC1761, 2006AM2872> or porphyrins <2006CC3726, 2002CEJ3027> are linked with oligothiophenes either covalently or in the desired gadget <2006JA13988>. The thiophene units can also be linked by ‘simple’ aromatic moieties such as phenyl, biphenyl, fluorene <2006OL3701, 2007TL1151>, or phenanthrene 106 <2005JMC3026, 2006JOC4332, 2005CC5337>, or other planar aromatics, e.g. 107 <2005MI818>, pyrenes <2001CL420>, or perylenes <2005EJO3715, 2005CM2208, 2005PCA11687, 2005OBC985> and heteroaromatics such as pyridazine <2006OL4699>, carbazole <2006CM6194>, or 1,3,4-oxadiazole <2006JA3789>. Another possibility is to fuse thiophene rings together to form planar extended acenes <2006OM2374, 2006OL5033, 2006JOC3264, 2007JOC442> for organic semiconductor applications <2006CEJ2073>, 108 <2006JA16002>, 109 <2006JA12604>, 110 <2007CEJ548>. Cyclic thiophenes are discussed in Section 3.12.6 (macrocycles).
Combining various functional units in a big designed (metal) organic molecule gives rise to multidomain compounds. An elegant example is an ‘all-in-one molecule for organic solar cells’ 111 (A–Ru–B) <2006JOC5546>. Another useful approach is to exploit (in)organic/oligothiophene hybrid materials incorporating perovskite <1999IC6246>, potassium hydrogen phthalate single crystals <2006JA13378>, CdSe <2003OL1879, 2004CM5187, 2006JCD2778>, Au <2004CM2712, 2005IC620, 2006CEJ607, 2007CM443>, or polymers grafted with oligothiophenes <1998JA2798, 2001PSA4119, 2004OBC3541, 2005CM2672, 2005OM4494, 2005SM(149)31, 2006OL1585>.
952
Thiophenes and their Benzo Derivatives: Applications
3.12.5 Optical Applications 3.12.5.1 Donor/Acceptor-Substituted Dyes Push–pull-substituted thiophenes posses extended dipolar chromophores of the form donor–p-system–acceptor that show large molecular second-order nonlinear optical (NLO) response or high solvatochromic behavior. Therefore, such dyes have found great interest in the last decade and many derivatives following the general D–p–A outline have been synthesized and tested for either NLO or solvatochromic properties, or both. In Table 3 some structures are highlighted, especially cyanovinyl(oligo)thiophenes, which are very successful as NLO dyes <2006CEJ5458>.
Table 3 Thiophene dyes for NLO, solar cells, or solvatochromic purposes
(Continued)
Thiophenes and their Benzo Derivatives: Applications
Table 3 (Continued)
No.
Reference
Use
112 113 114 115 116, 117 118 119 120 121 122 123
2006EJO3938 2006OL3681 2006JOC7509 2004T4071 2001TL1507 2005CC4098 2006CC2792 2007T1553 2002BKC1253 2005JA9710 2006S1009
NLO NLO NLO, theoretical calculations Solvatochromism NLO Solar cells Solar cells Solar cells NLO NLO NLO
Also dyes consisting of a center such as platinum (e.g., <2006OM5045>), ruthenium (e.g., <2006IC9729>), or boron <2006JCD3777, 2006JOC6485> have been reported.
3.12.5.2 Photochromic Dyes Diarylethenes with hetaryl groups are an important class of compounds for thermally irreversible (P-type) photochromic materials. The most striking feature of the compounds is their resistance to fatigue. The coloration/ decoloration cycle can be repeated more than 104 times. Thermal irreversibility and fatigue resistance are the most important features for technical application of such compounds in devices such as memories and switches <2000CRV1685, 2000CRV1777>. According to the Woodward–Hoffmann rules <1968ACR17>, the basic ringclosing/ring-opening principle for dithienylethenes shown in Equation (5) should be conrotatory <1992JA3150>.
ð5Þ
The dithienylperfluorocyclopentenes 124 are very successful photochromic compounds. Scheme 9 shows a general synthetic route toward such derivatives <2000CRV1685>.
Scheme 9
953
954
Thiophenes and their Benzo Derivatives: Applications
Although the photochromic reactions usually occur in solution, some examples are know for photocolorations in the single-crystalline phase <1999JA2380, 2000CRV1685>. Upon irradiating a single crystal of 1,2-bis(2,4-dimethyl-3thienyl)perfluorocyclopentene (124, R1 ¼ R2 ¼ CH3, R3 ¼ H) <2002BCJ167, 1999JA2380> with UV light ring closure to a red-colored product occurs; irradiation with visible light reverses the process and the color disappears again. Owing to the fact that the ring closure is a conrotatory process parallel conformers are photochemically inactive <2002BCJ167> and the efficiency of the photo-reaction depends on the ratio of photoactive antiparallel to photoinactive parallel conformers in the crystal. Many dithienylethene derivatives have been examined recently for their photochromic properties (Table 4) <2002RCB2097, 2003T7615, 2004CC72, 2005CC3921, 2006AG7623, 2006CC2656, 2006CC3930, 2006JA14542, 2006JOC7499, 2006NJC1595, 2006OL5381>. Even oligothiophenes 133 <2005CL1580> have been synthesized to study the influence of the length of the conjugation onto the photochromic reaction. To trigger the photo-switching process various key stimuli have been used: OH–N–hydrogen bonds <2006CEJ4275>, pH changes <2006CEJ4283>, or fluoride recognition by organoboron dithienyl ethenes <2006OL3911>. Other photochromic systems are using the ring opening/ring closing of thienyl pyrans. Examples are 134 <2006OL4931> as a biphotochromic system or 135.
Table 4 Photochromic dithienylethene derivatives
(Continued)
Thiophenes and their Benzo Derivatives: Applications
Table 4 (Continued)
No.
Reference
No.
Reference
125 127 129 131
2006SL737 2003BCJ363 2002CL58 2003T7615
126 128 130 132
2003BCJ363 2003BCJ355 2001CC1744 2003CL848
955
956
Thiophenes and their Benzo Derivatives: Applications
3.12.6 Cyclophanes, Macrocycles, and Supramolecular Applications In the last decade interest in the synthesis and characterization of macrocycles containing thiophene units, or other carbon–sulfur structures such as thiahelicenes <2003T6481>, cyclophanes <2001JOC713>, catenanes <2007AG367> increased significantly <2006AG8270>. For the first time, cyclic oligothiophenes (e.g., 136) could be obtained in good yields through the use of selfassembling building blocks to a bis-platinum macrocycle and subsequent C–C bond formation accompanied by metal elimination <2003CC948>. Previous attempts by the same group yielded the same class of cyclic oligothiophenes but in poorer yields <2000AG3623>. Calculations of geometry and HOMO–LUMO gaps (HOMO – highest occupied molecular orbital; LUMO – lowest unoccupied molecular orbital) of these highly symmetric macrocycles containing 6–30 thiophene units were performed <2006JOC2972>. Supramolecular platinum complexes are interesting not only as metal templates but also for the introduction of stereocenters into metallacycles through ligand exchange, self-assembling motives for host complexes, in achiral catalysis and as organic photocells, light emitting diodes and as models for triplet manifold studies of conjugated polymers. Their introduction into metallacycles such as 137 and the corresponding nonmetal analogue 138 leads to a bathochromic electron absorption shift and might be used to tune materials properties <2006JOM(691)413>. Using a source of palladium, metallacycle 139 is formed starting from terthiophene building blocks <2005JCD652>. Several rhenium(I) carbonyl complexes 140 using pyridine rings as chelating ligands have been synthesized and characterized concerning their electrochemical, photophysical, photochemical, and host–guest chemistry <2000JA8956>. It is possible to convert the trimer to the dimer just by heating. These compounds are suitable hosts for aromatic nitro compounds. By the use of copper or zinc templated synthesis in order to form thiophene-modified metallarotaxanes polymers, good electrochemical properties are obtained <2000AG622>.
Compound 141 can be synthesized by reacting the corresponding zirconocene derivative with S2Cl2 to give the thiophene (Equation 6) <2003JOM(666)15>. The SiMe3 substituents are chosen in order to stabilize the zirconocene intermediates and thus make this new approach to the thiophene ring possible.
Thiophenes and their Benzo Derivatives: Applications
ð6Þ
Besides these metallamacrocycles or metal-assisted ring-formation reactions, some other approaches have been developed. In the synthesis of a fully conjugated 304-membered macrocycle 142 <2003AG3284>, the crucial cyclization step is performed using the open chain analogue and 150 equiv of copper acetate under high dilution conditions yielding a very good 38% yield of the macrocycle. An azulene incorporating cyclic thiophene 143 can be made using a Friedel–Crafts reaction to introduce azulene into the ring <2006CC3346>. A ruthenium complex with this ligand has been formed and characterized and UV spectra measured for both complex and free ligand.
The azoxa-crownethers 144 can be obtained by a Mannich-type reaction of bridged bithiophenes with N,N9-dialkylated ethylenediamines <2000J(P1)1877, 2001J(P1)1398>. These compounds can be obtained in very good yields without the need for templates or high dilution conditions. Similar crownether derivatives 145 can be synthesized by reductive amination followed by acylation or tosylation <2002J(P1)717>. Chiral diamide-ester macrocycles 146 were formed by amidation followed by a 4-dimethylaminopyridine (DMAP) catalyzed bis-esterification sequence <2004JHC899>. Association constants of selected ligands in methanol indicate that the thiophene ring increases the selectivity for the binding of Co(II) vs. Pb(II), Cu(II), Ag(I), or Hg(II). For the chiral macrocycle 147 <2003OBC2801> the protonation constant and metal–ion binding have been evaluated and its tris-Zn(II) complex used as a catalyst in an asymmetric Henry reaction.
957
958
Thiophenes and their Benzo Derivatives: Applications
Under high dilution conditions the thiophenophanes 148 can be made <2001AM133, 2006JOC6516>. Wolff– Kishner reduction was found to be suitable for the reduction to the thiophenophanes (Equation 7). Under similar conditions, a dimeric disulfide can be obtained.
ð7Þ
The thiophene-bridged 4,49-bipyridinium salts 149 and 150 can be prepared by alkylation of bis-bipyridinium cations <1999T4709>. The order of alkylation is crucial. Whereas in the thiophene derivative the xylene core is introduced in the last step, it is not possible to obtain the benzothiophene derivative in the same way due to the less stable bis-cation. Therefore, the benzothiophene unit is introduced in the last ring-closing step.
Thiophenes and their Benzo Derivatives: Applications
Glaser-type reactions yield compounds 151 and 152 containing thiophene–bisacetylene–thiophene units that were characterized by X-ray crystal analysis <2006EJO5264>. Unfortunately, these compounds are obtained only in low yields (<10%).
A very large class of macrocyclic thiophene derivatives is the thiophene-modified porphyrins. Several compounds (153–157) with ter- or quaterthiophene subunits <2006OL2325, 2006OL4847, 2007CC43> have been reported. All of them have been synthesized by the classical acid-catalyzed porphyrin synthesis. Solution and solid-state structures have been investigated using nuclear magnetic resonance (NMR) and ultraviolet (UV) spectroscopy, calculations, and X-ray structures.
959
960
Thiophenes and their Benzo Derivatives: Applications
Macrocycles 158 and 159 containing alternating thiophene and pyrrole rings are obtained by a Rothemund-type synthesis <2001CEJ5099>. The so-called tetrathiaoctaphyrin can be reduced to the dihydrotetrathiaoctaphyrin. Two dithiaporphyrin-like pockets behave as independent proton acceptors. Stepwise protonation leads to several cationic species. The interconversion of isomers in solution has been discussed and a new mechanism proposed.
The tetraporphyrin derivative 160, which shows the formal exchange of one pyrrole ring by a carbon–carbon triple bond, and of two pyrrole rings by thiophene units, has been synthesized and characterized in solution and the solid state <2005AG5422>. It is also possible to react this compound with Ru3(CO)12 which leads to a significant decrease in symmetry. The metal binds to the nitrogen and both sulfur atoms and due to the octahedral coordination chemistry of Ru(II), the almost planar geometry of the ligand has to twist to a less symmetric geometry with both sulfur atoms pointing out of the plane. Interestingly, regioselective methanolysis leads to compound 161.
Thiophenes and their Benzo Derivatives: Applications
A different way to introduce thiophene rings into a porphyrin is to attach them to the porphyrin core giving 162 and its zinc complex 162-Zn <2005CC1974>. Self-assembling at the solid–liquid interface was studied and some calculations performed. An interesting approach toward the chiral porphorynoids 163 and 164 was described <2001TL1969>.
Besides porphyrins, calixpyrroles 165 are interesting compounds and the inclusion of thiophene rings is a synthetic challenge <2001T7323>. Dimers, trimers, and tetramers can be isolated. Unfortunately, further studies have only been performed with the furan compounds. The calixpyrrole 166 with a thiophene and phosphole incorporated and its platinum(II) complex has been described <2006OM3105>. Interestingly, the metal is bound by the phosphorus atom and an 5-coordinated pyrrole-ring leaving two sites that are occupied by chloride ions. This fact leads to several possible isomers. The main product shows a cone-shaped structure where the remaining NH group is coordinated to a chloride ion.
Calixarenes are widely used platforms in supramolecular chemistry and by ring closing of acyclic thiophene precursors in the final step a thiophene ring can be included into the calixarene moiety <1999H(51)2807>. The isomers 167–169 can be isolated serving as good hosts for N-methylpyridinium iodide.
961
962
Thiophenes and their Benzo Derivatives: Applications
Furthermore, the calix[4]arene scaffold can be modified with mono-, di-, ter-, and quaterthiophene units. In the case of tetra-thiophene-substituted calixarenes in the cone conformation some interactions of the thiophene chains within the molecule can be observed creating interesting optical and electrochemical properties <2006T7846>. Also, the flexibility of bithiophene substituted calixarene 170 with interconverting conformers has an influence on the electronic state <2006JOC6952>. Conducting polymers consisting of calixarene–crownether–thiophene conjugates are extremely sensitive toward metal ions such as Kþ and Ca2þ. This principle might be used for sensor design <2004AG3786>.
In the following paragraphs the supramolecular behavior of thiophene and its acyclic derivatives is briefly summarized. The weak binding of hydrogen halides was calculated and compared with experimental values. The proton interacts with the p-system of the thiophene <2005CPL(407)222>. The interaction of thiophene with C60-fullerene was studied using calorimetric methods. Complex nanoaggregates are formed and a new physical model for the aggregation has been presented <2005MI167>. A noncharged polythiophene solubilized by oligoethylene glycol side chains forms a folded structure in water without intermolecular interactions <2005CC5503>. This gives interesting perspectives in the field of organic electronics and biosensing, since the secondary structure will have a huge influence on the desired properties. Besides solution studies, a variety of thiophene derivatives have been studied in respect of their self-assembling behavior at the solid/liquid interface. Andostrene-based compounds arrange in lamellae <1999CEJ96>, urea-functionalized thiophenes assemble also in lamellae but the thiophene rings are tilted with respect to the surface due to some steric hindrance within the monolayer <2000L10385>.
3.12.7 Organometallic and Coordination Chemistry The organometallic chemistry of thiophenes and benzothiophenes has been reviewed extensively up to the year 2001 <2001AHC7, 2001OM1259>. Therefore, only some contributions of the last 5 years are presented in this section. Activation of covalent bonds is a key feature during catalytic processes such as hydrodesulfurization (HDS) (cf. Section 3.12.3.5). Here, many mechanistic studies are available dealing with various metals (e.g., Mn, Pt <2003ASC1053, 2005IC4475, 2007CEJ1047>, W <2004OM4349>, Ni <2004OM4534>, Mo <2002JA4182>, Ru <2004CC204, 2003OM1585> used in HDS processes.
Thiophenes and their Benzo Derivatives: Applications
3.12.7.1 Metals Bound to Sulfur Thiophilic metals tend to bind directly to the sulfur atom of the thiophene skeleton. Therefore, many transition metal complexes of the type C4H4S–Met have been structurally characterized, for example, iridium 171 <2005JCD1422, 2003ICA(345)367>, tungsten 172 <2004OM4349>, manganese 173 <2002OM1262>, rhenium 174 <2003OM4861>, iron 175 <2002EJI2891>, rhodium 176 <2004NJC625>, palladium 177 <2003JMO27>, and ruthenium 178 <2002OM749>.
3.12.7.2 Metals Bound 1–5 to Thiophenes Binding of metals directly to the carbon skeleton of the thiophene ring is a common binding scheme, especially at the activated C-2 position. Attack at this C–H bond is usually regarded as a possible first step in the activation of the carbon–sulfur bond important for the HDS process <2001OM1259, 2003CL14, 2006POL499>. Titanium complex 179 <2003JOM(678)5> or ruthenium compound 180 <2003JA2064> serve as examples for this binding motif. Interesting linkages are also possible; in the ruthenium oligothiophene complex 181 <2005JA6382, 2006IC7044>, both direct binding of the metal to the thiophene backbone as well as by a phosphine ligand is used to form a range of both electrochemically and spectroscopically interesting oligothiophene complexes. In bimolecular rhodium complexes of the general type 182 <2006OM3156> both an attachment of the Rh-atom to C-2 (as shown) and C-3 of the thiophene is possible and the acid-induced dynamic processes in such complexes are studied. Recently, the first 2,3,4,5-tetrakis(dimethylsilyl)thiophene has been synthesized <2006OM2761> as the first tetrasilylated thiophene.
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Tungsten(0) Z2-complexes play an important role in the dearomatization of thiophenes; by the binding of the metal fragment, the basicity of the heterocycle is strongly increased and can be protonated by weak acids such as methylimidazolium triflate <2005OM1876>. Binding of thiophenes Z5 is quite a common binding scheme and many examples with a full range of metals are available <2001AHC7>.
3.12.8 Further Developments In this section developments described during 2007 are highlighted with the main focus on medical, photo- and electrochemical applications.
3.12.8.1 Medical Applications Various thiophene derivatives have been developed as novel drugs against cardiovascular diseases <2007WO2007096362>. Tyrosine kinase modulators/inhibitors <2007WO2007075567, 2007WO2007071455>, factor Xa <2007JMC2967> or XIa inhibitors, such as 183 <2007WO2007070816>, exemplify the current efforts in finding new thiophene based drugs.
Thiophenes and their Benzo Derivatives: Applications
3.12.8.2 Electrochemical and Optical Applications Polymers based on 3,4-dialkoxythiophenes have been used as conductive materials <2007WO2007217355>, solar cells <2007JPP2007128757>, electroluminescent <2007JPP214517>, or light emitting devices <2007JPP2007208019>. Such polymers have also found an interesting application as material for extracellular electrodes for measuring the electrical activity of nerve cells <2007JPP2007205756>, for conductive nanotubes <2007JA4483>, or as polymers as sensing moieties in quartz crystal microbalances <2007ACA223>. Mixed polymers such as pyrrole-thiophene hybrids <2007MI1263, 2007MI622, 2007PAC73> or furan-thiophene co-polymers <2007MI5896> have been used for conducting applications. The basic principle for photochromic dyes, as shown in Equation (5) and highlighted in Table 4, have produced many new examples <2007T5437, 2007MI786, 2007MI90>, such as photochromic polymers <2007WO2007105699>, terpyridine dithienylethenes for fluorescent photoswitching <2007MI307>, an organoruthenium analog 184 <2007OM5030>, or complex functional units 185 <2007CEJ2503>. Fluorene- or fullerene-thiophene blends have been developed for enhanced photogeneration <2007CPC1497>, and use in light emitting diodes <2007MM6164>, and copolymers of oxadiazoles and thiophenes <2007MI236> have been used for non-linear optical applications.
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Thiophenes and their Benzo Derivatives: Applications
Biographical Sketch
Born in the middle of Bavaria, Germany, in 1966, Dr. Ju¨rgen Schatz finished his studies in chemistry in 1992 (Diplom) at the University of Regensburg. In his PhD thesis (1992–94) under the supervision of Prof. Ju¨rgen Sauer (Univ. Regensburg, Germany) the Diels–Alder reaction of thio- and selenocarbonyl compounds was the main focus. After that, one postdoctoral year (1995) at the Imperial College London in the research group of Prof. C. W. Rees was dedicated to the chemistry of sulfur–nitrogen heterocyclic compounds. In 1996 his independent research started at the University of Ulm mainly in the area of supramolecular chemistry (enzyme mimics, receptors, and supramolecular catalysis).
Thomas Brendgen was born in Aachen/Germany (1978) and found his way to the University of Ulm to start his education in chemistry in 1999. After his final grade (Diplom) in 2004 having investigated several supramolecular and smaller imidazolium salts in their performance as precursors in the aqueous Suzuki-reaction in Ju¨rgen Schatz’ group, he focuses now on a project on anion receptors and sensors as his PhD work.
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Thiophenes and their Benzo Derivatives: Applications
Daniel Schu¨hle, born in 1978, studied chemistry at the University of Ulm and received his Diploma in 2004 dealing with calix[4]arenes as selective Naþ-hosts and performing some basic research in the field of N-heterocyclic carbenes. Currently, he is doing his PhD in a joint project at the University of Ulm/Germany and at the Delft University of Technology/The Netherlands under the supervision of Ju¨rgen Schatz, Ulf Hanefeld, and Joop A. Peters dealing with the synthesis and characterization of new MRI contrast agents. His special focus lies in the design of medium-sized contrast agents suitable for higher magnetic fields.
3.13 Selenophenes E. T. Pelkey Hobart and William Smith Colleges, Geneva, NY, USA ª 2008 Elsevier Ltd. All rights reserved. 3.13.1
Introduction
976
3.13.2
Theoretical Methods
976
3.13.3
Experimental Structural Methods
977
3.13.3.1
Molecular Structure
977
3.13.3.2
Molecular Spectroscopy
978
3.13.3.2.1 3.13.3.2.2 3.13.3.2.3 3.13.3.2.4 3.13.3.2.5
1
H NMR spectroscopy C NMR spectroscopy 77 Se NMR spectroscopy Ultraviolet, infrared, Raman, and photoelectron spectroscopy Mass spectrometry 13
978 978 978 978 979
3.13.4
Thermodynamic Aspects
979
3.13.5
Reactivity of Fully Conjugated Rings
980
3.13.5.1
Thermal and Photochemical Reactions
980
3.13.5.2
Substitutions at Selenium
980
3.13.5.3
Electrophilic Substitutions
981
3.13.5.4
Reactions with C-Anion Equivalents
982
3.13.5.5
Organometallic Reactions
982
3.13.5.6
Reactions of p-Metal Complexes
984
3.13.5.7
Nucleophilic Substitutions
984
3.13.5.8
Radical Reactions
985
3.13.5.9
Pericyclic Reactions
3.13.5.10
985
C–Se Bond Cleavage
985
3.13.6
Reactivity of Nonconjugated Rings
985
3.13.7
Reactivity of Substituents Attached to Ring Carbon Atoms
986
3.13.8
Reactivity of Substituents Attached to Selenium
987
3.13.9
Ring Synthesis
987
3.13.9.1
Formation of One Bond
3.13.9.1.1 3.13.9.1.2 3.13.9.1.3
3.13.9.2
988
Category Ia cyclizations Category Ib cyclizations Category Ic cyclizations
988 988 989
Formation of Two Bonds
989
3.13.9.2.1 3.13.9.2.2 3.13.9.2.3 3.13.9.2.4 3.13.9.2.5 3.13.9.2.6 3.13.9.2.7
Category IIab cyclizations Category IIac cyclizations Category IIad cyclizations Category IIae cyclizations Category IIbc cyclizations Category IIbd cyclizations Category IIbe cyclizations
989 989 990 990 993 993 993
Formation of Three Bonds
993
3.13.9.4
Synthesis of Nonconjugated Rings
994
3.13.10
Ring Synthesis from Another Ring
995
3.13.9.3
975
976
Selenophenes
3.13.11
Selected Syntheses
996
3.13.12
Important Compounds and Applications
996
3.13.12.1
Compounds of Biological Interest
996
3.13.12.2
Compounds with Applications in Materials Science
997
3.13.13
Further Developments
References
1000 1001
3.13.1 Introduction This chapter serves as a continuation of Chapters 3.16 <1984CHEC(3)935>, 3.17 <1984CHEC(3)973>, and 2.13 <1996CHEC-II(2)731> that appeared in CHEC(1984) and CHEC-II(1996) detailing the synthesis, chemistry, and applications of selenophenes and their fused derivatives. The first two chapters covered the literature through 1982, whereas the latter covered the literature through 1993. Given the coverage of CHEC-II(1996), the present chapter herein focuses on the literature reported from 1994 through the end of 2006. During this time frame, five significant monographs have appeared that detail the synthesis and reactions of selenophenes 1 <2001SOS(9)423, 2005MI375>, benzo[b]selenophenes 2 <2001SOS(10)265>, benzo[c]selenophenes 3 <2001SOS(10)301>, and dibenzoselenophenes 4 <2001SOS(10)307>. In addition, Gronowitz has published an account that describes the work accomplished by his research group on selenophenes during a 30þ year span <1998PS59>. A periodical treatment of selenophenes (along with thiophenes and tellurophenes) has regularly appeared in Progress in Heterocyclic Chemistry <1994PHC(6)88, 1995PHC(7)82, 1996PHC(8)82, 1997PHC(9)77, 1998PHC(10)87, 1999PHC(11)102, 2000PHC(12)92, 2001PHC(13)87, 2002PHC(14)90, 2003PHC(15)116, 2004PHC(16)84, 2005PHC(17)98, 2007PHC(18)126>. All other specialized review articles are cited in the appropriate section. Finally, in terms of the organization of this chapter, selenophenes and fused derivatives will be treated together in each section.
3.13.2 Theoretical Methods Various ab inito methods have been applied to study and compare the physical properties of selenophenes with the other chalcogen homologs. These properties include linear and nonlinear polarizability, hyperpolarizability, aromaticity, molecular parameters, bond geometries, the Cotton–Mouton effect, and the Wellington elimination, with hyperpolarizability being the most studied. Calculations using the electron core potential (ECP) method showed that the polarizabilities and secondary hyperpolarizabilities of chalcogenophenes systematically increased as the heteroatom was replaced with heavy atoms, whereas the first hyperpolarizability did not <2000PCA4723>. This study also found a discrepancy between the experimental and theoretical secondary hyperpolarizabilities as the heteroatom became larger. Calculations using 6-31Gþpdd basis sets determined that the large discrepancy between theoretical and experimental second hyperpolarizabilities of the heavy chalcogenophenes could not be explained by frequency dispersion <2000SM(115)185>. Additional studies using various Hartree–Fock methods concluded that relativistic effects were not sufficient to explain the discrepancy between experimental and theoretical nonlinear polarizabilities for selenophene and tellurophene <2003JST(633)237>. Similar conclusions were obtained using time-dependent density functional theory <2002PCA10380>. Dispersion effects on hyperpolarizabilities were also studied by Millefori using the B3LYP basis set <2000CPL(332)175> and the 6-31G* , the Sadlej POL (polarized), correlation consistent Dunning and aug-CEP-31G basis sets <2000PCP2495>. In contrast, the linear and quadratic dipole polarizabilities calculated with conventional ab initio and density functional theory methods were found to increase from furan to tellurophene, and agreed well with experimental data <1998JST(431)59>. The pair density description of aromaticity of the chalcogenophenes was calculated using the atoms-in-molecules (AIM) and electron localization function (ELF) methods, with both methods yielding equal results for the formally single C–C single bond but differing for almost all other bonds <2000CPH(257)175>. The molecular parameters of the
Selenophenes
chalcogenophenes were calculated using the B3LYP basis set; the calculated selenophene bond angles agreed well with experimental data <1997JST(436)451>. Using the B3LYP/6-31G methods, the relative stability of the onium states of the chalcogens were calculated to explain the relative reactivity and positional selectivity of the chalcogenophenes and their corresponding benzannelated derivatives <2003CHE36, 2005RCB853>. Other properties that were studied for the chalcogenophenes include the Cotton–Mouton effect and the Wellington elimination <2003JCP10712, 2005CPL(416)113>. The properties of fused five-membered chalcogenophenes (e.g., selenoselenophenes) were also calculated. Using the BLYP/DZVP basis set, the selenolo[3,2-b]selenophene was found to be the most stable among the various selenoselenophene isomers while the selenolo[3,4-c]selenophene was the most stable <1997JST(398)315>. Ab initio calculations of selenophene in comparison to other heterocycles were also reported. The bandgap energies of p-conjugated polymers were calculated at the B3LYP/6-31G(d) level. In these calculations, the predicted values agreed well with experimental data, confirming that polyselenophene has the lowest bandgap energy among the unsubstituted polychalcogenophenes studied <2006OL5243>. The vibrational frequencies were calculated for selenophene, tellurophene, and the corresponding 1,2,5-seleno- and 1,2,5-tellurodiazoles using the 6-31G(p) basis set <2001JST(572)81>. Additional ab initio calculations reported on the properties of selenophenes exclusively. The molecular structure and conformational behavior of selenophene, bi-, ter-, and quarterselenophene were reported using the 6-31G* level of theory. These calculations showed that the conformational behavior of oligoselenophenes was dependent on torsional potentials between adjacent rings and predicted that polyselenophenes would likely adopt a planar conformation <1998SM(95)217>. The theoretical 77Se chemical shifts of selenium compounds were calculated at the GIAO-MP2 and GIAO-SCF levels while 13C chemical shifts of selenium compounds were calculated using the 6-311þþG* level of theory <1995JPC4000, 2002JST(616)17, 2005MI1119>. The mass fragmentation of selenoketene and selenoketyl cumulene ions was studied at the B3LYP/6–31G(d,p) and G2/G2(MP2) levels while the Renner–Teller effect of the selenoketyl radical was studied at the B3LYP level <2004JCP5801, 2005JMP796>. In addition to the many ab initio calculations, there was one report using semi-empirical calculations to study the relative geometry and charge distribution of selenophene and its azido derivatives <1994J(P2)1815>.
3.13.3 Experimental Structural Methods 3.13.3.1 Molecular Structure A review of X-ray diffraction studies of selenophene compounds and transition metal selenophene complexes has been published <2002CHE763>. X-Ray structures have also been reported for the following compounds: tetraphenylselenophene 1,1-dioxide 5 <1996CL269>, tris(selenophen-2-l)stibine 6 <2005JOM(690)3286>, benzo[c]selenophene 7 <2003OL2519>, dibenzoselenophene 8 <1995BCJ744>, fused benzoselenopheno[3,2-b][1]benzoselenophene 9 <2006JA3044>, selenophene-fused tetrathiafulvalene 10 <1995AM644>, and tetraselenafulvalenes 11 <2005PS873>.
The structures of various macrocyclic selenophenes, including selenaporphyrins, have been determined. Examples include a monoselenaporphyrin featuring an inverted pyrrole ring 12 <2000JOC8188>, a tetraselenaporphyrin in which all four heterocycles are selenophenes 13 <1997AGE2609>, a sapphyrin containing two selenophene rings 14 <2000J(P2)1788>, and an octaphyrin containing four selenophene rings <2003CEJ2282>.
977
978
Selenophenes
Efforts to understand the conducting properties of the oligomeric selenophene compound quaterselenophene focused on X-ray crystallographic analysis, which revealed a unit lattice of two crystallographically independent molecules in a planar conformation with herringbone packing <1999SM(101)639>. The structure of a bis-selenoselenophene was also reported <1996T471>. X-ray absorption fine structure (XAFS) and extended X-ray absorption fine structure (EXAFS) have been used to study catalyst structure in hydrodesulfurization and hydrodeselenization reactions. Using Se K-edge XAFS, the exchange of S–Se during the hydrode–selenium reaction of selenophene was investigated over Mo sulfide clusters <2003CPL(370)813>. The hydrodeselenization of selenophene over sulfided (Co)Mo/Al2O3 catalysts was investigated using EXAFS <1997PCB11160>.
3.13.3.2 Molecular Spectroscopy 3.13.3.2.1
1
H NMR spectroscopy
1
H and 2D NMR (nuclear magnetic resonance) studies of an octaphyrin with two selenophene rings indicated a C2 symmetric conformation <2007CC43>. Sapphyrins containing two thiophene rings were found to have inverted rings at 50 C, whereas the corresponding selenophene compound did not <1999JA9053>. For rhodium rubyrin complexes containing selenophene units, the rhodium was found to bind in an 2 fashion to the bipyrrole nitrogens, as determined by 1H and 2D NMR studies and additional spectroscopic work <2001IC1637>. Dynamic NMR studies were used to examine the rotational barriers of chromium cobalt selenophene complexes <1994OM1821>.
3.13.3.2.2
13
C NMR spectroscopy
Computational 13C NMR studies using the 6-311þþG* level of theory found that the theoretical and experimental chemical shifts agreed well <2002JST(616)17>.
3.13.3.2.3
77
Se NMR spectroscopy
A comprehensive review of 77Se NMR spectroscopy that includes data for inorganic, organic, and metal complexes of selenium compounds has been published <1995MI1>. Substituent effects on the 77Se NMR shifts in selenophenes were also reviewed <1998PS59>. The 77Se NMR shifts for numerous organoselenium compounds have been measured using indirect detection methods (e.g., HSQC), an approach that could prove useful for the spectroscopic studies of selenoproteins <1995MRC191>. For transition metal complexes with an 5-selenopehene ligand, the 77Se NMR shifts were influenced by the metal and its ligands, the charge on the complex, and the number of methyl groups on the selenophene <1994OM1821, 1995OM332>. A 77Se NMR study compared free selenophenes with their ruthenium complexes and established characteristic 77Se shift ranges for 1, 2, and 5 modes of selenophene binding to transition metals <1994OM4474>. The C–Se insertion product of selenophene with Cp* Rh(PMe3)PhH displayed an upfield resonance consistent with a nonaromatic metallaselenabenzene ring <1997OM2751>. Finally, the theoretical 77Se chemical shifts of selenium compounds have been calculated at the GIAO-MP2 and GIAO-SCF levels of theory <1995JPC4000, 2005MI1119>.
3.13.3.2.4
Ultraviolet, infrared, Raman, and photoelectron spectroscopy
The ultraviolet (UV) spectroscopic data for several nonmacrocyclic selenophene compounds were reported. The photolysis products from laser irradiation of gaseous selenophene were examined using UV spectroscopy and identified as C2H2 and H2CTCH-CCH <2000JOC2759>. The UV data of donor–acceptor 2-aminoselenophenes
Selenophenes
demonstrated absorption maxima that were strongly dependent on the substitution pattern of the selenophene moiety <2002ZNB420>. Finally, studies on the unimolecular and bimolecular photoprocesses of a fused selenophene compound were reported <2001SAA1427>. The visible/electronic spectra for various selenaporphyrins have been reported. The electronic spectrum of a selenaporphyrin was found to closely resemble that of its thiaporphyrin analog, displaying a Soret band in the nearUV region and four Q bands <1996IC566>. Other selenaporphyrins for which electronic spectra were reported include octaphyrins <2003CEJ2282, 2007CC43>, sapphyrins <1999JA9053, 1999J(P2)961>, rubyrins <2001IC1637, 1999T6671>, and a monoselenaporphyrin featuring an inverted pyrrole ring <2000JOC8188>. The electronic absorption maxima of a series of oligoselenophenes systematically changed depending on the chain length of the oligomers <1997SM(84)341>. The absorption spectra of several biselenophene dyes were measured to assess their suitability for determining solvent polarity <2000AGE556>. The long-wave absorption bands of (2Z)-2(N-acetyl-N-arylaminomethylene)benzo[b]selenophene and the corresponding furan, thiophene, and tellurophene derivatives were also measured <2005ARK60>. Femtosecond optical heterodyn-detected optical Kerr effect spectroscopy and low-frequency Raman spectroscopy were used to study the molecular dynamics of selenophene <1998JCP10948>. Femtosecond Kerr effect spectroscopy was also used to examine the third-order polarizabilities of furan, thiophene, and selenophene, which was found to increase from furan to thiophene to selenophene <1996CPL(263)215>. The photoelectron spectra of bichalcogenophenes that contain a selenophene were measured, with the data indicating various interactions among the furan, thiophene, and selenophene p-orbitals <1994JPC5240>. The charge-transfer complexes of tetracyanoethylene with selenium donors were also studied using photoelectron spectra <1995JOC2891>.
3.13.3.2.5
Mass spectrometry
A combination of mass spectrometry studies and ab initio calculations was used to identify the products of dissociative electron ionization of selenophene <2005JMP796>. Cobalt–chalcogenophene ion complexes were generated in a mass spectrometer and subsequently irradiated to study their photodissociation thresholds and measure their bond energies <1997JMP475>.
3.13.4 Thermodynamic Aspects Several reviews have been reported on the aromaticity of selenophenes. Using conceptual and computational density functional theory (DFT), aromaticity has been discussed using energetic, structural or geometrical, magnetic, and reactivity-based measurements <2001CRV1451>. The HOMO–lowest unoccupied molecular orbital (LUMO) gap approximates hardness and measures stability. The highest occupied molecular orbital (HOMO) and LUMO energies of selenophene were calculated to be 8.15 and 12.28 eV, respectively. Aromaticity indices have been proposed based on polarizability; the polarizability exaltation of selenophene was calculated to be 25.06 au. Additionally, the aromatic stabilization energy of selenophene was calculated at 17.05 kcal mol1, which is less than thiophene (18.74 kcal mol1) but greater than furan (15.47 kcal mol1). This is consistent with other studies on the aromaticity of five-membered heterocycles, where aromaticity decreases as follows: thiophene > selenophene > pyrrole > tellurophene > furan <2004CRV2777>. The aromaticity of fused selenophenes has also been discussed using nuclear-independent chemical shifts (NICSs), a magnetic criterion that is a widely used aromaticity probe <2005CRV3842>. Using the BLYP/DZVP basis set, the seleno[3,4-c]selenophene was calculated to be the most aromatic among the various selenoselenophene isomers; however, this isomer was also the least stable <1997JST(398)315>. The pair density description of aromaticity of the chalcogenophenes was calculated using the atoms-in-molecules (AIMs) and electron localization function (ELF) methods, with both methods yielding equal results for the formally single C–C single bond but differing for almost all other bonds <2000CPH(257)175>. The acidities of several rhenium carbene complexes that represent derivatives of furan, thiophene, and selenophene were investigated and found to depend on aromaticity <2003JA12328>. The physiochemical properties of numerous selenophene compounds have been investigated by means of cyclic voltammetry. These compounds include benzodiselenophenes <2005JOC10569>, conjugated biselenieno-quinones <1996H(43)941, 1996JOC4784>, seleno-substituted tetrathiafulvalenes <1997H(45)1051>, seleno-fused tetrathiafulvalenes <1997CL1091>, ethylenedioxyselenophene <2001OL4283>, benzo[c]selenophene dimers
979
980
Selenophenes
<2004OL3039>, and diarylbenzo[c]selenophenes <2005TL7201>. The reversible redox reactions of ferrocenesubstituted benzo[c]selenophenes 15 were also studied and established a new type of multistep reversible redox system <2006TL2887, 2007JOM(692)60>.
Rubyrins containing two selenophene units led to a reduced cavity size, easier oxidations and reductions potentials, and a reduction in the HOMO–LUMO energy gap <1999T6671>. The cyclic voltammagrams of a series of oligoselenophenes systematically changed depending on the chain length of the oligomers <1997SM(84)341>. The electrochemical behavior of polyselenophene films <2005JEC345>, a bis(seleninyl)ethene polymer <1998MM1221>, and a polyselenienyl thiophene polymer <1996SM(82)111> have been reported.
3.13.5 Reactivity of Fully Conjugated Rings 3.13.5.1 Thermal and Photochemical Reactions Photochemical reactions of selenophene–metal complexes (Section 3.13.5.6) and photocycloadditions of selenophenes (Section 3.13.5.9) are treated later in this subsection. The photolysis of gaseous selenophene (and also tellurophene) has been studied <2000JOC2759>. Interestingly, the cleavage of both Se–C carbons gave elemental Se in the process. Selenophene 1,1-dioxides have been found to be more thermally labile than the corresponding thiophene 1,1dioxides. While dimerization is often observed in the thermal decomposition of the latter, the neat thermolysis of selenophene 1,1-dioxides leads primarily to ring-opened products. For example, thermolysis of 2,3,4,5-tetraphenylselenophene 1,1-dioxide 5 gave a variety of a ring-opened products (Equation 1) <1998H(48)61>, whereas thermolysis of compound 5 in toluene leads to the formation of 2,3,4,5-tetraphenylfuran.
ð1Þ
3.13.5.2 Substitutions at Selenium The synthesis and chemistry of selenophene 1-oxides, selenophene 1,1-dioxides, and fused derivatives has been investigated in some detail by the Nakayama group and this work has been reviewed <1999TCC131, 2000BCJ1>. The preparation of benzo[b]selenophene-1-oxide 16 was accomplished by oxidation of benzo[b]selenophene with m-chloroperbenzoic acid (MCPBA), whereas application of the same conditions to tetraarylselenophenes led to ringopened products <1995CL485>. Alternatively, utilizing dimethyldioxirane (DMD) as an oxidant allowed for the preparation of 5, 16, benzo[b]selenophene-1,1-dioxide 17, and 2,4-di-tert-butylselenophene-1,1-dioxide 18 <1996CL269, 1996PS227>. The structure of compound 5 was confirmed by X-ray single-crystal structure analysis. Subsequently, the mono-oxidation of 2,4-disubstituted selenophene 1-oxides was reported. Notably, selenophene-1oxides (e.g., 2,4-di-tert-butylselenophene-1-oxide 19) are easier to isolate than the corresponding thiophene-1-oxides given their lower relative reactivity, which can be explained by weaker aromaticity (selenophenes < thiophenes) and lower electronegativity (Se < S) <1998JA12351>.
Selenophenes
The bromination of dihydrobenzo[c]selenophene 20 led to the formation of the corresponding 1,1-dibromo derivative 21 (Scheme 1) <2003OL2519>. Treatment of the latter with lithium hexamethyldisilazane (LiHMDS) produced benzo[c]selenophene 3 which was subsequently converted to the stable diester 23 via dilithiation. The structure of 23 was confirmed by X-ray crystallographic analysis.
Scheme 1
3.13.5.3 Electrophilic Substitutions Similar to its chalcogenic congeners and other p-excessive five-membered ring heterocycles, the electrophilic substitution of selenophenes proceeds regioselectively at free -positions. Computational methods were utilized to investigate the regioselectivity ( : ratio) of electrophilic substitution reactions of five-membered ring heterocycles including selenophenes <2003CHE36, 2005RCB853>. The relative rates were correlated to the relative stability of the onium ions (Seþ). N-Bromosuccinimide (NBS) is the reagent of choice for the synthesis of -bromoselenophenes and other p-excessive heterocycles <1996T471, 2005TL2647, 2006JOC3786>. Recent examples include the monobromination and dibromination of selenolo[3,2-b]selenophenes <1996T471> and the dibromination of diselenophen-29-yl-2,1,3benzothiadiazole <2005MM244>. The regioselectivity of the bromination of 2-acylselenophenes with bromine in the presence of aluminium trichloride was investigated <1995JHC53>. As expected, the major products obtained were the corresponding 4-bromo-2-acylselenophenes. Vilsmeier–Haack formylation of selenophene with N-phenylN-methylformamide produced selenophene-2-carboxaldehyde which was converted into 1,2-bis(2-selenophen-29yl)ethene using a McMurry-type coupling <1998MM1221>. The latter was utilized as a building block for a novel selenophene polymer containing an ethenyl spacer. Reductive dehalogenation of perhaloselenophenes preferentially removes halogens from -positions. This method is useful for the preparation of -substituted selenophenes. This procedure was utilized to prepare 3-cyanoselenophene 26 (Scheme 2), useful in the preparation of selenophene analogs of tiazofurin, an antitumor agent
Scheme 2
981
982
Selenophenes
<1997JME1731>. Exhaustive iodination of selenophene 1 with iodine mediated by mercuric acetate gave tetraiodoselenophene 24. Reductive dehalogenation with zinc powder in acetic acid gave 3-iodoselenophene 25 which underwent a palladium-catalyzed (2 mol%) cyanation with trimethylsilyl cyanide producing 3-cyanoselenophene 26. Structure 26 was converted into ethyl selenophene-3-carboxylate which underwent Friedel–Crafts acylation reactions with -O-acetylribofuranoses to give the corresponding C-(selenophen-2-yl)glycoside antitumor agents.
3.13.5.4 Reactions with C-Anion Equivalents Treatment of selenophenes with alkyllithiums leads to selective -lithiation (e.g., 27). Lithiation of selenophene followed by quenching with iodine leads to the formation of -iodoselenophenes <1996H(43)1927, 2005TL2647, 2006JOC1552, 2006JOC3786>. The preparation of tris(selenophen-2-yl)stibine (antimony) 6 from 27 (R ¼ H) was reported <2005JOM(690)3286>. Selenophenethiols 29 have been prepared in two steps from 2-selenophenyllithiums 27 (Scheme 3) <1997CHE426>. Treatment of 27 with elemental sulfur and trimethylsilyl chloride gave the silyl thioether 28 which was converted into 29 by hydrolysis with 1 equiv of water. The reaction of 27 (R ¼ H) with 2-pyridyl 2-thienyl sulfoxide led to the formation of 2-(29-pyridyl)-selenophenes and the corresponding disulfides indicating a ligand exchange process was taking place <1994HAC223>. Treatment of -lithiated selenophenes with copper leads to the formation of 2,29-biselenophenes <1999JOC8693>, useful reagents for the preparation of selenophene-modified pyrrole macrocycles. As depicted earlier, the in situ formation and dilithiation of benzo[c]selenophene 3 provided dianion 22, which was trapped with ethyl chloroformate giving diester 23 (Scheme 1) <2003OL2519, 2005PS787>.
Scheme 3
3.13.5.5 Organometallic Reactions Organopalladium chemistry has increasingly been utilized for the preparation of highly functionalized selenophenes and the majority of this work has appeared during the past 10 years. The palladium-catalyzed cross-coupling of Grignard reagent 30 and bromo derivative 31 produced selenolo[3,2-b]selenophene dimer 32 (n ¼ 1) in good yield (Equation 2) <1996T471>. Similar chemistry was utilized to prepare trimer 32 (n ¼ 2) and tetramer 32 (n ¼ 3). The attempted synthesis of dimer 32 (n ¼ 1) using a nickel-catalyzed homocoupling reaction was very low yielding.
ð2Þ
High-yielding syntheses of biselenophenes and related chalcogenophenes were accomplished utilizing a homocoupling reaction <2006TL795>. Treatment of bromoselenophene 33 with hexabutylditin and palladium(0) led to the formation of biselenophene 34 in 92% yield (Equation 3).
ð3Þ
Selenophenes
Several examples of Suzuki [Ar–X þ Ar–B(OH)2], Stille [Ar–X þ Ar–SnR3], and Negishi [Ar–X þ Ar–ZnX] crosscoupling reactions involving selenophenes have been reported. The Suzuki reaction has received the most attention. Recently, Suzuki cross-coupling reactions of 2-haloselenophenes were examined in some detail in the context of preparing 2-arylselenophenes 35, 2,5-diarylselenophenes 36, and 2-arylselenophenyl ketones 37 <2006JOC3786>. Optimized conditions for the Suzuki cross-coupling of pentafluorophenylboronic acid 39 with thiophenes, thiophene oligomers, fused thiophenes, and selenophenes were revealed <2005S1589>. For example, treatment of 2,5-dibromoselenophene 38 with boronic acid 39 in the presence of silver(I) oxide, potassium phosphate, and palladium(0) led to the highly fluorinated 2,5-bisarylselenophene 40 (Equation 4). A double Suzuki cross-coupling of selenophene-2boronic acid with 2,5-dibromopyridine gave 2,5-bis(selenophen-2-yl)pyridine, a building block utilized for the preparation of conducting copolymers <1996CM2444>. A double Suzuki cross-coupling reaction was also utilized to prepare fluorene–biselenophene copolymers <2006MM4081>.
ð4Þ
Suzuki cross-coupling reactions of 3-halobenzo[b]chalcogenophenes were utilized to prepare tetracyclic chalcogenophenes <2006ZNB427>. In the event of the fused selenophene (Scheme 4), a Suzuki cross-coupling with 41 and boronic acid 42 gave dialdehyde 43. A McMurry cyclization of the latter gave fused selenophene 44. Suzuki and Sonogashira cross-coupling reactions of 3-iodobenzo[b]selenophenes 71 (see Equation (8), Section 3.13.9.1.1) were also recently reported <2006JOC2307>.
Scheme 4
Polymer starting materials have been prepared utilizing Stille cross-coupling reactions including 4-(selenophen-2yl)aniline <1998AM1525> and diselenophen-29-yl-2,1,3-benzothiadiazole <2005MM244>. Negishi cross-coupling reactions have also been utilized to prepare biselenophenes <1996H(43)941, 1996JOC4784>. A novel set of tris(oligoarylselenophenyl)amines were prepared utilizing a Negishi cross-coupling reaction <2004CL1266>. These compounds were investigated as novel amorphous molecular materials with interesting charge transfer properties. The synthesis of 3-arylbenzo[b]selenophenes was accomplished utilizing both Stille and Suzuki cross-coupling reactions <2000EJO1353, 2002ARK40>. Palladium cross-coupling reactions of -haloselenophenes are a useful tool for the preparation of selenophenecontaining copolymers <2005PSA823, 2005MM244>. Palladium chemistry is useful for linking selenophene and an activated carbon nucleophile (Equation 5). Treatment of 2-iodoselenophene with sodium malonitrile in the presence of a palladium(II) catalyst provided malonitrile derivative 46b formed by tautomerization of the initial adduct 46a <1996H(43)1927>.
983
984
Selenophenes
ð5Þ
The Sonogashira cross-coupling reaction has been utilized to prepare a variety of alkynyl-substituted selenophene building blocks <2003OM3659>. A recent advance in alkynylselenophene synthesis (e.g., 47) involved a Sonogashira coupling that did not require an additive (co-catalyst free) <2006TL2179>.
A few reports involving copper-mediated substitution of selenophenes with heteroatoms (N, S) have appeared. The preparation of 2-amidoselenophenes (e.g., 48) was accomplished by treating 45 with amides in the presence of copper(I) iodide and ethylenediamine <2006JOC1552>. A similar copper-mediated reaction involving thiols was utilized to prepare sulfur-substituted selenophenes (e.g., 49) <2005TL2647>.
3.13.5.6 Reactions of p-Metal Complexes The synthesis and chemistry of an 2-selenophene osmium complex 50 has been studied <1999OM1559>. Protonation and electrophilic substitution with acetaldehyde diethyl acetal occurred at C-2. Methylation of complex 50 with methyl triflate gave 51 which upon treatment with tetrabutylammonium borohydride (TBAB) led to the selenophene ring-opened complex 52 (Scheme 5).
Scheme 5
3.13.5.7 Nucleophilic Substitutions A new solvent was investigated for the introduction of amine nucleophiles onto the selenophene nucleus via nucleophilic aromatic substitution. Treatment of 5-bromoselenophene-2-carboxaldehyde 53 with secondary amines in water produced 5-aminoselenophenes 54 (Equation 6) <1999T6511>.
ð6Þ
Selenophenes
3.13.5.8 Radical Reactions No articles regarding the radical chemistry of selenophenes were abstracted.
3.13.5.9 Pericyclic Reactions The synthesis and cycloaddition chemistry of selenolo[3,4-c]thiophenes 55 and telluro[3,4-c]thiophenes 56 was compared <2002OL1193>. The latter was claimed to be the first example of a tellurium-containing diheteropentalene.
A few reports of the [2þ2] photocycloaddition of selenophenes with various alkenes have been reported <1994M1153, 1997JPH53, 2001JPH1>. Cycloadducts that have been characterized include compounds 57 <1994M1153>, 58 <1997JPH53>, and 59 <2001JPH1>.
3.13.5.10 C–Se Bond Cleavage Removal of thiophene impurities from petroleum feedstocks is accomplished by a process called hydrodesulfurization (HDS) which involves the insertion of metals into the thiophene ring between the C–S bond. In order to better understand the mechanism of this reaction, different groups have utilized selenophene model systems due to the enhanced NMR characteristics of 77Se. Metal complexes of selenophenes that have been studied include rhodium <1997OM2751>, molybdenum <2006POL499>, manganese <2001OM3617, 1995OM332>, chromium <1994OM1821>, ruthium <1994OM4474>, and iridium <1995OM332>.
3.13.6 Reactivity of Nonconjugated Rings Only two reports involving the reactivity of nonconjugated selenophenes were uncovered. Both involved the preparation of selenoether carbohydrate derivatives. The preparation of selenonium inner salt 62 was accomplished by treatment of selenoether 60 with cyclic sulfate 61 (Equation 7) <2004CAR2205>. The salt 62 was utilized as a building block for the preparation of inhibitors of UDP-galactopyranose mutase.
985
986
Selenophenes
ð7Þ
Treatment of a selenoether-based carbohydrate derivative with ozone followed by acetic anhydride led to a mixture of Pummerer-type rearrangement products <2006JA227>.
3.13.7 Reactivity of Substituents Attached to Ring Carbon Atoms The preparation of various nitrogen-substituted selenophenes has been accomplished utilizing the Curtius rearrangement of carbonyl azides. Selenophene-2-carbonyl azide 64 was prepared by treating the corresponding carboxylic acid 63 with methyl chloroformate and trimethylsilyl azide <2000ARK58>. The thermal Curtius rearrangement of 64 in the presence of 1-methylpyrrole led to the formation of carboxamide 65 (Scheme 6). A modified Curtius rearrangement was employed in the preparation of BOC-protected 2-amino-3-iodoselenophene <1995T10323>. The latter was utilized to prepare the fused selenophene, selenolo[2,3-b]pyrrole. The mechanism of the Curtius rearrangement for a series of chalcogenophene-2-carbonyl azides has been studied by differential scanning calorimetry <2002ARK6>.
Scheme 6
A series of synthetic methods have been adapted to the preparation of quinoline-fused and naphtho-fused benzoselenophenes (C–C bond forming steps indicated by arrows). A Curtius rearrangement leading to a 2-aminobenzoselenophene followed later by a Bischler–Napieralski cyclization provided benzoselenolo[2,3-c]isoquinoline 66 <2000EJO1353>. A thermal electrocyclization of a benzoselenophenyl ketoxime produced benzoselenolo[2,3-c]quinoline 67 <2002ARK40>. Syntheses of a variety of nitrogen heterocyclic (triazole, tetrazole, pyrimidine) fused benzoselenophenes have been reported <2005RJO396>. McMurry-type coupling involving a benzoselenophene-2carboxaldehyde gave benzo[c]dibenzoselenophene 44 <2006ZNB427>.
The addition of an alkyllithium nucleophile onto a 2-acylselenophene was the key step in the preparation of a selenophene-based tamoxifen derivative 68 <1997JCM274>.
Selenophenes
A side-chain decarboxylation of a barbituric acid provided a convenient route to benzoselenophene-3-acetic acid 69 <2003CHE539>.
The kinetics of the enolization of 2-acetylselenophene was studied in the presence of a variety of metal ions <1998EJO1867>.
3.13.8 Reactivity of Substituents Attached to Selenium There were no reports of the reactivity of substituents attached to the selenium atom of selenophenes. The oxidation of selenophenes to selenophene-1-oxides and selenophene-1,1-dioxides is discussed in Section 3.13.5.2.
3.13.9 Ring Synthesis Selenophene ring synthesis has been organized in the fashion utilized by Sundberg in CHEC-II(1996) <1996CHECII(2)119> for a monograph describing pyrrole ring synthesis. Intramolecular approaches (category I) and intermolecular approaches (category II) are classified by the number and location of the new bonds that describe the selenophene ring forming step as shown below. This section then concludes with syntheses of selenophenes involving the formation of three bonds and the preparation of nonconjugated rings. The preparation of selenophenes, benzo[b]selenophenes, and other fused derivatives is treated together. Two monographs describing synthetic approaches to selenophenes have appeared <2001SOS(9)423, 2005MI375>. Thermal methods utilized for the preparation of selenophenes and thiophenes have also appeared <2000CHE1>.
Many synthetic strategies that have been developed to prepare selenophenes involve modifications (S to Se) of the corresponding route to thiophenes. Given the significant amount of synthetic attention directed to thiophenes and a comparative lack of focus on selenophenes until recently, new ‘syntheses of selenophenes’ continue to be reported.
987
988
Selenophenes
3.13.9.1 Formation of One Bond 3.13.9.1.1
Category Ia cyclizations
Electrophilic iodocyclization reactions of 1-alkynyl-(methylseleno)arenes provide a convenient route to benzo[b]selenophenes. Treatment of selenoethers 70 with iodine or iodine monochloride gives 3-iodobenzo[b]selenophenes 71 <2006JOC2307> (Equation 8). The latter were elaborated into 2,3-diarylbenzo[b]selenophenes and other functionalized benzo[b]selenophenes utilizing palladium-catalyzed cross-coupling reactions. Additional electrophiles (NBS, Br2, Hg(OAc)2, PhSeBr, PhSeCl) were also investigated in the selenophene-forming reaction. The analogous iodocyclization reaction has been adapted to the solid phase for the preparation of a small library of benzo[b]selenophene-5-carboxamides <2006JCO163>. Similar chemistry was utilized in the preparation of [1]benzoselenopheno[3,2-b][1]benzoselenophene <2006JA3044>.
ð8Þ
A novel procedure for the generation of functionalized alkyllithium reagents involved a category type Ia cyclization leading to dibenzoselenophene 4 <2001SL791>. Halogen–metal exchange of biphenyl derivative 72 followed by treatment with benzaldehyde led to the formation of 4 together with alcohol 73 (Equation 9). The latter was produced by the addition of the alkyllithium intermediate, derived from cleavage of the selenoether, to benzaldehyde.
ð9Þ
3.13.9.1.2
Category Ib cyclizations
The synthesis of the benzoselenophene analog 76 of the photochemotherapeutic psoralen was developed (Scheme 7) <1994JPH9, 1994T9315>. Benzo[b]selenophene 75 was prepared in three steps from dialdehyde 74 including an intramolecular type Ib cyclization to form the selenophene ring. The former was converted into 76 in five steps including a decarboxylation sequence and a Perkin condensation. A similar intramolecular cyclization involving a nitrile was utilized to pepare a -aminoselenophene derivative which served as an intermediate in the preparation of the pyrimido[49,59-4,5]selenolo[2,3-b]quinoline 77 <1995SC451>.
Scheme 7
Selenophenes
The effects of replacing thiophene rings with selenophene rings were studied in a series of biothiophene-type dyes (e.g., 78) <2000AGE556>. The preparation of the selenophene ring in these compounds involved a type Ib cyclization of an iminium salt. A related strategy was utilized to prepare 2,5-disubstituted donor–acceptor selenophenes from thioacrylamides <2002ZNB420, 2004ZNB439>.
3.13.9.1.3
Category Ic cyclizations
The polyphosphoric acid (PPA)-catalyzed cyclocondensation of ketone 79 gave the 3-aryl-2-benzylbenzo[b]selenophene 80 (Scheme 8) <1994JCM98>. The latter was converted into derivative 81 which was evaluated as a ligand for antiestrogenic binding sites.
Scheme 8
3.13.9.2 Formation of Two Bonds 3.13.9.2.1
Category IIab cyclizations
No IIab-type selenophene syntheses were abstracted.
3.13.9.2.2
Category IIac cyclizations
After some optimization, a novel one-pot preparation of 2-alkoxyselenophenes was developed utilizing a lithium selenolate <1995TL2807>. Treatment of selenoester 82 with lithium diisopropylamide (LDA) followed by propargyl bromide gave selenophene 84 via allenic intermediate 83 (Equation 10).
ð10Þ
The reaction between benzyne derivatives and selenium analogues of Barton’s thiopyridone esters provided a convenient entry into complex, fused benzo[b]selenophenes <2004JHC13, 2004ARK51>. For example, the generation of the benzyne 86 in the presence of selenoester 85 provided benzo[b]seleno[2,3-b]pyridine 87, presumably via a single electron transfer (SET) pathway (Equation 11). This methodology was examined utilizing a number of benzyne precursors (anthranilic acids, iodium triflates, and trimethysilyl triflates) and provided access to an impressive number of fused benzo[b]selenophenes.
989
990
Selenophenes
ð11Þ
A [3,3]-sigmatropic rearrangement reminscent of the Fischer indole synthesis was proposed as a mechanism for the formation of 2,5-diarylselenophenes from arylhydrazones <2005BCJ1121>. Treatment of arylhydrazone 88 with diselenium dibromide produced selone 89 en route to 2,5-diphenylselenophene 90 via a mechanism that included a [3,3]-sigmatropic rearrangement (Equation 12). A similar oxidative dimerization of selenothioic acid S-alkyl esters gave 2,5-bis(alkylthio)selenophenes <1996CL877>.
ð12Þ The production of selenophene via the thermolysis of dialkyl selenides in the presence of acetylene was explored <2004RJO290>. Thermal reactions leading to selenophenes and thiophenes have also been reviewed <2000CHE1>.
3.13.9.2.3
Category IIad cyclizations
No IIad-type selenophene syntheses were abstracted.
3.13.9.2.4
Category IIae cyclizations
The most utilized de novo synthetic routes to selenophenes involve reactions between selenium reagents and 4-carbon units, which are therefore category IIe cyclizations. Many of these routes have close analogs in the thiophene synthesis literature. For example, one of the more common thiophene syntheses involves the condensation of 1,4-dicarbonyl compounds with Lawesson’s reagent <2003S1929>. An equivalent reaction with selenium involved the condensation of bis(dimethylaluminium) selenide with ortho-diferrocenoylbenzene which produced compound 15 <2006TL2887, 2007JOM(692)60>. The selenium analog of Lawesson’s reagent, Woolin’s reagent 92 <2005CEJ6221>, provides another route to selenophenes from 1,4-dicarbonyl compounds and their synthetic equivalents. The synthesis of selenophene 94 was attempted by treating the unsaturated -ketoalcohol 91 with Woolin’s reagent 92 (Scheme 9) <2005TL7201>. Unexpectedly, the yield of 94 was very low and the major product obtained was furan 93. Interestingly, resubmitting 93 to Woolin’s reagent in dry dichloromethane produced selenophene 94 in 67% yield.
Scheme 9
Selenophenes
Selenolo[3,4-b]furan 97 was prepared utilizing the organic selenium transfer reagent N,N-diethylselenopropionamide 96 (Equation 13) <1998JHC71>. Treatment of bromoketone 95 with 96 gave the [c]-fused selenophene 97.
ð13Þ
The gas-phase thermal reaction of cinnamaldehyde with dimethyl diselenide at 630 C gave benzo[b]selenophene 2 <1998RCB447>. An electrophilic cyclization of allene 98 with phenylselenyl chloride led to the formation of selenophene 99 along with dihydroselenophene 100 (Equation 14) <2004PS(179)1681>.
ð14Þ
A number of different inorganic selenium reagents have been utilized to prepare selenophenes via category IIae cyclizations (4C þ Se). The central selenophene ring in the terchlcogenophene, 2,5-bis(2-tellurienyl)selenophene, was formed by combining sodium selenide (Na2S) with a butadiyne <2000H(52)159>. A group of [c]-fused selenophenes was prepared by the reaction of 1,2-(bromomethyl)arenes/heteroarenes with sodium selenide followed by an oxidation of the intermediate dihydroselenophene. For example (Scheme 10), treatment of the dibromide 101 with sodium selenide gave compound 102, and the latter was converted into 4-nitrobenzo[c]selenophene 103 utilizing two different approaches (Se bromination/elimination or a mild oxidation with phenyl iododiacetate) <2003OL2519>. Additional heterocycles that have been prepared utilizing this sequence include seleno[3,4-b]quinoxaline <2003OL4089> and 3,4-ethylenedioxyselenophene <2005PS787>.
Scheme 10
An inorganic selenium electrophile, selenium oxychloride (SeOCl2), has been utilized to prepare fused selenophenes <2002JOC2453>. Deprotonation of bis(cyanide) 104 with LDA followed by treatment with selenium oxychloride gave the benzo[c]selenophene 105 (Equation 15). This sequence also allowed for the preparation of a thieno[3,4-c]selenophene.
ð15Þ
991
992
Selenophenes
A convenient one-step synthesis of fused selenophenes has been developed <1994H(38)143, 1996T471>. For example, heating ynediol 106 in the presence of selenium metal gave selenolo[3,2-b]selenophene 107 (Equation 16).
ð16Þ
Metal-mediated category IIae cyclizations comprise the next group of selenophene syntheses to be discussed. Dibenzoselenophenes (and dibenzotellurophenes) have been prepared from 2,29-diiodobiphenyl derivatives <1995JOC5274>. Treatment of the biphenyl 108 with selenium–copper slurry, generated from disodium diselenide and copper(I) iodide, produced 3,7-dinitrodibenzoselenophene 109 (Equation 17).
ð17Þ
An approach amenable to the preparation of various fused selenophenes and benzo[b]selenophenes involves the treatment of 1,4-dilithiated intermediates with bis(phenylsulfonyl)selenide 112 <1994CPB1437>. The synthetic sequence to the selenolo[2,3-b]selenophene 113 from 3-ethynylselenophene 110 is shown in Scheme 11 <1997H(45)1891>. A stereoselective hydroalumination of 110 with diisobutylaluminium hydride (DIBAL-H) followed by bromination with NBS gave dibromo compound 111. Dilithiation of 111 followed by treatment with selenium electrophile 112 gave 113.
Scheme 11
A related lithiation approach to fused selenophenes involves o-bromoethynyl arenes. The synthesis of benzo[b]selenophene 115 utilizing this chemistry is shown in Equation 18 <1998SC713>. Lithiation of bromoarene 114 followed by treatment with selenium powder gave 115 via a 5-endo-dig cyclization. This chemistry was applied to the synthesis of a number of fused selenophenes including [1]benzoseleno[3,2-b][1]benzoselenophene <1998JHC725>, benzo[1,2-b:-4,5b’]diselenophenes <2005JOC10569, 2005PS873>, and heteroacene 166 (Section 3.13.12.2) <2005OL5301>.
ð18Þ
Additional examples of selenophene ring-formation reaction that result from the treatment of 1,4-dienes with selenium dioxide have been reported. For example, treatment of verbenone derivative 116 with selenium dioxide in the presence of pyridine gave fused selenophene 117 in 92% yield (Equation 19) <2001OL3161, 2002JOC6553>. Additional applications of this reaction include taxol analog 150 <1997BML1941> and a [1]benzopyrano[3,2-b]selenophene-9-one derivative <2001SAA1427>.
Selenophenes
ð19Þ
3.13.9.2.5
Category IIbc cyclizations
No IIbc-type selenophene syntheses were abstracted.
3.13.9.2.6
Category IIbd cyclizations
The classical Hinsberg thiophene synthesis has been adapted for the preparation of 3,4-ethylenedioxyselenophene 120, a starting material for the preparation of electron-rich selenophene polymers <2001OL4283>. The double condensation of diethyl selenodiglycolate 118 with diethyl oxalate gave 3,4-dihydroxyselenophene 119 (Scheme 12). Alkylation with dibromoethane followed by saponification and decarboxylation then provided 120. This sequence was also utilized to prepare 1,3-dicyanoseleno[3,4-b]quinoxaline <2003OL4089>. A related reaction sequence involving a type IIbd cylization was utilized to prepare a 2,5-dibenzoylselenophene, another monomer that was elaborated into selenophene polymers <2001JAP2019>.
Scheme 12
3.13.9.2.7
Category IIbe cyclizations
No IIbe-type selenophene syntheses were abstracted.
3.13.9.3 Formation of Three Bonds A few three-component reaction sequences leading to selenophenes have been reported. Lithiation of diphenylacetylene followed by treatment with elemental selenium led to 2,3,4,5-tetraphenylselenophene 121 (Equation 20) <1999JOM(573)267>.
ð20Þ
The preparation of highly functionalization selenophenes has been accomplished utilizing a three-component condensation reaction involving ketene dithioacetals, sodium selenide, and an activated carbonyl component (Scheme 13) <2003SL855, 2004S451, 2005PS939>. Ketene dithioacetal 122 was prepared from 2,4-pentanedione by condensation with carbon disulfide followed by methylation. Treatment of compound 122 with sodium selenide and ethyl bromoacetate gave selenophene 123 in modest yield.
993
994
Selenophenes
Scheme 13
An unusual four-component reaction between a phosphorus ylide (2 equiv), elemental selenium, and tetracyanoethylene (TCNE) produced a 3,4-dicyanoselenophene derivative <1995TL8813>.
3.13.9.4 Synthesis of Nonconjugated Rings The synthesis and chemistry of selenosugars (tetrahydroselenophene derivatives) has been studied <2004T2889, 2004CAR2205>. A reductive cyclization approach to tetrahydroselenophenes has been reported <1996CC1461>. Specifically, treatment of selenothioester 124 with sodium borohydride led to tetrahydroselenophene 125 (Equation 21).
ð21Þ
Phenyltelluroformates provide a new leaving group for intramolecular cyclizations <1998JOC3032>. Heating selenide 126 led to the formation of tetrahydroselenophene 127 via an intramolecular nucleophilic substitution of the telluroformate group (Equation 22).
ð22Þ
Titanium-based reductive cyclizations of dicarbonyl compounds provide a good method for preparing heteroarenes. Treatment of selenoester 128 with titanium tetrachloride in the presence of zinc produced the dihydroselenophene 129 (Equation 23) <1998CL645>. The addition of zinc proved to be crucial for this transformation.
ð23Þ
Due to their interesting electronic properties (e.g., conductors), synthetic approaches to dihydroselenophenes that are fused to tetrathiafulvenes (TTFs) have been developed <1997CL1091, 1998JOC8865>. A seleno-Claisen rearrangement was utilized to prepare dihydrobenzo[b]selenophenes <2003SC2161>. Heating selenide 130 in quinoline produced the dihydrobenzo[b]selenophene 131 after cyclization of the selenophenol Claisen product (Equation 24).
ð24Þ
Selenophenes
An alkyltelluride-mediated reductive cyclization provided a route to benzo[b]selenophenes that are potential antioxidants <1999JOC6764>. Finally, an intramolecular condensation of a 1,6-dicarbonyl derivative was utilized to prepare oxygenated benzo[b]selenophenes <2001CL826, 2001TL4899>. Treatment of 2-chloroselenoylbenzoyl chloride 132 with acetone gave 3-hydroxybenzo[b]selenophene 133 via a selenophen-3(2H)-one intermediate (Equation 25).
ð25Þ
3.13.10 Ring Synthesis from Another Ring The contraction of 1,2- and 1,4-chalcogenides (S, Se) to the corresponding chalogenophenes (S, Se) can be accomplished under photochemical or thermal conditions. 1,2-Diselenide 135 have been prepared in two steps from zincocene 134 (Scheme 14) <1999AGE1604, 2000JA5052>. Photolysis of 135 then gave selenophene 136 quantitatively. Additional methods reported for the formation of 1,4-deselenides (and subsequent conversion to selenophenes) include dimerization of bis(benzylseleno)ethene <2003SUL137> and a cycloaddition between diselenoamides and dimethyl acetylenedicarboxylate (DMAD) <1994CL77>.
Scheme 14
A Pummerer-type ring contraction of benzoselenopyrans led to the formation of benzo[b]selenophenes in modest yields <2000H(52)1021>. Another unique route to 2-cyanobenzo[b]selenophene resulted from the reaction between a selenabicyclo[3.1.0]hexene derivative with benzyne <2000H(55)465>. Mechanisms for these transformations were presented in each paper. The formation of selenophenes has also been investigated by the transformation of selenazine and selenadiazole hetereocycles. Selenazines have been prepared by utilizing cycloaddition reactions of selenoacylamidines (e.g., 137) <1995TL237, 1998T2545, 1998SC301>. The cycloaddition of 137 with butynal 138 gave selenazine 139, which was transformed into selenophene 140 in two steps (retro-cycloaddition and oxidative cyclization) (Scheme 15).
Scheme 15
The thermolysis of 1,2,3-selenadiazoles in the presence of arylacetylenes provides another route to 2,5-disubstituted selenophenes <2002TL4817>. Heating 4-phenylselenadiazole 141 in the presence of 2-pyridininylacetylene 142 gave the 2,5-diarylselenophene 143 (Equation 26). Similar radical extrusion cyclizations of 1,2,3-selenadiazoles in the presence of alkenes have been reported to give fused selenophenes and 2,3-dihydroselenophenes <1999TL6293, 2000JOM(611)488, 2002JOC1520>.
995
996
Selenophenes
ð26Þ
Finally, selenophenes have been prepared by treatment of zirconium metallocenes (e.g., 134) with diselenium dibromide (Se2Br2) <1994JA1880> or Se(SeCN)2 <1999AGE1604, 2000JA5052>.
3.13.11 Selected Syntheses No syntheses have been selected for discussion in this section because of the relative paucity of reports of selenophene synthesis which makes comparisons difficult to fully develop.
3.13.12 Important Compounds and Applications 3.13.12.1 Compounds of Biological Interest Various selenophene compounds have been found to possess anticancer activity. A tris(2-selenophenyl)stibine 6 showed selectivity for carcinogenic cell K and U growth inhibition <2005JOM(690)3286>. Selenophenfurin 144 demonstrated inhibitory activity against recombinant human inosine monophosphate dehydrogenase (IMPDH) <1997JME1731>. Structurally related selenophene diphosphate 145, an isosteric analog of a nicotinimide adenine dinucleotide, also demonstrated inhibitory activity against IMPDH <1998JME1702>. Finally, a selenophene analog of (Z)-tamoxifen 146 demonstrated a lower binding affinity for a Molt 4 cell line than the parent compound <1997JCM274>.
Selenophenes show a wide range of additional biological activity including antioxidant, antiestrogen, and antifungal. Dihydrobenzo[b]selenophene 147 was designed as a novel antioxidant <1999JOC6764>, while a 3-arylbenzo[b]selenophene 81 was designed as a selective ligand for antiestrogen-binding sites <1994JCM98>. A triazine-fused selenophene 148 possessed moderate antifungal activity against several fungi <2005RJO396>.
Selenophenes
Selenophene analogs of selected biomolecules have also been prepared. A synthesis of selenolo[3,2-b]pyrrolyl-Lalanine 149 was developed for incorporation into proteins <2002BBR257, 2001JMB925, 1999BML637>. A selenophene-fused taxol analog 150 <1997BML1941> and various indolocarbazole analogs (e.g., 151) have also been reported <1998SC1239>.
Several reviews of heteroporphyrins have been reported <2003ACR676, 2006CCR468, 2005CCR2510>. Heteroporphyrins (e.g., 152) have been identified as G-quadruplex binding agents <2005JA2944> and as sensitizers for photodynamic therapy (e.g., 153) <2000JME2403, 2002JME449, 2003JME3734>.
3.13.12.2 Compounds with Applications in Materials Science In addition to their biological applications, heteroporphyrins also serve as novel materials. Various porphyrins have been studied, including pyrrole-inverted porphyrins 12 <2000JOC8188>, tetraselenaporphyrins 13 <1997AGE2609>, sapphyrins, and rubyrins with a varying number of selenophene rings (e.g., 14) <1995IC3567, 1999JA9053, 1999JOC8693, 1999J(P2)961, 1999T6671, 2000J(P2)1788>, a meso-substituted octaphyrin featuring four selenophene rings <2003CEJ2282>, an octaphyrin 154 with a quarterthiophene unit <2007CC43>, rhodium(I) hetero-rubyrin complex 155 <2001IC1637>, and nickel(II) selenaporphyrin complexes <1996IC566>. Additional porphyrins that have been characterized include N-confused selenaporphyrins <2001JOC153>, N-confused expanded porphyrin 156 <2001JA5138>, hexaphyrins (e.g., 157) <2005JA11608, 2003OL3531, 2001TL3391>, heptaphyrins (e.g., 158) <2002JOC6309>, inverted heptaphyrins (e.g., 159) <2000OL3829>, and inverted octaphyrins (e.g., 160) <2001JA8620>.
997
998
Selenophenes
Fused selenophene ring systems have potential applications in materials science and selected syntheses highlighted in previous sections. Examples include benzo[b]seleno[2,3-b]pyridines (e.g., 87) <2004JHC13, 2004ARK51>, thienoselenophenes 161–163 <1997H(45)1891>, selenolo[3,4-b]furans 97 <1998JHC71>, selenolo[3,2-b]selenophene 164 <1994H(38)143>, selenolo[2,3-b]thiophenes 165 <2004S451>, selenophene-based heteroacene 166 <2005OL5301>, seleno[3,4-c]thiophenes <2002JOC2453>, pyrimidoselenolo[2,3-b]quinoline-4(3H)-one 167 <1995SC451>, and various other fused selenophene systems <1997CLY547>.
Selenophenes
Selenophene-containing quinones were prepared to explore their potential use as dyes and photomaterials. They were found to have good physical and chemical properties for use as dyestuffs for laser-driven high-density optical storage media <1996H(43)941, 1996JOC4784>. 2-Aminoselenophene derivatives were synthesized as indicators for measurement of solvent polarity <2002ZNB420>. Other applications include the use of selenophene-containing tris(oligoarylenyl)amines as amorphous glass materials <2004CL1266> and self-assembled monolayers of selenophene on gold <2000L4213>. A zirconocene complex featuring ligands containing a cyclopentadiene ring fused to selenophene demonstrated activity as an alkene polymerization catalyst <2005PS827>. The field of organic conducting materials has grown significantly since the initial discovery in 1977 that doped polyacetylene demonstrated excellent conducting properties. The synthesis and properties of tetrathiafulvalenes and tetraselenafulvalenes, which have generated interest as functional molecular materials and devices, have been reviewed <2004CRV5289>. Other tetrathiafulvalene (TTF) and tetraselenafulvalene (TSF) donor systems that demonstrate conducting properties include TTFs extended by selenophene (e.g., 168) and benzo[c]selenophene (e.g., 169) substitution <1997H(45)1051, 1997JMC2375>, diselenolotetrathiafulvalene 170 <1997CL1091>, bis(ethyleneseleno)tetraselenafulvalene 171 <1998JOC8865>, and a TTF 172 extended by selenophene fusion <1995AM644>. Fused benzodiselenophenes (e.g., 9) have demonstrated relatively high hole mobilities and have potential applications in field effect transistors <2006JA3044, 2005PS873, 2005JOC10569, 2004JA5084>. The field effect mobilities of quinoidal biselenophenes (e.g., 173) were comparable to or higher than those of the corresponding thiophene derivatives <2004JMC1367>. Biisoselenophene derivatives <2004OL3039>, 1,3-diarylbenzo[c]selenophenes (e.g., 94) <2005TL7201>, and other selenophene-based tetracyanoquinodimethane derivatives (e.g., 174) <2004BCJ463> have also been prepared to explore novel conducting materials.
Several selenophene oligomers have been reported. These include selenolo[3,2-b]selenophene dimers, trimers, and tetramers 175 <1996T471>, quarterselenophenes <1999SM(101)639, 2003CM6>, and alkyl-substituted oligoselenophenes 176 <1997SM(84)341>.
999
1000 Selenophenes Polyselenophenes have also generated significant interest for their potential use as conducting materials. The bandgap energy of p-conjugated polyselenophene was calculated at the B3LYP/6-31G(d) level <2006OL5243>. A high-quality polyselenophene film was prepared that showed good redox activity and high thermal stability <2005MAL1061, 2005JEC345>. The vibrational spectra of polyselenophene was calculated using the semiempirical method PM3 <1995JST(348)91>. The geometries and electronic structures of polyselenophene were compared with various polymers <1998SM(96)177>. Other polyselenophenes include polymers of 3,4-ethylenedioxyselenophene 177 <2001OL4283>, 2,5-diketoselenophene 178 <2001JAP2019>, and biselenophene 179 <2003PLM5597>.
Various copolymers of selenophene have also been reported. These include polymers of selenophene–ethene <1998MM1221>, selenophene–thiophene <1996SM(82)111>, selenophene–pyridine 180 <1996CM2444, 1996JA10389, 2005PCB10605>, selenophene–benzothiadiazole 181 and selenophene–benzoselenadiazole 182 <2005MM244>. Addition copolymers that have been investigated include: pyridine–selenophene 183 <1999SM(100)187>, selenophene–aniline 184 <1998AM1525>, selenophene-oxygenated phenylene 185 <1995MM8363>, and selenophene–tetrafluorophenylene 186 <2005CM6567>. Finally, several selenophene copolymers incorporated fluorene subunits (e.g., 181, 182, and 187) <2006MM4081, 2005PSA823, 2005MM244>.
3.13.13 Further Developments A few recent developments involving the synthesis and evaluation of funtionalized selenophenes have appeared during 2007. An electrophilic cyclization of (Z)-selenoenynes with iodine provided access to 3-iodo-2,5-disubstituted selenophenes <2007JOC6726>. The iodide moiety was later elaborated into other groups utilizing halogen-metal exchange or cross-coupling reactions. The addition of sodium hydroselenide to two equivalents of bis(diethoxyphosphoryl)acetylene followed by oxidation with m-CPBA provided access to 2,3,4,5-tetraphosphorylselenophenes
Selenophenes
<2007OL1729>. Extended heteroarenes containing selenophene rings were prepared and investigated as field-effect transistors <2007JA2224>. Finally, the mode of action of a promising anti-cancer 2,5-di(selenophen-2-yl)pyrrole has been evaluated. The compound was found to induce apoptosis through a p53-associated pathway <2007BP610> and its mode of activity was linked to DNA adduct formation <2007MI193>.
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1003
1004 Selenophenes
2003CHE36 2003CHE539 2003CM6 2003CPL(370)813 2003JA12328 2003JCP10712 2003JME3734 2003JST(633)237 2003OL2519 2003OL3531 2003OL4089 2003OM3659 2003PHC(15)116 2003PLM5597 2003SC2161 2003SL855 2003SUL137 2003S1929 2004ARK51 2004BCJ463 2004CAR2205 2004CL1266 2004CRV2777 2004CRV5289 2004JA5084 2004JCP5801 2004JHC13 2004JMC1367 2004OL3039 2004PHC(16)84 2004PS(179)1681 2004RJO290 2004S451 2004T2889 2004ZNB439 2005ARK60 2005BCJ1121 2005CCR2510 2005CEJ6221 2005CM6567 2005CPL(416)113 2005CRV3842 2005JA2944 2005JA11608 2005JEC345 2005JOC10569 2005JOM(690)3286 2005JMP796 2005MAL1061 2005MI375 2005MI1119 2005PCB10605 2005PSA823 2005MM244 2005OL5301 2005PHC(17)98 2005PS787
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Selenophenes
2005PS827 2005PS873 2005PS939 2005RCB853 2005RJO396 2005S1589 2005TL2647 2005TL7201 2006CCR468 2006JA227 2006JA3044 2006JCO163 2006JOC1552 2006JOC2307 2006JOC3786 2006MM4081 2006OL5243 2006POL499 2006TL795 2006TL2179 2006TL2887 2006ZNB427 2007BP610 2007CC43 2007JA2224 2007JOC6726 2007JOM(692)60 2007MI193
2007OL1729 2007PHC(18)126
R. L. Jones, M. J. Elder, and J. A. Ewen, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 827. K. Takimiya and T. Otsubo, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 873. G. Sommen, A. Comel, and G. Kirsch, Phosphorus, Sulfur Silicon Relat. Elem., 2005, 180, 939. L. I. Belen’kii, T. G. Kim, I. A. Suslov, and N. D. Chuvylkin, Russ. Chem. Bull., 2005, 54, 853. Sh. H. Abdel-Hafez, Russ. J. Org. Chem., 2005, 41, 396. K. Takimiya, N. Niihara, and T. Otsubo, Synthesis, 2005, 1589. G. Zeni, Tetrahedron Lett., 2005, 46, 2647. A. K. Mohanakrishnan and P. Amaladass, Tetrahedron Lett., 2005, 46, 7201. I. Gupta and M. Ravikanth, Coord. Chem. Rev., 2006, 250, 468. N. Veerapen, S. A. Taylor, C. J. Walsby, and B. M. Pinto, J. Am. Chem. Soc., 2006, 128, 227. K. Takimiya, Y. Kunugi, Y. Konda, H. Ebata, Y. Toyoshima, and T. Otsubo, J. Am. Chem. Soc., 2006, 128, 3044. C. T. Bui and B. L. Flynn, J. Comb. Chem., 2006, 8, 163. ˆ Barros, C. W. Nogueira, E. C. Stangherlin, P. H. Menezes, and G. Zeni, J. Org. Chem., 2006, 71, 1552. O. S. de Rego T. Kesharwani, S. A. Worlikar, and R. C. Larock, J. Org. Chem., 2006, 71, 2307. P. Prediger, A. V. Moro, C. W. Nogueira, L. Savegnago, P. H. Menezes, J. B. T. Rocha, and G. Zeni, J. Org. Chem., 2006, 71, 3786. Y. M. Kim, E. Lim, I.-N. Kang, B.-J. Jung, J. Lee, B. W. Koo, L.-M. Do, and H.-K. Shim, Macromolecules, 2006, 39, 4081. S. S. Zade and M. Bendikov, Org. Lett., 2006, 8, 5243. D. G. Churchill, B. M. Bridgewater, G. Zhu, K. L. Pang, and G. Parkin, Polyhedron, 2006, 25, 499. M. A. Ismail, D. W. Boykin, and C. E. Stephens, Tetrahedron Lett., 2006, 47, 795. ˆ Barros, A. Favero, C. W. Nogueira, P. H. Menezes, and G. Zeni, Tetrahedron Lett., 2006, 47, 2179. O. S. de Rego S. Ogawa, K. Kikuta, H. Muraoka, F. Saito, and R. Sato, Tetrahedron Lett., 2006, 47, 2887. G. Kirsch and S. Deprets, Z. Naturforsch., B, 2006, 61B, 427. H.-S. Shiah, W.-S. Lee, S.-H. Juang, P.-C. Hong, C.-C. Lung, C.-J. Chang, K.-M. Chou, and J.-Y. Chang, Biochem. Pharmacol., 2007, 73, 610. R. Kumar, R. Misra, T. K. Chandrashekar, and E. Suresh, Chem. Commun., 2007, 43. T. Yamamoto and K. Takimiya, J. Am. Chem. Soc., 2007, 129, 2224. D. Alves, C. Luchese, C. W. Nogueira, and G. Zeni, J. Org. Chem., 2007, 72, 6726. A. Ogawa, H. Muraoka, K. Kikuta, F. Saito, and R. Sato, J. Organomet. Chem., 2007, 692, 60. S.-H. Juang, C.-C. Lung, P.-C. Hsu, K.-S. Hsu, Y.-C. Li, P.-C. Hong, H.-S. Shiah, C.-C. Kuo, C.-W. Huang, Y.-C. Wang, L. Huang, T. S. Chen, S.-F. Chen, K.-C. Fu, C.-L. Hsu, M.-J. Lin, C.-J. Chang, C. L. Ashendel, T. C. K. Chan, K.M. Chou, and J.-Y. Chang, Mol. Cancer Ther., 2007, 6, 193. S. Sasaki, K. Adachi, and M. Yoshifuji, Org. Lett., 2007, 9, 1729. T. Janosik and J. Bergman; in ‘Progress in Heterocyclic Chemistry’, G. Gribble and J. Joule, Eds.; Elsevier, Amsterdam, 2007, vol. 18, p. 126.
1005
1006 Selenophenes Biographical Sketch
Dr. Erin T. Pelkey (born in 1972) obtained his PhD degree in organic chemistry from Dartmouth College with Prof. Gordon Gribble (1998) where he invesigated the synthesis and chemistry of electron-deficient indoles. He was then an NIH postdoctoral fellow (1999–2001) at Stanford University in the laboratory of Prof. Paul Wender where he investigated the design, preparation, and evaluation of novel guanidine-rich drug delivery agents. In 2001, he joined the Chemistry Department at Hobart and William Smith Colleges located in the Finger Lakes region of upstate New York. He has been a regular contributor to Progress in Heterocyclic Chemistry (1997–present) including chapters on thiophene chemistry and pyrrole chemistry. His research interests are directed at the development of new methods for the preparation of biologically active fivemembered ring nitrogen heterocycles.
3.14 Tellurophenes V. I. Minkin and I. D. Sadekov Rostov State University, Rostov on Don, Russia ª 2008 Elsevier Ltd. All rights reserved. 3.14.1
Introduction
1007
3.14.2
Theoretical Methods
1008
3.14.3
Experimental Structural Methods
1008
3.14.3.1
Molecular Structure
1008
3.14.3.2
NMR Spectroscopy
1009
3.14.3.3
Infrared and Raman Spectroscopy
1011
3.14.3.4
Dipole Moments and Polarizabilities
1011
3.14.4
Thermodynamic Aspects
1011
3.14.5
Reactivity of Substituents Attached to Ring Carbon Atoms
1012
3.14.5.1
Organolithium Derivatives
1012
3.14.5.2
Halogen Derivatives
1014
3.14.5.3
Aldehydes and Ketones
1014
3.14.5.4
Carboxylic Acids and Esters
1016
3.14.6
Reactions of Fully Conjugated Rings
1016
3.14.6.1
Electrophilic Substitution Reactions
1016
3.14.6.2
Reactions with Organolithium Compounds, Grignard Reagents, and Other
3.14.6.3
Organoelement Compounds
1017
Extrusion of Tellurium
1018
3.14.7
Metal and Charge-Transfer Complexes
1019
3.14.8
Polymerization of Tellurophene and Its Derivatives
1020
3.14.9
Ring Syntheses from Acyclic Compounds
1020
3.14.9.1
From Acetylenes
1020
3.14.9.2
From 1,3-Dienes
1021
3.14.9.3
From -Chlorovinylaldehydes
1021
3.14.9.4
From 1,3-Diynes
1022
3.14.9.5
From 1-En-3-ynes
1023
3.14.10
Ring Synthesis by Transformation of Another Ring
1024
3.14.10.1 3.14.10.2 3.14.11
From Rhodium Complexes
1024
From Tellurapyranes by Ring Contraction
1024
Important Compounds and Applications
References
1024 1025
3.14.1 Introduction The scope of tellurophenes was well defined at the beginning of Chapter 3.16 in CHEC(1984) <1984CHEC(4)935> and a number of general reviews on this subject published between 1986 and 1991 were indicated in the introduction to Chapter 2.14 of CHEC-II(1996) <1996CHEC-II(2)749>. A comprehensive review of the chemistry, structural and physical properties of tellurophene, dihydro- and tetrahydrotellurophenes and their benzoanalogues that covered
1007
1008 Tellurophenes literature up to 1992 was presented in a monograph <1994HC53>. A review paper on benzotellurophenes <2004KGS974> also deals with some aspects of the preparative chemistry of tellurophene. In this chapter, the literature is covered through to 2006.
3.14.2 Theoretical Methods Molecular orbitals and the bonding of tellurophene have been examined at the ab initio Hartree–Fock, MP2, and density functional theory (DFT, B3LYP) levels of theory with the use of both effective core potential (ECP) and nonECP (6-31G* and 6-311G** ) basis sets <2000SM185, 2001JMT81, 2003JMT207, 2005JMT209>. The calculated geometries and ionization potentials correlate well with the experimental data and are in general agreement with the results obtained in the early theoretical studies of the electronic structure of tellurophene obtained on the basis of semi-empirical methods of quantum chemistry <1977AHC119>. The aromaticity of tellurophene was intensely studied in the context of its position in the range of five-membered heterocycles p-isoelectronic with benzene. According to various approaches for estimation of the aromaticity of heterocyclic compounds <1991H(32)127, 1993AHC303, B-1994MI1> the aromatic character of the five-membered heterocycles decreases in the order thiophene > selenophene > tellurophene > pyrrole > furan. Apart from the most important energetic and magnetic criteria, some other approaches have been used to evaluate indexes of aromaticity P (A, B, N, J) of tellurophene and congenerous heterocycles in early studies <1973G1041, 1974J(P2)332>. More recently, new indexes of aromaticity have been proposed based on molecular polarizability (D) and hardnesses () related to the electronic part of the electrostatic potential <1998JMT59, 2001CRV1451>. The results are presented in Table 1. Table 1 Aromaticity indexes for five-membered heterocycles Heterocycle
A
B
N
J
D (a.u.)
(eV)
Furan Thiophene Selenophene Tellurophene
7.67 11.56 10.44 8.50
1.72 3.85 2.94 1.85
1.42 0.90 1.02 1.30
0.87 0.93 0.91 0.88
26.45 25.63 25.06 24.65
5.33 5.01 4.91 4.48
The aromaticity index A ¼ 1Vm2\3 is based on the dilution shift method: 1 is the 1H nuclear magnetic resonance (NMR) chemical shift difference in pure liquid and in nonpolar solvent at infinite dilution, Vm being the molar volume of a compound. The greater A values correspond to greater aromaticity. The index B was introduced based on the assumption that the influence of a 2-methyl group on the 1H NMR chemical shifts of protons in the rings is more uniform the greater the aromatic character of the heterocycle: B ¼ 1/ij[(2)i (2)j], where 2 is the difference in chemical shifts of ring protons of 2-methyl-substituted and unsubstituted heterocycle; indexes i and j relate to all inequivalent protons. As structural criteria of aromaticity, indexes N ¼ aR2 þ b (where R are bond lengths, and a and b are parameters characteristic for a given pair of atoms) and Julg’s parameter J ¼ 1 225/nrs(1 drs/a)2 (where n is the number of peripheral bonds rs, drs are their lengths, and d is their mean length) have been applied. The less the value N and closer to 1 the value J, the greater is the aromaticity of a heterocycle. Polarizability exaltations D ¼ <>M <>M’, where <>M and <>M’ are the mean dipole polarizability and the mean atomic or group polarizability, respectively.
3.14.3 Experimental Structural Methods 3.14.3.1 Molecular Structure The geometry of tellurophene in the gas phase was determined based on its microwave (MW) spectrum <1973CPH217>. Tellurophene is a liquid at room temperature and X-ray crystallography has not been applied to the parent compound. The molecular structure of the tellurophene nucleus was derived from the X-ray crystallographic analysis of its crystalline derivatives <1977AHC119, 2002CHE763>. X-Ray structures have been reported
Tellurophenes
for the following substituted tellurophenes: tellurophene-2-carboxylic acid 1 <1972CSC737>, 3-telluranyl derivative 2 <1998OM1901>, 2,5-diphenyl-3-iodotellurophene 3 <1992AXC767>, 2,2-ditellurophene 4 <1994TL8009>. X-ray structural determinations have also been performed for 21-telluraporphyrine <1978TL1885, 1995AGE2252, 2001AG4598, 2002OM4546, 2004OM4513> and several derivatives of dibenzotellurophene <2002CHE763>. Ph
Cl2 Te
I Te Te
COOH
Te
Te
1
Ph
Ph
2
Te
Ph
3
4
Table 2 contains data on bond lengths and valence angles of the tellurophene ring.
Table 2 Molecular geometry of tellurophene ˚ Valence angles (deg) Bond lengths (A)
MW 1973CPH217
X-Raya 2002CHE763
Te–C(2) C(2)–C(3) C(3)–C(4) C(2)–Te–C(5) C(3)–C(2)–Te C(2)–C(3)–C(4)
2.055 1.375 – 82.53 110.81 117.93
2.046 1.371 1.478 82.00 111.83 116.76
a
These values were obtained by averaging of the data on geometries of the substituted tellurophenes 1–4.
3.14.3.2 NMR Spectroscopy Data on 1H NMR spectral parameters of tellurophene <1972J(P1)199, 1974MP257>, 2-substituted tellurophenes <1974ACB175, 1976ACB605> and, for comparison, furan, thiophene and selenophene <1965SA85> are listed in Table 3.
Table 3 1H NMR parameters for tellurophene and congenerous rings (in CDCl3) and 2-substituted tellurophenes 2-RC4H3X (in CDCl3 or (CD3)2CO) (ppm)
JHH (Hz)
X
2-R
H-2
H-3
H-4
H-5
2,3
2,4
2,5
3,4
3,5
4,5
O S Se Te Te Te Te Te Te Te Te Te Te Te Te Te
H H H H CHO COMe CO2H CO2Me SMe CH2OH Cl Br I Me CH(OCOMe)Me CONMe2
7.29 7.18 7.88 8.87
6.24 6.99 7.22 7.78 8.62 8.44 8.53 8.49 7.42 7.41 7.33 7.72 8.11 7.23 7.60 7.94
6.24 6.99 7.22 7.78 8.05 8.00 7.93 7.92 7.55 7.64 7.34 7.41 7.32 7.47 7.67 7.87
7.29 7.18 7.88 8.87 9.56 9.41 9.40 9.38 8.81 8.77 8.75 8.91 9.13 8.64 8.87 9.19
1.75 4.90 5.40 6.58
0.85 1.04 1.46 1.12
1.40 2.84 2.34 1.82
3.30 3.50 3.74 3.76 4.10 4.22 4.20 4.11 4.03 3.88 4.26 4.27 4.06 3.90 4.10 4.10
1.32 1.16 1.34 1.33 1.28 1.25 1.47 1.49 1.54 1.26 1.82 1.95
6.77 6.78 6.76 6.79 6.93 6.83 7.33 7.28 7.10 7.14 6.10 6.00
1009
1010 Tellurophenes With decrease in electronegativity of the heteroatom in the ring, the chemical shifts of -protons in the parent compounds move downfield and vicinal coupling constants (3J2,3, 3J3,4) increase. Irregularities in chemical shifts of -protons are, most probably, due to paramagnetic contributions of shielding by the heteroatoms. The 13C NMR parameters of five-membered heterocycles <1974ACB175> and 2-substituted tellurophenes <1974ACB1751, 1976ACB605> are given in Table 4.
Table 4 13C NMR chemical shifts of tellurophene and congenerous rings and 2-substituted tellurophenes ((CD3)2CO), 2-RC4H3X (ppm) X
R
C-2
C-3
C-4
C-5
O S Se Te Te Te Te Te Te Te Te Te Te Te Te Te
H H H H CHO COMe CO2H CO2Me SMe CH2OH Cl Br I Me CH(OCOMe)Me CONMe2
143.6 125.6 131.0 127.3 151.5 153.5 137.6 139.0 142.1 155.3 136.4 110.0 68.9 144.6 152.7 146.6
110.4 127.3 129.8 138.0 148.1 143.4 144.7 144.5 136.3 132.2 139.1 142.6 149.2 137.5 134.8 138.4
110.4 127.3 129.8 138.0 139.4 139.8 138.6 138.6 137.8 137.4 136.0 137.4 139.4 136.8 137.4 138.4
143.6 125.6 131.0 127.3 138.7 137.8 138.1 137.4 125.6 124.9 128.7 131.5 135.0 124.9 127.1 132.6
In five-membered heterocycles, 13C NMR signals of -carbons shift upfield with decrease in electronegativity of the heteroatoms. There exists good correlation between H-5 and C-5 chemical shifts in 2-substituted tellurophenes which indicates similarity in the transmission mechanism operating for carbon and proton chemical shifts. The effect of substituents on 13C and 1H NMR chemical shifts in 2- and 3-substituted furans, thiophenes, selenophenes, and tellurophenes has been studied by means of principal components and partial least squares analyses <2005MRC397>. 125 Te chemical shifts in 2-substituted tellurophenes <1976CS139, 1981ZOR947, 1982MR504> are given in Table 5. 125Te chemical shifts of tellurophenes correlate well (r ¼ 0.98) with 77Se chemical shifts of similar substituted selenophenes <1976CS139>. This fact suggests an identical mechanism of transmission of electronic effects of substituents in both heterocycles. The slope of the correlation indicates that the tellurophene ring transmits the effects 2.44 times better than the selenophene ring. The sign of Te–H and Te–C coupling constants in tellurophenes was determined by selective population transfer experiments <1981MR155>.
Table 5 125Te NMR chemical shifts (, ppm; relative to Me2Te) and 1JTe–C and 2JTe–C coupling constants (Hz) for 2-substituted tellurophenes 2-RC4H3Te (CD3COCD3) R
JTe–C(2)
JTe–C(3)
JTe–C(4)
JTe–C(5)
H CHO COCH3 COOMe Br CH2OH SMe
793 804 825 862 960 775 886
302.4 290.2 274.3 299.6 373.8 289.2 335.4
5.6 3.5 5.4 5.3 4.7 <3 <3
5.6 15.1 14.0 13.5 7.0 7.0 6.7
302.4 321.6 317.7 317.8 310.5 297.5 304.5
Tellurophenes
3.14.3.3 Infrared and Raman Spectroscopy High-quality experimental vibrational spectra have been reported for tellurophene and some of its derivatives <1985SPL759, 1987CPL244, 2000PCP2495, 2003JMT207>. The normal-mode frequencies and corresponding vibrational assignments were examined theoretically on the basis of Hartree–Fock and MP2 quantum chemical calculations and attributed to one of eight types of motion (C-H, CTC, C–C, Te–C stretches, in-plane and out-ofplane C–H bends, CTC–C bend and ring torsion) <2005JMT209>. Theoretical infrared (IR) and Raman intensities have also been reported. A force field for tellurophene, allowing good correlation of theoretical and experimental data on its vibrational spectrum, has been calculated using various levels of approximation and different basis sets <2001JMT81>.
3.14.3.4 Dipole Moments and Polarizabilities The dipole moment of tellurophene in the gaseous phase was found to be 0.19D <1973CPH217>. In benzene solution (25 C), dipole moments (, D) have been measured for a number of 2-substituted tellurophenes 2-RC4H3Te <1973CC342, 1973CR(C)203, 1977J(P2)775>: R ¼ H (0.46), R ¼ Cl (1.43), R ¼ Br (1.44), R ¼ Me (0.64), R ¼ SMe (1.30), R ¼ COMe (2.97), R ¼ CHO (3.18), R ¼ COOMe (1.95), R ¼ CONMe2 (3.60), R ¼ CH2OH (1.75) <1977J(P2)775>. The direction of the dipole moment vector of tellurophene is from the center of the ring to the heteroatom <1973CC342, 1973CR(C)203, 1974JHC827>. The difference between the dipole moments of a heteroaromatic fivemembered heterocycle and its tetrahydro derivative is considered as the mesomeric moment of the conjugated heterocycle and is directed opposite to the vector of its dipole moment. From the values indicated above and the dipole moment of tetrahydrotellurophene (1.63D) <1977J(P2)775, 1973CR(C)203>, the mesomeric moment of tellurophene is evaluated to be 1.17D. First-principles quantum chemical calculations including relativistic effects have been carried out for dipole moments, polarizabilities, and first- and second-order hyperpolarizabilities for tellurophene. The estimated values were compared with the observed ones measured by the optical Kerr effects <2000SM185, 2003JMT207>.
3.14.4 Thermodynamic Aspects The acidity constants of 5-substituted tellurophene-2-carboxylic acids have been measured in aqueous and aqueousethanolic solution. Table 6 presents the data obtained in comparison with those for the acids of the congeneric fivemembered heterocycles <1960SK(B)87, 1968RS1048, 1970JCB867>.
Table 6 pKa values of 5-substituted tellurophene-2-carboxylic acids 5R-C4H2Te-COOH-2 X
R
pKa (H2O, 25 oC)
pKa (H2O–EtOH/1:1, 25 oC)
O S Se Te Te Te Te Te
H H H H CH3 COOCH3 COOH COO
3.16 3.53 3.60 3.97 4.16 3.36 3.11 4.24
4.54 5.05 5.14 5.48
Although tellurophene-2-carboxylic acid (R ¼ H) is the weakest acid in the series, it is stronger than benzoic acid. pKa values of 5-substituted tellurophene-2-carboxylic acids correlate well with the p constants of the substituents. For the five-membered ring 2-carboxylic acids, the values are 1.41 (X ¼ O), 1.23 (X ¼ S), 1.23 (X ¼ Se), and 1.20 (X ¼ Te) <1972J(P2)1738>. This sequence is indicative to the approximately equal transmittance of electronic effects of substituents across the five-membered heterocycle.
1011
1012 Tellurophenes
3.14.5 Reactivity of Substituents Attached to Ring Carbon Atoms 3.14.5.1 Organolithium Derivatives Some derivatives of tellurophene, for example, halogenotellurophenes, cannot be obtained directly from the parent compound. A number of less-accessible derivatives of tellurophene have been obtained by transformations of lithiotellurophenes. The best and most common route to deuterated tellurophenes is the reaction of lithiotellurophenes 5 with deuterated water <1976SAA1089>, which affords 2-deuterotellurophenes (Equation 1). D2O R
Te
R
Li
Te
D
ð1Þ
5 R = H, Ph
2,5-Dideutero-, 2,3,4-trideutero-, and 2,3,4,5-tetradeuterotellurophenes have been prepared from 2-deuterotellurophene (Scheme 1) <1976SAA1089>. With the exception of the tetradeuteroderivative, deuterotellurophenes were purified by crystallization of their readily formed dibromo derivatives (oxidation addition reaction with bromine) and subsequent reduction of the latter. Polydeuterated tellurophenes, for example, 2-phenyl-3,4,5-trideuterotellurophene, can be prepared by the addition of sodium ditelluride in deuteromethanol to 1-phenylbutadiyne <1976JOM183>.
D
D i, BuLi ii, D2O
D
Te
D
D
Te
ii, D2O
D
i, BuLi
i, BuLi D
Te
D
ii, D2O
D
Te
D
Scheme 1
2-Lithiotellurophene was employed for the synthesis of 2-halogenotellurophenes (Scheme 2). 2-Chloro- and 2-bromotellurophenes have been prepared in moderate yields by the reactions with hexachloro- and hexabromoethanes, respectively <1976ACB605>. With symmetric dichlorotetrabromoethane instead of hexabromoethane, 2-bromotellurophene was obtained in 64% yield <1994TL8009>. 2-Iodotellurophene was prepared by coupling 2-lithiotellurophene with 2-chloroethylene-1-iodoso dichloride and the subsequent treatment of the formed iodonium salt with sodium nitrite <1976ACB605>. This reaction is accompanied by the formation of small amounts of 2-nitrotellurophene. A preparatively more convenient approach to 5-substituted 2-iodotellurophenes is based on the reaction of the corresponding 2-lithiotellurophenes with iodine <2005TL2647>. By this reaction, 2-iodo-5-butyl- and 2-iodo-5-phenyltellurophenes have been prepared in 72% and 85% yields (Scheme 2).
C2Cl6 Te
Cl C2Br6
Te
Scheme 2
Te
+
) I
(
Br
R I2
R
ClCH=CHICl2
I (R = Bu, Ph)
Te
Li
5 (R = H, Bu, Ph)
Te
2
Te
I
Tellurophenes
2-Lithiotellurophene 5 (R ¼ H) is the main precursor to various 2-chalcogenotellurophenes. 2-Methylthiotellurophene was prepared by reaction with dimethyl disulfide in 50–55% yield (Scheme 3) <1973CPL132, 1977J(P2)775>. The first step of the preparation of 2-ethylselenotellurophene involves the insertion of selenium into the C–Li bond of compound 5 (R ¼ H). The subsequent treatment of the formed lithioselenium derivative affords 2-ethylselenotellurophene in 43% yield (Scheme 3) <1997T4199>.
Me2S2 Te
EtBr
Se
SMe
Te
Te
Li
SeLi
Te
SeEt
5: R = H Te O2 Te
– Te Te
TeLi
)2 Te2
Te
)2 Te
7
6 Scheme 3
The analogous reaction of compound 5 (R ¼ H) with powdered tellurium gives rise to di(2-tellurienyl) telluride in very low yield (11%). The main product of this reaction is, most probably, di(2-tellurienyl) ditelluride 6, which transforms to compound 7 by elimination of a tellurium atom. A number of organometallic derivatives of tellurophene and 2,29-bitellurophene 4 were obtained by reactions of 2-lithiotellurophene with metal salts (Scheme 4). 2-Coppertellurophene was prepared by a treatment of compound 5 (R ¼ H) with CuI, whereas reaction with CuCl2 in ether leads to the formation of 2,29-bitellurophene 4 in yields ranging from 14% <1998JCM438> to 39% <1994TL8009, 1995SM537, 2000H(S2)159>.
CuCl2, – 78 °C to 20 °C
CuI
Te Te
Cu
Te
5: R = H
Li
Te
4
Scheme 4
Reacting dimethyl sulfate with 2-lithiotellurophene readily forms 2-methyltellurophene 8 (R ¼ H) in 75% yield (Scheme 5) <1972JP1199>. Unexpectedly, no formation of 2-ethyltellurophene was observed when coupling compound 5 (R ¼ H) with ethyl bromide. Tellurophene-2-carbaldehyde 9 (R ¼ H) was prepared by a treatment of 2-lithiotellurophene with N-methylformanilide in 24% yield <1972J(P1)199>. Carboxylation of lithiotellurophenes 5 (R ¼ H, Me) affords the corresponding tellurophene-2-carboxylic acids 10 in 37% and 35% yields, respectively <1972J(P1)199>. By the condensation of 2-lithiotellurophene with aldehydes, 2-(1-hydroxyethyl)tellurophene 11 (R1 ¼ Et) <1972J(P1)199, 1997T4199> and 2-(hydroxybenzyl)tellurophene 11 (R1 ¼ Ph) <1997T4199> were obtained in 50–57% and 60% yields, respectively (Scheme 5). Tellurophene-2,5-dicarbaldehyde 12 was obtained in 43% yield <1995MM8363> by treatment of 2,5-dilithiotellurophene with dimethylformamide (DMF) (Equation 2).
1013
1014 Tellurophenes
R
CH(OH)R1
Te
11: R1 = Et, Ph R1CHO Me2SO4
PhN(Me)CHO R
Te
R
CHO
Te
Li
R
5
9: R = H CO2
R
Me
8
H+
Te
Te
COOH
10: R = H, Me Scheme 5
Me2NCHO Li
Te
OHC
Li
Te
CHO
ð2Þ
12
3.14.5.2 Halogen Derivatives Nucleophilic substitution of halogens in the ring or in side chains have been used for the synthesis of various derivatives of tellurophene. The reaction of 2-iodotellurophene with thiols catalyzed by Cu(I) ions gives rise to 2-organylthiotellurophenes 13 in 77–90% yields (Equation 3) <2005TL2647>.
R1SH, Cu(I) R
Te
I
KOH
R
Te
SR1
ð3Þ
13 R = Ph, Bu, R1 = Pr, C12H25, 4-MeOC6H4, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4; R = R1 = Ph
Based on the exchange reactions of 3,4-bis(chloromethyl)-2,5-diphenyltellurophene 14, a number of derivatives of tellurophene have been prepared in 49–98% yields (Scheme 6) <1976ZNB367, 1977CZ303>. The reaction of 2-iodotellurophene with sodium malonitrile catalyzed by PdCl2(PPh3)2 results in the formation of 2-dicyanomethylene-2,5-dihydrotellurophene in 46% yield (Scheme 7) <1996H(43)1927>.
3.14.5.3 Aldehydes and Ketones Tellurophene aldehydes and ketones readily undergo reduction reactions typical of carbonyl compounds. The Wittig reaction of 2,5-bis(dodecyloxy)-p-xylene-bis(triphenylphosphonium bromide) with tellurophene-2,5-dicarbaldehyde leads to poly(2,5-tellurophenediylvinylene) (MW 7000–29 000 Da) in 65% yield <1995MM8363>. The condensation reactions of 2,5-diphenyl-3,4-diformyltellurophene 15 have been employed for the synthesis of a number of bi- and polycyclic heterocycles with a fused tellurophene ring (Scheme 8) <1976CB3886>.
Tellurophenes
N+
+N
CH2
H2C
Ph
Te
Ph
Py
X
ClH2C
Ph
Ph
Te
CH3
Na2Te
Na2X Ph
H3C
CH2Cl
Te
Ph
Ph
Te
Ph
14
X = S, Se
RONa ROH2C
CH2OR
Ph
R = H, Me, Et
Ph
Te
Scheme 6
NaCH(CN)2 Te
I
PdCl2(PPh3)2, THF
H H
CH(CN)2
Te
CN Te CN
Scheme 7
EtOOC
Ph
S
Te
EtOOC
Ph S(CH2COOEt)2 Ph
Ph OHC N
Te
CHO
1,2-C6H4(NH2)2
H2NNH2 Ph
N
Te
16 (RCH2)2CO
R
Ph
O
Te R
17
Ph
R = COOMe, Ph Scheme 8
Te N
Ph
15
Ph
N
Ph
1015
1016 Tellurophenes
3.14.5.4 Carboxylic Acids and Esters Tellurophene carboxylic acids are obtained in quantitative yields by alkaline hydrolysis of the corresponding esters <1972J(P1)199, 1975CR(C)187, 1975CS113, 1980J(P2)971>. Tellurophene-2-carboxylic acid reacts with diazomethane to give 2-methoxycarbonyltellurophene <1972JP1199>. The reaction with hexamethylphosphoramide (HMPA) gives rise to tellurophene-2-N,N-dimethylcarboxyamide (Scheme 9) <1974T4129>.
CH2N2
HMPA Te
CONMe2
Te
COOMe
Te
COOH
Scheme 9
Decarboxylation of tellurophene carboxylic acids occurs readily in quinoline solution under the action of copper chromite. In this way, 2-(39(49)-methoxyphenyl)tellurophenes have been obtained from 2-(39(49)-methoxyphenyl)tellurophene-5-carboxylic acids <1980J(P2)971>.
3.14.6 Reactions of Fully Conjugated Rings 3.14.6.1 Electrophilic Substitution Reactions With electrophiles acting also as oxidants of dicoordinate tellurium (HNO3, halogens), tellurophenes enter into oxidative addition reactions to give corresponding Te(IV) derivatives. Therefore, tellurophenes are not susceptible to direct nitration. Moreover, when treated with strong mineral or Lewis acids (e.g., AlCl3), tellurophenes undergo decomposition, which requires the reactions of tellurophenes to be carried out in neutral, alkaline, or low-acid solutions. Bromination of tellurophenes results in formation of low-soluble 1,1-dibromotellurophenes (Equation 4) <1966AG940, 1961JA4406, 1968BRP1107698, 1978CB3745>. Upon reaction with sulfuryl chloride, tellurophene forms 1,1-dichlorotellurophene in 61% yield <1997T4199>. R2
R2
R2
R2
+ Br2 R1
R1
R1
Te
Br 1
2
2
ð4Þ
R1
Te Br
1
R = R = H; R = H, R = Bu, Ph
2-Bromo-5-phenyltellurophene was prepared in 62% yield by a treatment of 2-phenyltellurophene with N-bromosuccinimide (NBS) in methylene dichloride (Equation 5) <2005TL2647>. NBS Te
Ph AcOH
ð5Þ Br
Te
Ph
Treatment of tellurophene with 10% D2SO4 in deuteromethanol gives rise to 2,5-dideuterotellurophene, whereas reaction with Hg(OAc)2 affords 2,5-(diacetoxymercuri)tellurophene (Scheme 10) <1966AG940>.
10%D2SO4/CH3OD
Hg(OAc)2/EtOH AcOHg Scheme 10
Te
HgOAc
Te
D
Te
D
Tellurophenes
Reaction of tellurophene with acetic anhydride in the presence of SnCl4 forms 2-acetyl-tellurophene (Scheme 11) <1972J(P1)199, 1971CC1441>. 2-Trifluoroacetyltellurophene has been obtained by coupling tellurophene with trifluoroacetic anhydride. No Lewis acid catalysts are needed in this reaction (Scheme 11) <1971CC1441, 1973J(P2)2097>. Formylation of tellurophene occurs readily under the action of a complex formed by DMF and phosgene (Scheme 11) <1971CC1441, 1973J(P2)2097>.
Ac2O/SnCl4
(CF3CO)2O/Δ
Te
Te
COCF3
Te
COMe
DMF/COCl2/CHCl3
CHO
Te Scheme 11
2-Carbomethoxytellurophene enters into a Friedel–Crafts reaction with Ac2O/SnCl4 (Equation 6) <1972J(P1)199>. Ac2O/SnCl4 CO2Me
Te
ð6Þ MeCO
CO2Me
Te
Chloromethylation of 2,5-diphenyltellurophene affords 3,4-di(chloromethyl)tellurophene in 61% yield (Equation 7) <1976ZNB367>. ClCH2
CH2Cl
HCHO / HCl / AcOH Ph
Te
ð7Þ Ph
Ph
Te
Ph
Table 7 contains data on the relative reactivity of tellurophene and related heterocycles in typical electrophilic substitution reactions <1973J(P2)2097>.
Table 7 Relative reactivities (k/kthiophene) of tellurophene and congeneric heterocycles Compound
Acetylation (25 C)a
Trifluoroacetylation (75 C)b
Formylation (30 C)c
Furan Thiophene Selenophene Tellurophene
11.9 1 2.28 7.55
140 1 7.33 46.4
107 1 3.64 36.8
a
Ac2O/SnCl4. (CF3CO)2O. c COCl2/DMF. b
3.14.6.2 Reactions with Organolithium Compounds, Grignard Reagents, and Other Organoelement Compounds Lithiation of tellurophene <1972J(P1)199, 1976SAA1089, 1976ACB605, 1977J(P2)775, 1981JOM43, 1994TL8009, 2000H(52)159> and 2-R-substituted tellurophenes (R ¼ Me, Bu, Ph) <1972J(P1)199; 2005TL2647> proceeds smoothly at room temperature when their ether solutions are treated with butyllithium in hexane. With twofold
1017
1018 Tellurophenes excess of butyllithium, tellurophene forms 2,5-dilithio derivative <1995MM8363>. The reaction of 2,5-diphenyl-3iodotellurophene with butyllithium leads to the ring opening to give di(1,4-diphenylbut-1-ene-3-ynyl) ditelluride in 54% yield (Scheme 12) <1996JOC9503>.
I
Ph
Ph
Li
Ph
BuLi / THF, 78 °C Ph
Te
Ph
Ph
Te Te
Te
Ph
Te
Ph
Ph
Ph
Scheme 12
Under slow addition of 2 equiv of BuLi to a solution of tellurophene in tetrahydrofuran (THF) at room temperature, di(1,4-diphenylbut-1-ene-3-ynyl)telluride is formed in 60% yield <1996JOC9503>. Another Te–C cleavage reaction occurs upon coupling 2,5-diphenyltellurophene with BuLi in the presence of tetramethylethylenediamine [1,2 bis(dimethylamino)ethane] (TMEDA) <1976ZNB1654>. The 1,4-diphenyl-1,4-dilithiobuta-1,3-diene reacts with various electrophilic reagents giving 1,4-disubstituted 1,4-diphenylbuta-1,3-dienes in 20–58% yields. This reaction performed without the use of TMEDA was extended to s-BuLi and t-BuLi <1998OM5796>. Buta-1,3-dienes can also be obtained by coupling tellurophene (as well as other congeneric five-membered heterocycles) with Grignard reagents in the presence of 10 mol% Ni(PPh3)2Cl2 <1984CC617>. The reaction with aliphatic Grignard reagents occurs selectively affording (Z,Z)-dienes. Di-(t-butyl)silene generated by the photolysis of hexa-(t-butyl)-cyclotrisylane reacts with 2,5dimethyltellurophene to form 2,2,4,4-tetra-(t-butyl)-1,3-ditellura-2,4-disiletane in 63% yield <1997ZFA1277>.
3.14.6.3 Extrusion of Tellurium ArF (193 nm) and KrF (248 nm) laser-induced photolysis of gaseous tellurophene occurs via cleavage of both Te–C bonds and yields elemental tellurium, 1-buten-3-yne, acetylene, and butadiyne, as a very minor product, and results in chemical-vapor deposition of tellurium films <1999JMC563, 2000AM715, 2000JOC2759>. The mechanism of homogeneous decomposition of gaseous tellurophene was investigated by using IR laser-induced pyrolysis and trapping experiments <2005MI1>. It was proposed that the reaction involves an intermediate _HCTCHTCHTCH_ diradical. Under Hg-lamp photolysis of 2-phenyltellurophene ( max 292 nm), through Pyrex in argon-degassed ether, phenylvinylacetylene and elemental tellurium are formed <1976JOM183>. UV illumination of air-exposed solutions of compounds 16 and 17 results in elimination of the elemental tellurium to give 4,5-dibenzoylpiperazine in 40% yield and 4,5-dibenzoyl-2,7-diphenyl-2,4,6-cycloheptatrien-1-one in 43% yield (Scheme 13) <1976CB3886>.
Ph
Ph N Te
hν/O2
N
Te O O
PhCO
N N
–Te
PhCO
Ph
Ph
16 Ph
Ph
O
Te
hν/O2 –Te
Ph
Ph
17 Scheme 13
Ph PhCO O PhCO Ph
N N
Tellurophenes
3.14.7 Metal and Charge-Transfer Complexes Tellurophenes readily form metal complexes with Lewis acids, metal ions, and metal carbonyls. A mixture of monoand binuclear complexes 18 and 19 is obtained by coupling tellurophene (L1) with Na2PdCl4 <1972JOMC87>. With tetrachlorotellurophene (L2), the complex 20 with trans-configuration was prepared <1972JOMC87>. L1
L1
Cl Pd
L
1
Cl
Cl
18
Cl
Cl Pd
Pd
Pd Cl
L2
Cl
1
L2
Cl
L
19
20
The structure and composition of products of reactions between tellurophene and metal carbonyls depends on the nature of the metal <1999UK415>. A monomeric complex was obtained in 80% yield when treating tellurophene with Cr(CO)3(MeCN) in dibutyl ether solution at 50–60 C (Equation 8) <1972JOMC87, 1981MCL3>. + Cr(CO)3(MeCN)3 Te
−MeCN
Cr(CO)3
Te
ð8Þ
Telluraferrole 21 is the main product of the reaction of tellurophene with Fe3(CO)12 under short-term (45 min) reflux of a heptane solution. Under prolonged heating (2.5 h), ferrole and FeTe are formed (Scheme 14) <1996JCD1545>. This reaction can be accelerated by MW heating <1995MI1>.
Δ
Fe3(CO)12 +
Te Fe(CO)3
Δ
Fe(CO)3 + FeTe
Te Fe(CO)3
Fe(CO)3
21 Scheme 14
Reaction of tellurophene with osmium or ruthenium clusters [M3(CO)10(MeCN)2] (Equation 9) is accompanied by cleavage of a Te–C bond resulting in the formation of the complexes [Os3(CO)10C4H4Te] <1990CC1568> and [Ru3(CO)10C4H4Te] <1991JOM63>. (CO)3 M [M3(CO)10(MeCN)2] Δ, hexane
Te
(CO)4M Te
M = Os, Ru
ð9Þ
M (CO)3
With cyclopentadiene ruthenium p-complex [C5Me5Ru(MeCN)3](OTf), tellurophene reacts to form a stable sandwich p-complex 22 in 82% yield (Equation 10) <1998BKC706>. The 5-coordination of the tellurophene ring is confirmed by the strong high field shift of the 125Te NMR signal (107 ppm to be compared with 782 ppm signal of tellurophene). Te [C5Me5Ru(MeCN)3](OTf)
Ru+
(OTf)–
Te
22
ð10Þ
1019
1020 Tellurophenes Similar to other congeneric five-membered heterocycles, tellurophene readily forms charge-transfer complexes with tetracyanoethylene <1975JF12045>.
3.14.8 Polymerization of Tellurophene and Its Derivatives Under the action of FeCl3, tellurophene undergoes polymerization and forms powdered poly(tellurophene) <1985MI1, 2000H(52)159>. Compressed pellets of the polymer are characterized by very low conductivity (1012 S cm1 at room temperature). Doping poly(tellurophene) with iodine raises the electric conductivity to 106 S cm1. Galvanostatic polymerization of tellurophene in nitrobenzene or benzonitrile containing Me4NClO4 required a high electrical current of 1 mA and give an insoluble black powder of poly(tellurophene) <1994TL8009, 1995SM537, 2000H(S2)159>. The low conductivity of the polymer was explained by its partial decomposition under severe electrolytic conditions and relatively low degree of polymerization.
3.14.9 Ring Syntheses from Acyclic Compounds 3.14.9.1 From Acetylenes Tellurophene is obtained in low yield (3%) by reaction of powdered tellurium with acetylene in a KOH–HMPTA– H2O system (HMPTA ¼ hexamethylphosphorotriamide) <1989ZOR39>. The reaction proceeds through the intermediate formation of divinyl telluride. Heating divinyl telluride with acetylene at 420–450 C affords tellurophene in 30% yield (Equation 11) <1990MOK1201>.
420 – 450 °C (CH2=CH)2Te
ð11Þ Te
Tellurophene and its mono- and disubstituted derivatives 23 have been prepared in 10–50% yields by coupling acetylene chlorohydrins with NaHTe (Scheme 15) <1987PS119>.
1
RC CCR1 – CH2Cl
NaHTe
OH
RC CCR1 – CH2TeH OH
R
AcOH/EtOH R
Te
23: R = R1 = H, Me; R = H, R1 = Me Scheme 15
Another approach to 2,4-disubstituted tellurophenes is based on the use of acetylenic chloromethyl oxiranes (Equation 12) <1988TL4923>. By coupling the oxiranes with Na2Te in aqueous methanol, 2-substituted 4-hydroxymethyltellurophenes have been prepared in 59–73% yield.
O Cl R
+ Na2Te
MeOH−H2O /−40 °C / 3 − 4 h
HOCH2
Te
23: R = H, Bu, Ph, C8H17
R
ð12Þ
Tellurophenes
The [3þ2] cycloaddition reaction of sodium phenyl ethynyl tellurolate with di(methoxy-carbonyl)acetylene affords a trisubstituted tellurophene 24 in low yield (7%) (Equation 13) <1981ZOR2064>. Ph CTeNa + MeO2CC
PhC
CO2Me
CCO2Me H
CO2Me
Te
ð13Þ
24
3.14.9.2 From 1,3-Dienes The first representative of the tellurophene family, its tetraphenyl derivative 25 was synthesized in 1961 <1961JA4406, 1963USP3151140>. The reactions of 1,4-dilithiobuta-1,3-diene with TeCl4 and 1,4-diiodobuta-1,3diene with Li2Te afford compound 25 in 56% and 82% yields, respectively (Scheme 16).
Ph Ph
Li Li
Ph
+ TeCl4
Ph
Ph
Ph
Ph I –LiI
–LiCl
Te
Ph
Ph
Ph
25
Ph
I
+ Li2Te
Ph
Scheme 16
Tetrachlorotellurophene 26 has been prepared by heating hexachlorobuta-1,3-diene with powdered tellurium (Equation 14) <1965AG260>. Cl Cl
Cl Cl
+ Te
ð14Þ
Cl
Cl
Cl
250 °C/40h Cl
Cl
Te
Cl
26
3.14.9.3 From -Chlorovinylaldehydes 2,5-Disubstituted tellurophenes 27 and 28 were prepared in 25–30% yields based on -chlorovinylaldehydes (Equations 15 and 16) <1975CR(C)187, 1975CS113, 1980J(P2)971>.
H
CHO DMF + Na2Te + CH2R
R1
Cl
X
−NaX R
Te
R1
27 R1 = But, R = CO2Et, COMe, CHO, NO2; R = CO2Et, R1 = 4-MeOC6H4, 3-MeOC6H4
ð15Þ
1021
1022 Tellurophenes
CHO
DMF
+ Na2Te + CH2R
(CH2)n
(CH2)n
−NaX
Te
X
Cl
ð16Þ
R
28
n = 4: R = CO2Et, COMe, NO2; n = 5: R = CO2Et
With -substituted -chlorovinylaldehydes, 2,4-disubstituted tellurophenes 23 were obtained (Equation 17) <1979PS161>. Ar
Ar
CHO + Na2Te + CH2CO2Et
H
Cl
ð17Þ
−NaBr
Br
Te
CO2Et
23
3.14.9.4 From 1,3-Diynes Nucleophilic addition of sodium telluride to 1,3-diynes serves as a general method for the synthesis of 2- and 2,5disubstituted tellurophenes (Equation 18) <1966AG940, 1968BRP1107698, 1972ADC777, 1972J(P1)199, 1976SAA1089, 1976JOM183, 1990JOM301, 1995JRM2642, 1997ZFA1277, 1998OM5796>. RC
C−C
CR1 + Na2Te
MeOH(EtOH) / rt R
Te
R1
ð18Þ
R, R1 = H, Me, CH2OH, Bu, Ph, 4-MeOC6H4, 4-CF3C6H4, 2-thienyl, 3-pyridyl
One-step synthesis of tellurophene (in 15% yield) can be realized by bubbling diacetylene in the suspension of elemental tellurium in KOH-DMSO-N2H4-H2O at 0–20 C <1990MOK1197>. 2,5-Diphenyltellurophene is obtained by treatment of diethyl ditelluride with diphenyldiacetylene in N2H4– KOH–DMSO–H2O at 55 C (DMSO ¼ dimethyl sulfoxide; Scheme 17) <2002KGS280>. CPh Et 2Te 2
H
N2H4·H2O/KOH −DMSO −H2O
EtTe–
PhC
C
C
C
EtTe−
CPh
− Et2Te
H2O Ph
TeEt
CPh H
Ph
C − Te
H2O Ph
Te
Ph
Scheme 17
A preparatively convenient method for the synthesis of tellurophene is based on the use of stable and accessible 1,4-bis-(trimethylsilyl)buta-1,3-diyne (Scheme 18) <1972JOMC66, 1978CB3745>. Purification of the tellurophene product can be achieved through an oxidation–reduction (Br2/Na2SO3) cycle. The yields of pure tellurophene are in the range 53–59%.
Me3SiC
C–C
CSiMe3 + Na2Te
Br2
MeOH/rt Te
Na2SO3
Te Br
Scheme 18
Br
Tellurophenes
3.14.9.5 From 1-En-3-ynes 3-Methyltellurophene is obtained in 50% yield by a series of reactions starting from but-1-ene-3-yne (Scheme 19) <1983TL2203>.
BuLi, KOBut, LiBr HC
C
C
CH2
C
LiC
C
CH2
t
Bu OH, HMPA
Te
C
LiC
C
CH2TeLi
CH2Li
CH3
CH2
CH2
CH3 Δ
Te
Te
Scheme 19
Derivatives of tellurophene are formed <1998OM1901> in refluxing 85% formic acid solutions of 1-butyltellurobut-1-ene-3-ynes, which are readily obtained by hydrotelluration of 1,4-bis(organyl)-1,3-butadiynes (Scheme 20) <1992TL2261, 1992TL7353, 1995T9839, 2005T1613>.
Ph Ph
Te HCOOH Ph
Te
Ph
BuTe
HCOOH (R = H)
(R = Ph)
Te
Ph
R Scheme 20
By reaction with iodine, (Z)-1-(butyltelluro)but-1-ene-3-ynes afford 3-iodotellurophenes 29 in 40–90% yield (Scheme 21) <1996JOC9503, 1992TL7353, 1995T9839>.
I R
I NaBH4
I2 BuTe
R R1
R1
Te I
R
I
Te
R1
29
R = R1 = H, Me, Ph, 4-MeC6H4, 4-MeOC6H4; R = H, R1 = Ph Scheme 21
When 3 equiv of iodine was used in the reaction with (Z)-1-(butyltelluro)but-1-ene-3-ynes, 2,3-diiodotellurophene was obtained in low yield (4%) (Equation 19) <1996JOC9503>.
H
I
H
3I2 / rt / 4 h
ð19Þ BuTe
H
Te
I
1023
1024 Tellurophenes An iodine atom in position 3 can be substituted by nucleophiles, for example, by a tellurobutyl group to give 2,5diphenyl-3-butyltellurotellurophene in 72% yield (Equation 20) <1996JOC9503>.
TeBu
I THF / rt / 10 min + BuTeLi Ph
−LiI
Ph
Te
ð20Þ Ph
Te
Ph
3.14.10 Ring Synthesis by Transformation of Another Ring 3.14.10.1 From Rhodium Complexes A series of quinones containing a tellurophene moiety 30 was obtained in 10–63% yield by coupling rhodium complexes with powdered tellurium (Equation 21) <1975S265, 1975CB237>. In a similar way, the derivative 31 has been prepared (Equation 22) <1976LA1448>.
A
A
O
O + Te
R
Rh
L
L
xylene / Δ / 7–10 h −RhL2Cl
R
O
R
Cl
O
Te
R
ð21Þ
30
L = Ph3P; R = Ph, A = 1,2-phenylidene, 2,3-naphthalenilidene, 2,3-dimethyl-3,4-thiophenilidene, 2,3-benzo[b]thiophenilidene; R = 4-MeC6H4, A = 1,2-phenylidene, 2,3-naphthalenilidene
O
O + Te
Ph L
Rh L
−RhL2Cl Ph
Ph Cl
Te
Ph
ð22Þ
31 L = Ph3P
3.14.10.2 From Tellurapyranes by Ring Contraction The hydrolysis of telluropyrylium dyes under aerobic conditions leads to the contraction of the tellurapyrane ring affording merocyanines containing a tellurophene ring in 29–53% yield (Scheme 22) <1997JOC4692>.
3.14.11 Important Compounds and Applications Tetrachlorotellurophenes have been used to increase the fire resistance of hydraulic fluids <1973USP3795619>. Semiconductors derived from 3,4-disubstituted tellurophenes have been patented for use as photosensors <199OJAP(K)O241317>.
Tellurophenes
Bu
t
+ Te
But
Bu
t
Te
OH t Bu
Bu
H2O
t
O2
Te
Bu
OOH But
t
Te
But O
– H2O2
–
HO
But
But X
X Bu
t
Bu
t
But
But X
X Bu
t
t
Bu
X = S, Se, Te Scheme 22
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1025
1026 Tellurophenes
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Tellurophenes
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1027
1028 Tellurophenes Biographical Sketch
Vladimir Minkin received his Candidate (Ph.D.) and Doctor of Science (Chemistry) degrees from Rostov on Don State University. In 1967, he was appointed professor at the same university, and since 1981 he has held the position of head of the Institute of Physical and Organic Chemistry. He was a visiting professor or visiting scientist at the Havana, Strathclyde, Cornell, Florida, Regensburg, and Humboldt universities, received his Dr. honoris causa degree from the university of Aix-Marseille, Rostov and Taganrog universities, and was elected a member of the Russian Academy of Sciences. Among his awards are State Prize of USSR (chemistry), Butlerov and Chugaev prizes of Russian Academy of Sciences, and Senior Humboldt Award. His research interests include quantum organic chemistry, photochemistry, stereodynamics of metal coordination compounds, new types of tautomeric rearrangements, and organotellurium chemistry.
Igor D. Sadekov was born in 1940 in Rostov on Don. After graduation from Rostov State University in 1962, he took a position of research associate in the Institute of Physical and Organic Chemistry at Rostov University and in 1976 was promoted to a position of head of laboratory of organotellurium compounds. In 1966, I. D. Sadekov got a degree of Candidate of Science (Ph.D.) and in 1982 Doctor of Science (Organic Chemistry). Since 1987, he is a professor at Rostov University. He has published more than 200 papers, including 33 review papers, in refereed journals and is the co-author of a monograph on organotellurium chemistry.
3.15 Phospholes R. Re´au University of Rennes 1, Rennes, France P. W. Dyer Durham University, Durham, UK ª 2008 Elsevier Ltd. All rights reserved. 3.15.1
Introduction
3.15.2
Theoretical Methods
3.15.2.1 3.15.2.2 3.15.3
1030 1032
The Phosphole Ring
1032
Extended p-Conjugated Systems Based on Phospholes
1038
Experimental Structural Methods
1041
3.15.3.1
X-Ray Diffraction Analysis
1041
3.15.3.2
NMR Spectroscopy
1049
3.15.3.2.1 3.15.3.2.2 3.15.3.2.3
31
P NMR spectroscopy 1 H NMR spectroscopy 13 C NMR spectroscopy
1049 1058 1058
3.15.3.3
Mass Spectrometry
1058
3.15.3.4
UV–Vis and Fluorescence Spectroscopy
1059
3.15.3.5
Infrared and Raman Spectroscopy
1064
Photoelectron Spectroscopy
1065
3.15.3.6 3.15.4
Thermodynamic Aspects
1065
3.15.4.1
Physical Properties
1065
3.15.4.2
Thermal Stability
1065
3.15.4.3
Resonance Energies
1066
3.15.4.4
Annular Tautomerism
1066
Reactivity of Phospholes
1067
3.15.5 3.15.5.1
Reactivity of CN 3 Phospholes
3.15.5.1.1 3.15.5.1.2 3.15.5.1.3 3.15.5.1.4 3.15.5.1.5
3.15.5.2
General Unimolecular thermal and photochemical reactions Electrophilic attack at phosphorus Cycloadditions with the dienic moiety Substitution and cleavage at phosphorus; phospholide ions
Reactivity of CN 4 Phospholes
3.15.5.2.1 3.15.5.2.2
3.15.5.3
1067 1067 1067 1069 1070 1072
1073
Phosphole oxides, sulfides, and selenides Phospholium salts
1073 1079
Reactivity of CN 2 and CN 5 Phospholes
1080
3.15.5.3.1 3.15.5.3.2
2H-Phospholes Five-coordinate phosphole (phosphoranes)
1080 1080
3.15.6
Reactivity of Reduced Phospholes
1080
3.15.7
Reactivity of C-Substituents
1081
3.15.8
Reactivity of P-Substituents
1084
3.15.9
Ring Synthesis
1086
3.15.9.1
General
1086
3.15.9.2
Reaction of 1,4-Dimetallic Derivatives of Dienic Systems with Phosphorus Dihalides
1086
1029
1030 Phospholes 3.15.9.3
Some Synthetic Approaches to Reduced Phospholes
1092
3.15.10
Phosphole Synthesis by Ring Transformation
1095
3.15.10.1
General
1095
3.15.10.2
Dehydrohalogenation of C-Halo and P-Halo Phospholenes and Phospholanes
1096
3.15.10.3
Displacement of P-Substituents
1098
3.15.10.4
Displacement of C-Substituents
1104
3.15.11
Synthesis of Particular Classes of Phospholes
1105
3.15.11.1
General
1105
3.15.11.2
Carboxylic Acids and Derivatives
1105
3.15.11.3
Aldehydes and Ketones
1105
3.15.11.4
Halo Substituents
1108
3.15.11.5
Silyl Derivatives
1109
3.15.11.6 3.15.12 3.15.12.1
0
1,1 -Diphospholes Important Compounds and Applications Phospholes as Precursors for Other Phosphorus Heterocycles
3.15.12.1.1 3.15.12.1.2 3.15.12.1.3 3.15.12.1.4
3.15.12.2
7-Phosphanorbornenes and 7-phosphanorbornadienes 1-Phosphanorbornadienes and 1-phosphanorbornenes Phosphinines Phospholyl complexes
Phosphole Ligands for Homogeneous Catalysis
3.15.12.2.1 3.15.12.2.2 3.15.12.2.3
Coordination to metals and binding modes Mono- and bi-dentate ligands Chiral ligands
1110 1111 1111 1111 1116 1119 1120
1127 1127 1127 1132
3.15.12.3
Phospholes and Their Transition Metal Complexes as Therapeutic Agents
1133
3.15.12.4
Phosphole-Based p-Conjugated Materials for Optoelectronic Applications
1135
3.15.13
Further Developments
References
1140 1141
3.15.1 Introduction The chemistry of phospholes is in its infancy compared to that of pyrrole and thiophene (compounds that were discovered during the nineteenth century) with the first compounds, dibenzophosphole 1 and pentaphenylphosphole 2, being described in the 1950s <1953LA44, 1959CIL1250, 1959JA3163, 1961JA4406>. This is illustrated by the facts that the parent phosphole 3 was only characterized by nuclear magnetic resonance (NMR) spectroscopy as recently as 1983 <1983JA6871> and that in CHEC(1984) only four pages were devoted to phospholes <1984CHEC-I(1)518>. Synthetic methods combining high yields and diversity of substitution pattern were developed only in the 1970s and 1980s <1988CRV429>. This subject was covered previously in Chapter 2.15 of CHEC-II(1996) <1996CHEC-II(2)757>. Today, however, the chemistry (synthesis, reactivity, coordination behaviour, etc.) of this P-based heterocycle has reached a much more mature state to such an extent that it has been used as a building block for the synthesis of novel Pheterocycles, the preparation of finely tuned ligands for transition metal-based catalysts, and for the engineering of pconjugated materials. This interest has meant that in the last 10 years, a great array of variously functionalized phospholes with widely differing properties has appeared. The ease with which the preparation of such a diverse range of phospholes has been achieved can be attributed, in part, to the ability to vary the number (defined as its coordination number, CN) and nature of the substituents at the P-atom. Notably, phospholes with coordination numbers from 2 to 6 are known; however, the most common are those where CN is 3 or 4. Phospholes 1–3 are designated as having CN ¼ 3 with their P-atoms bearing a lone pair. They behave as classic two-electron donor ligands and exhibit a rich coordination chemistry. A crucial property of these compounds (that will be discussed in detail), which affects both their structure and reactivity, is the extent of their aromatic character, a property that differs significantly from that of their aromatic N-based analogues, pyrroles.
Phospholes
Derivatives with CN ¼ 4 include phosphole oxides and sulfides, phospholium salts, imine and ylide derivatives. Their reactivity is completely different to that of phospholes having CN ¼ 3 since the lone pair of the P-atom is not available. In most cases, the CN ¼ 4 compounds behave as functionalized cyclic dienes. However, phosphole oxides and sulfides can also be employed as ‘protected’ CN ¼ 3 phospholes for synthetic purposes.
Phosphole derivatives with CN ¼ 5 and CN ¼ 6 are hypervalent species, which are quite rare. Indeed, the phosphoranes (CN ¼ 5) are stable only when the P-atom bears electronegative substituents such as fluorine atoms or alkoxy groups. The geometry adopted at phosphorus is distorted trigonal bipyramidal, something enforced by the small endocyclic CPC bond angle. Compounds with CN ¼ 6 are anions with octahedral phosphorus atoms.
Species with CN ¼ 2 comprise phospholide anions 4 and 2H- and 3H-phospholes 5 and 6, respectively. The chemistry of these compounds has experienced an extraordinary development in the last 10 years. Nowadays, they are key synthons for the synthesis of phosphole derivatives with CN ¼ 3 or for a range of other P-heterocycles. Furthermore, phospholide anions 4 are versatile 5-ligands affording a variety of phosphametallocene complexes such as mono- and di-phosphoferrocenes 7 and 8. Chiral derivatives based on monophosphoferrocene units are powerful ligands in asymmetric catalysis.
The phosphole ring can be fused to a number of other cyclic structures. The most widely found are the dibenzo- and dithieno-derivatives 9 and 10. It is noteworthy that these compounds display few properties associated with phospholes. Instead, they behave as diarylphosphines due to the presence of the highly aromatic fused benzene or thiophene rings.
A great number of dihydrophospholes, namely 2- and 3-phospholenes, and tetrahydrophospholes (phospholanes) are known. These compounds have found significant utility as building blocks for the preparation of chiral ligands.
This chapter presents the progress achieved in phosphole chemistry from 1996, a period that has seen two notable developments in the area. The first is that the parameters governing the extent of the aromatic character of the phosphole ring are now well understood. This development, mainly due to theoretical studies, has been elegantly
1031
1032 Phospholes exploited to tune the reactivity patterns of phospholes and has made it possible to obtain ‘highly aromatic’ or ‘dearomatized’ derivatives by varying the nature of the P-substituent. Secondly, the chemistry of phospholes now approaches a degree of maturity comparable to that of their pyrrole and thiophene analogues, something that is reflected by the use of these P-rings for many diverse purposes (e.g., ligand design, materials synthesis, etc.) by an increasing number of research groups whose interests lie outside specialized phosphorus chemistry.
3.15.2 Theoretical Methods An understanding of the extent of the aromaticity associated with the phosphole ring is fundamental to rationalizing the properties and the reactivity of this heterocycle. In the CHEC-II(1996) chapter devoted to phospholes <1996CHEC-II(2)757>, L. D. Quin noted that ‘‘. . .the degree of cyclic electron delocalization remains unclear.’’ At that time, some studies were in favor of a certain degree of delocalization, while others ruled it out almost completely. This puzzling and contradictory state of affairs was probably due to the fact that, as demonstrated in recent years, the delocalization within the phosphole ring is rather subtle and strongly influenced by the nature of the P-substituents. The debate has been somewhat clarified over the last 10 years, with the electronic structure of the phosphole ring having been the subject of several high-level theoretical studies. Their conclusions, based on energetic, structural, and magnetic criteria, are that the aromaticity of the parent phosphole is in fact very low. Furthermore, the electron delocalization mainly involves a combination of interactions of the dienic p-system with (1) the P-lone pair (conjugation) and (2) the exocyclic P–R -bond (hyperconjugation). Varying the electronic and steric properties of the substituent at phosphorus allows the degree of electronic delocalization within the phosphole ring to be increased or completely suppressed. Some of these theoretical studies are discussed in more detail in Section 3.15.2.1. Section 3.15.2.2 describes calculations devoted to conjugated p-systems based on phosphole rings, which have quite recently appeared in the literature as promising materials for optoelectronic applications.
3.15.2.1 The Phosphole Ring X-Ray diffraction studies performed on a wide variety of phosphole derivatives have shown that the tricoordinate phosphorus atom has a pyramidal geometry (see Section 3.15.3.1). The fact that the nonplanar geometry (Cs symmetry) is more stable than the planar C2v situation was confirmed by theoretical calculations <1996JOC7808, 2000JOC2631, 2001CRV1229>. In fact, planar phosphole is a first-order saddle point on the potential energy surface, 16–24 kcal mol1 higher in energy than the Cs form depending on the level of theory. Several aromaticity indexes based on different criteria have been used to evaluate the aromaticity of phosphole having a Cs symmetry, that is, a pyramidal P-atom <2001CRV1229>. The aromatic stabilization energy (ASE) has been deduced from semi- <1998IC4413> (B3LYP/6311þG** ) and homo-desmotic reactions <1996JPC6194> (MP2/6-31G* ) <2006STC13> (B3LYP/ and MP2/6311þþG** ), including Equations (1) <1995AGE337, 1997JHC1387, 2002JOC1208> and (2) <2002JOC1333> (Scheme 1). The ASEs range from 0.5 to 7.0 kcal mol1, according to the equation and level of theory that are used, the most recent values being 3.20 and 5.87 kcal mol1. These values are low compared to those for the aromatic pyrrole ring (Table 1) <1995AGE337, 1996JA6317, 2002JOC1333>. Geometric criteria, such as the harmonic oscillator model of aromaticity (HOMA), and magnetic criteria <1995AGE337, 1998CPH1>, such as the widely used nucleus-independent chemical shifts indexes NICS(0) and NICS(1) <1996JA6317, 2001CRV1229, 2002JOC1333>, confirm the low degree of aromaticity (Table 1). For example, the NICS values for phosphole are much higher than those of pyrrole (Table 1) and only slightly inferior to those computed for cyclopentadiene <1996JA6317, 1998IC4413, 2002JOC1208>. Similarly, studies based on electron localization function data <1998CPH1, 2000CPH175> and differential ring proton NMR shielding <2000CPH1> are also consistent with the data from the other approaches. Together, these theoretical investigations clearly show that nonplanar phosphole is only poorly aromatic compared to pyrrole.
Scheme 1
Phospholes
Table 1 Calculated aromatic indexes for parent phosphole and pyrrole (Scheme 1, R ¼ H)
Phosphole Cs Pyrrole Phosphole Cs Cyclopentadiene
ASE (kcal mol 1)
HOMA
NICS(0)
NICS(1)
Reference
þ3.20 þ20.57 þ5.87
0.236 0.876
5.43 14.86 4.98 3.26
5.97 10.60
2002JOC1333 2002JOC1333 2002JOC1208 2002JOC1208
It was suggested as early as 1976 that the aromatic character of the phosphole ring results from hyperconjugation involving the exocyclic P–R -bond and the p-system of the dienic moiety <1976JA407>. This hyperconjugation is possible since the P-atom adopts a tetrahedral geometry and the exocyclic P–R bonds are relatively weak, a situation that is reminiscent of that for siloles <1998JCD3693>. Note that interactions between the endocyclic dienic * p* -orbital and the low-lying (P–R)-orbital have been proposed to account for the lowering of the lowest unoccupied molecular orbital (LUMO) level of the parent phosphole ring by about 0.2 eV compared to cyclopentadiene (calculations at the HF/6-61þG* //B3LYP/6-31þG* level of theory) <2001CEJ4222>. Interestingly, calculated aromaticity indexes based on geometric or magnetic parameters and isodesmic reaction energies revealed that planar phosphole (C2v point group) has a greater aromaticity than pyrrole <1994JA9638, 1995JPC586, 1996JPC13447, 1998IC4413, 2000JOC2631, 2002PCA6387>! For example, the NICS value of planar phosphole is 17.2 0.2 kcal mol1, while that of pyrrole is 14.7 kcal mol1 at the same level of theory <1998IC4413, 2000JOC2631>. This is due to the fact that the inherent p-donor capability of the P-lone pair is comparable to or even higher than that of N <1996AGE2236>. However, nitrogen can easily achieve an optimum planar configuration (sp2hybridization), favoring the interaction of its lone pair with neighboring carbon p-orbitals, whereas, for phosphorus, this planar geometry is more difficult to attain. In other words, the aromatic stabilization associated with planar phosphole is insufficient to overcome the planarization barrier of a tricoordinate P-atom (ca. 35 kcal mol1). It is noteworthy that the aromatic character of the planar form is responsible for the reduced P inversion barrier in phosphole (ca. 16 kcal mol1 versus 36 kcal mol1 for phospholanes) <1971JA6205, 1998NJC651, 2000JOC2631, 2002PCA6387>. Considering that the aromaticity in phosphole involves hyperconjugation of the exocyclic P–R -bond and the p-system and that the geometry of the P-atom dramatically influences the cyclic delocalization, it is not surprising that the electronic properties of phospholes can be strongly influenced by the nature of the P-substituent. The aromaticity indices of P-alkyland P-phenyl-phospholes are comparable with those of the parent phosphole (Table 2) <2000JOC2631, 2002JOC1208>. In contrast, introduction of methoxy or halogen substituents at the P-atom results in a decrease in the cyclic delocalization (Table 2). This behavior is not governed by the degree of pyramidalization of the P-center, but by the extent of the hyperconjugation involving the exocyclic P–R -bond and the endocyclic p-system <2002JOC1208>. Increasing the electronegativity of the P-substituents decreases the effectiveness of the hyperconjugation, due to a lowering of the P–R -bond energy, which results in an attenuation of the aromatic stabilization (Table 2) <2002JOC1208>. However, as stated by the authors in their conclusion, ‘‘hyperconjugation dominates, but cannot alone explain the overall variation in aromaticity observed: while conjugation is generally less important, it may become significant. . .’’ <2002JOC1208>. Indeed, it is difficult to outline a clear-cut strategy for tuning the aromaticity of phospholes via modification of the electronic properties of the P-substituent since the variations are generally relatively small (Table 2) and the delocalization involves subtle phenomena. In fact, phosphole represents an ‘aromatic borderline case’ <1998PA9912>. This is nicely illustrated by the fact that the isomerization stabilization energy (Equation 3), which is a good measure of aromatic stabilization <2002OL2873>, is only slightly negative for tricoordinate phosphole and becomes slightly positive upon oxidation of the P-center (Table 3) <2006OBC996>. Indeed, chemical modification of the P-atom of the weakly aromatic 3-phosphole affords 4-derivatives exhibiting limited antiaromatic character. Table 2 B3LYP/6-31G* magnetic (NICS) and energetic (ASE, in kcal mol1) aromaticity indexes for P-substituted phospholes <2002JOC1208>
ASE NICS
þ5.87 4.98
þ5.60 4.91
þ3.91 4.13
0.97 3.05
1.10 1.81
2.20 1.57
2.56 0.87
1033
1034 Phospholes Table 3 B3LYP/6-311þG* isomeric stabilization energy (ISE) in kcal mol1 <2006OBC996>
Y
Lone pair
O
S
CH2
NH
ISE
2.6
4.4
5.7
4.5
5.3
The second way to influence phosphole aromaticity is to reduce the pyramidal geometry of the P-atom. Theoretical studies revealed that the presence of p-acceptor groups such as BH2 on the P-atom affords an almost planar phosphole with extremely low inversion barriers (ca. 1–2 kcal mol1) <1995JPC586, 2000JOC2631>. The aromaticity of P–BH2 phosphole (NICS ¼ 9.1) lies in between that of nonplanar (NICS ¼ 5.7) and planar (NICS ¼ 16.9) P–H phosphole. This intermediate situation can be explained by two opposing factors: (1) planarization of the P-atom results in an increase in cyclic delocalization, but (2) the interaction of the P-lone pair with the vacant boron orbital somehow reduces the extent of this cyclic delocalization. It is noteworthy that a F-substituent on the P-atom considerably affects the electronic properties of phosphole due to a significant stabilization of the LUMO (ca. 1 eV) <2004CPL138>. An alternative means of flattening phosphole is to introduce bulky substituents at phosphorus. This concept has been illustrated by ab initio calculations, which show that the introduction of a 1-(2-tert-butyl-4,6-dimethylphenyl) substituent results in a flattening of the P-center with an associated increase of the C–C double bond lengths and a shortening of the P–C and C–C single bonds (Table 4) <1996JOC7808>. These changes in bond length are consistent with an enhanced endocyclic electron delocalization as indicated by the higher Bird aromaticity index (BI) of molecule 11 compared to those of P–H or P–Ph phosphole (Table 4) <1998JOM29>. For comparison, at the same level of theory (HF/631G* ), the Bird aromaticity indexes of furan and pyrrole are 46 and 67, respectively. The influence of bulky substituents upon the phosphole ring is maximized using the supermesityl group (derivative 12, Table 4). The resultant flattening at phosphorus and the consequential bond length equalization were supported by an X-ray diffraction study (Table 4) <1997JA5095>. Although the complete planarization of the P-atom is not achieved using the mesityl substituent, the Bird aromaticity index of molecule 12 (Table 4) is similar <1998JOM29> or even larger <1997JA5095> than that of furan. As expected, the presence of sterically demanding substituents on the P-atom considerably decreases the inversion barrier. For example, the calculated inversion barrier for mesitylsubstituted phosphole 12 is much smaller (10.98 kcal mol1) than that of the parent derivative (26.5 kcal mol1) <1998JOM29>. Finally, two other strategies for obtaining planar phospholes have been proposed. The first involves the incorporation of the P-atom into the bridgehead position of fused rings, as exemplified by phosphindolizine 13 (Scheme 2). According to B3LYP/6-311þG** calculations, the inversion barrier for derivative 13 is only 3.5 kcal mol1, which contrasts with 18.0 kcal mol1 for the parent phosphole at the same level of theory, while the sum of the bond angles about the tricoordinate P-atom reaches 325 <1998NJC651>. In spite of its nonplanarity, this compound exhibits a rather significant aromatic character as shown by geometric (BI, 75) and magnetic (NICS, 10.8) criteria for the five-membered ring. The second strategy involves the replacement of CH units of phospholes by P atoms <2001CRV1229>. Such changes result in a decrease in the inversion barrier of the tricoordinate P-center and an increase of the aromatic character according to magnetic and geometric criteria <1996JPC6194, 1996JPC13447, 1998IC4413>. These effects are attributed to alleviation of the ring strain in the planar form and the intermediate electronegativity of the P atom, which facilitates electron delocalization. For example, pentaphosphole 14 is planar and all the computationally-based measures of aromaticity show that it is more aromatic than pyrrole <1996IC4690, 1996JPC13447, 1998IC4413>. Unfortunately, HF/6-31G(d) calculations showed that dimeric structures are more stable than the monomer 14 by 28–35 kcal mol1 <1996IC4690>. In contrast, 1,2,4-triphosphole 15 is stable enough to be isolated and this compound was characterized by an X-ray diffraction study <1998AGE1083>. Remarkably, the ring is fully planar, with a sum of angles at the tricoordinate P-atom of 358.7 and equivalent P–C bond distances. The Bird aromaticity index of derivative 15 is 84 – a value higher than that obtained for thiophene <1998AGE1083>.
Phospholes
˚ sum of the bond angle at P in deg) and aromaticity indexes Table 4 HF/6-31G* calculated geometric parameters (a–c in A; (Bird index) a
b
c
SBA(P)
BI
1.821
1.332
1.471
291.3
33
1.817
1.333
1.473
300.1
34
1.802
1.339
1.463
314.9a
42
1.790
1.342
1.459
325.5b
46
Me
: P t
Bu
Me
But
11 Me
.. P
But
But
But
12 a
314.4 from X-ray structure <1996JOC7808>. 331.7 from X-ray structure <1997JA5095>.
b
Scheme 2
2H-Phospholes 17 and 3H-phospoles 18 are tautomers of 1H-phospholes 16 (Scheme 3). Derivatives 17 are versatile intermediates for the synthesis of 1,19-diphospholes and phospholyl anions, as well as a variety of other P heterocycles due to their cyclopentadiene-like reactivity in Diels–Alder reactions (see Section 3.15.5.1.2(i)) <2004ACR954, 2005AGE1082, 2005OL4511>. The relative stability of derivatives 16–18 depends on the calculation method used <2000JOC2631>. In the case of the parent systems (R ¼ H, Scheme 3), CCSD(T)/6-31G* calculations concluded that 2H-phosphole 17 is more stable than 1H-phosphole 16 by 6.0 kcal mol1 and more stable than 3H-phosphole 18 by 3.7 kcal mol1 <2003PCA5479>. A B3LYP/aug-cc-pVTZ study found that 17 is more stable
1035
1036 Phospholes than 16 and 18 by 2.2 kcal mol1 and 3.9 kcal mol1, respectively <2005CPH123>. Similar values were obtained at the B3LYP/6-311þG(d,p) level of theory (Table 5) <2004ACR954>. The [1,5]-sigmatropic shift is facilitated as a result of the significant interaction of the exocyclic P–R bond with the endocyclic p-system (hyperconjugation). This phenomenon probably contributes to the fact that the activation barrier for the isomerization is lower for phosphole (19.6 kcal mol1, Scheme 3) compared to pyrrole (44.7 kcal mol1) <2003PCA5479>. It is noteworthy that the transition state (TS) for the 2H-phosphole 17 ! 3H-phosphole 18 transformation is 30.6 kcal mol1 higher in energy than 2H-phosphole 17 (Scheme 3). These data suggest that the 1H-phosphole 16 ! 2H-phosphole 17 isomerization is a viable reaction pathway, while the 2H-phosphole 17 ! 3H-phosphole 18 transformation is much more difficult.
Scheme 3
B3LYP/6-31G* calculations revealed that the relative stability of 1H-, 2H-, and 3H-phospholes having methyl or vinyl substituents is similar to that observed with the parent derivatives <2003JPO298>. The influence of the nature of the migrating R group on the transformation of 1H-phosphole 16 to 2H-phosphole 17 has been studied in detail at the B3LYP/6-311þG(d,p) level of theory <2004ACR954>. These data clearly show that H migrates more easily than alkyl, vinyl, or ethynyl groups (Table 5). Note that the 1H-phosphole ! 2H-phosphole isomerization is thermodynamically strongly disfavored with an OH substituent (Table 5), due to the high strength of the P–O bond which stabilizes the 1H-phosphole relative to the 2H-phosphole <2004ACR954>. In the case of the methyl-substituted derivative, isomerization is difficult due to the high energy of the TS (Table 5). Note that all these theoretical conclusions agree well with the experimental observations, that is, H migrates at room temperature, aryl and alkynyl migration requires heating, while alkyl and alkoxy do not migrate below the decomposition temperature of phospholes <1981JA4595, 1993BSF843>. The ease of migration of the formyl group (Table 5) is attributed to the weakness of the P–C bond and the high degree of pyramidalization of the P-atom that favors the shift <2004ACR954>. The high migrating ability of the formyl group was exploited to prepare 3-acylphospholes (see Section 3.15.10.1), since in this particular case the TS for the 2H-phosphole ! 3H-phosphole transformation is quite low (14.30 kcal mol1, B3LYP/6-311þG(d,p)) <2005OL4511>. Table 5 B3LYP/6-311þG(d,p) relative energies (in kcal mol1) for the interconversion between 1H- and 2H-phospholes (16 ! 17, Scheme 3) <2004ACR954> R
E(2H-phosphole) E(1H-Phosphole)
E(TS) E(1H-phosphole)
H Me Vinyl Ethynyl OH CHO
3.4 2.1 0.4 1.4 16.1 3.7
18.3 37.7 25.5 30.0 46.7 8.3
Phospholes
Dimerization reactions through [4þ2] cycloadditions of 1H-, 2H-, and 3H-phospholes have been studied at the B3LYP/6-311þG(d,p) level <2003OM5526>. These reactions are concerted although the TSs are nonsynchronous in nature. The cyclodimerization of 1H-phospholes has much higher activation energies (19.4–29.1 kcal mol1) associated with them compared to the reactions involving their 2H- (2.3-13.7 kcal mol1) and 3H-tautomers (8.5–25.2 kcal mol1). The [4þ2] cycloaddition of 2H-phosphole across the CTP bond of a second molecule has a considerably lower activation energy barrier (7–13 kcal mol1) than that for the addition across the more stable CTC bond <2003OM5526>. This trend is also valid for 3H-phosphole. For all compounds, the endo-TS is slightly more stable than the exo-TS (ca. 2 kcal mol1) due to favorable secondary orbital interactions. In 1H-phosphole dimerization, endoproducts are more stable than their exo-counterparts by about 1 kcal mol1. In contrast, as observed for cyclopentadiene, the exo-products are more stable than their endo-isomers in the case of 2H- and 3H-phospholes <2003OM5526>. Interestingly, in the case of 2H-phosphole, the formation of dimers having a P–P bond is thermodynamically favored, a feature that has been established experimentally (see Section 3.15.5.1.2(ii)) <1983JA6871>. [4þ2] Cycloadditions of 1H-, 2H-, and 3H-phospholes with ethylene and acetylene have also been probed computationally at the B3LYP-6-31G* level <2003PCA5479>. A previous paper has clearly established that the B3LYP method with the 6-31G* basis set is more reliable than the HF and MP2 methodologies for modeling Diels– Alder reactions involving cyclic five-membered dienes (cyclopentadiene, pyrrole, phosphole, etc.) <2002PCA1627>. Symmetry considerations make the mechanism of the reaction synchronous for 1H-phosphole and nonsynchronous for 2H- and 3H-phospholes. Indeed, these P compounds act as dienes with an inverse electron demand on reaction with both dienophiles. The reaction exotherms are comparable for the three phospholes, but the activation energy calculated for 2H-phosphole is lower by at least 10 kcal mol1, relative to that for the two other tautomers, irrespective of the dienophile. A comparison of the activation barrier for sigmatropic shifts and Diels–Alder reactions clearly established that 1H-phosphole isomerizes into 2H-phosphole prior to undergoing cycloaddition reactions. This reaction pathway was proposed previously by Mathey following experimental observations <1981JA4595, 1983JA6871, 1989JOC4754> and is supported by a theoretical study performed at a lower level of theory <1993JOC5414>. The Diels–Alder reactions of methyl- or vinyl-substituted phospholes possess slightly higher activation energies than the reactions involving the parent phospholes <2003JPO298>. Theoretical examination of the reaction of 2H-phosphole with 1,3-butadiene showed that kinetic control leads to phosphanorbornene (2Hphosphole acting as a diene), while thermodynamic control leads to the bicyclo[4.3.0]cyclononadiene (2H-phosphole acting as a dienophile) <1996CJC839>. This result is consistent with the experimental results <1981JA4595>. A more recent study explored the Diels–Alder reactions of 1H-, 2H-, and 3H-phospholes with butadiene, considering the reactants as both diene and dienophiles at the B3LYP level using 6-31G(d) and 6-311þG(d,p) basis sets, augmented by single point CCSD(T)/6-31G(d) calculations <2005PCA9310>. Theoretical calculations have shown that the [4þ2] cycloaddition reaction between phosphaketene and 2H-phosphole is kinetically favored over the corresponding [2þ2] process by 6.2 kcal mol1 <1997JOM15>. Tautomerism in 1,3-diphospholes has been studied at the B3PW91/aug-cc-pVTZ level <2005CPL173>; the C2H 1,3-diphosphole derivative appears to be the most stable tautomer. The phospholide anion is a key building block for the synthesis of phosphole derivatives such as phosphaferrocenes or functionalized phosphinines (see Section 3.15.12). The structure of the phospholide anion 4 (Table 6), calculated at different levels of theory, shows significant bond length equalization. Geometry optimization at the B3LYP/6-311þG** level of density functional theory (DFT) affords P–C distances of 1.773 A˚ and C–C bond lengths of 1.396 and 1.418 A˚ <1998IC4413>. Calculations performed at the B3LYP/6-311þþG(3df,2p) level give P–C distances of 1.764 A˚ and C–C bond lengths of 1.393 and 1.413 A˚ <2005CEJ6829>. These values, obtained without the alkaline counteranion, are comparable to those given by an X-ray diffraction study of [Li(TMEDA)][5-C4Me4P] ˚ C–C, 1.396 and 1.424 A) ˚ (TMEDA ¼ tetramethylethylenediamine) <1989AGE1367>. Interestingly, (P–C, 1.751 A; 31 the P NMR chemical shift (þ73.9 ppm) calculated at the HF/6-311þG(2p,d) <2005CEJ6829> is in agreement with the experimentally observed value (þ77.2 ppm) recorded in THF with Liþ as the counteranion <1987TL5025>. All the usual aromaticity criteria show that the aromaticities of the phospholide and cyclopentadienide anions are similar (Table 6) <2002JOC1333>. The introduction of a bromine substituent at the P–C() carbon atom has a marginal effect on the structural parameters, but does induce a small decrease in the NICS(1)tot value (10.19) compared to that of the parent derivative (10.86) <2005CEJ6829>. The ordering of the highest occupied molecular orbitals (HOMOs) is pp > pc > p (in plane lone pair) <2005CEJ6829>. Notably, gradually increasing the number of P-atoms within the ring induces a small decrease in the extent of aromatic stabilization <1998IC4413>.
1037
1038 Phospholes
Table 6 Calculated aromatic indexes for phospholide and cyclopentadienide anions <2002JOC1333> ASE (kcal mol 1)
HOMA
NICS(0)
NICS(1)
þ23.12
0.730
13.41
11.03
þ22.05
0.736
13.99
10.25
Finally, three studies devoted to phosphole derivatives are noteworthy, but beyond the scope of this chapter. The first concerns the stereospecific cyclodimerization of phosphole oxide (PM3 semi-empirical and ab initio 3-31G* calculations) <1999JOM166>. The second is a DFT study of the reduction products of phospholium cations <2006PCP862>. The third is a structure and bonding study in the isolectronic series CnHnP5nþ <2004JCD2080>.
3.15.2.2 Extended p-Conjugated Systems Based on Phospholes The inherent properties of phospholes described above make these P-heterocycles appealing building blocks for the preparation of tailored conjugated systems. First, it is well established that conjugation is enhanced in derivatives built from monomer units that exhibit low resonance energies due to the competition between intraring delocalization (aromaticity) and inter-ring delocalization (backbone p-conjugation) <1997CRV173, 2005MI1197>. Hence, the low aromatic character of phosphole compared to other heteroles (thiophene, pyrrole, etc.) or benzene means that the use of phosphole units should considerably enhance backbone p-conjugation. Second, since the P-atom is intimately electronically coupled with the endocyclic p-system via hyperconjugation effects, it can be expected that chemical modification of the reactive P-center should modify the electronic properties of phosphole-based conjugated systems. These possibilities, which have been experimentally proved and exploited (see Section 3.15.12.4), have been the subject of several theoretical studies in the last few years. Polypyrrole (PPy) and polythiophene (PTh) are among the most widely studied p-conjugated organic polymers . This is due to their high conductivity upon doping, to their linear and nonlinear optical properties, and also to the rich chemistry of the underlying monomers, which allows for the preparation of numerous structural variants. Theoretical studies on polyphosphole (PPh) materials have been performed in order to investigate the influence of the heteroatom on the band gap using the ‘oligomer extrapolation technique’ . This approach relies on the fact that the properties of the high molecular weight polymers can be estimated from calculations on oligomers of increasing length (n ¼ 2–10) and subsequent extrapolation to infinite chain length. The band gaps of poly(heterole)s including poly(phosphole)s have been evaluated by this method on the basis of calculated HOMO and LUMO levels (DFT/hybrid study) by Lagowski and co-workers <1998SM177> and on vertical ionization energies (time-dependent density functional theory (TDDFT) study) by Ma et al. <2002MM1109>. Nguyen has used both these approaches to study a series of oligo(phosphole)s up to the octamer <2002PCP1522>. TDDFT predictions systematically underestimate the band gaps of polymers; however, there is a linear correlation between the TDDFT excitation energies and the HOMO–LUMO gaps for heteroles (Table 7) <2002MM1109, 2002PCP1522>. Both theoretical studies revealed the same general trends: (1) the excitation energies of oligo(phosphole)s decrease regularly with increasing chain length and (2) they are significantly lower than those predicted for the corresponding oligo(pyrrole)s or oligo(thiophene)s (Table 7). It is particularly noteworthy that the estimated band gap for poly(phosphole) is almost half that for poly(pyrrole) according to TDDFT <2002MM1109> and DFT <1998SM177> calculations. It would appear that the band gaps of oligo(cyclopentadiene) and oligo(phosphole) lie in the same range (Table 7, <2002MM1109>) as a result of the high polarizability of the endocyclic dienic system, which arises due to the lack of aromaticity of phosphole subunits <2002PCP1522>. Another useful parameter in understanding the properties of a homologous series of linear conjugated polymers is the effective conjugation length (ECL), that is, the number of monomer units at which saturation of conjugation occurs . The ECLs are slightly lower for poly(phosphole)s (ca. 21) than for poly(pyrrole)s (ca. 24) <2002MM1109>. Note that a DFT/hybrid study predicted that planarization of the P-atoms of oligo(phosphole)s
Phospholes
Table 7 TDDFT(B3LYP) calculated excitation energies (eV) for oligo(cyclopentadiene)s, oligo(pyrrole)s, oligo(phosphole)s (Ph)n, oligo(thiophene)s (Th)n, and the corresponding polymers (DFT HOMO–LUMO gaps in parentheses) n 1
2
3
4
5
1
5.04
3.40
2.67
2.27
2.00
0.98 (1.58)
5.73
4.40
3.87
3.33
3.07
1.95 (3.16)
4.66
3.29
2.65
2.28
2.03
1.08 (1.49)
5.76
3.87
3.23
2.81
2.56
1.52 (2.30)
results in a significant increase of the HOMO–LUMO gaps <2002JOM194>. These theoretical studies predicted that phosphole would indeed be a promising building block for the design of low-band-gap p-conjugated systems. Notably, the phosphorus atoms of oligo(phospholes) are chirogenic centers; thus the number of possible diastereoisomers rapidly increases on lengthening the chain. Consequently, since quaterphosphole 19 was prepared and structurally characterized by Mathey et al. in 1994 <1994AGE1158>, it has been the subject of several theoretical investigations. DFT calculations have predicted that an anti-conformation of the P-ring is preferential <2002MM1109, 2002JOM194>. Quite surprisingly, the (Ph)4 non-alt oligomer is predicted to be slightly more stable than its (Ph)4 alt counterpart; however, their band gaps and vertical ionization energies are almost comparable <2002MM1109, 2002JOM194>. The (Ph)4 alt isomer is planar, while the (Ph)4 non-alt derivative suffers from a rotational disorder with torsion angles of 15–20 <2002JOM194>. However, this distortion does not prevent the delocalization of the p-system over the entire molecule since the energy gap is not significantly altered for torsion angles below 30 .
The electronic properties of mixed derivatives having a central phosphole ring and different aromatic substituents (phenyl, 2-thienyl, 2-pyridyl) at the 2- and 5-positions have been studied theoretically by several groups. The phosphole ring and its aromatic 2,5-substituents are nearly coplanar (B3LYP/6-31þG* ) <2001CEJ4222>, with only a small deviation from coplanarity (14.4 ) being predicted for bis(2-thienyl)phosphole <2003PCA838>. The LUMO and HOMO of these compounds are p-orbitals and TDDFT calculations show that the ultraviolet–visible (UV–Vis) absorption spectrum basically results from p* p transitions <2003PCA838, 2006CEJ3759>. Analysis of the
1039
1040 Phospholes inter-ring distances and of the aromaticity indexes of the central phosphole ring shows that the most effective linear p-conjugation is achieved for the thienyl-capped derivative <2001CEJ4222, 2003PCA838>. This feature is ascribed to a strong orbital interaction between the HOMO of the phosphole ring and the HOMO of the thienyl substituent <2003PCA838>. It is of note that, in line with experimental results, the HOMO–LUMO gap of bis(2-thienyl)phosphole is lower than that of tert-thiophene (Table 8) <2001CEJ4222, 2005SM249, 2006CEJ3759>. Oxidation of the P-atom induces a stabilization of the HOMO and LUMO levels along with a lowering of the energy gap (Table 8). These data nicely illustrate that chemical modification of the P-center allows the electronic properties (e.g., reduction potentials, absorption spectrum, etc.) of these small phosphole-based conjugated molecules to be tuned <2001CEJ4222, 2003PCA838, 2006CEJ3759>. Table 8 HF/6-31þG*//B3LYP/6-31þG* LUMO and HOMO energies of 2,5-di(2-thienyl)-heterocyclopentadienes LUMO
HOMO
1.29
7.37
0.96
7.17
0.33
7.57
The possibility of through-bond and/or through-space interactions between the two di(2-thienyl)phosphole moieties of 1,19-biphosphole 20 has been investigated theoretically. B3LYP/6-31G* <2004JA6058> and B3LYP/6-31G** <2006CEJ3759> calculations reveal that (1) the C2-gauche-conformation is the more stable, probably due to a secondary orbital interaction between the HOMO and LUMO at one C–P atom of each conjugated subunit, and that (2) the barrier to rotation about the P–P bond is low. The most important result of this study is that the LUMO is the antibonding combination of orbitals and the LUMOþ1 is the bonding combination, a situation that is characteristic of through-bond coupling of two p-systems over an odd number of -bonds <1971ACR1>. This through-bond interaction via the P–P bridge results in a lowering of the HOMO–LUMO gap of compound 20 compared to di(2-thienyl)-1-phenylphosphole. This conclusion was confirmed by theoretical calculations coupled with a Raman spectroscopic study <2005SM249, 2006CEJ3759>. The absorption spectra of 1,19-biphospholes 20 and 21 simulated by TDDFT agree nicely with the experimentally determined data and reproduce the changes attributable to the through-bond –p conjugation <2004JA6058>.
Theoretical studies have also suggested that phospholes can be useful building blocks for the engineering of chromophores with nonlinear optical (NLO) properties. The archetypical molecular NLO-phores can be represented as D-(pbridge)-A, where D and A are donor and acceptor groups, respectively <2005ACR691, B-1997MI1>. The modification of the p-bridge is an efficient way to optimize the NLO response of such a chromophore; therefore, phospholes 22 and 23 bearing donor and acceptor groups at the 2- and 5-positions were investigated in this regard <1997JA6575, 2000JOC2631>. Donor/acceptor-substituted phosphole 22 exhibits classical properties, namely the phosphorus atom has a pyramidal geometry and the aromatic character of the heterole is similar to that of cyclopentadiene <2000JOC2631>. Due to the push–pull substitution pattern, significant delocalization of the endocyclic p-electron density over the entire system
Phospholes
occurs, as indicated by a combination of structural (Julg index) and magnetic (NICS) criteria <2000JOC2631>. These studies show that the p-electrons of the phosphole ring are readily polarizable, a feature crucial in achieving a high NLO response. For push–pull phospholes 23, and related chromophores based on other five-membered rings, NLO response factors have been computed <1997JA6575>. Chromophore 23 (x ¼ 6.17 1030 e.s.u.) exhibits a significantly greater NLO response than those of related derivatives featuring a pyrrole (x ¼ 5.59 1030 e.s.u.), a thiophene (x ¼ 5.49 1030 e.s.u.), or a cyclopentadiene (x ¼ 6.04 1030 e.s.u.) central ring. This large response for derivative 23 can be explained by comparing the aromatic character of the heterole bridges. However, the electronic density (i.e., the excess/deficiency of electrons) and (hyper)polarizability <2006PCA5909> of the p-bridge also play a crucial role. For example, derivative 24 exhibits a higher NLO activity than 25, showing that the P-ring acts as an auxiliary donor <1997JA6575>, as expected from the quite high electronic density found on the -P carbon atoms of the phosphole <2001CRV1229>.
The calculated structural parameters (B3LYP/6-31G* ) of dithieno[3,2-b:29,39-d]phospholes match the X-ray structural data closely <2005EJC4687>. Aromaticity indexes and molecular orbital shapes clearly show the delocalization extends over the entire molecule. Oxidation of the P-atom by oxygen or sulfur induces a significant lowering of the LUMO energy. These data indicate that the electronic properties of conjugated materials based on this type of phosphole building block can be tuned via modification at the P-center, a methodology that has been fully exploited experimentally <2004AGE6197, 2005EJC4687, 2006JCD1424>. The structure, magnetizability, and nuclear magnetic shielding tensors of dihydrophospholophosphole isomers 26a–d have been investigated <2006JCC344>. The [3,4-c] isomer 26a is considered to be the most aromatic on the basis of magnetic quantifiers. Its aromatic character is higher than that of phosphole.
3.15.3 Experimental Structural Methods 3.15.3.1 X-Ray Diffraction Analysis In Section 3.15.2, the significance of the degree of pyramidalization of the phosphorus center and the length of the two P–C bonds of phospholes in terms of assessing the extent of electronic delocalization within the heterole ring was discussed. Consequently, the experimental determination of these metric parameters by X-ray crystallography remains a key objective. An examination of the Cambridge Structural Database <2004CSR463> for the period 1996–2006 reveals that the structures of about 35 3 1H-phospholes have been determined by X-ray diffraction; this compares with only six prior to 1996. Representative examples are shown in Table 9. Largely irrespective of the structure and substitution pattern of the 3 1H-phospholes reported, the geometry about phosphorus retains considerable pyramidal character as indicated by Pang (typically 285–311 ) and the ‘out-of-plane’ angle <1996JOC7808>, defined as the angle between the P-substituent and the C(1)–P–C(4) ˚ are plane (64–76 ). Furthermore, in all but a few cases, the C(1)–P/C(4)–P (C–P) bond distances (1.796–1.824 A) comparable with C–P single bonds <1987J(P2)S1>, exhibiting little shortening that would be indicative of endocyclic delocalization. In contrast, the sterically encumbered 1-(2,4,6-triisopropylphenyl)- 27 <1997JA5095>
1041
1042 Phospholes Table 9 Structural parameters of 3-phospholes C
C
3
C
2
P
1
C
α X
Bond anglesa (deg) Compound
Me
A
B
C
D
B
C
4
P D
A
X
˚ Bond lengthsa (A) Panga a (deg) (deg) P–X P–C(1) C(1)–C(2) C(2)–C(3) Reference
Me 90.9 110.5 113.5
P CN
Ph
99.7 290.3
76.0
1.802 1.794
1.348
1.484
2001JOC755
91.7 109.6 114.2 107.4 306.9
65.0
1.830 1.791
1.353
1.468
2000JOM261
91.1 109.4 114.1 111.7 314.5 91.7 109.1 114.0 120.0 331.6
58.0 45.0
1.836 1.781 1.813 1.744
1.338 1.350
1.436 1.402
1997JOM109 1997JA5095
93.1 108.4 114.7 104.4 302.0
69.0
1.856 1.805
1.363
1.471
1999OM4205
64.0
1.669 1.798
1.339
1.473
2002EJO675
Me
Ph
Me
P Ph
Me
P R
R
R
27: R = Pri 12: R = But Me R
Me R
P
CN
Me R=
Si
Me
Me
Me
Me
P
89.6 111.3 113.7
99.9 306.1b
N Pr i
Pr i (Continued)
Phospholes
Table 9 (Continued) Bond anglesa (deg) Compound
mn
A
B
C
D
Bond lengthsa (A˚) Panga a (deg) (deg) P–X P–C(1) C(1)–C(2) C(2)–C(3) Reference
mn
P Ph
91.5 107.6 114.8 109.0 306.3
65.0
1.838 1.824
1.331
1.336
2001OM1014
90.5 110.7 113.7 103.2 299.1
69.0
1.829 1.807
1.355
1.479
1999CC345
90.9 110.2 114.9 104.3 299.3
70.0
1.828 1.818
1.357
1.465
2000AGE1812
89.4 110.1 113.0 104.2 296.3 113.0 113.9
71.0
1.842 1.821 1.815 1.325
1.403
1.471
2004OM3683
89.9 111.9 113.2 100.1 289.5
76.0
1.894 1.821
1.408
1.468
2005CC1592
89.4 113.3 111.6 104.3 295.2
72.0
1.867 1.811
1.418
1.494
1999JA3357
89.3 111.3 113.7 103.8 293.0
73.0
1.837 1.819
1.384
1.440
2004AGE6197
mn = menthyl
Ar
Ar
P Ph N
Ar =
S
Ar =
P Ph
P
R
R P
R
RR R = Pri S
R
S
P Ph
(Continued)
1043
1044 Phospholes
Table 9 (Continued) Bond anglesa (deg) Compound
R
A
R R
B
C
D
Bond lengthsa (A˚) Panga a (deg) (deg) P–X P–C(1) C(1)–C(2) C(2)–C(3) Reference
R
P
P
Ph
Ph
90.3 112.5 113.4 105.0 300.8
68.5
1.823 1.793
1.330
1.474
1996CC2287
R = Me a
The average for some parameters is quoted. The N atom is planar (ang 360 ).
b
and 1-(2,4,6-tri-tert-butylphenyl)-3-methylphospholes 12 <1997JOM109> exhibit short C–P bond distances (1.781 ˚ respectively), in conjunction with small values of , 58.0 and 45.0 , respectively. These metric parameters and 1.744 A, are consistent with considerable flattening at phosphorus and consequent endocyclic electronic delocalization. Only a comparatively small number of 1,19-diphospholes have been structurally characterized (selected examples in Table 10). Both 2,3,4,5-29,39,49,59-octaphenyl-1,19-biphosphole 28 <2000CC1037> and 2,5-29,59-dithienyl-1,19diphosphole 29 <2004JA6058> adopt a trans-configuration in which the two phosphorus lone pairs are orientated ˚ are recorded in both cases (Table 5). Each of away from one another. Relatively short C–P distances (1.798–1.807 A) the phosphorus atoms assumes a distorted pyramidal geometry as expected, while the bond distances and angles of the butadienyl rings are unremarkable and comparable with regular 1H-phospholes. As a result of significant polarization within the P–P bond, the unsymmetrical P–P-bonded phosphole-1,3-diazaphosphole 30 exhibits a long P–P bond ˚ and greatly reduced bond angles (81.4 ) about the P atom of the phosphole component <2004AGE4801>. (2.484 A) Table 10 Structural parameters of selected 1,10-biphospholes ˚ Bond lengthsa (A)
Bond anglesa (deg) Compound
A
B
C
D
Panga (deg) a (deg) P–P
P–C(1) C(1)–C(2) C(2)–C(3) Reference
Ph Ph
Ph P:
Ph
Ph
:P
Ph
91.2 110.2 113.8 103.6 298.4
70.5 2.205 1.798
1.361
1.470
2000CC1037
90.8 112.3 114.2 100.8 293.7
74
1.362
1.459
2004JA6058
Ph Ph
28
S P: S
:P
S
2.224 1.807
S
29 (Continued)
Phospholes
Table 10 (Continued) Bond lengthsa (A˚)
Bond anglesa (deg) Compound
A
B
C
D
Panga (deg) a (deg) P–P
P–C(1) C(1)–C(2) C(2)–C(3) Reference
P:
:P
89.4 112.2 113.1
97.82 285.07
79
90.2 111.4 113.4 95.0c 108.3c 113.9c
92.3b 274.8b
95b
90.5 111.2 113.5
81.4 253.4
P: Cl P
2.250 1.824
1.407
1.464
2001CJC1321
2.191 1.827 1.411 1.777c 1.402c
1.469 1.484c
1996PS227
102
2.484 1.788
1.446
2004AGE4801
74d 66d
2.214d 1.807d 1.366d
1.468d
1996AGE1125
[Al 2 Cl 7 ]
Et Et
Et P mes
Et P N
1.370
mes N
30 Me Me
P
P
Na
P
Na
Ph Ph
91.9d 109.5d 114.4d 105.1d P
Me Me 2DME a
The average for some parameters is quoted. 1H-Phosphole fragment only. c 4 1H-Phosphole ring. d Biphosphole only. b 3
CN 4 1H-phospholes make up the largest class of structurally characterized phospholes and encompasses their metal complexes, 4,4- and 4,5-derivatives (Table 11). The metric parameters associated with these ring systems are consistent with structures adopting a tetrahedral geometry at phosphorus, something generally accompanied by a slight widening of the endocyclic CPC angle denoted A. A number of molecular structures for phospholes with CNs greater than 4 have been determined (Table 12). In addition to the features described in CHEC-II(1996) <1996CHEC-II(2)757> for these types of compounds, of
1045
1046 Phospholes
Table 11 Structural parameters of selected CN 4 Phospholes ˚ Bond lengthsa (A)
Bond anglesa (deg) Compound
Ph
A
B
C
P–C(1)
C(1)–C(2)
C(2)–C(3)
Reference
93.4
108.7
114.5
1.802
1.345
1.503
2000JOM261
93.9
108.5
114.5
1.790
1.350
1.496
2005JCD92
94.5
108.3
114.3
1.779
1.368
1.486
2006PCP862
93.0
109.8
113.5
1.796
1.405
1.482
2004JCD1610
92.8
108.9
114.3
1.797
1.334
1.504
2000T85
91.4
110.2
114.0
1.803
1.380
1.460
2005EJC4687
91.4
109.6
114.4
1.819
1.353
1.487
2001CEJ4222
Me
Ph
Me
P S
Ph
Ph OH Ph
P Cy
PF6 Cy
Me
Me
P
I Me
P pTos
N
Ph
R
R R
R
P Ph
P O
Ph
O
R = Me
S
R
S
R
P Ph
S
R = SiMe 3
P
S Ph a
S W(CO)5
The average for some parameters is quoted.
Phospholes
Table 12 Structural parameters of 5 - and 6-phospholes ˚ Bond lengthsa (A)
Bond anglesa (deg) Compound
P
N
P
B
C
P–C(1)
C(1)–C(2)
C(2)–C(3)
Reference
88.8
111.8
113.6
1.832 1.815b 2.358c
1.350
1.481
2001AGE228
84.9d
113.7d
113.8d
1.929d
1.404d
1.473d
Ph N Pd
Pd N Ph
A
N
SbF6
31
P
2000MI191
P
94.4e
109.1e
113.7e
1.777e
1.406e
1.477e
32 a
The average for some parameters is quoted. P–CPh distance. c P–Pd distance. d Anion. e Cation. b
particular note is the structure of the complex 31 that contains a very rare example of an unsupported 2-bridging phosphine unit, in which the phosphole spans two palladium centers in a symmetrical fashion. The structure of the so-called Hellwinkel’s salt 32 has been determined, which contains both phosphole moieties with both 4- and 6-coordination, with the five-membered rings of the anion showing considerable deviation from less sterically congested systems <2000MI191>. Molecular structures of phospholide anions with both CN 2 and 3 have been determined (Table 13). In both cases, there is considerable structural evidence of significant electronic delocalization within the heterocyclic ring system; the P–C is shortened to ca. 1.77 while the C–C and CTC bond lengths become more comparable. It is noticeable that for the -bound CN 3 phospholides, the phosphorus atom is very flexible and may tolerate a number of different bond angles. The structure of the nickel carbonyl complex 33a is significant since the P-center is truly two coordinate with no close contacts. Complex 33b presents an unusual structure in which two palladium centers are bridged by a phospholyl moiety. The phosphole ring is near-planar, with all bond angles and distances being comparable to that of related 3-phospholes <2003CEJ3785>.
1047
1048 Phospholes Table 13 Structural parameters of 2- and 3-phospholide anions Bond anglesa (deg) Compound
A
B
C
89.9
112.8
112.2
PMe3
92.1
108.2
115.3
Sn
Bu t
89.8
112.2
112.9
P
t
92.8
111.5
112.2
90.8
111.0
113.4
88.8
114.5
112.5
D
Panga (deg)
˚ Bond lengthsa (A) P–X
P–C(1)
C(1)–C(2)
C(2)–C(3)
Reference
1.779
1.423
1.436
2004EJI3476
P Fe P
But
Ni P
333.6
2.219
1.803
1.367
1.426
2005CEJ5381
233.1
2.739
1.784
1.384
1.442
2003ZFA2398
1.740
1.434
1.437
1999EJI1169
1.793
1.357
1.472
2003CEJ3785
1.786
1.409
1.421
2005OM5369
But
Bu t P
Bu
t
Bu
71.6
Li Ph2P
PPh2
P
Ni(CO)3
Ni(CO3 )
33a
P
N Pd Cl
N Pd
L Ph
2.197 2.285
Cl
33b: L = PPh 3
Fe S a
P
S
The average for some parameters is quoted.
There remain no X-ray crystallographically determined structures of 2H- and 3H-phospholes as a result of their low stability. A number of structures of 2,3- and 2,5-dihydrophospholes have been determined since 1995 and are collected in Table 14, with most possessing a tetrahedral four-coordinate phosphorus center. Although a variety of structures of coordination complexes containing the phosphole moiety have been determined, they are beyond the scope of this chapter.
Phospholes
Table 14 Structural parameters of selected 2,3- and 2,5-dihydrophospholes ˚ Bond lengthsa (A)
Bond anglesa (deg) Compound
Me Br
A
B
C
92.1
106.9
92.1
D
Panga (deg)
P–C(1)
C(1)–C(2)
C(2)–C(3)
Reference
116.4
1.842
1.487
1.347
2002EJO675
106.8 113.1
114.0 113.9
1.817 1.831
1.348 1.513
1.460
2004OM1961
95.7
112.3 105.8
117.5 108.4
1.831 1.755
1.354 1.565
1.525
2001MC98
94.5
104.2
106.1
1.818
1.501
1.348
2004OM3683
89.3
112.5 105.9
116.4 105.8
1.825 1.870
1.349 1.870
1.565
1997OM2370
Me Br
P
NPr i2
O
O EtO
P S
Ph
NMe2 P O
Ph CH2Ph
P Ph
O
Ph Ph
Ph
P
Ph
101.8
292.9
Ph a
The average for some parameters is quoted.
3.15.3.2 NMR Spectroscopy 3.15.3.2.1 31
31
P NMR spectroscopy
P NMR spectroscopy remains a powerful tool not only for the identification of phosphorus-containing compounds of all types, but also for monitoring their reactions; the study of phospholes is no exception. In general, the 31P NMR signals of 3 1H-phospholes are found to occur at higher frequency to those of comparable saturated tertiary phosphines (e.g., 1-methylphosphole 8.7 ppm, 1-phenylphosphole 6.4 ppm compared with Me3P 62.0 ppm and Ph2PMe 20.0 ppm). The 31P NMR chemical shifts of phospholes are dependent upon a number of factors, which include: (1) the nature of the substituents at phosphorus; (2) its CN; (3) the presence of conjugating, halo, and heteroatom groups on the butadienyl fragment; and (4) benzo fusion. Notably, it has become apparent that caution should be exercised in linking any changes in 31P NMR chemical shift of a particular phosphole with the degree of aromaticity exemplified by that compound (see Section 3.15.2.1). Efforts have been made to enhance the aromaticity of these P-heterocycles by the introduction of sterically demanding groups at their periphery in order to ‘flatten’ the endocyclic P-atom, which should be accompanied by a shift to higher frequency of the phosphorus resonance. Although ‘flattening’ has been observed for the bulky P-aryl phospholes 12 and 27 in the solid state by X-ray crystallographic studies, only very small variations in 31P NMR chemical shift have been observed <1997JA5095>.
1049
1050 Phospholes Detailed and comprehensive accounts of the influence of all of the various factors described above upon the 31P NMR spectra of phospholes have been presented previously by Quin in CHEC-II(1996) <1996CHEC-II(2)757> and elsewhere <2001PCHC307, 2006COR43>. Consequently, only representative examples of data from more recent compounds are presented here (Tables 15 and 16). Without exception, the new examples presented here all fit with the previously reported trends in chemical shift. Since the use of 31P NMR spectroscopy is now essentially routine for the study of phospholes, data for individual compounds of interest have been quoted throughout this chapter. Hence Tables 15 and 16 are not exhaustive in their coverage, but serve to illustrate how 31P NMR chemical shifts vary with differences in structure for various classes of phosphole.
31
Table 15
P NMR chemical shifts of CN 3 phospholes Pa (ppm)
Compound
P N
31
Reference
þ1.8
1997AGE98
R ¼ Me þ11.0 R ¼ Et þ15.7 R ¼ nPr þ9.7
2000JOM261
0.2
2003OM1580
7.0 (phosphole P)
1998OM2996
32.0
1998OM2996
0.4
1997JA5095
þ12.7
2000AGE1812
Ph Ph P N
R R Ph P N Ph
PA PPh2
P N
P
S S
P Ph (Continued)
Phospholes
Table 15 (Continued) Pa (ppm)
Compound
Me3Si
SiMe 3
P
31
Reference
þ77.6
1999OM4205
þ77.0
1996PS309
þ22.6
1996BSF33
R ¼ CH2Ph þ15.2 R ¼ CH2CO2Et 1.0 R ¼ 1/2 o-C6H4(CH2Br)2 þ19.4 (d4-MeOH)
2002OL1245
Br
Ph Ph
Ph Ph
P Cl
P
Ph
Ph
Ph
O
O P
HO
OH
R
PA
PB
9.5 (PA) 1 JPP ¼ 292 Hz
1997JOM75
3
PA
17.3 (PA) 1 JPP ¼ 281 Hz
1997JOM197
21.2 (d8-THF)
2001OM5513
þ7.8 (PA)
2005SOS1097
PBEt 2
Li
P
PB
PA
P P
(Continued)
1051
1052 Phospholes
Table 15 (Continued) Pa (ppm)
Compound
S
S
Me 3Si
R
O
Ph
P
þ96.5, þ97.6
2001JOC755
0.5
1999OM4765
Ar ¼ 2-thienyl 0.5 Ar ¼ phenyl 13.6
2004JA6058
þ127.6, þ129.4 Mixture of conformers
2003HAC360
þ0.0
2004OM3683
þ4.2
2004OM3683
Ph
Ph Ph Ph
2003MIS279
Ph
O P
R ¼ Ph 12.5 R ¼ 4-But-C6H4 25.9 R ¼ But þ9.7
P
O
Ph
Reference
SiMe3
P
P
31
Ph
Ar P Ar
Ar P Ar
MeO
P
MeO
Cl
P Ph
P Ph
(Continued)
Phospholes
Table 15 (Continued) Pa (ppm)
Compound
31
Reference
14.3
2002MI245
þ23.1 (PA) 1 JPP ¼ 188 Hz
2004AGE4801
P Fe P
mes
Et Et
N PB N
PA Et
mes
Et
a
Chemical shifts are those obtained in CDCl3 unless stated otherwise.
31
Table 16
P NMR chemical shifts of phospholes with CN 2, CN 4, CN 5, phosphole anions, and 2H-phospholes 31
Compound
P a(ppm)
Reference
þ46.9
2002EJO675
þ53.4 (not isolated)
1996JOC7801
Oxides
Ph
O P N
Ph
P O
O N O PB N
þ51.3 (PA) 1 JPP ¼ 35 Hz
PA O
2000J(P1)1495
O
S S
þ42.3
2001CEJ4222
P O
Ph
(Continued)
1053
1054 Phospholes
Table 16 (Continued) P a(ppm)
Compound
P
Ph
O
31
Reference
þ37
2004OM3683
Sulfides and selenides O
Ph Ph S
þ46.1
Ph
P
2005OL4511
Me
R1 R
S
R1 ¼ H; R ¼ Me R1 ¼ H; R ¼ Ph R1 ¼ Br; R ¼ Me R1 ¼ Br; R ¼ Ph
P N
R
P Ph
P S
S
R
P
Ph
Two diastereomers þ47.9 (major), þ48.0 (minor)
2001JOM105
R ¼ Me þ68.2 (single diastereomer) R ¼ Ph þ75.8 (49%), þ69.3 (51%)
2002EJO675 2001CEJ4222
R
P S
2002EJO675
Ph
RR
N
þ65.5 þ64.5 þ63.0 þ63.6
S
N
Ph
Br
P S
Ph
þ51.3
2000J(P1)1519
þ51.2
2003HAC326
þ64.0
2005JOM450
Ph
Ph
P S
Ph
S P S
P O O (Continued)
Phospholes
Table 16 (Continued) P a(ppm)
Compound
S
P
E
S
Ph
Salts PhN
Reference
E ¼ S þ52.6 E ¼ Se þ41.5 (1JSeP ¼ 372 Hz)
2001CEJ4222
R ¼ R1 ¼ CO2Me þ31.6, þ29.2 (2JPP ¼ 34 Hz) R ¼ CO2Me; R1 ¼ H þ29.8, þ28.4 (2JPP ¼ 38 Hz)
2002CEJ3872
þ64.1 (d6-acetone)
2005JCD92
R
O Ph P B Ph
31
R1
PA Ph
Ph
Ph OH Ph
PA Cy
Cy
PF 6 CN 4 phospholes
(OC)5W
P
25.3
2001AGE1253
þ17.8
2004JCD1610
þ29.5 (CD2Cl2)
2003CEJ3785
Ph
P pTos
N
Ph
PA
N Pd Cl
N Pd
L Ph
Cl
L = PBPh3 Phosphole anions and 2H-phospholes
TMS
TMS
P
þ145 (THF)
2002OL1245
Li
(Continued)
1055
1056 Phospholes
Table 16 (Continued) P a(ppm)
Compound
31
Reference
þ190.2 (2JPP ¼ 88 Hz)
2001EJI2763
53.0 (d6-acetone)
2004OM3683
63.4 (CN 2 P)
2001OM3913
þ62.6 (C6D6)
2001OM3453
PA PBPh3
P Mn(CO)3
R P R
Fe
Ph2P R= (–)-menthyl Me
Ph
Me Me
P Zr P
Me Me
Ph
Me
rac
CN 2 phospholes
P
þ225
1999TL5271
þ106.7 (d6-acetone)
2004JCD1610
CN 5 phospholes
P O O a
Chemical shifts are those obtained in CDCl3 unless stated otherwise.
Since 1996, only a few reports of the use of solid-state 31P NMR spectroscopy for the study of phospholes have appeared, the emphasis having largely been on the identification and characterization of phospholes in solution. However, a detailed DFT investigation of the one-bond phosphorus–phosphorus indirect nuclear spin–spin coupling tensor, 1J(31P,31P), of the phosphole tetramer 34 has been reported <2000CJC118, 2004JPC(A)4895>. The calculated and experimental <1983JCS(D)841, 1997MR366> values are in very good agreement. The sign of the PA–PB coupling constant was assigned through detailed analysis of spinning side bands.
Phospholes
PA
PA
PB
δ (CP MAS) = +1.7 ppm 1
PB
J (31 P, 31 P) iso = –362 Hz (expt.); –411 Hz (calc.)
34 A systematic solid-state study of the magic angle spinning (MAS) 31P NMR spectra of 5-phenyldibenzophosphole 35a (E ¼ lone pair), its chalcogenides 35b–d, M(CO)4(35a)2, and M(CO)5(35a) (M ¼ Cr, Mo, and W) complexes has been undertaken and reports their shift tensors <1996IC3904>. The spectra for powdered samples of 35a and its corresponding CN 4 compounds all exhibit the number of isotropic peaks consistent with the number of phosphorus environments in their asymmetric units as determined by X-ray crystallography. The trends observed in these solidstate NMR data mirror largely those found for the same and related species in solution and are summarized in Table 17. Similarly, the NMR data recorded for the various group 6 metal carbonyl complexes of 35a again parallel those of these compounds in solution and agree well with data obtained from X-ray diffraction studies. In some cases, 1 JMP coupling constants were discernible, despite long quadrupolar relaxation times and the broad 31P peaks; again, these data are comparable to those obtained in solution for related systems. Table 17 Solid-state 31P NMR data for compounds and complexes of 35a
Ph P E
35a: E = l.p. 35b: E = O 35c: E = S 35d: E = Se 1
Compound
iso (ppm)
35a 35b 35c 35d Cr(CO)5(35a) Mo(CO)5(35a) W(CO)5(35a) cis-Cr(CO)4(35a)2 cis-Mo(CO)4(35a)2 cis-W(CO)4(35a)2
17.1, 18.3 þ31.1 þ40.4 þ29.3, þ28.2 þ46.8 þ28.0 þ7.7 þ52.4, þ43.8 þ33.3, þ24.5 þ14.4, þ3.7
JMP (Hz)
732, 765 120 128, 128 216, 222 95, 216
Note that insoluble mixed thiophene–phosphole conjugated polymers have been characterized by MAS 31P NMR spectroscopy <2006AGE6152>. The chemical shifts recorded in the solid state for polymers having 3-phosphole, 4phosphole sulfide, or phosphole–Au(I) moieties compare well with those recorded in solution for the corresponding molecular monomers.
S P
S ClAu
δ
31
S P
S Ph
P = +39
ClAu
δ
31
n
Ph P = +45
1057
1058 Phospholes 1
3.15.3.2.2
H NMR spectroscopy
1
The use of H NMR spectroscopy in the study of phospholes with protons attached directly to the heterocyclic ring skeleton has been extensively described in CHEC(1984) and CHEC-II(1996). The assignment of spectroscopic data for compounds that have been reported over the last decade can generally be interpreted in terms of these previous observations.
3.15.3.2.3
13
C NMR spectroscopy
As is the case with 1H NMR spectroscopic data, the 13C NMR spectra of phospholes reported since 1996 can be largely accounted for in terms of the previously established trends described in detail in CHEC-II(1996) <1996CHEC-II(2)757>, with both chemical shifts and 31P–13C coupling constants giving important structural information. It should be noted that 13C NMR spectroscopy gives little insight into the degree of electronic delocalization within the phosphole ring, but is considerably more sensitive to steric constraints imposed by bulky pendant groups, which in turn reflect the gross molecular structure. For example, Quin and co-workers have observed 31 P–13C coupling constants for 12 (Figure 1) that are indicative of hindered rotation of the P-substituent <1997JA5095>. The different chemical shifts observed for the pairs of ortho- and meta-carbon atoms of the supermesityl ring clearly indicate blocked rotation about the P–Cipso bond and the orthogonal disposition of the two ring systems (Figure 1). This is supported by the stereospecific magnitudes of the two- and three-bond P–C coupling constants observed for the aryl substituent: (1) 2JPC is larger where the dihedral angle is 0 between the P-lone pair and ortho-C-2 and (2) 3JPC is greater for C-3, situated closer to the P-lone pair, than for C-5. A similar type of effect has been noted for 1-(1-methyl-2-pyrrolyl)-3,4-dimethylphosphole 36 (Figure 2), where a large 2JPC coupling was observed for C-2, something that has been attributed to the adoption of rotameric form 36a <1998OM2996>.
P C6
C2 C3
C5
12
Cx
δ13C (ppm)
JPC (Hz)
C2 C3 C5 C6
158.6 122.9 119.6 151.9
12.3 9.1 0 2.2
Figure 1 Selected 13C NMR chemical shifts and JPC coupling constants for 12.
P
C2
P
N
36a
N C2
36b
Figure 2 Rotameric forms of 1-(1-methyl-2-pyrrolyl)-3,4-dimethylphosphole 36.
As is illustrated in Section 3.15.12.4 the use of phospholes as building blocks of extended p-conjugated materials is an area of considerable interest due to the ease with which the photophysical properties of the various materials may be tuned at the molecular level by exploiting the now well-established reactivity and synthetic flexibility of these P-containing heterocycles. Representative 13C NMR data are presented for a number of compounds in Table 18.
3.15.3.3 Mass Spectrometry Mass spectrometry is a useful analytical tool for the analysis of phospholes, the heterocyclic P-containing ring usually showing good stability under electron impact ionization conditions, with molecular ions generally being observed. As with the mass spectrometric study of conventional heterocyclic ring systems, the precise nature of the fragmentation and ions observed is dependent on the actual molecular structure. There have been no notable developments in this area over the last decade and the reader is directed to CHEC-II(1996) <1996CHEC-II(2)757> for a discussion of this
Phospholes
topic. However, for reference, Quin et al. have provided a detailed analysis of the mass spectrometric data obtained under electronic impact conditions for 11, its corresponding dimer 37 and cycloadduct 38; as expected from previous studies, a peak for the molecular ion is obtained for each compound <1996JOC7801>. Table 18 Selected 13C NMR spectroscopic data for endocyclic C and C carbon atoms of certain p-conjugated phosphole compounds 13C PC (1JPCHz)
13C PC (2JPCHz)
Reference
125.5 (0)
155.4 (9.3)
1996BSF33
S
137.5 (0)
144.4 (9.1)
2000AGE1812
S
125.5 (19.6)
148.7 (15.6)
2003JA9254
S
131.1 (19.3)
144.2 (0)
2004JA6058
Compound
P
S
Ph
P
S ClAu
Ph
S P S
P
S
31
Ar
O
Ar
P
O P O
P Ar O
N
P Ar
Ar = Ph
O
11
37
38
M + : 300 (92%)
M + : 632 (13%)
M + : 489 (6%)
3.15.3.4 UV–Vis and Fluorescence Spectroscopy UV–Vis spectroscopy has been intensively used in the last years to elucidate the electronic properties of p-conjugated oligomers and polymers incorporating phosphole rings. The first series that was investigated in detail includes 2,5di(hetero)arylphospholes, which show one strong absorption in the UV–Vis region (Table 19). The absorption and emission maxima of these derivatives are influenced by both the nature of the 2,5-substituents and chemical modifications of the P-atoms <1999CC345, 2001CEJ4222, 2000AGE1812>. A bathochromic shift was recorded upon replacing
1059
1060 Phospholes
Table 19 Photophysical data for mixed thiophene–phosphole derivatives (max and em in nm, quantum yield determined using fluorescein as standard) <2003OL3467> max
log "
em
354
4.20
466
0.14
390
4.02
463
0.011
412
3.93
501
0.05
432
3.98
548
0.046
428
4.10
544
508
4.26
615
550
4.42
12.9
0.002
Phospholes
the phenyl groups either by 2-pyridyl (max ¼ 36 nm) or 2-thienyl rings ( max ¼ 58 nm) (Table 19). It is interesting to note that the value of max recorded for 39c (412 nm) is considerably more redshifted than those of related 2,5-dithienylsubstituted pyrrole (322 nm) or thiophene (355 nm) <1998JOC7413, 1993JA887>, and very close to that of the 2,5dithienyl-derivatives based on a nonaromatic silole unit (420 nm) <1998OM4910>. Since theoretical calculations have clearly established that UV–Vis absorptions result essentially from p* p transitions <2003PCA838, 2006CEJ3759>, these data show that phospholes are valuable building blocks for the construction of co-oligomers exhibiting low HOMO–LUMO separations. Varying the nature of the 2,5-substituents is also an effective way of tuning the emission behavior of phosphole-based p-conjugated systems. A blue-green emission is observed for diphenyl- 39a and di(2pyridyl)-phospholes 39b, whereas the emission of di(2-thienyl)phosphole 39c is redshifted (Table 19). The quantum yields also depend on the 2,5-substitution pattern, the most efficient fluorophore being the 2,5-diphenylphosphole 39a ( ¼ 14%, Table 19). This value is remarkable as chromophores featuring 3-P-centers usually exhibit almost no fluorescence as a result of quenching by the P-lone pair <2005TCC127>. The chemical modifications of the P-center have a profound impact on the optical properties of the phosphole-based conjugated systems. For example, upon oxidation or coordination of 3-phosphole 39c to give the derivatives 40 and 41, respectively, a red shift in their absorption and emission spectra is observed (Table 19). It is also noteworthy that the quantum yield of the gold complex 41 is much higher than those of the corresponding phosphole 39c or its thioxoderivative 40 (Table 19) <2003JA9254, 2006JA983>. Another interesting observation is that the quantum yields for 4thioxophospholes are higher in the solid state than in dilute solution <2006JA983>. This behavior is probably due to the steric protection provided by the substituents (Ph, S) of the tetrahedral P atom, which precludes a close cofacial organization of these P-chromophores in the solid state. This hypothesis is also supported by the fact that the UV–Vis and fluorescence spectra of 4-thioxophospholes in solution and as thin films are very similar. In marked contrast, the solution and thin-film emission spectra of the gold complexes (i.e. 41, Table 19 and its 2,5-diphenyl analogue) are different. Two broad emission bands are observed for the thin films, one at a wavelength similar to that of the solution spectrum, and a second, which is considerably redshifted. These low-energy luminescence bands observed in the thin films most likely arise from the formation of aggregates. This dichotomy shows that the presence of reactive phosphorus atoms affords a unique approach for tuning the electronic structures of p-conjugated materials at the molecular level. The evolution of optical properties with increasing chain length is one of the central principles used in the understanding of the characteristics of novel p-conjugated systems . Hence, this feature has been investigated for ,9-(thiophene–phosphole) oligomers 42 and 43 (Table 19) <2003OL3467>. The longest wavelength absorptions are gradually shifted to lower energies with increasing chain length, reflecting the decrease in the HOMO–LUMO gap upon elongation of the chain of the ,9-(thiophene–phosphole) oligomers (Table 19). Notably, the max value for the CN 3 phosphole-based analogue of derivative 42 (490 nm) is considerably redshifted compared to that of quinquethiophene (ca. 418 nm), again showing that replacing a thiophene subunit by a phosphole ring induces an important decrease in the optical HOMO–LUMO gap. The UV–Vis spectra of thienyl- and phenyl-capped 1,19-diphospholes differ notably from those of the corresponding phospholes <2004JA6058>. They show several bands with one redshifted broad shoulder. These data, which are well reproduced by TDDFT calculations, support the presence of through-bond –p-conjugation in such 1,19diphospholes <2004JA6058, 2006CEJ3759>. The absorption spectra of homopolymers having derivatives 39c <2006AGE6152>, 40 <2001CEJ4222>, 41 <2006AGE6152>, and 42 <2003OL3467> as repeating motifs are considerably redshifted compared to those of their monomer units. Furthermore, as observed for the corresponding monomers, their optical properties depend on the nature of the P-moiety. Biphenyl–phosphole copolymers, obtained as a 85/15 mixture of 2,4- and 2,5-connected isomers (see Scheme 51, Section 3.15.9.2), exhibit a rather wide band gap (max ¼ 308 nm) due to the preponderance of nonconjugated 2,4-linkages <1997MM5566>. This polymer emits at 470 nm with a quantum yield reaching 9.2%. Well-defined phenyl– phosphole copolymers possess a max at 500 nm . p-Conjugated polymers 44a–c (Scheme 4) featuring 3phosphole moieties with degrees of polymerization ranging from 7 for 44c to 15 for 44a show UV–Vis absorptions slightly redshifted in comparison to that of 2,5-diphenylphosphole <2003MM2594>. The emission properties of these macromolecules depend on the nature of the co-monomer. Green and blue emission is observed for 44a, 44b and 44c, respectively. However, the quantum yields in chloroform solution are rather modest (9–14%). The impact of the coordination of phosphole-based chromophores to transition metals has been investigated. Push–pull phospholes 45a,45b (Scheme 5) show a broad absorption in the visible region (415–417 nm) <2002CC1674>. Upon coordination to a square planar Pd2þ center (Scheme 5), this p* p transition is redshifted and low-energy absorptions appear due to charge transfer from the metal or the phosphorus–metal fragments to the pyridine ligands. In contrast, coordination of chromophore 46 to ruthenium centers (Scheme 5) has only a marginal effect on the p–p* transition of the extended conjugated system <2002JOM494>.
1061
1062 Phospholes
Scheme 4
Scheme 5
[CpRu(1-phenyl-3,4-dimethylphosphole)L] complexes (L ¼ CO or CH3CN) display intense absorptions (" about 104) in the 228–240 nm range and one with a much lower intensity centered at 310 nm (L ¼ CO) and 375 nm (L ¼ CH3CN) <1997JOM395>. These complexes are phosphorescent (lifetimes, 0.2–2 ms) at 77 K in the solid state with significant Stokes shifts. Their emission properties are very sensitive to the nature of the ligand L. 1-Phenyldibenzophosphole and its derivatives (P-oxo, P-thioxo, gold(I) complex) show absorption maxima between 332 and 333 nm, indicating that these derivatives possess large ‘optical’ HOMO–LUMO gaps <2006JA983>. This feature is in accordance with the view that dibenzophospholes have to be considered as P-bridged biphenyl derivatives <1988CRV429>. Dibenzophosphole derivatives emit in the UV region at similar wavelengths (366 nm) with relatively modest quantum yields (0.2–13.4%). Note that the Stokes shifts are relatively small (ca. 32–36 nm), suggesting minimal rearrangement of these rigid molecules upon photoexcitation. Homopolymers having dibenzophosphole repeat units show photoluminescence (PL) in the solid state (em ¼ 516 nm) <2003JP2003231741>. Poly[2,7-(oxobenzophosphole)alt-co-(1,4-arylene)]s display absorption maxima in solution and thin film between 384 and 390 nm <2004CL44>. These polymers are photoluminescent with small Stokes shifts, but quite high quantum yields (68–81%). Copolymer 47 containing dithienophosphole oxide and spirofluorene moieties exhibits similar absorption spectra in dilute solution and thin films <2006CL958>. These polymers show emission due to the dithienophosphole oxide (540 nm) and the fluorene (410–430 nm) subunits with high quantum yields (72–85%).
Phospholes
The optical properties of a variety of dithieno[3,2-b:29,39-d]phospholes have been studied in detail (Table 20). Dithienophospholes display optical band gaps of ca. 3.0–3.2 eV, as estimated from the onset values of their UV absorptions. They show very intense blue emissions with high PL quantum yield efficiencies (Table 20) <2004AGE6197, 2005EJC4687, 2006OL503>. Variation of the silyl groups and chemical modification of the nucleophilic phosphorus atom allows the optical properties of the dithienophospholes to be tuned (Table 20) <2005EJC4687, 2006OL503, 2006JCD1424>. The wavelength maxima for absorption and emission are redshifted upon complexation or oxidation (Table 20). The fact that the optical properties can be fine-tuned by variation of the substituents at the phosphorus and silicon centers makes these derivatives very attractive for optoelectronic and sensing applications. Indeed 5,59-bis(pinacolboryl)dithieno[3,2-b:29,39-d]phosphole is a very sensitive and selective sensory material for the fluoride ion (Section 3.15.12.4, Scheme 126).
Table 20 Photophysical data for dithieno[3,2-b:20,30-d]phosphole derivatives (max and em in nm, quantum yield determined using quinine sulfate as standard) max
log "
em
338
4.38
415
0.78
344
4.26
422
0.60
420
0.81
366
374
4.00
460
0.56
355
4.10
432
0.55
445
0.56
290, 375
1063
1064 Phospholes Dithienophosphole units have been incorporated into polymers as either (1) pendant groups or (2) constituent repeat units of the extended polymer backbone itself (Scheme 6). Polymers of the first type exhibit a blue fluorescence with a high PL quantum yield (0.75); their max (352 nm) and em (424 nm) values match those observed for the corresponding dithienophosphole monomer <2004AGE6197>. The P-atoms can be functionalized leading to polymers exhibiting similar optical properties to the corresponding dithieno[3,2-b:29,39-d]phosphole monomers. Polymer 49, obtained via a Stille coupling, displays redshifted values of max (502 nm) and em (555 nm), compared to those of the corresponding monomer (max, 379 nm; em, 463 nm) <2005EJC4687>. Polymers 50a and 50b (Scheme 6) show absorption maxima at 378 and 393 nm, respectively <2006OL503>. The presence of a second strong transition for polymer 50b suggests an interaction of the disilane linker with the dithienophosphole moiety. As observed for polymer 48, their emission wavelength maxima are similar (460 and 459 nm) and match those of the monomeric dithienophosphole oxides.
Scheme 6
3.15.3.5 Infrared and Raman Spectroscopy Infrared (IR) spectroscopy is not a particularly useful tool for the characterization of phospholes, and is mostly used for the characterization of functional groups grafted to the phosphole ring, with these data showing no unusual features. Raman spectroscopy has been used to probe the electronic property of 2,5-di(2-thienyl)phosphole derivatives and thienyl-capped 1,19-diphospholes <2005SM249, 2006CEJ3759>. The central focus of these studies was to study the balance between intraring (aromaticity) and inter-ring delocalization (backbone p-conjugation), as well as its modification following chemical functionalization of the P-atom. The suitability of Raman spectroscopy to study the properties of conjugated materials lies in the existence of an intimate connection between the observed Raman lines and the p-conjugated structure. The phenomenon originates in the existence of a very effective electron– phonon coupling resulting in some vibrational modes that mimic the evolution of the skeletal/electronic structure from the ground electronic state to the first accessible electronic state (S1) . Theory (B3LYP/6-31G** ) reproduces the vibrational Raman profiles of phosphole-based conjugated systems quite well <2005SM249, 2006CEJ3759>. The most noticeable feature upon P-functionalization is the upshift of the band associated with the phosphole s(CTC) mode which moves from 1470 cm1 in 3-di(2-thienyl)phosphole 39c to 1481 cm1 in its gold(I) complex 41 and to 1486 cm1 in its thioxo derivative 40 (see Table 19 for structures). These shifts to higher energies of the Raman lines associated with ring stretches show that upon oxidation or coordination of the P-atom the double bonds of the central five-membered ring are strengthened and the single bond is weakened. This increase in bond-length alternation clearly reflects a decrease in the endocyclic delocalization. The (CTC) Raman lines assigned to the P-ring of thienyl-capped 1,1-diphosphole are displaced to lower energies with respect to di(2thienyl)phosphole 39c, while the thienyl bands remain unaltered. This observation has been rationalized by considering that the hyperconjugation between the p(butadiene) and the exocyclic P–C/P–P–P bonds increases
Phospholes
with increasing P–P bond polarizability. The through-bond interaction between the two p-chromophores in 1,19diphospholes induces a slight increment in aromaticity within the P-ring, followed by some bond-length equalization and, consequently, a redshifting of the stretching Raman modes.
3.15.3.6 Photoelectron Spectroscopy Photoelectron spectroscopy has been used to study the interaction of the phosphorus lone pair with the p-system upon flattening of the P-atom by increasing the steric hindrance of the P-substituent <1996JO7808, 1998JOM29>. The phosphorus lone pair ionization energy decreases upon flattening of the P-atom due to an increase in the p-character of the P-lone pair orbital <1996JO7808, 1998JOM29>. The extremely bulky 1-(2,4,6-tri-tertbutylphenyl)-3-methylphosphole 12 (see Table 4) exhibits the lowest ionization energy value ever recorded for a phosphole (7.5 eV); it is some 0.9–1.0 eV below that for 1-phenylphosphole <1998JOM29>.
3.15.4 Thermodynamic Aspects 3.15.4.1 Physical Properties The physical states, ease of handling, and purification methods of phospholes are directly related to the nature and the number of the ring substituents. Phospholes are generally prepared and manipulated under an inert atmosphere, because of the possibility for oxidation at phosphorus. The air and moisture sensitivity of phospholes generally decreases upon increasing the number of substituents on the C-atoms. For example, the procedure leading to 2,5bis(phenylethynyl)-3,4-dimethyl-1-phenylphosphole involves a hydrolysis performed under air <1996BSF33>. However, the nature of the P-substituent also plays a crucial role in governing phosphole stability. For example, 1-phenylphosphole 39b (Table 19) is an air-stable solid, which does not oxidize in solution under air. In contrast, its 1-alkyl analogue can only be handled under an inert atmosphere, while the 1-amino version is an extremely air- and moisture-sensitive compound that decomposes upon purification <2001CEJ4222>. Other fully substituted 1-alkylphospholes are reported to be only slightly oxygen-sensitive solids <1999OM4205>. Increasing the steric hindrance about the P-substituent is also an effective way of enhancing the stability of phospholes. 1-(2,4-Di-tert-butyl-6methylphenyl)-3-methylphosphole 11 is air stable unlike the corresponding 1-phenylphosphole, which is readily oxidized <1996JOC7801>. 1-Phosphinophospholes are thermolabile and sensitive toward air and moisture <1997JOM197>, whereas fully substituted 1,19-diphospholes are not air and moisture sensitive <2004JA6058>. 2,5-Substituted phospholes are generally robust derivatives. For example, 1-(2-methylpyridyne)-2,5-diphenylphosphole and 1-phenyl-2,5-dimenthylphosphole are air-stable solids, which can be stored without special precautions <2001OM1014, 2003OM1580>. 1,3,4-Triphenylphosphole was found to oxidize only very slowly: a sample kept in air afforded only a few percent of oxide after 6 months <2000J(P1)1519>. However, in solution, these compounds have to be handled under an inert atmosphere. Many of the phospholes prepared over the last few years are substituted derivatives with rather high molecular weights and hence are solids. They are soluble in most common organic solvents, with the most widely used solvents for extraction purposes being dichloromethane, tetrahydrofuran (THF), and toluene. The most commonly used methods for isolation and purification of phospholes are crystallization, generally performed at low temperature, and column chromatography on alumina or silica gel. A wide variety of solvents have been used as eluents, including protic solvents such as methanol. It is noteworthy that phosphole derivatives with CN 4 (oxo-, thiooxo-phospholes, phospholium salts, etc.) as well as transition metal complexes are generally air stable and can be purified by crystallization or column chromatography.
3.15.4.2 Thermal Stability A variety of studies have been undertaken that show that there are a range of factors that control the thermal stability of phospholes, something which makes it difficult to rationalize any observable trends. In contrast to 1H-phosphole derivatives, which are stable only at low temperature (less than 70 C), CN 3 phospholes bearing alkyl, phenyl, alkoxy, or dialkylamino groups at P are stable at room temperature. However, phospholes having silyl- or carbonylbased (carboxylate, carboalkoxy, acyl, etc.) substituents on the P-atom are not stable at 25 C <2002OL1245, 2002CC2976, 2001SL1977, 2004ACR954>. This thermal instability of phospholes is essentially due to their ease of isomerization into 2H- and 3H-phospholes (see Section 3.15.2.1, Scheme 3).
1065
1066 Phospholes The thermal stability of a family of 2,5-arylphospholes has been assessed quantitatively by thermogravimetric analysis (TGA) performed under nitrogen <2001CEJ4222, 2006JA983>. The decomposition temperatures (Td5, temperature at which 5% weight loss is observed) for phospholes featuring phenyl, 2-pyridyl, and 2-thienyl substituents are comparable (Td5 ¼ 199–210 C) and similar to that recorded for dibenzophosphole (Td10 ¼ 213 C). Note that a phosphole bearing 2-pyridyl and 4-stilbenyl substituents at the 2- and 5-position displays a high decomposition temperature (Td10 ¼ 306 C) <2006JA983>, and that the thermal stability decreases in the series P–Ph (Td5 ¼ 210 C), P–NPri2 (Td5 ¼ 198 C), P–NPri2 (Td5 ¼ 182 C) <2001CEJ4222>. An approach that can be used to increase the thermal stability of phospholes involves the chemical modification of the P-atom, since it is known that the 1H-phosphole ! 2H-phosphole isomerization process is less favored for 4phospholes <1983JA6871>. Indeed, the decomposition temperatures of 2,5-diphenyl- and 2,5-di(2-thienyl)-4thiooxophospholes are increased by 86 and 48 C, respectively, in comparison to their 3-phosphole precursors <2006JA983>. However, the reverse trend is observed with 2-pyridyl- and 4-pyridyl-capped phospholes – oxidation of the P-atom with sulfur results in a decrease of their thermal stability <2006OBC996>. Once again, it is difficult to establish a correlation between the substitution pattern of phospholes and their thermal stability. However, it should be noted that varying the substitution pattern of the phosphole ring has afforded a range of derivatives, including Au(I) complexes, which are thermally stable enough to be deposited on tin–indium oxide by vacuum sublimation, something of significant importance for the fabrication of organic light-emitting diodes (OLEDs) (see Section 3.15.12.4) <2003JA9254, 2006JA983>.
3.15.4.3 Resonance Energies To the best of our knowledge, no experimental studies devoted to the determination of resonance energies of phospholes have been reported since 1996. High-level theoretical calculations detailed in Section 3.15.2.1 now converge, and their conclusion is that the resonance energy of the parent phosphole ring is ca. 3–5 kcal mol1.
3.15.4.4 Annular Tautomerism The isomerization of 1H-phosphole into its 2H- and 3H-tautomers is a key reaction since 2H-phospholes are versatile building blocks in phosphole chemistry due to their cyclopentadiene-like reactivity (see Sections 3.15.5.1.2(i) and 3.15.5.1.2(ii)) and the ease with which they may be deprotonated to afford functionalized phospholide ions (see Section 3.15.10.1). Theoretical studies (see Section 3.15.2.1) have established that 1H-phosphole ! 2H-phosphole tautomerism is a viable process, while 2H-phosphole ! 3H-isomerization is much more difficult (Scheme 3). This annular tautomerism is governed by the migrating aptitude of the P substituent. Basically, the substituents can be divided within three groups: those that migrate at low temperature (i.e., H, SiR3, CHO, CO2R), those that migrate below the decomposition temperature (typically between room temperature and 200 C) of phospholes (i.e., Ph, CN, ethynyl, vinyl), and those that do not migrate prior to phosphole degradation (i.e., OR and alkyl) <2004ACR954>. Note that the high migrating ability of the acyl group has been exploited in order to prepare 3H-phosphole derivatives (see Section 3.15.10.1). The first isolated 3H-phosphole, namely 3H-phosphaindene 50, was obtained as a 1:1 mixture with its hydration product 51 by gas-phase pyrolysis (flash vacuum pyrolysis, FVP) over a solid base (Scheme 7) <1999TL5271>. The hindered PTC bond of compound 50 is unreactive.
Scheme 7
Phospholes
3.15.5 Reactivity of Phospholes 3.15.5.1 Reactivity of CN 3 Phospholes 3.15.5.1.1
General
It is important to recall that the reactivity pattern of phospholes is very different from that of the related S, N, and O ring systems due to their limited aromatic character. For example, electrophilic substitution takes place only with a handful of phospholes that have been specifically tailored via increasing the bulkiness of the P substituent (see Section 3.15.10.4, Scheme 83). In fact, electrophiles react at the phosphorus atom affording a panel of neutral and cationic CN 4 derivatives (Scheme 8). Phospholes are also versatile synthons for the preparation of other heterocyclic systems via Diels–Alder reactions. The cycloaddition can involve the dienic moiety of the phosphole ring or can occur following a 1,5-shift of the P-substituent (Scheme 8). Finally, phospholes can be transformed into phospholide ions, which are powerful nucleophiles that have found a variety of applications (Scheme 8). All these facets of phosphole reactivity are presented in this section. It should also be noted that CN 3 phospholes exhibit a rich coordination chemistry toward transition metals (see Section 3.15.12.2).
+ P
P R
E
..P
E
..
E
δ+
R
P
δ–
R1
R
R P
:
R
Δ
E+
R1
M M+
– P
Scheme 8
3.15.5.1.2
Unimolecular thermal and photochemical reactions
As discussed in Section 3.15.2.1 (Scheme 3), 1H-phospholes can be transformed into 2H-phospholes upon heating. To date, very few stable 2H-phospholes are known <2004ACR954>. However, a great variety of 2H-phospholes are accessible using the 1H-phosphole/2H-phosphole equilibrium, and their heterodiene behavior makes them powerful intermediates for the synthesis of P-heterocycles. Only the results that have appeared since 1996 are presented in this section; for a general overview of the chemistry of 2H-phospholes, an excellent review by Mathey is available <2004ACR954>.
3.15.5.1.2(i) [1,5] Sigmatropic rearrangement of P substituents The synthetic sequence involving the thermal [1,5] sigmatropic rearrangement of 1H-phospholes and cycloaddition with dienophohiles has been mainly used to prepare 1-phosphanorbornadiene and 1-phosphanorbornene derivatives. These P-heterocyles are appealing chiral ligands for transition metal-based homogeneous catalysis since they possess a nonracemizable P-donor group due to its bridgehead position <1997CEJ1365, 2000T101, 2003TA3137> (see Section 3.15.12.1). The synthesis of 1-phosphanorbornadienes involves [4þ2] cycloaddition of 2H-phospholes with alkynes. It has been extended to (phenylethynyl)phosphonates, (phenylethynyl)phosphoramides, and phenylpropargylic aldehyde diethyl acetate for the preparation of water-soluble and enantiopure ligands (Scheme 9) <1996JOC3531, 2000TA4601>. This reaction is regioselective; only 1-phosphanorbornadienes 52 and 53 (80–90% yields) with the functional group at the C-2 carbon atom are formed. In contrast, using ethynylphosphonamide <1996JOC3531> or phenylpropiolate <2000OL2885> as dienophiles, a mixture of the two possible regioisomers is obtained. For example, derivatives 54a and 54b are formed as a 2:1 mixture (Scheme 9). Note that the resolution of aldehyde 53, as well as its analogue obtained from 1,2,5-triphenylphosphole, has been carried out by crystallization or chromatography of the corresponding acetals derived from (S,S)-1,2-diphenyl-1,2-diol <2000TA4601>.
1067
1068 Phospholes Tin-functionalized 1-phosphanorbornadienes can be prepared from tin-substituted alkynes using this type of methodology. Subsequent tin–halogen exchange affords the corresponding halo derivatives, which may be further elaborated using palladium-catalyzed reactions such as Stille coupling, for example (see Section 3.15.12.1.2).
Scheme 9
Hetero-Diels–Alder reactions have also been conducted with aldehydes (Scheme 10) <2003JOC2803>. The reaction is very sensitive to the substitution pattern on the aldehyde and on the phosphole. Reaction of 1-phenyl-3,4dimethylphosphole with benzaldehyde or its para-derivatives afforded the corresponding adducts 55 in quantitative yields (Scheme 10). An increase in the steric demands of the aldehydes or of the phosphole results in a dramatic decrease in the yield. For example, with 2,4,6-trimethylbenzaldehyde, no reaction takes place and only 30% conversion is observed with 2,6-dimethoxybenzaldehyde. Similarly, using the more sterically hindered 1-phenyl2,3,4,5-tetraethylphosphole, no cycloadduct formation is observed with benzaldehyde. Note that with decanal, the yield reaches only 40%. The reaction affords a mixture of endo- and exo-phosphinites 55, the major component being the endo-derivative. With trans-cinnamaldehyde, a mixture of adducts 56 and 57 was obtained (Scheme 10), showing that the 1-phosphadiene can react either via the CTO or via the CTC moieties of ,-unsaturated aldehydes <2003JOC2803>.
Scheme 10
The same reactivity pattern, namely a 1,5-shift followed by cycloaddition, was observed with ‘aromatic’ phospholes (see Section 3.15.2.1) such as 1-(2,4,6-triisopropylphenyl)phosphole 27 (Scheme 11) <2005HAC104> and 1-(2,4-ditert-butyl-6-methylphenylphosphole 11 <2003HAC316>. This [1,5]-shift also takes place with the ferrocenyl moiety, which affords the 1,19-ferrocenylene-bridged bis-1phosphanorbornadiene 58 when undertaken in the presence of diphenylacetylene (Scheme 12). This derivative is obtained as a 50/50 mixture of the meso (24% yield) and racemic (20% yield) products, which were separated by column chromatography <2002MI245>.
Phospholes
Scheme 11
Scheme 12
3.15.5.1.2(ii) Thermal dimerization of phospholes In the absence of trapping agents, transient 2H-phospholes dimerize via cycloaddition processes to give adducts having a P–P bond (Scheme 13) <2003HAC316, 2005HAC104>. This dimerization is reversible upon heating. At low temperature, the endo-dimer is produced first, which evolves to afford the more stable exo-isomer (see Section 3.15.2.1 for theoretical studies). Note that [4þ2] endo-dimers are interesting synthons for the preparation of chelates featuring biphospholene moieties (see Section 3.15.9.3, Scheme 63) <2003OM1356>.
Scheme 13
3.15.5.1.3
Electrophilic attack at phosphorus
As observed with classical CN 3 phosphines, phospholes react with a broad range of electrophiles. For example, oxidation of the P atom can be accomplished using hydrogen peroxide <2000J(P1)1495>, bis(trimethylsilyl)peroxide <2001CEJ4222>, or meta-chloroperbenzoic acid (MCPBA) <1998AXC676>. In the case of thienyl-substituted 1,19biphosphole, the mono-oxidized derivative was prepared in 86% yield using bis(trimethylsilyl)peroxide <2004JA6058>. Phosphole sulfides and selenides are generally obtained in good yields at room temperature using elemental sulfur and selenium as reactants <2005OM5549, 2005EJC4687>. Note that the thiolation can be
1069
1070 Phospholes accelerated upon addition of tertiary amines. Interestingly, these modifications of the P-atom can also be accomplished on insoluble <2006AGE6152> or soluble <2005EJC4687> phosphole-based polymers. Phospholium salts are accessible by treatment of phospholes with alkyl halides or triflates <2001EJC4222>. Phosphole sulfides are the most stable of these three CN 4 derivatives and they are often used as ‘protected phospholes’ (see Section 3.15.5.2.1). However, the stability of these compounds is considerably influenced by their substitution pattern <2006OBC996>.
3.15.5.1.4
Cycloadditions with the dienic moiety
Diels–Alder reactions involving the dienic moiety of the phosphole ring and activated dienophiles (e.g., N-phenylmaleimide, fumaronitrile, etc.) have been known since the early 1980s <1996CHEC-II(2)757>. These cycloadditions offer a straightforward route to 7-phosphanorbornadienes, which are important ligands for homogeneous catalysis, especially in enantiopure versions <2006OM2585>. 1,4-Cycloadditions with the dienic moiety can also be conducted in the coordination sphere of transition metals when the P-atom is coordinated. This type of reaction has been extensively investigated in the last 10 years and is described in Section 3.15.12.1. In fact, the dienic behavior of phospholes can be fine-tuned by varying the P-substituent since the nature of this group dramatically influences the aromatic character of phospholes (see Section 3.15.2.1). As expected, phospholes 11, 12, and 27 (Scheme 14) that have a quite significant aromatic character due to the presence of sterically demanding P-aryl substituents are less reactive dienes compared with more usual phospholes. For example, they react with N-phenylmaleimide at 60 C with reaction time varying from 1 to 3.5 days for compounds 11 and 12, respectively. For comparison, the same cycloaddition reaction conducted with 1-phenyl-3,4-dimethylphosphole requires a lower temperature (40 C) and a much shorter reaction time (4 h) <1981T319>. With phospholes 11, 12, and 27, a mixture of cycloadducts was obtained (Scheme 14). In all cases, the predominant isomers are the derivatives 59a–c (62–95%) having the P substituent anti to the double bond. Note that all the cycloadducts have been isolated as their phosphine oxides. A related combined experimental and theoretical study of Diels–Alder reactions of this family of sterically encumbered 1-(2,4,6-trialkylphenyl)-3-methyl-phospholes with maleic acid derivatives including N-methylmaleimide and maleic acid anhydride has been conducted <2002T9801>.
Scheme 14
Phospholes
In contrast, phospholes having electronegative substituents at the P-atom are excellent dienophiles due to their extremely low aromatic character (see Section 3.15.2.1). For example, 1-cyano-3,4-dimethylphosphole 61 reacts quantitatively with acrylonitriline at 80 C over 18 h to give a mixture of adducts 62a (35%) and 62b (50%) (Scheme 15) <2001JOC755>. For comparison, using the same reaction conditions, the corresponding 1-phenylphosphole is completely unreactive. The reason why the syn-product 62b is the predominant form obtained is still unclear <2001JOC755>. 1-iso-Propoxyphosphole 63, which has even lesser aromatic character, is a very reactive diene. Cycloaddition reactions with acrylonitrile and diethylvinylphosphonate afford the adducts 64 and 65 quantitatively at 30 C after only 1 h (Scheme 15) <2001JOC755>. Their anti-stereochemistry was established by NMR spectroscopy and X-ray diffraction studies. From a synthetic point of view, alkoxyphospholes are very interesting synthons since only one diastereoisomer is formed with these two dienophiles. Chiral bis(7-phosphanorbornadiene) 66 was obtained as a single enantiomer using this approach (Scheme 15) <2003OL3093>. The potential of this ligand in enantioselective catalysis has been illustrated by the achievement of high enantiomeric excesses in the rhodium-catalyzed reduction of functional alkenes <2003OL3093>.
Me
..
80 °C
+
P CN
CN
Me CN
62a
OPr i
.. 30 °C R
Me
1h Me
OPr i
R
64: R = CN 65: R = P(O)(OEt)2
63 Ph
Ph
P
+ Me
Me Me
N Ph O
50 °C 12 h
Ph
O O
N
O
N
..P
..
P
O
Ph
O
O O
CN
62b
P
+
P
Ph
Me
18 h
Me
..
+
Me
..
P
Me
61 Me
NC
..P CN
Me
Me
Me
Ph
P
O
O
Me Me
66
Me
Scheme 15
Intramolecular Diels–Alder reactions provide a general and efficient route to tricyclic phosphines, phosphinites, and aminophosphines having a 7-phosphanorbornadiene framework (derivatives 67a, 67b, and 68, Scheme 16) <2002JOC5422>. In line with the results presented above, Diels–Alder reactions involving 1-alkoxy- and 1-aminophospholes are extremely fast at room temperature (reaction times: 10–60 min). In contrast, the reaction conditions necessary to obtain the tricyclic phosphines 69a–c from the corresponding 3-buten-1-ylphospholes are much more severe (Scheme 16). Note that using the enantiopure endo-2-vinylborneol skeleton, the corresponding tricyclic phosphinites 70a,b (Scheme 16) were obtained as a 98:2 mixture of diastereoisomers with the major product having the (S)-configuration at phosphorus <2002JOC5422>. Two other examples are worthy of note. First, 1-benzyl-3,4-dimethylphosphole reacts with an excess of various phosphaalkynes at 160–170 C to give phosphorus–carbon cage compounds and phosphinines via the formation of 1-benzylphosphinidene <1995CB991>. Second, [2þ2] cycloaddition reactions involving phospholes have been studied since it was expected that the low aromaticity of these P-rings should facilitate the reaction of the double bonds <2004JPH63>. However, 1-phenyl-3,4-dimethylphosphole is inert toward dibenzophenone under photolytic conditions, probably due to the 3,4-dimethyl substitution. In contrast, this phosphole reacted with 2,3-dimethylmaleic anhydride, in the presence of dibenzophenone as a photosensitizer, to afford the adduct 71 in 80% yield (Scheme 17).
1071
1072 Phospholes
Scheme 16
Me
Me P Ph
O
+ Me
Me hν Ph 2 CO
..
..
Me
O
Me
P Ph
O
O
Me Me
71
O
O
Scheme 17
3.15.5.1.5
Substitution and cleavage at phosphorus; phospholide ions
Phospholide anions [PC4R4] are the P-heterocyclic analogues of the well-known cyclopentadienide anions, [C5H5], and, just like Cp, phospholides exhibit significant aromatic character <1992JOC3694, 1994JA9638, 1996OM1755>. They are key nucleophilic synthons that are usually obtained by reductive cleavage of the P-phenyl or P-halogeno bond of phospholes <2000OM4899, 2002NJC1378> (Scheme 18). This type of reaction can be conducted in the presence of various functional groups, including, for example, cyano <1996BSF541> and trialkylsilyl <2005EJI637> moieties, phenyl or 2-thienyl rings <2005OM5369>, but this reaction failed with 2,5-bis(naphthyl)phospholes <2006OM2715>. Note that one drawback of this methodology when using 1-phenylphosphole is the formation of
..
R
P
M = Li, Na, K R = Ph, Cl, Br
R
.. P
P
Scheme 18
..
R
–
R
P M = Li, Na, K
R M
+
ButOK
..
R
P
CH 2 CH2 Z
72 Z = CO 2Et, CN
Phospholes
phenyl-containing by-products, which are also nucleophilic in character. This problem can be overcame using other approaches such as the reductive cleavage of the P–P bond of 1,19-diphospholes <2003OM1580, 2003CC1154, 2005OM5369, 2005EJI637> or the base-induced dealkylation of phospholes 72 (Scheme 18) <1996BSF541, 1997AGE98>. This last route can also be useful when it is necessary to avoid the potential for radical side reactions (i.e., the cleavage of P–P or P–Ph bonds with alkali metals) due to the presence of other reducible functions such as C–Br bonds <2005CEJ6829>. An important class of phospholide anions whose synthesis differs slightly are the fused benzophospholides <1995BSF280>. An elegant methodology has been described by Gudat that exploits chemistry well known for the synthesis of tertiary phosphines, namely reductive cleavage of phosphonium salts <1999EJI1169>. Thus, treatment of bis(phosphonio)-substituted isophosphindolide 73 with lithium naphthalenide affords a mixture of the phosphinesubstituted benzophospholide anions 74 and 75 and Ph2PLi (Scheme 19). Reaction of salt 74 with Ni(CO)4 affords the novel benzophospholide complex 33a in which the two pendant phosphine moieties are bound to nickel, while the endocyclic P atom remains uncoordinated.
PPh3 PPh3
PCl 3
PPh 3
NEt 3
P
PPh2 LiC10H8
Cl
P
PPh2 P
+
THF
PPh3
Li
73
74
PPh2
+ Ph2 PLi
Li
75
Scheme 19
Li Ph2P
P
Ni(CO) 3
PPh 2 Ni(CO3 )
33a The use of phospholide anions as nucleophilic synthons for the synthesis of phospholes is presented in Section 3.15.10.3. It is noteworthy that phospholyl anions exhibit a rich coordination chemistry with transition, lanthanides and alkali metals. They can act as 2-bridging ligands through the lone pair available on the P-atom, as 5-C4P or as 1-P,5-C4P ligands <1996JOM293, 1996AGE1125, 2001OM3884>. A review on phosphametallocenes is available <2002TCC27>, and the coordination chemistry of phospholide anion is described in Section 3.15.12.1.4.
3.15.5.2 Reactivity of CN 4 Phospholes 3.15.5.2.1
Phosphole oxides, sulfides, and selenides
The general methods of preparation of phosphole oxides, sulfides, and selenides have been described in Section 3.15.5.1.3. A tentative resolution of chiral phosphole 76 under kinetic dynamic resolution conditions is noteworthy, despite only low enantioselectivities (10–20%) having been obtained (Scheme 20) <2004TA3519>.
Scheme 20
1073
1074 Phospholes A previously unknown series of 4,5,8,7-tetraflourobenzo[d]phosphole oxides 78 has been obtained by reacting diethylpentafluorophenylphosphinites and ethyl bis(pentafluorophenyl)phosphinites with activated alkynes (Scheme 21) <2004RJC189>. The CN 5 derivatives 77 are stable enough to be characterized by NMR spectroscopy, and one derivative 78 (R1 ¼ C6F5, R2 ¼ R3 ¼ CO2Me) has been studied by X-ray diffraction.
Scheme 21
-Bridged diphosphole disulfide 80 was obtained according to the synthetic route depicted in Scheme 22, starting from the 1-phenyl-3,4-dimethylphosphole complex 79. The protection of both the dienic system and the lone pair of the phosphole with iron carbonyl permits regiospecific deprotonation at one -methyl group, although the subsequent coupling reaction proceeds in low yield (20%). Simultaneous P-demetallation and P-oxidation is accomplished by reaction with sulfur in toluene at reflux (77% yield), with the liberation of the noncomplexed dienic moiety being achieved using cerium ammonium nitrate (CAN) in 82% yield <2001JOM105>.
Scheme 22
Phosphole oxides are generally unstable since they dimerize rapidly via Diels–Alder reactions. Sterically demanding aryl substituents at the P-atom can provide some stabilization of the phosphole oxide, but not enough to allow for their isolation <1996JOM7801, 1997JOM109>. Note that such sterically hindered phosphole oxides can also be trapped by N-phenylmaleimide to give [4þ2] cycloadducts (Scheme 23) <1997JOM109>. As already noted in CHEC-II(1996) <1996CHEC-II(2)757>, introduction of substituents at the 2- and 5-positions with respect to the P-atom stabilizes phosphole oxides. For example, compounds 81 and 82 have been isolated and fully characterized <2001CEJ4222>, although the bis(2-pyridyl)phosphole oxide 83 could only be observed by 31P NMR spectroscopy, since it decomposes rapidly in solution. In contrast, phosphole sulfides and selenides are generally more stable than their oxide congeners and can be purified using traditional organic chemistry methods (crystallization, chromatography, etc.). For example, thioxophosphole 84 bearing 2-pyridyl substituents can be isolated following column chromatography.
Phospholes
Ar
O P
Me
H Me H
1/2 Me
O
Me Ar
P
N Ph
Ar
Me
Ar
O
O
Me
P
Me
O P
Ar = Me
H O H N Ph O
O
Me Me
Scheme 23
Today, several efficient methods are available for the reduction of phosphole sulfides to the corresponding CN 3 phosphole derivatives. Hence, phosphole sulfides can be used as ‘protected phospholes’ in which the nucleophilic and oxidizable P-center is masked. However, the thermal stability of phosphole sulfides depends on their substitution pattern as illustrated with a series of thioxophospholes 86a–d having a fused carbocycle (Scheme 24) <2006OBC996>. Upon oxidation of the P-center with sulfur, the thermal stability is increased when the R1 substituent is a 2-thienyl or phenyl group <2003JA9254>. In contrast, the oxidation of 2-pyridyl- or 4-pyridyl-capped phospholes 85a and 85b results in a decrease in their thermal stability; these latter phosphole sulfides are transformed quantitatively into their 2-phospholene isomers 87a and 87b upon heating for 2 days at 40 C <2006OBC996>. The transformation of thienyl- and phenyl-substituted thioxophospholes 86c and 86d requires the presence of a base (Et2NH) and much higher temperatures. The driving force for this isomerization has been attributed to the fact that the oxidation of the P-center of the slightly aromatic 3-phospholes 85a–d affords 4-thioxophospholes 86a–d, which are weakly antiaromatic in character. A theoretical study <2006OBC996> suggests that it is probable that the isomerisation mechanism involves an intermediate allylic anion <1994OM925>, in accordance with the experimental observation that the reaction requires the presence of a base.
R1
.. P
S8
R1
R1 S
Ph
R1
P
a: R 1 =
b: R1 = N
R1
1 N c: R =
R1
P S
Ph
86a–d
85a–d
Δ
Ph
87a–d
d: R 1 = S
Scheme 24
A very nice example of the use of thioxophospholes as ‘protected phospholes’ is given by Matano et al., as part of the synthesis of phosphole-containing calixphyrins <2006OM3105, 2006JA11760>. The key to the success of this approach lies in the use of Friedel–Crafts condensations involving phospholes 88 and 89 (Scheme 25). These
1075
1076 Phospholes reactions are conducted with thiooxophospholes due to the high reactivity of the nucleophilic P-atom of CN 3 phospholes. The deprotection of calix[1]phosphole[1]thiophene[2]pyrroles and calix[1]phosphole[1]furan[2]pyrroles 90a and of calixphyrins 91a and 92a was achieved by treatment with P(NMe2)3 in toluene at reflux with satisfactory yields (66–92%) <2006OM3105, 2006JA11760>. Note that the thioxophosphole 90a (X ¼ S) has been characterized by X-ray diffraction.
Scheme 25
Asymmetric dibenzophosphole oxide 93 (Scheme 26) was obtained from dibenzophosphole oxide using classical organic transformations <2001TL7791>. This compound is isolated as a 1:1 mixture of two diastereoisomers with different configurations at the phosphorus atom. The dibenzophosphole oxide 93 was reduced quantitatively using trichlorosilane, affording dibenzophosphole 94. This compound was then reacted with an optically active cyclopalladated compound to give the complex 95 as a mixture of diastereoisomers, which were separated by column chromatography (Scheme 26). The enantiomerically pure dibenzophospholes were displaced from the metal by 1,2-diphenylphosphinoethane (DPPE) and subsequently oxidized with hydrogen peroxide. These two steps proceed with retention of configuration at P <2001TL7791, 2001TA1987>. Notably, the presence of a stereogenic P-center is sufficient to generate a chiral cholesteric phase <2002MCLC43>. The fact that phosphole sulfides are stable derivatives has been exploited in the preparation of enantiomerically pure 2,29-diphospholes <1996CC2287>. 2,29-Diphospholes 96a and 96b (Scheme 27), possessing a combination of axial and central chirality, react with elemental sulfur to give the corresponding sulfides 97a and 97b that can be separated by column chromatography. Diastereoisomers 96a and 96b can be quantitatively transformed into the corresponding enantiomerically pure 2,29-diphospholes upon addition of methyltrifluorosulfonate followed by addition of tert-butyllithium sulfide (Scheme 27) <1996CC2287>. The stereoselective desulfuration has also been exploited to study isomerization processes in stereochemically dynamic 2,29-biphospholes in which the two P-atoms are bridged by a chiral tether <2005OM5549>.
Phospholes
Scheme 26
R
R R
R
R MeOTf
R
R
R
R
..
..
Ph
Ph
P
P
P
S
S
S
Ph
97a
S8 R
R 2TfO–
+ P S
Ph
Me
But SLi
96b
+
R R
P
R
R
R R + P
P Ph
96a
Ph
R
MeOTf S
But SLi
Me
+
96a,b R = Me
+ P
P Ph
R R
S
Ph
S
97b
Me
+ P Ph
S
2TfO– Ph
Me
Scheme 27
P-Sulfide 99 reacted with Ph3PBr2 to give a 2-bromomethylphosphole sulfide (75% yield), which, upon addition of magnesium, afforded the diphosphole 100 (90%) (Scheme 28) <2001OM1499>. The deprotection step, reduction by an excess of P(CH2CH2CN)3 in boiling xylene, proceeded in 60% yield (Scheme 28). The direct synthesis of 101 is not possible from the CN 3 phosphole 98 due to the formation of unstable tervalent derivatives following treatment with Br2.
Scheme 28
1077
1078 Phospholes 2,2-Diphospholes bearing an amino group at the P-atoms have been prepared according to a synthetic procedure previously established by Mathey <1992BSCF486>. The reductive coupling of 2-bromophosphole sulfides 102 gave the corresponding 2,29-diphosphole sulfides 103 in rather low yields (14–45%) (Scheme 29) <2002EJI1657>. The reduction of these derivatives is very difficult and the corresponding trivalent 2,29-diphospholes have not been isolated.
R
R
R
ii, CuCl 2
S
S
P Pr i 2 N
S
102
R
R
i, BuLi
Br P Pr i2N
R
P NPr i2
103
R = Me, Ph
Scheme 29
1-(2-Ethoxycarbonylethyl)phosphole 105 (Scheme 30) is a useful precursor for the synthesis of the corresponding 2-bromophospholide ion and bromophosphaferrocene. Key compound 105 was prepared according to a classic multistep process involving phosphole oxides and sulfides (Scheme 30) <2005CEJ6829>.
Me
Me
Me Br2
P
P
O
Me
Me Br Br
P4S 10 P
Me
Br Br
CO2 Et
Me
Bu t OK
S
O CO 2 Et
Me
P
Br
Y CO 2 Et
CO 2 Et
104: Y = S 105 : Y = lone pair
P(CH 2 CH2 CN)3
Scheme 30
Finally, phosphole sulfides can behave as 4-4-electron or 4-C,1-S-6-electron donors toward transition metals. For example, derivative 106 reacts with CpCo(CO)2 to afford the [4-(phosphole sulphide)]cobalt(I) complex 107 (Scheme 31), which was characterized by X-ray diffraction <2006HAC344>. The chromium complex 109 was obtained in high yield from thioxophosphole 108 and its molecular structure determined crystallographically (Scheme 31).
Scheme 31
Phospholes
3.15.5.2.2
Phospholium salts
Phospholium salts are readily available by reaction of alkyl halides with CN 3 phospholes. The high nucleophilicity of the phosphole P-atom facilitates alkylation reactions with a range of potentially poorly reactive moieties such as those bearing heterocylic substituents (Scheme 32) <2001CEJ4222>. Indeed, such reactions were used to prepare the 4-pyridine-capped phospholium salt 110b and its 2-thienyl-analogue 110c; the former slowly decomposes in solution whereas the latter is quite stable. These compounds are significant since they were prepared with a view to tuning the optical properties of phosphole-based p-conjugated systems (see Section 3.15.12.4). Notably, phospholium salt 110c exhibits the most redshifted max (i.e., the smallest ‘optical band gap’) of all known di(2-thienyl)phosphole-based derivatives.
..
R
MeOTf
R
P
R
RT Ph
Ph 39b,c
R
+ P Me
TfO –
110b,c
c: R =
b: R =
S
N Scheme 32
The one-electron reduction of phospholium salts 111a–c has been studied by electron paramagnetic resonance (EPR) and DFT calculations, which conclude that they are good electron acceptors <2006PCP862>. Their reduction affords neutral radicals where the unpaired electron is mainly delocalized over the carbon skeleton of the P-ring. These compounds have been characterized in the solid state by X-ray diffraction and exhibit metric data that are typical of this type of compound (see Table 11). Me
Me + P
Ph
Ph Me
Ph
111a
+ P
Ph
+ P
Ph
Me
Me
111c
111b
P-Alkylation has also been shown to take place in the coordination sphere of transition metals affording the corresponding coordinated phospholium cations 112a and 112b in high yields <2001JOM131>.
Me
Mn(CO)3 Me P
Ph
Me PhLi
Me
P:
Mn(CO)3
BrCH2 CH2R
Me Me
Ph P+ CH2CH 2R Mn(CO)3
112a: R = CO 2Et 112b: R = CN Note that phospholium salts are also important intermediates in the deprotection of thioxophospholes, as depicted in Scheme 27. Another appealing application of phospholium salts is their use as Lewis acid catalysts for organic transformations. With this in mind, dibenzophosphole derivatives 113–116 (Scheme 33) have been designed that bear electron-withdrawing oxygenated functionalities in order to enhance the Lewis acidity of the P-centers <2006T401>. These compounds have been evaluated as catalysts in Diels–Alder reactions, with the catecholbased derivative 114 being the most efficient <2006T401>.
1079
1080 Phospholes
TfO – CF 3 O + CF 3 P
113
TfO –
TfO –
+ O P O
+ O P O
114
115
TfO – + O P O
116
Scheme 33
3.15.5.3 Reactivity of CN 2 and CN 5 Phospholes 3.15.5.3.1
2H-Phospholes
2H-Phospholenes have been used extensively as transient building blocks due to (1) their cyclopentadiene-like behavior for the synthesis of 1-phospha-norbornenes and -norbornadienes (see Section 3.15.5.1.2(i)), and (2) their easy deprotonation by ButOK leading to phospholide anions (see Section 3.15.10.1). The chemistry of these species with a focus on their use as synthons has been recently reviewed <2004ACR954>.
3.15.5.3.2
Five-coordinate phosphole (phosphoranes)
To the best of our knowledge, five-coordinate phospholes have not been investigated in the last decade. Only a series of five-coordinate benzophospholes 77 (Scheme 21, Section 3.15.5.2.1) has been described and characterized by NMR spectroscopy <2004RJC189>.
3.15.6 Reactivity of Reduced Phospholes The chemistry of reduced phospholes has been extensively developed since the two dihydro isomers, namely 2- and 3-phospholene, together with phospholanes are easily accessible and generally stable derivatives.
Some recent routes for the synthesis of these derivatives are presented in Section 3.15.9.3, but a detailed presentation of their reactivity is beyond the scope of this chapter. It should be noted, however, that in recent years these P-containing rings have been used for the tailoring of chiral ligands for homogeneous catalysis (Scheme 34). Two recent reviews describe the chemistry of this type of ligand and their applications <2003CRV3029, 2006COC>.
Scheme 34
Phospholes
3.15.7 Reactivity of C-Substituents It is amazing to note that in CHEC-II(1996) <1996CHEC-II(2)757> this head contained only six lines due to the lack of examples of this type of reactivity at that time. The situation has completely changed over the last decade with the discovery by Mathey and co-workers of several powerful chemical transformations of 2- and 2,5-halogenophosphole synthons. Despite the very extensive application of metal-catalyzed C–C cross-coupling reactions using a wide range of aromatic halide building blocks, these types of transformation are not efficient with phospholes. For example, neither 2-bromo-5-iodophosphole 117 nor its dibromo analogue 118 (Scheme 35) undergo Stille-type couplings with 1-stannyl-alkynes, while the Sonogashira coupling of 117 with phenylacetylene afforded derivative 120 in only 10% yield (Scheme 35) <1996BSF33>. The key to developing chemical modifications that employ the halide C-substituents of phospholes was the mono- and dilithiation of 2,5-dibromo derivative 118. These reactions are landmarks in phosphole chemistry since they provided the first direct means for the functionalization of the phosphole ring and have opened the way to metal-catalyzed coupling reactions of these P-heterocycles. The intermediate 2-lithio-5-bromophosphole is formed and treated with electrophiles at low temperature (100 C). It reacts with arylsulfonylacetylene 119a (Scheme 35) giving rise to derivative 120, which can be converted into ,9-di(acetylenic)phosphole 121 according to the same general strategy outlined above. Although the yields of these reaction sequences are rather modest (typically around 30%), this synthetic approach allows the stepwise preparation of derivative 124 from 123 by employing trimethylsilyl-protected alkynes 119b (Scheme 35) <1996BSF33>. Finally, the reaction of intermediate 2-lithio-5-bromophosphole with N-phenylformanilide affords 5-bromo-1-phenyl-3,4dimethyl-2-carbaldehyde phosphole 122 (Scheme 35) <2000J(P1)1519>.
R1 Br
R1 H
..
I
Ph
R1
R1
R1
R1
Pd(II), Cu(I)
P
Ph
Br
..
..
P
P
117
Ph SO 2 R 2
Ph
121
120
Ph
R 1 = Me R 2 = p -CH3C6 H 4 or Bu t
119a
R 3 = Me3Si
R1 Br
R1
..
R1 Br
Bu n Li
..
Br
P
R1
R1 Li
R 2O 2 S
SO2 R 2
R1
..
Br
Ph
Ph
R1
..
P
P
Ph
R1
123
118
Ph
i, 2Bu n Li
PhNHCHO
ii, 2 R 3 R Br
1
R
.. P
Ph
SO2 R 2
1
R1 CHO
122
Br
P
R3
R1
R1
..
..
P
Ph
R1
119b
R3
P
124
Ph
Scheme 35
The bromide–lithium exchange involving 3,3-diphenyl-2,5-dibromophosphole 125 takes place at very low temperature (Scheme 36). The reaction is feasible only with BuLi and affords the monolithiated derivative 126 quantitatively <2000J(P1)1519>. This intermediate reacts with a number of electrophiles giving rise to phospholes 127–129 (Scheme 36). Note that a halogen exchange occurs during the synthesis of phosphine 127, and that during
1081
1082 Phospholes its purification on silica, the alcohol 129 yielded the corresponding alkene. The reaction with iodine afforded an inseparable mixture of the iodo–bromo derivative 131 (90%) and of the starting material (10%). A copper coupling reaction of the lithium reagent 126 afforded a mixture of dimers 130a (33%) and 130b (19%) (Scheme 36).
Scheme 36
Derivative 132 is the sole 2,5-dilithiophosphole to have been generated to date. It is a very unstable and reactive compound that can be obtained from the 2,5-dibromo derivative 118 under rather harsh conditions (Scheme 37) <1998CR715>. The dilithiophosphole 132 reacts with trimethylsilyl chloride and carbon dioxide giving the phospholes 133 (67.7% yield) and 134 (95%), respectively (Scheme 37) <1998CR715>.
Scheme 37
Another efficient route to 2-lithiophospholes involves the deprotonation of protected phosphole 135 (Scheme 38). In fact, the phosphole–borane adduct 135 undergoes an allylic metallation affording the anion 136, which is a versatile nucleophile <1994OM925>. More recently, it has been shown that treatment of 136 with N-bromosuccinimide (NBS) led to the previously unknown phosphole dimer 137 (Scheme 38) <1998CR53>.
Phospholes
Scheme 38
Carboxaldehydephospholes are appealing starting materials due to the versatile and extensive reaction chemistry possible with the aldehyde function. Indeed, a broad range of classic organic transformations of this carbonyl group can be conducted without protection of the CN 3 P-atom of the phosphole ring. For example, the 24-membered macrocyclic tetraphosphole 139 is obtained in 60% yield following a Wittig reaction involving the 5,59-bis(carboxaldehyde) 138 (Scheme 389) <1995CC1561>. An X-ray diffraction study of heterocycle 139 revealed that the four P-phenyl groups adopt an all-trans-disposition and that the cavity is rather large with a diagonal distance between two ˚ P-atoms of almost 6.1 A.
Scheme 389
MacMurry reaction of 2-bromo-5-carboxaldehydephosphole 128 and of its 3,4-dimethyl analogue 122 (Scheme 39), which was obtained according to the synthetic approach described in Schemes 35 and 36, afforded 140a and 140b, respectively, as a mixture of (E)- and (Z)-isomers (90:10) in good yields <2000JP(1)1519>. The aldehyde function of phosphole 141a can be reduced by NaBH4 in a conventional manner, affording, after thiolation, the 2-hydroxymethylphosphole 141b in 90% yield <2001OM1499>.
R Br
R
R
R R
..
CHO
P
TiCl 4 –Zn
..
Br
..
P
P
Ph
Ph
140a,b 122 : R = Me 128 : R = Ph Me
a: R = Ph b: R = Me Me
.. P
Ph
141a Scheme 39
Me CHO
Me
i, NaBH4
CH 2 OH
P
ii, S8 S
R
Ph
141b
Ph
Br
1083
1084 Phospholes Just as is the case for aldehydes, ester groups display classic chemical reactivity when they are linked to phosphole rings. For example, derivative 142a is reduced with DIBAL or undergoes nucleophilic attack by Grignard reagents to afford primary and tertiary diols in reasonable yields (Scheme 40) <2006JOC5792>. These derivatives are moderately air sensitive, but can be oxidized by elemental sulfur to give air-stable derivatives 142b and 88 (40–63% overall yields).
Scheme 40
The low reactivity of the P-lone pair of the readily available 2-COOH phosphole 143 allows its conversion to the amide and nitrile derivatives 144 (62% yield) and 145 (72% yield), respectively, using classical methods (Scheme 41) <1996BSF541>. The substituent at the P-atom can be modified via a two-step sequence involving the formation of a nucleophilic phospholyl anion (Scheme 41).
Scheme 41
In conclusion, this section shows that many chemical transformations of C-substituents can be conducted in the presence of the phosphole ring and that the organic moieties grafted onto this P-heterocyclic fragment retain their classic reactivity patterns.
3.15.8 Reactivity of P-Substituents Reactions involving chemical modification of the substituents at phosphorus of CN 3 phospholes are extremely rare. The usual reaction sites of these P-containing rings are the nucleophilic P-atom and the dienic system. However, it should be noted that the P-substituent can be displaced either by (1) reductive cleavage leading to phospholide ions, or by (2) nucleophilic attack (see Section 3.15.10.3), or (3) 1,5-sigmatropic processes (see Section 3.15.5.1.2(i)). One remarkable example of the reactivity of a phosphole P-substituent is the radical copolymerization of dithienophosphole 146 with styrene using 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) as the initiator (Scheme 42) <2004AGE6197>. Copolymers 48 are high molecular weight materials with relatively narrow polydispersities. They have been characterized by 1H, 13C, and 31P NMR spectroscopy.
Phospholes
S
S
R S
R
..
P
S
R
R
.. P
TEMPO
+
110 °C m
48
n
146 R = SiMe2 But Scheme 42
Reaction at the P-substituent of a phosphole has been proposed to rationalize how 2-acylphospholide anions 147 react with dihalogenomethanes in the presence of a strong base to give the -functionalized phosphinines 148 (Scheme 43) <2005AGE1082>. The proposed mechanism, supported by DFT calculations, involves the formation of intermediate phospholes 149 that evolve to yield the bicyclic phosphoranes 150 via an intramolecular SN2 reaction.
Me
Me –
CH 2 X 2
C(O)R
P
Me
C(O)R
Bu t OK
147
P
148
X = Cl, Br, I R = Me, Ph CH 2 X 2
CH 2
Me
..
C(O)R
P X
ButOK
149
..
C(O)R
P
150
Scheme 43
Importantly, chemical modification of the P-substituent can be conducted with a metal-coordinated phosphole as exemplified by the dehydrohalogenation of 1-chlorobutenylphosphole complex 151, which leads to the butadienylphosphole derivative 152 (Scheme 44) <2006OM3152>.
Me
Me
Me
Me
t
Bu OK P
151 Scheme 44
P Cl
(OC)5W
(OC)5W
152
1085
1086 Phospholes
3.15.9 Ring Synthesis 3.15.9.1 General Since 1996, no new general ring syntheses of phospholes have been described and most of the novel phospholes that have appeared since this date have been prepared using the classic methods depicted by Quin in CHEC(1984) and CHEC-II(1996). For example, the first phosphole with a chiral substituent attached to the carbon atom 153a was prepared in 78% yield by condensation of 1,3-butadiyne with PhPH2 (Scheme 45) <2001OM1014>, a method discovered by G. Ma¨rkl in 1967 <1967AGE86>. Phosphole 153a was subsequently used as a synthon for the preparation of the corresponding C2-bridged diphosphole, 1,19-diphospharuthenocenes <2002OM3062> and chiral phosphinophosphaferrocenes <2001OM3913>. Using the same method, phospholes 153b and 153c possessing axially chiral atropoisomeric biaryl substituents <2006OM2715> and 1-phenyl-2,5-cyclohexylphosphole 153d (Scheme 45) were obtained in reasonable yields <2002OM3062>. Note that a series of phospholes bearing alkyl and silyl groups have also been prepared using this route <1998JMO155>.
PhPH2
R
R
R
BuLi
P
..
R
Ph
153a–d
Me OMe
b: R =
a: R = Me
OMe
c: R =
d: R =
Me
Scheme 45
3.15.9.2 Reaction of 1,4-Dimetallic Derivatives of Dienic Systems with Phosphorus Dihalides Basically, this approach encompasses two main synthetic routes. The first involves the reaction of acyclic 1,4dimetallic species 154 that, in most cases, are dilithio derivatives (route a, Scheme 46). Historically, this route was the first to be used for the preparation of phospholes and since then has remained very popular since many dilithio precursors 154 are available, starting from alkynes, bromo, or biaryl derivatives <1996CHEC-II(2)757>. The second uses metallacycles 155 as key intermediates (route b, Scheme 46). This approach has been used extensively in the last few years mainly employing zirconacyclopentadienes 155a (the so-called ‘Fagan–Nugent method’). These organometallic intermediates are prepared by oxidative coupling of alkynes with low-valent metal species. R
R
R
R R
M M
154 M = Li
R1PX 2 a
R
R
R
.. P
R1
R
R1PX 2 R
b
R
M Ln
R
155a: ML n = ZrCp 2 155b: ML n = Ti(OPr i)2
Scheme 46
1-Chloro-2,3,4,5-tetraphenylphosphole 156 and 1-chlorodibenzophosphole have been obtained using synthetic route a in satisfactory yields (57–77%), providing that the addition of phosphorus trichloride was performed at 196 C (Scheme 47) <1996PS309>. Using PBr3, the outcome of the reaction is different however. For example, treating 1,4-dilithiotetraphenylbutadiene with PBr3 afforded the phenyl-substituted 1,19-diphosphole 28 (34% yield), which was characterized by an X-ray diffraction study <2000CC1037>. The mechanism of this reaction is still
Phospholes
unclear. A series of functionalized 1-chlorodibenzophospholes were prepared via route a and directly transformed into phosphonic esters by methanolysis followed by oxidation with iodine <1996J(P1)2889>. 1-Phenyl-2,3-di(tert-butyl)3,4-dimethylphosphole 157 was prepared in 79% yield according to this procedure, demonstrating that the presence of bulky substituents on the nucleophilic carbon atoms is not a limiting factor <2002CC1646>. Ph Ph
Ph Ph
..
Ph
Ph
PCl 3 Ph
P
–196 °C
Li
Li
–110 °C
Ph
Cl
Ph
PBr 3 –78 °C
Ph
Ph
.. P
Ph
Ph
..P
Ph
156 Ph Me Bu t
Me
Ph
28
Me I
I Me
Bu t
i, 2BuLi ii, PhPCl 2
Bu t
..
P
Bu t
Ph
157 Scheme 47
1-Phenyl-2,5-bis(trimethylsilyl)phosphole 158 was obtained in fair yield according to the two-step sequence depicted in Scheme 48 <2005EJI637>. Phosphole 158 was subsequently used to prepare the corresponding phospholide anion via the corresponding 1,19-diphosphole.
Scheme 48
A series of novel dithieno[3,2-b:29,39-d]phospholes 159 have been prepared in good yields by reacting 3,39-dibromo2,29-dithiophene derivatives with butyllithium and subsequent addition of dichlorophosphines (Scheme 49) <2004AGE6197, 2005EJC4687>. Note that 5,59-bis(pinacolboryl)-functionalized dithieno[3,2-b:29,39-d]phospholes 160 have been prepared by sequential lithiation and addition of isopropoxy(pinacol)borane to the unsubstituted dithienophosphole (Scheme 49) <2006OL495>.
Scheme 49
The synthesis of phospholes involving the oxidative coupling of dienes with zirconocenes followed by zirconium– phosphorus exchange upon addition of dihalogenophosphine (Fagan–Nugent method) has been used extensively in the last few years for the preparation of functionalized phospholes. For example, 1-chlorophospholes 162 and
1087
1088 Phospholes C2-bridged bis(phosphole) 163 were obtained by reacting PCl3 and 1,2-bis(dichlorophosphino)ethane, respectively, with tetraalkylzirconacyclopentadienes 161 (Scheme 50) <1999OM3558, 2002NJC1378, 2000OM4899>. Alternatively, diphosphole 163 can be obtained from the reaction of the tetramethylphospholide anion with 1,2dibromoethane.
R PCl 3 R 2R
R
‘Cp 2 Zr’
R
R = Et, Pr n
R
.. P
Cl
R
162
ZrCp2 R
Me R
161
R
Cl 2P (CH 2)2 PCl2 R = Me
Me
..
Me
P
(CH 2)2
Me
163
..
Me
P
Me
Me Me
Scheme 50
The first polymer incorporating a phosphole moiety was prepared by Mao and Don Tilley using this type of organometallic approach <1997MM5566>. The zirconocene coupling of rigid diynes 164 proceeded in a nonregioselective manner affording an 80/20 isomeric mixture of 2,4- and 2,5-connected metallacycles 165a and 165b, respectively, in the polymer backbone (Scheme 51). The reactive zirconacyclopentadiene moieties can be converted subsequently to biphenyl–phospholyl polymers 166a and 166b, which are isolated as air-stable, soluble powders. They have been characterized by multinuclear NMR spectroscopy and their molecular weights determined by gel permeation chromatography (GPC) analysis (Mw ¼ 16 000; Mn ¼ 6200). Although NMR spectroscopy and elemental analyses support the proposed structures, the presence of a small number of diene units cannot be ruled out <1997MM5566>.
Scheme 51
Notably, phospholes with controlled regioselectivity can also be obtained from zirconium complexes using silylated alkynes. For example, sequential treatment of Schwartz’ reagent 167 with 2-butyne, MeLi, and silylated alkynes
Phospholes
affords zirconacyclopentadienes 168 with the silyl group occupying the -position only (Scheme 52) <1998OM5445>. A rather high reaction temperature is needed to perform the subsequent Zr/P exchange, but the transformation is almost quantitative (Scheme 52). Similarly, 2,5-disilyl-substituted zirconacyclopentadienes 169 are the sole coupling products obtained using various 1-(trimethylsilyl)-1-alkynes (Scheme 52) <1999OM4205, 1999OM2491, 2002OL1245>. However, the transformation of these metallacycles into the corresponding phospholes is very difficult. They do not react with PhPCl2, while treatment with PCl3 gives rise to 1-chlorophosphirenes <1999OM4205>. Another report described that the reaction of 169 with PCl3 gave a mixture of 1-chloro- and 1-cyclopentadienyl-phospholes <1999OM2491>; optimization of the reaction conditions allowed the pure 1-chlorophosphole derivative to be isolated. A successful transfer reaction was achieved with the 3,4-dimethyl derivative 169 and PBr3, affording the highly moisture-sensitive 1-bromophosphole 170 in 61% yield (Scheme 52). Notably, the nature of the silyl group also has a dramatic influence on the Zr/P exchange process, since 1-chlorophosphole 171 was isolated in 71% using PCl3 <1999OM4205>.
Me
Me
Me
i, 2-butyne Cp2 ZrCl(H)
167
ii, MeLi, –78 °C
PhPCl2 Me
Zr Cp 2
iii, MeCCSiMe 2 Cl
..
Me
100 °C
SiMe2 Cl
Ph Me
R
i, 2BuLi ii, 2 RCCSiMe 3
Me
PBr3 Me3 Si
Zr Cp2
169
SiMe2Cl
P
168 R
Me
SiMe 3
35 °C
..
Me3 Si
SiMe3
P
Br R = Ph, Bu n , Me
170
Cp2 ZrCl 2 Me Me3Si
i, 2BuLi ii, 2(MeCC)2 SiMe2 iii, PCl3
Me SiMe3
.. Si Si P Me Me Me Me Cl 171
Scheme 52
Another strategy to control the substitution pattern of phospholes is to prepare a zirconocene stabilized by 4-dimethylaminopyridine (DMAP) (Scheme 53) <2000JOM261>. This type of complex can react with the 1 equiv of alkyne to give a zirconacyclopropene derivative that, upon addition of a second alkyne, affords an unsymmetrical zirconacyclopentadiene, which can be trapped with phenyldichlorophosphine to give the corresponding phospholes 172 (Scheme 53). Note that in the case of 2-propyne, the unsymmetrical phosphole 172 is obtained together with 1-phenyltetramethylphosphole (80/20 ratio). The yields from this type of procedure are rather modest (20–50%) due to the difficulty of the Zr/P exchange step.
Cp 2 ZrCl 2
i, 2BuLi
Cp 2 Zr(DMAP) 2
Ph
Ph
ii, 2DMAP R 1 = Me, Et, Pr n
i, R
Cp 2 Zr DMAP
Ph
R1
Ph
Ph 1
ii, PhPCl2
R
1
Ph
.. P Ph
172 Scheme 53
R1
1089
1090 Phospholes Symmetrical and unsymmetrical 2,5-di(heteroaryl)phospholes can be selectively obtained using diynes 173 possessing a (CH2)3 or a (CH2)4 spacer (Scheme 54). The zirconacyclopentadiene intermediates 174 are extremely air- and moisture-sensitive derivatives, which react with dihalogenophosphines to give the corresponding phospholes 175a–j in medium to good yields (Scheme 54) <1999CC345, 2000AGE1812, 2002OM1591, 2003MM2594, 2006JA983>. This route is highly flexible since it not only allows electron-deficient and electron-rich rings to be introduced at the 2,5-positions, but also permits the nature of the P-substituent to be varied. The diyne precursors are accessible using classical Sonogashira coupling reactions using commercially available hepta-1,6- and octa-1,7-diynes. It is noteworthy that the stability of these phospholes is intimately related to the nature of the P-substituent. 1-Phenylphospholes 175a can be isolated, following flash column chromatography on basic alumina, as air-stable solids, yet its 1-alkylphosphole and 1-amino analogues are extremely air- and moisture-sensitive compounds.
n –2
Ar
(CH 2 )n
Ar
Cp 2 ZrCl 2
Ar
2 Bu Li
173 n = 3, 4
..
P
N
..
X
P
S
P
X = Cl, Br
R
175
..
S
P
..
S
N
Ph
R
175c
175d: R = Ph, Cy
..
OCH 3 N
P
NBu 2
S
.. P
N
R
175h: R = Ph, Cy
..
..
Ph
Ph
P
S
175g
175f
N
N
Ph
Ph
S
P
Ph
175e
..
Ar
175b: X = H, Br
Ph
N
Ar P
X
P
N
175a: R = Ph, Cy, Pri, Pri2 N
..
RPX 2
174
R
N
Ar Zr Cp 2
n
n –2
P
175i
175j
Scheme 54
This type of diyne coupling methodology has also been used to prepare well-defined longer-chain mixed derivatives using the corresponding oligodiynes as starting materials (Scheme 55) <2001CEJ4222, 2002JOM494, 2003OL3467>. The limits of this synthetic approach are (1) that the preparation of the oligodiynes requires several metal-catalyzed C–C bond formation steps, and (2) that the yield of the Zr/P exchange reaction decreases with increasing chain length. It is noteworthy that the reaction of 2,5-diphenyl- and 2,5-dithienyl-zirconacyclopentadienes with tribromophosphine afforded intermediate 1-bromophospholes, which spontaneously reductively couple to afford the corresponding 1,19-diphospholes in high yields <2004JA6058>. The mechanism for this transformation is unclear.
Phospholes
Scheme 55
Zr/P exchange processes have been also exploited for the synthesis of fused-phosphole derivatives. 2-Phosphinobenzophospholes 176 have been obtained by treatment of 2-phosphino-1-zirconaindenes with dichlorophosphines <1997CC279>. Similarly, 1,4-diphosphaindenes 177a (15% yield) and 177b (80% yield) were prepared using PhPCl2 and PBr3, respectively, as transfer reagents <1999CC537>. Me
..
PPh 2
Me
R P Et
P
R
P Et
176: R = Ph, But
177a: R = Ph 177b: R = Br
1091
1092 Phospholes Oxidative coupling of diynes with Ti(II) complexes has been less investigated for the preparation of phospholes. Titanacyclopentadienes have been used as intermediates for the synthesis of a family of 2,5-difunctional phospholes 178 bearing ester groups (Scheme 56) <2006JOC5792>. Although the isolated yields are moderate (ca. 30–50%), this synthetic approach nevertheless offers a straightforward route to functionalized phospholes.
X CO2 R 1
i, Ti(OPr i) 4 , Pr i MgCl
R
.. P
R2
X ii, PhPCl 2
2
CO 2 R 1
Ph
178 X = CH2 , CH 2 –CH 2, O R 1 = Et, Me R2 =
CO2 R 1 ,
,
,
,
S
N
Scheme 56
The reaction of 1,4-diethynyl-2,5-dioctyloxybenzene with a low-valent Ti(II) complex generated from Ti(IV) isopropoxide affords the titanacyclopentadiene-containing polymer 179 having a regioregular backbone (Scheme 57) . This polymer can be converted into the corresponding phospholebased macromolecule 180 upon addition of dichlorophenylphosphine.
Me R = C 6 H 17
..
nPhPCl 2
Ti(OPr i) 2
+ RO
OR
OR
OR
i
RO
Pr O
Ti
P
n
OPr
i
179
n
Ph
RO
180
Scheme 57
3.15.9.3 Some Synthetic Approaches to Reduced Phospholes As already mentioned, the chemistry of reduced phospholes is extremely vast and the description of all the synthetic methods leading to these species is beyond the scope of this section. The reader should refer to a number of excellent reviews to give an overview of the syntheses and applications of reduced phospholes <1994CRV1375, 2002CRV201, 2003CRV3029>. In this section, selected examples illustrating new trends are presented. Chiral 2,5-diphenylphospholanes have been prepared by Fiaud and co-workers according to the synthetic approach depicted in Scheme 58. The meso-phospholene 181 was obtained by a McCormak cycloaddition involving an aminophosphenium cation, with the resulting carbon–carbon double bond being removed by hydrogenation over Pd on carbon to give the corresponding phospholane 182 (Scheme 58) <2002T5895>. Isomerization of 182 into the more stable trans-isomer 183 was achieved by reaction with sodium methanolate that, following hydrolysis, affords the 1-hydoxy-r-1oxo-c-2,t-5-diphenylphospholane 184 (Scheme 58). This compound was readily resolved (ee > 99%) by fractional crystallization of its disatereoisomeric quinine salts. Subsequently, alkyl or aryl groups were introduced at the P-atom and, following reduction of the phospholane oxides 185, optically pure derivatives 186 were isolated <2002T5895>. They are efficient ligands for the Rh-catalyzed asymmetric hydrogenation of acyclic enamides. Note that an enantiopure 1-r-H-2-c,5-t-diphenylphospholane <2006TA2354> and a diverse range of 1-r-aryl-2-c,5-t-diphenylphospholane oxides and boranes <2003TA1141, 2006EJO650> have also been prepared using the same general approach.
Phospholes
i, Me2NPCl2, AlCl3
Ph
Ph
Ph
H 2 (50 b)
Ph P
ii, NaHCO3
O
Ph
Ph P
Pd/C
NMe2
O
181
NMe 2
182 MeONa H3O+
i, quinine Ph
Ph P
Ph
Ph
Ph P
+
O
OH (R,R )-184
Ph P O
R
Ph
Ph
P
ii, crystallization O
O OH (S,S )-184
Ph
Ph
P OH
O
184
i, MeOTf
..
Ph
NMe2
183
Ph
P
ii, LiAlH 4
R
186
185
R = Me, PhCH 2, Ph Scheme 58
3-Phospholene was obtained in 95% yield by ring-closing metathesis (RCM) of diallylphenylphosphine initiated by a cyclometallated aryloxycarbene tungsten complex <1995BSF1069>. Likewise, the RCM of acyclic dienes featuring a phosphinate moiety initiated by Cl2(PCy3)2RuTCHPh provides straightforward access to a family of 3-phospholene oxides <1999JOC2119>. The transient electrophilic terminal phosphinidene 188, which is readily accessible by thermolysis of 7-phosphanorbornadiene complex 187 (Scheme 59), is a powerful precursor to phospholenes. For example, it reacts with ethoxyacetylene to give phosphole 189, which upon hydrolysis affords the 2-phospholene complex 190 (Scheme 59) OEt HC COEt
O
H2O
EtO
EtO
P
P Ph
(OC)5W
189 Me
(OC)5W
Ph
Me
CO2Me
Me
187
190
Me (OC)5W
P
P
CO2Me
(OC)5W 110 °C or CuCl, 50 °C
PhP W(CO)5
Ph
(OC)5W
Ph
Ph P
Ph P
191
(OC)5W
188
Me
Me
192 W(CO)5
Ph P
+
P
W(CO)5 Ph
193
Scheme 59
194
1093
1094 Phospholes <2004OM1961>. The decomplexation step was accomplished by electrochemical reduction and the free 2-phospholene was oxidized with sulfur. The transient phosphinidene 188 also reacts with coordinated phosphole 191 to give the adduct 192 in 17% yield, which has been characterized by an X-ray diffraction study <2002CEJ58>. Reaction of 1,2-dimethylenecycloheptane with intermediate 188 affords a mixture of 2-vinylphosphirane 193 and phospholene 194 (Scheme 59) <2000T129>. Vinylphosphirane 193 is converted to phospholene 194 on heating at 100 C. The mechanism of this rearrangement has been investigated theoretically and is similar to that for their hydrocarbon analogues (i.e., rearrangement of vinylcyclopropane to cyclopentene) <2000JA3033, 2002JA13903>. Compound 194 was characterized in the solid state by an X-ray diffraction study. The reaction of 188, generated by the CuCl-catalyzed method, with cyclopropenes affords a mixture of compounds, one of which is a 3-phospholene derivative <2005AGE6579>. Note that a phospholene with exocylic isopropylidene groups has been obtained by reaction of the transient intermediate [Pri2N-PTFe(CO)4] with tetramethyldiallene <1999AGE2596>. Complex 196 was obtained by a Diels–Alder reaction involving one coordinated phosphole ligand of 195 and dimethyl acetylenedicarboxylate (Scheme 60) <2002CEJ58>. Thermal decomposition of 196 at 80 C yielded phospholene complex 197 as the major product.
Me Ph (OC) 4 Mo
Me Ph
Me
P
Z
Z
Me
P
(OC)4Mo
Ph P
Ph P
P Me
Me
Me
197
Z
Me
195
Ph
Ph
P
Me
Me
(OC) 5Mo 80 °C
Z
Z = CO2 Me
196
Scheme 60
An expedient route to cyclopentannulated 3-phospholenes such as compound 199 has been developed by Pietrusiewicz and co-workers. The general synthetic approach involves the deprotonation of 3-phospholene oxides, for example, 198, followed by quenching with 1,3-dihalogenopropane and subsequent reduction (Scheme 61) <2003TL5469>. This latter step proceeds with complete retention of configuration at phosphorus. The determination of enantiomeric purity and absolute configuration of phospholene chalcogenides has been the subject of several studies <2003TA1459, 2003CH391, 2006CH395>.
i, 2LDA
Ph3SiH
P O
P Ph
198
ii, X
X X = Br, I
O
..
P Ph
Ph
199
Scheme 61
2,29-Biphospholenes are readily available from the coupling of phospholes having no substituents at the 2,5position in the coordination sphere of nickel(II) (e.g., NiBr2, NiCl2), as illustrated in Scheme 62 <1999TA4701>. Optical resolution of these ligands has been achieved using chiral organopalladium complexes as resolving agents <1999OM4027, 1999TA4701>. Note that in the coordination sphere of a chiral Pt-complex, the [4þ2] cycloaddition of two molecules of 1-phenyl-3,4-dimethylphosphole occurs producing a chiral diphosphine having a 2-phospholene ring <2000CC167>.
Phospholes
Me
Me Me
Me
Me
Me Me
Me
Me
NiCl 2, cyclohexanol P
Me
NaCN P
>140 °C
P
Ph
Cl
P P Ph Ph
CH 2 Cl 2 , H 2 O
Ph
Ni
Ph
Cl
200 Scheme 62
3-39-Biphospholenes have also been prepared. The [4þ2] dimerization of transient 2,5-diphenyl-5-H-phosphole yields exclusively the P–P dimer 201, which reacts with MeI to give the monoquaternized product 202 (Scheme 63) <2003OM1356>. The nucleophilic attack of EtO induces the cleavage of the P–P bond with formation of the -bridged bisphospholene 203 (Scheme 63). This compound acts as a 1,4-chelate toward transition metals <2003OM1356>. Ph Ph
– P
Ph
H+
Ph
Ph
Ph
P
Ph
Ph
H
+ P P
MeI
P P
Ph
Ph Me
Ph Ph
EtOTl
EtO Ph
P P
Ph
201
Ph Me
Ph
202
203
Scheme 63
3.15.10 Phosphole Synthesis by Ring Transformation 3.15.10.1 General Besides the classic ring transformations that are described in the following sections, an elegant and powerful method based on the deprotonation of transient 2H-phospholes by ButOK has been devised by Mathey and co-workers <1997AGE98, 1998OM2996>. This route offers simple and straightforward access to -functionalized phospholide anions, which can subsequently be transformed into phospholes by addition of electrophiles (Scheme 64). The scope of this synthetic method is broad, but the temperature required to drive the reaction depends on the migratory aptitude of the P-substituent (see Section 3.15.5.1.2(i)). With 1-ethoxycarbonylphospholes <1997AGE98> and 1-silylphospholes <2002CC2976>, the anion is formed between 25 and 60 C and with 1-acylphospholes the reaction proceeds at 78 C within a few minutes <2001SL1977>. In contrast, with 1-phenyl-, 1-(2-pyridyl)-, and 1-(2-pyrrolyl)-phospholes, the formation of the corresponding phospholide anions takes place at 120–140 C <1997AGE98>. The corresponding phospholes, formed by addition of electrophiles (Scheme 64), are isolated in good yields (typically >65%), illustrating the high thermal stability of the aromatic phospholide anions.
R2 .. P
Δ
R2
H P ..
base
R2
R1
P ..
R1 CO 2 Et
-
SiPr i 3
C(O)Me
R 3 Br R1
C(O)Ph
R = N Me R 2 = 3,4-Me2, 2-CO2 Et-3,4-Me2 R 3 = –CH2CH2CO2Et, –CH 2CH2CN Scheme 64
.. P R3
1
N
R2
Ph 2 P
R1
1095
1096 Phospholes The versatility of this synthetic method is nicely illustrated by the preparation of -imino-phospholide and -phosphole derivatives (Scheme 65) <2006JA7716>.
Me
Me
Me .. P Ph
Me
Me
Me
Δ
–
Bu t OK
P ..
– MeC(Cl)=NPh
Me
P ..
Ph
K+
K+
Me
N
Me
Me 3 Sn
Ph
Me
.. P
Me 3 SnCl
N
Ph
Scheme 65
The high migratory ability of carbonyl groups (see Section 3.15.2.1) has been exploited to prepare a variety of C-acyl-phospholes. The very fast addition of acyl and benzoyl chlorides to the 3,4-dimethylphospholide anion, followed by the addition of ButOK, affords the functionalized phospholides 204 very efficiently; these compounds may then be converted into phospholes 205 (Scheme 66) <2001SL1977>. This methodology has been used for the preparation of 2,5-di(acyl)phospholes, but the yields are rather low (ca. 13%) <2001SL1977>. In a similar manner, 3-acylphospholes 206 have been prepared starting from 2,5-substituted phospholes (Scheme 66) <2005OL4511>. This route represents the first synthetic application of 3H-phospholes and provides straightforward access to 3-acylphospholes, which are extremely rare derivatives <1997JA5095>.
Me
Li +
Me
Me
Me
R 1 C(O)Cl
– P
Me Bu t OK
.. P
–78 °C, 10 min
Li +
C(O)R 1
Me
Me – P
C(O)R 1
BrCH2CH 2CO2Et
Me C(O)R 1
.. P
CH 2CH2CO2Et
204
205
R1 = Me, Ph C(O)R 2 Ph
.. P
Ph
Li
Ph
– P
Ph
Ph R 2 C(O)Cl Li
.. P
Ph
+
Ph
i, But OK, 60 °C ii, MeI
C(O)R 2
R 2 = Ph, Me,
Ph
.. P
Ph
Me
206
S Scheme 66
3.15.10.2 Dehydrohalogenation of C-Halo and P-Halo Phospholenes and Phospholanes This synthetic route remains one of the best, most widely used, and most general methods for the preparation of phospholes on the gram scale. The compounds that can undergo dehydrohalogenation to give the corresponding phospholes are halophosphenium salts 207, 2,5-dihalo-3-phospholenes 208, and 3,4-dihalophospholanes 209. X X–
+ P R
207
X
.. P
X
X
X
.. P
R
R
208
209
The conventional route to 3-phosphelium salts 207 is via the MacCormack reaction in which the five-membered ring is formed via a cycloaddition reaction between a 1,3-diene and a dihalogenophosphine <1996CHEC-II(2)757>. A variant of
Phospholes
this reaction that employed chlorophosphenium ions as dienophiles (Scheme 67) afforded 1-aminophospholes 210, following dehydrohalogenation <2002EJO675>. However, this route failed with larger R substituents such as But groups.
Pr i 2 N
R P
+
AlCl 4–
R
R
R
LiHMDS
+
Cl
.. P
+ P Pr i2 N
R
R
Pr i 2 N
Cl
210 : R = Me, Ph Scheme 67
Phospholes 11 and 12, bearing a sterically demanding 2,4-di-tert-butyl-6-methylphenyl substituent at the P-atom, were prepared according to the routes depicted in Scheme 68 <1996JOC7801>. Addition of bromide to the double bond of 3-phospholene oxide 212a affords 3,4-dibromophospholane 213a (71% yield), which is quantitatively reduced with trichlorosilane and dehydrohalogenated in the presence of a strong base to give the phosphole 11 in 61% yield (Scheme 68). This synthetic route is not amenable to derivatives bearing the highly sterically demanding 2,4,6-tri-tert-butylphenyl substituent due to unsuccessful reduction of the corresponding dibromophospholane oxide 213b (Scheme 68) <1997JA5095>. In contrast, the target phosphole 12 was obtained using the procedure of Mathey, namely dehydrobromination of the bromophosphelium bromide 214b with 2-picoline (Scheme 68) <1997JA5095>. In general, these synthetic routes are important since they provide entry to ‘flattened phospholes’ 11 and 12, which exhibit exceptionally high aromatic character (see Section 3.15.2.1). Me
Me
Br
Br2
H 2O 2
.. P Ar
Me
Br
P O
211a,b
P Ar
Ar
O
212a,b
213a,b HSiCl 3
Br 2 Me
Me
Me
Br
Br Br +
2-picoline
+ P
Br
Ar
NaOMe
.. P
Ar
Ar
214b
.. P
11,12 11 and a
12 and b Bu t
Me Bu t
Ar = Bu t
Bu t
Ar = Bu t
Scheme 68
The dehydrogenation step can also be conducted on phosphole oxides and sulfides as illustrated with the synthesis of a series of previously unknown 1,3,4-triphenylphospholes. The starting material is 1,3,4-triphenyl-3-phospholene1-oxide 215, which was treated with 2 equiv of NBS to afford a 1.4:1:1 mixture of compounds 216–218, which were separated by column chromatography (Scheme 69) <2000J(P1)1519>. Derivatives 216 and 217 were converted into 2-bromophosphole 220 following a sulfurization/dehydrobromation/reduction sequence. Note that a similar synthetic
1097
1098 Phospholes approach allows 1-amino-phosphole sulfide derivatives to be prepared <2002EJO675>. The 2,5-dibromophosphole 221 was obtained in 81% yield by reduction of the corresponding phosphole oxide 218 by HSiCl3 (Scheme 69) <2000J(P1)1519>. Finally, 1,3,4-triphenylphosphole 219 was prepared in good yield from phosphole oxide 215 according to a related bromination/dehydrobromination/reduction sequence, as depicted in Scheme 69. Ph
Ph
2NBS P Ph
O
Ph
Ph Br
Br
P O
+
Br
Ph
Br
Br
P
Ph
O
Ph
Ph
Br +
P
216
215
Ph
Ph
O
217
Ph
218
i, NBS i, P 4 S 10 ii, KOH
ii, KOH iii, HSiCl3
iii, P(CH 2 CH 2 CN) 3
Ph
Ph
HSiCl 3
.. P
.. P
Ph
Ph
Ph
Ph
Br
Br
.. P
Ph
Ph
Ph
219
220
221
Br
Scheme 69
3.15.10.3 Displacement of P-Substituents The P-substituent of the phosphole ring can be formally displaced using two complementary approaches. The first involves the reductive cleavage of the P-substituent bond affording a nucleophilic phospholide anion that, upon reaction with electrophiles, gives rise to a novel phosphole 222 (Scheme 70). In most cases, this type of reaction employs readily available P-phenylphospholes, although phospholide anions can also be obtained from other phosphole precursors (see Section 3.15.5.1.5). The second strategy utilizes the attack of nucleophiles on halogeno- or cyano-P-substituted phospholes (Scheme 70). Note that P-halogenophospholes are generally too air and moisture sensitive to be isolated and hence are trapped by nucleophiles in ‘one-pot’ synthetic procedures. In contrast, P-cyanophospholes are stable and easy-to-handle building blocks.
M = Li, K, Na R2
R 1 = Ar, Br, Cl
R2
– P
M+
.. P R1
E+
R2 .. P E
Nu – R 1 = Cl, Br, CN
R
2
222
.. P Nu
Scheme 70
Phospholide anions can undergo coupling reactions with sp2-C-centers bearing halogens in the presence of metals. This method has been exploited with the 3,4-dimethylphospholide anion, which can be converted into 1-(8-quinolyl)phosphole 223 (52% yield) upon reaction with 8-chloroquinoline at 80 C in presence of CuI (Scheme 71) <1997JOM17>. In the presence of Ni2þ in THF at reflux, the same P-anion reacts with 1,2-dibromobenzene to give the phosphole derivative 224 in 55% yield (Scheme 71) <1998OM2996>.
Phospholes
Me
Cl
Me
N
.. P
N CuI, THF, 80 °C Me
Me –
223
Li +
Br
Br
Me
Me
P
.. P
Br
Ni 2+, THF, 80 °C
224 Scheme 71
Surprisingly, the reaction of diacyl dichloride electrophiles with 3,4-dimethylphospholide affords the 3,39-bis(phospholyl)lactones 225a and, 225b, which result from attack of the second molecule of phospholide at the phospholyl– C(O) group rather than the acyl chloride moiety (Scheme 72) <2005JOM450>. Note that the second attack was not observed using chloroformates as electrophiles (Scheme 72) <2004CC1144>. Me
Me
C(O)Cl Me
0.5
Me P
C(O)Cl
P
O M = Li, R = H O
225a Me Me
Me 0.5 Cl(O)C
R
– P
M
C(O)Cl
Me
Me
Me P
+
P
M = Li, R = H
O O
225b Me
Me (–)MenOCOCl
.. P
M = K, R = H, Ph O
R Me O i
Pr
Scheme 72
In phospholide chemistry, the most widely investigated electrophiles are sp3-C derivatives, chosen with the aim of preparing novel ligands for homogeneous catalysis in particular chiral P,P- and P,N-chelates of various sizes. C2-, C3-, and C4-bridged bisphospholes, including derivative 163 (Scheme 50), have been obtained by reacting
1099
1100 Phospholes tetramethyl- <1999OM3558> or 2,5-(di-()-menthyl)-phospholide anion <2001OM1014, 2001JOM182> with 1,2dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, ,9-dibromo-o-xylene, trans- and cis-11,12-bis(methanesulfonylmethyl)-9,10-dihydro-9,10-ethano-anthracenes (Scheme 73).
Scheme 73
A series of 1-(3-buten-1-yl)phospholes 226a–c have been obtained in good yields (Scheme 74) <2002JOC5422>. 1-(2-Methylpyridine)phosphole 227 was also prepared according to this synthetic methodology using 1,19-bis(2,5diphenylphosphole) as phospholide precursor and 2-chloromethylpyridine as electrophile <2003OM1580>. Phospholes 228 bearing optically active substituents at P have been prepared from phospholide anions and chiral electrophiles (Scheme 74) <2002EJI1657>. These chiral derivatives have been used as ligands for metal-promoted asymmetric catalysis and as precursors to chiral phosphinidene and phosphaferrocene derivatives. R1 Br
R
R1
..
2
R
P
a: R1 = Me; R2 = H b: R1 = H; R2 = Ph
2
c: R1 = R2 = H
226a– c R1 R2
R1 – P
..
Cl
Ph
P
N N
R2
Ph
227 Me
Me
..
R*X
P
R*
228 Me O
R*X = OMs
Scheme 74
OMs
F
N
Phospholes
This type of synthetic strategy is also efficient for the synthesis of 2,29-diphospholes as shown by the transformation of the P-phenyl derivative 229a into its P-cyano analogue 229b (71% yield) <2000T85> and the synthesis of the chiral derivatives 229c from the phosphole tetramer 230 (65% yield) <2003CC1154, 2005OM5549> (Scheme 75). 1-Cyano-2,3,4,5-tetramethylphosphole was also prepared according to this procedure in 56% yield <2002TA1097>.
R1
R1 R1
R1
R1
..
.. P
P
Ph
Ph
R
R2
R1 R1
..
R2 R1
1
R R –
R1
..
P
1
P R2
P
CN
1
CN
229b
– P R 1 = Me
R1 TsO
OTs
Ph
R1 R1
..
R1
..
P
*
Na-naphthalene
P .. R1 R1
R
R 2 = H, Ph
P
..P
1
R1
..
P
229a R1
..
BrCN
Li
R1 R1
Ph
P
*
R2
229c
R1
230 H TsO
OTs *
TsO
OTs
Me
Me
TsO
OTs
TsO
OTs
= Me
Me
Me
Me
O
TsO TsO
O
Me Me
H Scheme 75
Another facet of this versatile methodology is its potential for the synthesis of functionalized phospholes, which can be used for further chemical transformations. For example, anion 231, which was prepared by reduction with lithium of the corresponding P-chloro-phosphole and characterized by NMR spectroscopy, is an efficient intermediate for the preparation of functionalized phospholes 232 (66–80% yield) (Scheme 76) <1999OM4205>. These phospholes are useful precursors for the synthesis of mixed phosphinine- and phosphaferrocene-phosphole ligands. The 1-(2cyanoethyl)phosphole was characterized by an X-ray diffraction study <1999OM4205>.
Scheme 76
A remarkable ‘one-pot’ synthesis of various phosphole-2,5-dicarboxylic acids has been established, which involves nucleophilic attack of 2,5-disilyl-phospholide anions on carbon dioxide (Scheme 77) <2002OL1245>. The first step involves the formation of 1-carboxylatephosphole that undergoes a [1,5]-sigmatropic shift of the carboxylate group (see Section 3.15.5.1.2(i)) followed by a [1,3]-shift of the silyl group giving the intermediate 233 (Scheme 77). This species is sufficiently reactive to attack a second molecule of carbon dioxide giving a novel phospholide anion, which, when reacted with bromo compounds, yields the corresponding phospholes as their dicarboxylic acid derivatives 234 in good yields (72–82%) <2002OL1245>. 2-Acyl-3-methylphospholide also reacts with dichloromethane to give the corresponding 1-chloromethyl-2-acetyl-3-methylphosphole, which is a phosphinine precursor <2005AGE1082>.
1101
1102 Phospholes
Scheme 77
Nucleophilic substitutions involving phospholide anions and main-group electrophiles have also been investigated. For example, 1-phosphinophospholes have been prepared in good yields by nucleophilic attack of 3,4-dimethylphospholide anion on alkyl and aryl dichlorophosphines <1997JOM197>. This approach has also been used to prepare the diphosphine 30, which has a highly polarized P–P bond <2004AGE4801>. mes
Et Et
N P P N mes
Et Et
30 3,4-Dimethylphospholide anion also attacks tributyltin chloride to give the adduct 235, which has been used to prepare a family of phospholes 236 featuring a variety of aryl substituents at the P-atom through Pd-catalyzed coupling (Scheme 78) <2000OL2885>. However, this methodology is of limited value due to the low yields (7–30%) obtained even with iodoaryl derivatives. Note that 1-stannyl phospholes have also been engaged in transmetallation reactions with TiCl4 for the preparation of mono(phospholyl)titanium complexes <2006OM1079>. 1-Stannylphospholes with ()-menthyl and cyclohexyl substituents at the 2- and 5-positions have also been prepared and used as 1,19-diphospharuthenocene precursors <2002OM3062>. This synthetic approach to phosphametallocenes is also efficient with 1,2,4-triphosphaphospholes <2005CEJ5381>.
Scheme 78
In contrast, the rather low reactivity of 1-stannyl phosphole can be exploited to perform selective monosubstitution on dihalogeno-electrophiles as illustrated with 2-bromophosphinines, which are highly reactive electrophiles. They undergo nucleophilic attack by phospholyl anions to give 2-(1-phospholyl)phosphinines in 60% yield <1995BSF910>. The reaction can be catalyzed by Pd(0) and can be applied to 2,5-bromophosphinines to afford the corresponding 2,5-(1phospholyl)phosphinine 237 (Scheme 79) <1995BSF910>. Using less reactive 1-stannylphospholes, the Pd(0)-catalyzed cross-coupling reaction gives rise to only the monosubstituted derivatives 238 (Scheme 79).
Phospholes
Scheme 79
The displacement of leaving groups (e.g., -CN, Cl, Br, etc.) from the P-atom of phospholes by nucleophiles is a method of considerable value for the synthesis of functionalized phospholes (Scheme 70). For example, 1-cyano-3,4dimethylphosphole undergoes nucleophilic attack of 1-methyl-2-lithiopyrrole to afford the 1-(1-methyl-2-pyrrolyl)3,4-dimethylphosphole in 65% yield <1998OM2996>, while the dilithium salt of cyclohexane-1,4-diol gives rise to (axial-equatorial) 1,4-bis(3,4-dimethylphospholyl-1-oxy)cyclohexane <2001JOC755>. Chiral 1-pyrrolidinophospholes 239a and 239b have been prepared for use in asymmetric catalysis according to the same general route (Scheme 80) <2002TA1097>. This procedure employing lithium salts is more rapid and gives higher yields than that based on the attack of 1-cyanophospholes by pyrrolidone in the presence of triethylamine. The enantiopure bis(phosphole) 240 was prepared as a precursor to the corresponding chiral bis(7-phosphanorbornene) (see Section 3.15.12.1.1) <2003OL3093>.
Me
Me R1
..
+
R1
P
CN Me
Me R1
.. P
..
R1
R1
P
R2
Me
.. P
N
Ph
Ph
O
O
P
P
N O
239a
R 2Li
R 1 = H, Me Me
R1
Me
Me
O
O
239b
Me
Me Me
Me
240
Scheme 80
Using the same synthetic approach, phospholes 241 having anionic cyclopentadienide and tetramethylcyclopentadienide substituents at the P-atom have been obtained in good yields (60–90%) (Scheme 81) <2001OM5513>. When 1,19-dilithioferrocene is used as the nucleophile, the 1,19-ferrocenylene-bridged bis(phosphole) 242 is obtained in 74% yield (Scheme 81) <2002MI245>. This compound is a precursor of bis(1-phosphanorbornadiene) (see Section 3.15.12.1.1). Chiral (dialkylamino)methyl(phospholyl)ferrocenes 244 have been prepared via a multistep sequence starting with a diastereoselective ortho-lithiation to afford nucleophile 243 (Scheme 81) <2003EJI2820>. A similar synthetic approach has been used for the preparation of enantiomerically pure ferrocenyl derivatives containing the dibenzophosphole moiety <2006AXC188>. 1-Phospholyl-acetylenes 246a and 246b were synthesized by reaction of alkynyl Grignard reagents with 1-chloro2,3,4,5-tetraethylphosphole 245 (Scheme 82) <2006HAC344>. Ethynylphosphole 246a was transformed into the corresponding alkynyl Grignard reagent and reacted with phosphole 245 to afford the di(1-phospholyl)acetylene 247 (Scheme 82) <2006HAC344>. This derivative was characterized by an X-ray diffraction study after oxidation of the P-atoms with elemental sulfur.
1103
1104 Phospholes
Scheme 81
Et Et
Et
..
Et Et
P
Et
Cl
245
R
1
..
MgBr
R1
P Et
Et 246a: R 1 = H
246b: R 1 = Ph Et
Et
Et ii, 245
Et
:
i, EtMgBr
:
246a
P
P
Et Et
247
Et Et
Scheme 82
3.15.10.4 Displacement of C-Substituents Displacement of C-substituents of phospholes is not a well-documented process. However, there are two reactions that can be viewed formally as involving C-substituent displacement. The first involves phospholes bearing halides in the -position with respect to the P-atom. The halides can be formally ‘displaced’ by Sonogashira coupling or halogen–Li exchange reactions. These reactions are presented in detail in Section 3.15.7 (Schemes 35 and 36). The second type of reaction is electrophilic substitution in which an hydrogen atom is displaced by an electrophile. Remarkably, phosphole 12 bearing a sterically demanding substituent at phosphorus undergoes a Friedel–Crafts reaction to give a mixture of acylphosphole isomers 248a–c (Scheme 83) <1997JA5095>. In the presence of 2 equiv
Phospholes
of acetyl chloride and AlCl3, the P-aromatic substituent is acetylated. Electrophilic substitution is also observed with propionyl and butyl chlorides affording a mixture of monoacylated products 249a and 249b (Scheme 83) <2000J(P1)2895>. No reaction occurs with benzoyl and diphenylphosphinoyl chlorides probably as a result of steric constraints. The origin of this unprecedented reactivity pattern lies in the quite high aromatic character of 1-(2,4,6-tritert-bupylphenyl)phosphole 12, which itself arises from P-flattening (BI ¼ 56.5, see Section 3.15.2.1). This is nicely illustrated by the fact that using 1-(2,4,6-triisopropylphenyl)phosphole, which is less aromatic (BI ¼ 40.4), the yield of monoacylphospholes is extremely low (ca. 10%) <2000J(P1)2895>.
Me
.. Bu t
Bu t
CH3 C(O)Cl
Bu t
12
Bu t
Bu t
.. P
Bu t
+
P
But
Me(O)C
P
Bu t
+
AlCl3
.. Bu t
Me
..
C(O)Me
P
Me
Me
Me(O)C
Bu t
Bu t
Bu t
248a
248b
248c
49%
22%
22% Me
Me
.. AlCl 3
Bu
..
C(O)R
P
RC(O)Cl t
Bu
P
t
Bu
t
Bu t
R = Et, Pr n
+ C(O)R
Bu
t
Bu t
249a
249b
36%
17%
Scheme 83
3.15.11 Synthesis of Particular Classes of Phospholes 3.15.11.1 General Over the last decade, a wide variety of functionalized phospholes have been synthesized either directly by ring formation or via modification of preformed phosphole skeletons, as illustrated in Sections 3.15.9 and 3.15.10, respectively. Here, the structures of the previously described derivatives are presented in tabular form along with their precursors, the schemes in which their synthesis is described, and the references. Note that only isolated and fully characterized derivatives have been included.
3.15.11.2 Carboxylic Acids and Derivatives Notably, 5-bromo-1,3,4-triphenylphosphole-2-nitrile 125 (Table 21) is obtained in low yield by reacting 125 with CuCN. This reaction affords mainly 130a and 130b, the products resulting from coupling (see Scheme 36).
3.15.11.3 Aldehydes and Ketones Aldehyde- and ketone-functionalized phospholes are comparatively rare derivatives (Table 22). Note the unusual electrophilic substitution reaction performed with 1-(2,4,6-tri-tert-butylphenyl)-3-methylphosphole 12, which affords a series of ketone-functionalized phospholes (see Scheme 83, Section 3.15.10.4).
1105
1106 Phospholes
Table 21 Synthesis of phosphole carboxylic acids and derivatives Precursors
Products
Substituents
Scheme
Reference
37
1998CR715
R ¼ CH2Ph, CH2CO2Et, (CH2)2CO2Et, (CH2)2CN, 1,2(CH2Br)Ph, 1,4(CH2Br)Ph
77
2002OL1245
R1 ¼ Me, Et R2 ¼ CO2R1, Ph, 10-anthracyl, 2-thienyl, 2-pyridyl, X ¼ CH2, CH2-CH2, O
56
2006JOC5792
72
2005JOM450
72
2005JOM450
72
2005JOM450
R ¼ H, Ph
2000J(P1)1519
(Continued)
Phospholes
Table 21 (Continued) Precursors
Products
Substituents
Scheme
Reference
41
1996BSF541
R ¼ Ph, (CH2)2CO2Et
41
1996BSF541
R ¼ Me
75
2000T85
R ¼ Me
2002TA1097
Table 22 Synthesis of aldehyde- and ketone-functionalized phospholes Precursors
Products
Substituents
Schemes
Reference
R ¼ Me, Ph
35, 36
2000J(P1)1519
R ¼ Me, Ph
66
2001SL1977
R ¼ Me, Ph, 2-thienyl
66
2005OL4511
1107
1108 Phospholes
3.15.11.4 Halo Substituents Phospholes bearing halo substituents (Table 23) are key building blocks for the synthesis of other functionalized phospholes (see Section 3.15.10.4). The use of derivative 125 (R ¼ Ph) for the preparation of a series of halosubstituted 3,4-diphenylphospholes is presented in Section 3.15.7 (Scheme 36). Table 23 Synthesis of phospholes with halo substituents Precursors
Products
Substituents
Schemes
Reference
30
2005CEJ6829
35
1996BSF33
35
1996BSF33
35, 36
2000J(P1)1519
47
1996PS309
R ¼ Et, Prn
50
2000OM4899 2002NJC1378
R ¼ SiMe3 (X ¼ Br), Si(Me)2CUCSiMe3 (X ¼ Cl)
52
1999OM4205
R ¼ Me, Ph
(Continued)
Phospholes
Table 23 (Continued) Precursors
Products
Substituents
Schemes
Reference
69
2000J(P1)1519
69
2000J(P1)1519
3.15.11.5 Silyl Derivatives Numerous phospholes bearing silyl substituents have been prepared in the last decade and illustrative examples are presented in Table 24. Some examples of related tin derivatives are also provided in Table 24.
Table 24 Synthesis of phospholes with silyl and stannyl substituents Precursors
Products
Substituents
Scheme
Reference
37
1998CR715
48
2005EJI637
R1 ¼ SiMe3, SiButMe2, SiMe2H, SnMe3, (pin)B
49
2004AGE6197, 2005EJC4687, 2006OL495
R ¼ SiMe3 (X ¼ Br), Si(Me)2CUCSiMe3 (X ¼ Cl)
52, 76
1999OM4205
(Continued)
1109
1110 Phospholes
Table 24 (Continued) Precursors
Products
Substituents
Cp2ZrCl(H)
167
Scheme
Reference
52
1998OM5445
65
2006JA7716
78
2000OL2885
3.15.11.6 1,10-Diphospholes 1-19-Diphospholes are still comparatively rare compounds and their chemical behavior is largely unexplored. Four examples are given in Table 25. Table 25 Synthesis of 1,10-diphospholes Precursors
Products
Substituents
R ¼ Ph, 2-thienyl
Scheme
Reference
47
2002CC1646
Section 3.15.9.2
2004JA6058
2005EJI637
Phospholes
3.15.12 Important Compounds and Applications 3.15.12.1 Phospholes as Precursors for Other Phosphorus Heterocycles 3.15.12.1.1
7-Phosphanorbornenes and 7-phosphanorbornadienes
The vast majority of bicyclic phosphole derivatives with norbornene- and norbornadiene-derived skeletons are prepared via classical [4þ2] cycloaddition reactions of phospholes. While Diels–Alder reactions of phospholes with CN 4 (e.g., oxides and sulfides) are common through direct reaction with dienophiles, this type of reaction is comparatively rare for CN 3 phospholes (see Section 3.15.5.1.4). A good recent example of a direct cycloaddition reaction is that which occurs between N-phenylmaleimide and the sterically encumbered phospholes 11, 12, and 27. Here the exact nature of the products obtained is dependent on reaction temperature (Scheme 84) <2000HAC271>. Following heating at 60 C and subsequent oxidation, a mixture of 7-phosphanorbornenes 250 and 251 (total yield ca. 55%) is obtained in varying ratios, something that depends on both the nature of the Ar P-substituent and the reaction times (250c:251c ¼ 62:38, 250a,b:251a,b 93:7]. In contrast, heating the same reactants at 110 C affords a 9:1 mixture of syn-59c and anti-60c (68% combined yield), with the compounds being isolated as their oxides following treatment with H2O2. Results from a computational study of this reaction are in good agreement, and indicate that product 59c is indeed the more stable isomer <2002T9801>. O i, Δ, 60 °C, CH2Cl2
O
Ar
P
Ar H
Me
ii, H2O2, 0 °C, CH2Cl2
O
P P
1
H
3
Ar O
Me
O
H
NPh
+ NPh
3
11 and a: R = Me; R = R = Bu 12 and b: R1 = R2 = R 3 = Bu t 27 and c: R1 = R 2 = R 3 = Pr i
Ar =
R
2
O
251a–c P
27 R2
NPh
Ar
Me
Δ , 110 °C, C7H8
H H
t
O
H
ca. 55%
250a–c
O
R1
H
+ NPh
Me
Ar
O
Me
O
H
11, 12, 27
NPh
P
O
O
ca. 68%
59c
60c
Scheme 84
If similar Diels–Alder reactions are undertaken with equimolar mixtures of 1-arylphosphole oxides, four different [4þ2] cycloadditions take place <2001HAC633>. Both the expected symmetric phosphole oxide dimers as well as crossed cycloadducts are obtained. Reactivity analogous to that for phospholes 11, 12, and 27 is observed between N-phenylmaleimide and 3-methyl(2,4,6-trisopropylphenyl)-phosphole oxide and affords the corresponding 7-phosphanorborne oxide 251c directly <2004T2789>. Treating 251c with MCPBA in chloroform affords the corresponding aryl-2,3-oxaphosphabicyclo[2.2.2]octene 252a and 252b as a mixture of two isomers in approximately equimolar quantities (Scheme 85).
Ar Me
P
O H O H NPh
251c O Scheme 85
MCPBA 26 °C CHCl 3
O O Ar P Me
252a
Ar
O P
H O H NPh O
O +
Me
252b
H O H NPh O
1111
1112 Phospholes Reaction of phosphabicyclo[2.2.1]heptene 253a and 253b with 4.4 equiv of borane (Me2S?BH3) under mild conditions (22 h at 25 C; 5 h at 63 C) afforded borane derivatives 254a and 254b (Scheme 86) <2000J(P1)4451>. Notably, both imide carbonyl groups were reduced to methylene moieties. The use of 3.0 equiv of the borane led to mixtures containing predominantly 254a and 254b and only a trace quantity of the expected product 255a and 255b, as shown by 31 P NMR spectroscopy and fast atom bombardment (FAB) mass spectrometry <2000T7, 2000J(P1)4451>. Ph
P
O H O H NPh
Me R
253a,b O
Ph
4.4 Me 2 S•BH 3
P
Me
CHCl 3
R
i, 22 h at 25 °C ii, 5 h at 63 °C
BH 3 H H NPh
254a,b
a: R = H b: R = Me 3.0 Me 2 S•BH 3 CHCl 3 Ph
254a,b
P
BH 3 H O H NPh
Me
+
R
O
255a,b Trace Scheme 86
A further example of the influence of the P-substituent on the Diels–Alder reactivity of CN 3 phospholes is seen with compounds bearing electron-withdrawing groups. Such substituents reduce the aromaticity of the heterocycle and hence lower their reactivity, which is something that is evident in reactions of 3,4-dimethylphospholes 61 and 63 (Scheme 87) <2001JOC755>; for a detailed discussion, see Sections 3.15.2.1 and 3.15.5.1.4. While the reaction of acrylonitrile with phosphole 61 requires 18 h at 80 C and affords a mixture of syn/anti-endo-62a and -62b, the isopropoxy derivative 63 affords exclusively anti-endo-64 after only 1 h at 30 C. Similarly, a related 7-phosphanorbornene 65 is obtained from reaction of 63 with a vinylphosphonate under identical conditions. CN
NC P
P
R = CN
Me
H 2 C CH
+
CN
18 h, 80 °C
Me
Me
62a CN
Me
35% Me
Me
H 2 C CH P
OPr i
R = OPr i CN
1 h, 30 °C
R
61: R = CN 63: R = OPr i
R = OPr H 2 C CH
P Me Me
64 CN
i
OPr i P(O)(OEt)2
1 h, 30 °C
P Me Me
65 Scheme 87
P(O)(OEt) 2
62b 55%
CN
Phospholes
The presence of electronegative P-phosphole substituents also has the effect of facilitating reactions of these groups with unactivated alkenes. Such behavior is observed in reactions of P–CN phospholes 256a and 256b with lithium allyloxide (Scheme 88) <2002JOC5422>. For both substrates, initial substitution of the cyano group occurs at ambient temperature affording phospholes 257a and 257b, which are extremely reactive undergoing spontaneous, rapid intramolecular Diels–Alder reactions leading to the formation of the novel cycloadducts 67a and 67b; these latter reactions are favored entropically. The molecular structure of 67a has been determined by X-ray diffraction. Notably, identical reactivity is observed with lithium allylamides and even for 1-lithio-3-butene, although as would be expected for an unactivated alkene, the cyclization reaction for the latter requires considerably harsher reaction conditions (110–140 C, 10–12 h) (See Scheme 16, Section 3.15.5.1.4). R1
R1
R1
R1
O
R
P
R
–78 to 25 °C
CN
R
P
R1
R
OCH 2 CH
256a : R = H; R1 = Me 256b : R = Ph; R1 = H
P R
25 °C
THF
R
CH 2
257a,b
R1
67a,b
Scheme 88
It is now well established that Diels–Alder-type reactions of phospholes are facilitated in the coordination sphere of transition metals (the metal activating the cyclic diene fragment by further reducing the already small extent of cyclic delocalization <1981S983>). Subsequent decomplexation of the resulting 7-phosphanorbornenes is generally achieved on reaction with aqueous CN <2004ACR169>. Typically, this type of reaction sequence employs activated heteroatom-containing dienophiles that can coordinate to the metal alongside the phosphole component, something that gives rise to 7-syn, 2-exo-products in a template-type fashion. Significantly, this methodological approach can be extended to afford access to chiral, CN 3 7-phosphanorbornenes. These heterocyclic P-compounds have found use as ligands in a variety of asymmetric catalytic applications. A number of examples of the types of ligand available through this general synthetic sequence are given in Table 26; selected examples of this type of ligand have been reviewed recently <2004ACR169>.
Table 26 Selected examples of chiral 7-phosphanorbornene ligands prepared using a metal template strategy Ligand
Ph
Reference
S PR
PPh2
Ligand
References
2002OM3918
2000OM91
P
P
Ph
Ph HH
Ph P
R SMe
P:
2002OM171
:P
Ph
S CN
1999OM4027
Ph S PRC
Ph Ph P
R
P
S NMe2
O
2001JCD309
1998TA2961
O (Continued)
1113
1114 Phospholes
Table 26 (Continued) Ligand
Reference
Ligand
References
Ph
R/S
P
Ph P
R
N 2000IC3392
1998OM3931
N
Ph P
R
Ph P
R
O S
2000TA2661
1998JCD893 1995CC1747
E E = SO2 Ph E = C(O)NMe2
R PS P S S
Ph
Ph P
Ph P
P
PPh2
2000JOM177
PPh2
2000OM91
R
Ph P
R S
1998JCD893
AsPh2
1996OM3640 1997JA12560
R
Although widely applicable, the success of this type of metal-facilitated cycloaddition strategy for the preparation of 7-phosphanorbenes is sensitive to the nature of the complex, phosphole, and dienophile. For example, [4þ2] cycloaddition (affording 260) can compete with insertion into the Pd–C bond (to give 259) of the starting complex 258 when dimethyl acetylenedicarboxylate is employed (Scheme 89) <2002OM2041>.
Me
Me Me N Cl Pd P
R
259
R Ph
Me R Me Me
R
Me Me N Cl Pd
insertion Ph R = CO2Me
258
P
Me R Me
R
Me Me N Cl Pd
cycloaddition
R R
P Ph Me
Me
260
Me
Scheme 89
In an alternative metal-templating methodology (Scheme 90), cycloaddition between 3,4-dimethyl-1-phenylphospholesulfide and diphenylvinylphosphine has been achieved in the coordination sphere of a chiral Pd(II) complex <2002OM5301>. Following resolution of an intermediate Pd(II) complex by crystallization, subsequent treatment with cyanide liberates the optically pure thiolated cycloadduct ()-261 stereospecifically. Similar cycloaddition chemistry of 3,4-dimethyl-1-phenylphosphole may be achieved using cationic, half-sandwich Cp* Ru(II) complexes of diphenylvinylphosphine 262 <2005JCD92>. As above, the resulting Ph2P-substituted 7-phosphanorbornene remains bound to the metal center. Notably, reaction of 262 with 1,1-diphenylpropargyl alcohol affords phospholium salts rather than heterobicyclic compounds.
Phospholes
Me Me
Me Me
Me Ru
OC
P N Ph 2 C Me
262 Me
Me Me N OClO3 Pd
Me
Ph S
P
i,
Me Ph 2P
ii, HCl
PPh2
Ph
P
S
Me
R
iii, KCN
Me (–)-261
Scheme 90
Diels–Alder reaction of Mo(CO)5-bound 3,4-dimethylphospholes 263a and 263b with benzyne (generated in situ from anthranilic acid and isoamyl nitrite) affords the corresponding 2,3-benzo-7-phosphanorbornadiene complexes 264a and 264b, as illustrated in Scheme 91 <2005OM1762>. The molecular structure of the phenyl derivative has been determined in the solid state. Surprisingly, the free 7-phosphanorbornadienes could not be isolated. Reaction of complexes 264a and 264b with DPPE in toluene at 110 C affords PhPH2 as the only phosphorus-containing product (Scheme 91). This is presumed to form via reaction of phenylphosphinidene, generated by decomposition of the phosphole, following proton abstraction from the toluene solvent. Under similar conditions, treatment of 264b with excess sulfur leads to the formation of phenyldithioxophosphorane 265 that forms from cycloaddition of [PhPS2] with 2,3-dimethylbutadiene.
NH2 Me
Me
(OC)5 Mo
CO2H + isoamyl nitrite P (OC)5Mo
R
Me
C 7 H 8 , rt
R
P
a: R = H b: R = Me
Me
263a,b
264a,b DPPE
a,b
Δ , C 7H8
Δ
Ph P
PhPH2
264
Me
b
S8 Δ , C 7H 8
Ph P
S
S8 Δ
Me Me
Ph PS2
Δ
P S
Me
Ph
265 Scheme 91
In a similar manner, a nonchelating cis-bis(7-phosphanorbornadiene)–Mo(CO)4 complex 1959 may be prepared in 90% yield via a double Diels–Alder reaction, by treating the previously reported bis(3,4-dimethylphosphole)Mo(CO)4 complex 195 with dimethyl acetylenedicarboxylate (Scheme 92) <2002CEJ58>. On heating the new complex 1959 at 60 C in the presence of CuCl, intramolecular addition occurs, with the formation of 266 in 73% yield. Note that in
1115
1116 Phospholes the absence of CuCl, the reaction affords the 2-phospholene derivative 197 (see Scheme 60). The product 266 is believed to result from the initial decomposition of one of the metal-bound 7-phosphanorbornadiene groups. This generates a phosphinidene species, which subsequently adds intramolecularly to a CTC bond of the other ligand to give the novel, chelated diphosphorus complex 266. By 31P NMR spectroscopy, the expected two resonances are observed, with chemical shifts of þ159.7 and 79.7 ppm. The origin of the low-frequency chemical shift for the latter signal has been attributed to negative hyperconjugation between the phosphorus group and the adjacent CTC bond. Significantly, heating complex 266 in toluene at reflux neither liberates the diphosphorus compound nor causes any decomposition, which reflects the stability of this particular metal chelate.
Ph
(CO) 4 Mo P
Ph
R
(CO) 4 Ph Mo Ph P P
R
R
P 50 °C, 24 h
Me
Me Me
Me
R
Me Me
R
R
R = MeCO 2 Me
Me
195′
195
CuCl 60 °C (CO)4 Mo Ph P
P
Ph R
Me Me
R
266 Scheme 92
Notably, it is not just heteroatom-functionalized alkenes that can behave as dienophiles with metal-bound phospholes. It has been demonstrated that reaction of 2 equiv of 3,4-dimethyl-1-phenylphosphole with a cationic platinum(II) complex of an enantiomerically pure cyclometallated N,N-dimethyl-1-(1-naphthyl)ethylamine ligand affords, following decomplexation with cyanide, the novel optically pure diphosphine (þ)-267 quantitatively as an air-sensitive oil (Scheme 93) <2000CC167>. The high-frequency chemical shift of one of the phosphorus centers ( 31P: 4.9 and 104.2 ppm (JPP ¼ 43.9 Hz)) is indicative of exo-syn-stereochemistry. Similar reactivity has been demonstrated recently for related Pd(II) complexes <2006JOM3083>.
NCMe ClO 4
Me P
i, 2
Ph
Me
S Ph P
R
:
Me Me N NCMe Pt
:
Me
Me
ii, HCl iii, KCN
Ph
P
Me
Me Me (+)-267
Scheme 93
3.15.12.1.2
1-Phosphanorbornadienes and 1-phosphanorbornenes
1-Phosphanorbornadienes and -phosphanorbornenes are unusual heterocycles that can generally only be prepared by exploiting a specific feature of phosphole chemistry: high-temperature rearrangement of certain P-ring compounds via a [1,5] sigmatropic shift affords 2H-phospholes, which can be trapped through [4þ2] cycloaddition generating the desired bicyclic derivatives (see Sections 3.15.2.1 and 3.15.5.1.2(i)) <1997JA12560>.
Phospholes
For example, the readily accessible but transient 2-phenyl-3,4-dimethyl-5H-phosphole 269 reacts at 150 C with aldehydes (RCHO) to yield the corresponding [4þ2] P–O cycloadducts with both endo- (270, major) and exo-R-substituents (Scheme 94) <2003JOC2803>. Cycloaddition with R-unsaturated aldehydes takes place both at the CTO (major) and CTC bonds giving rise to compounds 271 and 272, respectively, following addition of sulfur (Scheme 94).
P O 270 R = Ph: 82% endo
2 h, xylene Me
Me
Me
150 °C Ph
P
Ph
Me
150 °C P
Ar-[1,5]
Me
Me
269
Ph
Me R
Me
RCHO
268
Ph
Ph CHO i, 2 h, xylene
Ph
P O S
271 20% +
ii, S 8 , 60 °C
Me Ph
Me P Ph
S
H CHO
272 14% Scheme 94
This type of reaction sequence has been used very effectively for the preparation of chiral, bidentate 1-phosphanorbornadiene-oxazoline ligands, for example 278 (Scheme 95), which proved effective in asymmetric Pd-catalyzed p-allyl alkylation and Heck couplings <2000OL2885>. On heating, the reaction of 268 with phenylpropiolate gives a 2:1 mixture of regioisomers with 273 and 274 as the major products following reaction with sulfur (Scheme 95). Subsequent conversion of the ester 273 to the acid and coupling with S-valinol gives two diastereomeric products 275 and 276. These compounds were separated and each transformed to their corresponding oxazolines, for example, 277, which were reduced to give the free CN 3 P-oxazolines (e.g., 278).
268
i, Ph
Me
Me
CO 2 Me, Δ
Ph +
P Ph
ii, S 8
S
Me
Me Ph
CO 2 Me
S
273
273
Ph
Ph
Ph
Me
Me
+
P
ii, S -valinol, EDC, HOBT DMF, RT, 24 h
Ph
274 Me
Me
i, LiI, pyridine, Δ
CO 2 Me
P
P
NH
S O
275
HN OH
S
Ph
O
HO
276
275
MsCl, Et 3N, DMAP
Ph
Raney-Ni, MeCN
277
Me
Me
P Ph
Scheme 95
Me
Me
Ph
P
S
O N
Ph
278
O N
1117
1118 Phospholes Similarly, the triisopropylphenyl-2H-phosphole 279 formed by sigmatropic rearrangement of the corresponding phosphole 27 has been used to prepare new 1-phosphanorbornene and -phosphanorbornadiene derivatives, such as 280 (isolated as its sulfide) and dimers 281a and 281b (isolated as their hemi-oxides) (Scheme 96) <2003HAC316, 2005HAC104>. Compound 279 could also be trapped by benzaldehyde to afford the oxaphosphanorbornene 282 (isolated as the oxide) as a single diastereomer. Me
Me 150 °C Ar
P
P
Ar-[1,5]
279
Ar
27 Ph
Ar =
Pr i
Pr i
no trapping agent
no trapping agent
O Ph
Ph Me
Pr i
Me
Ph
P
P Ar
Ar
Me
Me
Me Ph P
P
Ar
P
280
Ar
281a
P
Me Ar
Ph
281b
Ar
O
Me
282
Scheme 96
Further elaboration of the 1-phosphanorbornadiene skeleton is possible at the C-2 position using Stille-type chemistry <1998EJO2683>. Heating phosphole 268 in the presence of stannyl-functionalized alkynes affords the corresponding C-2 tin-substituted bicyclic compounds 283 in good yields (Scheme 97). Treating 283 with MCPBA affords the corresponding oxide 284 in near-quantitative yield, while reaction with excess H2O2 gives rise to the ringexpanded product 285. Stille cross-coupling undertaken directly with either of these tin derivatives proved
MCPBA
268
SnBu 3, Δ
R
Me
Me
C 7H 8 /CH2Cl 2 0 °C
R
Me
Me
R
P Ph
O
SnBu 3
284
P
150 °C, 2 h
Ph
SnBu 3
283
H2 O 2
R = Ph, n-C6H13
C 7H 8 , 80 °C
O Me R P O SnBu 3
Me Ph
285 R = Ph
284
I2 , CHCl3 5–25 °C
Me
Me P Ph
O
I
R
E
5% [Pd(PFu3)2 ] + CuI
286: R = Ph 287: R = n-C6H 13 a: E = O; b: E = S; c: E = NMe Scheme 97
SnBu 3
90 °C
Me
Me
Ph
P Ph
O
288a–c
E
Phospholes
ineffective. Consequently, tin–halogen exchange was undertaken for oxides 284 and 285 with elemental iodine in chloroform, to afford the corresponding iodo compounds 286 and 287. In contrast, reaction of these halo-phosphanorbornadienes with 2-stanna-heteroles in the presence of catalytic quantities of a palladium catalyst and CuI affords the cross-coupled products in ca. 70–80% yields, for example, 288a–c.
3.15.12.1.3
Phosphinines
The synthesis of the first phosphinines by Ma¨rkl and Olbrich is a significant milestone in organophosphorus chemistry <1966AGE588>. Not only are these heteroarenes of interest from electronic and structural viewpoints, but they now also form an important class of both 1()- and 6(p)-coordinating heteroatomic ligands <2006PCA10148>, an area that has been reviewed in depth <2001PIC455, 2006COR3>. Although a number of routes to such compounds now exist (e.g., from 2-halogenoderivatives <1995JOC7439> and references therein or via 2-azaphosphinines <1999JOC5524> and references therein), ring-expansion reactions of phospholes remain one of the most versatile and well established, and have been comprehensively reviewed <1992RHA1>. Consequently, only a selection of new phosphinine compounds prepared from phospholes that have appeared in the last decade are described here. Despite widespread interest in such P-based heteroarenes, few syntheses of -functionalized phosphinines have been documented. A new methodology has been described recently in which 2-acylphospholides 289 undergo ring expansion to afford 3-acylphosphinines 148 upon reaction with dihalomethanes (CH2X2) in the presence of ButOK (Scheme 98) <2005AGE1082>. The reaction is believed to occur via initial substitution by CH2X2 at phosphorus to afford 149, which is subsequently deprotonated at the exocyclic methylene carbon to yield bicyclic phosphirane 150. Further deprotonation induces ring expansion, generating the phosphines 148 following a final protonation step (Scheme 99). R
Me Me R P
Me
Li, THF, 3 h
R
R1C(O)Cl
Me CH 2 X 2 O
t
P
R
Bu OK
P
Li
Li
R1
t
Bu OK
P
R1
148
289
R = H, Me R1 = Me, Ph X = Cl
O
Scheme 98
R
R
Me O P
R1
Bu OK
O P
R1
R1
X
149
But OK
CH 2
t
O P
147
R
Me
R1C(O)Cl
CH 2 O
150 CH 2 O
R1 P
R1
H
148
P
Scheme 99
A contrasting synthesis of functionalized phosphinines has been described in which phosphole groups play a mere spectator role <2003HAC316>. Although this is not strictly relevant to this section (focusing on ring-expansion reactions of phospholes), this work has been included since it provides an elegant methodology for the preparation of unusual diphosphorus-based ligands containing both phosphinine and phosphole moieties. 1-(1-Phenylpropargyl)-2,5-diphenylphosphole 290 reacts with 3,5-di-tert-butyl-1,3,2-diazaphosphinine 291 to afford a mixture of isomeric diazaphosphaberrelenes 292a and 292b, which eliminate ButCN to give azaphosphinines 293 and 294 (Scheme 100). Subsequent
1119
1120 Phospholes treatment with excess trimethylsilylacetylene in toluene at reflux affords the desired substituted phosphinines 295 and 296 in a 4:1 ratio, respectively, with a combined yield of 40% based on phosphole 290. This strategy is very dependent on the exact nature of the phosphole component, since in many cases 7-[(phosphole)-methylen]-7,8-dihydro-2,6-diaza-1phosphabarrelenes are obtained through a (1,3)-shift, and these compounds cannot subsequently be converted to the phosphinines <2003HAC316>. Note that mixed phosphine–phosphole derivatives are also available from 1-stannylphospholes and phospholide anions (Scheme 79, Section 3.15.10.3). R1 Ph
Ph P
+
But
But N
Ph
290
P
R
C 7 H 8, 110 °C
But
Bu t
40 h –But CN
N
2
N P N
292a,b
291 R 1 = H; R 2 = phosphole R 1 = phosphole; R2 = H
–Bu t CN
Ph Ph Me3Si
+
P Ph
P
But
Ph Me 3Si (xs)
Ph Me3Si
295
P
P
296
Ph
+ N
P
Ph
But
P Ph
C7H8 110 °C, 40 h –Bu t CN
Ph
Ph
293
P
Ph
N
P
Ph
294
Scheme 100
3.15.12.1.4
Phospholyl complexes
Cyclopentadienyl ligands are commonplace throughout organometallic chemistry and catalysis. Their phosphoruscontaining counterparts, namely phospholyl ligands (PC4R4), have attracted ever-growing interest as alternative metal scaffolds, largely due to their ability to act as both -(1)- and p-(5)-ligands, sometimes simultaneously <1994CCR1, B-1998PTCC227>. This behavior is possible because the P-lone pair of an 5-bound phospholyl ligand resides in a highly spherical orbital with significant 3s-character and is thus available for donation to a second metal center. It should be noted, however, that this lone pair is only weakly basic and will bind BF3 and BBr3, but not BH3, for example <2002PCA5653, 2003EJI2049>. Recent theoretical studies are in agreement with these experimental observations, demonstrating that phosphaferrocenes are modest -donors, but good p-acceptors as a result of an energetically low-lying lone pair and the high pz-character of the LUMO on phosphorus <2002PS1529, 2003NJC1233>. It is now generally believed that the P-containing systems are better p-acceptors, but poorer p-donors than their all-carbon equivalents <1984OM1303, 2003ICA182, 2003JOM120>. Like 5-C5H5, phospholyl ligands form stable complexes with a diverse array of alkaline, transition, and lanthanide metals, in addition to a variety of main group elements. Although the coordination chemistry of phospholyl ligands is potentially complicated as a consequence of a variety of coordination modes, it is now well established that the presence of sterically demanding groups in the position to P on the ring favors 5-coordination. Taking into account all of the above features of phospholyl ligands, these Cp alternatives offer new perspectives in the catalysis arena. However, in this chapter, only a flavor of some of the types of metal phospholyl complexes prepared over the last decade and their reactivity is given, with emphasis being placed on the generation of such complexes and the particular role played by phosphole compounds. For further information, the reader is directed to a number of excellent reviews of the area <1994CCR1, 2001JCD3541, 2002TCC27, 2002JOM15, 2006CCR627, 2006COR43>. Access to metal phospholyl complexes is readily achieved via metathesis with easily accessible phospholide salts, themselves obtained using one of four main routes (see Section 3.15.5.1.5). These comprise: (1) two-electron reduction of P–Ph or P–halogen bonds with Li, Na, K; (2) cleavage of P–P or P–alkyl bonds; (3) from transient 2H-phospholes via [1,5] sigmatropic rearrangement in the presence of base <1997AGE98>; and (4) reaction of MP(SiMe3)2 with diynes <1999IC3207>.
Phospholes
The cleavage of a P–Ph bond (method (1)) has been widely used to create a variety of phospholide salts. Notably, this methodology has been employed in the synthesis of group 13 phospholyl complexes, which have come to the fore in recent years as potential single source substrates for the preparation of the corresponding metal phosphides by chemical vapor deposition (CVD). This is exemplified by the reaction of lithium 2,5-di(tert-butyl)phospholide with ‘GaBr’ to afford a Ga(I) polymer 297 (Scheme 101) <1999AGE1646>. Additionally, this synthesis nicely illustrates the use of bulky substituents in the position to phosphorus to favor 5-coordination. tBu
tBu ‘GaBr’ P
Li
P
P
tBu
tBu
tBu
Ga
Ga Ga
THF/C 7 H8
tBu
tBu
tBu
P
297 Scheme 101
An excellent example of the use of method (2) for the synthesis of phospholyl complexes is given by the preparation of the Ca and Sr complexes 299 and 300. Here, insertion of either of these two metals into the P–P bond of 1,19biphosphole 298 occurs readily, affording the corresponding group 2 metal complexes (Scheme 102) <1999IC3207>. Ph
Me3Si
Ph SiMe3
P
P
Ph
Ph
Me3Si
SiMe3
M THF
Ph
Me3 Si
Ph L L M P
P Me3Si Ph
L L
SiMe3 SiMe3
Ph
299: M = Ca 300: M = Sr
298
L = THF Scheme 102
A further example of the use of this route to phospholyl complexes is given by Mathey <1996AGE1125>. Here, the P–P bonds of the macrocyclic tetraphosphole 230 are cleaved by elemental Na or K in a coordinating solvent (1,2dimethoxyethane, DME) to afford new 2,29-biphospholyl complexes. The exact composition of the product obtained is intimately linked to the nature of the metal and reaction stoichiometry (Scheme 103). With sodium a complex 301 is obtained in which just one of the P–P bonds has been ruptured, and the phospholyl moieties are bound in both an Me
Me Ph Ph
Me Me
Me Me
Na
Me
DME Ph Ph Me
P
P
P
P
Me Me
P
Na
Na
2DME
301 Ph Me
K
Ph
P
Me THF Me
K
Ph
P
P
Ph
K
Me THF Me
P
Ph
Me Me Me Me
302 Scheme 103
Me
P
P
Ph
DME/ THF
230
P
2–
1121
1122 Phospholes 1- and an 5-fashion. In contrast, with potassium, both P–P bonds are broken to yield two 2,29-biphospholyl units that are bound together by two K atoms in a ‘sandwich’-type arrangement 302. Recently the chiral phosphatitanocene complex 303 has been reported <2002CC2996>. It was prepared by in situ generation of the potassium phospholide via formation of the corresponding 2H-phosphole (method (3)), according to Scheme 104. Complex 303 has been shown to undergo slow rac/meso-isomerization, via a process that is proposed to involve an 5-to-1-ring slippage/P–Ti -bond rotation/1-to-5 sequence. Similar behavior has been studied in detail for related Zr- and Hf-based systems <2001OM3453>. Ph Me
P
Me Me KOBu
t
140 °C
P Ph
Me
Me i, Me3SnCl, THF P
Me Me
ii, 0.5TiCl4, THF
Ph
Ti
Cl
Cl
Me
P
Ph
303 63–75% Scheme 104
Notably, a range of group 4 phosphametallocene complexes have been prepared and their utility in a number of industrially relevant catalytic processes explored <1998JMO155, 1996CB1517>. In particular, their application to the polymerization of alkenes has been studied in depth, as a result of their similarity to the well-known homogeneous polymerization proinitiators Cp2MCl2 (M ¼ Ti, Zr, Hz) <2000JA11737, 2001OM3453>. Emphasis has been on the use of the phospholyl systems in stereoregular -olefin polymerization, potentially exploiting the ease with which chirality may be introduced into such systems. Related ‘constrained geometry’ systems 304 (Figure 3) have been synthesized and screened for activity in alkene copolymerization, with the necessary silyl-amino-substituted phosphole being prepared via the Fagan–Nugent method <1998OM5445>. Ph P
P
P Ti
Si
Ph
Cl Cl
Ti
N R
P
Zr P
Ph
304 R = Me, But
CO CO
305
Ph
306
Figure 3 Phosphametallocene complexes of Ti(IV), Ti(II), and Zr(II).
Although it has been established that Ti(IV) phosphametallocenes are not configurationally stable, Hollis has shown that comparable Ti(II) complexes such as 305 exhibit much greater barriers to isomerization (Figure 3) <2003OM1432>. These differences have been probed using DFT calculations. For the Ti(II) system, these established that in the TS, a four-electron two-orbital destabilizing interaction occurs between the P-lone pair of the ‘slipping’ ligand with a nonbonding a1 orbital at Ti. This situation is not possible for Ti(IV), since in this case this metal-based orbital is unoccupied. Notably, magnesium reduction of [ZrCl2(5-PC4(Me3)Ph)2] affords the 14-electron phosphazirconacene 306 (Figure 3). This has been shown to undergo identical reactivity to its bis(cyclopentadienyl) counterpart [Zr(5C5H5)2], undergoing oxidative coupling of alkynes, for example <2002OM259>. Route (4) for the preparation of phospholyl complexes, namely insertion of diynes into metal phosphide bonds and subsequent cyclization, is the least used approach. However, an alternative synthesis of 299 and 300 using this type of methodology has been demonstrated successfully (Scheme 105) <1996AGE1125>.
Phospholes
L L SiMe3 P M P Me3 Si L SiMe3 L
Me3 Si
2 Ph
Ph
299: M = Ca 300: M = Sr
THF
L = THF Scheme 105
One of the most recent developments in phospholyl coordination chemistry is that of the lanthanide and actinides. Here the greater CNs possible for these metals means that the full potential of the various binding modes of phospholyl anions (1, 5, and 1:5) may be exploited to the full. Once again, variation in the steric demands of the phospholyl ring may be used to tune their coordination chemistry. A number of comprehensive reviews of these areas have appeared <1998CCR13, 2001EJI891>. A topic that has received particular attention since the synthesis of the first phospholyl complexes is the mono- and diphosphaferrocenes, as a result of the pioneering work of Mathey on their use as readily accessible, electronically unusual, chiral bidentate ligands <1994CCR1>. Again, the key to the success of this approach lies in the introduction of substituents in the position to phosphorus, which serves two purposes. First, this renders the metallocene planar chiral. Second, this substituent is used to introduce the supplementary donor moiety. A notable benefit of planar chiral phosphaferrocenes over traditional ferrocene-based chiral ligands is that the ring P-donor atom is in the immediate vicinity of the chiral metallocene unit, affording efficient transfer of chirality. Furthermore, since mixed Cp9/phospholyl sandwich complexes are readily prepared, the 5-Cp9-ring may be used to control the steric demands of such scaffolds as a whole. Ganter et al. have demonstrated that the easily synthesised formyl-phosphaferrocenes 307 provide straightforward and flexible entry to bidentate ligand frameworks by exploiting the classical reactivity of the carbonyl moiety <1997OM2862, 1997TA2607>. The racemic mixture of enantiomers of 307 is readily separated by chromatography. These metallocenes have been used for the preparation of a range of P,N- and P,P-bidentate ligand systems 308–312 <1997CB1771, 1998EJI1163>. The ready functionalization of metal phospholides has been used to access the wide bite-angle P,P-ligand 313 <1999OM5444>. In an extension to this work, Ganter et al. presented another approach for the resolution of a racemic mixture of phosphaferrocenes <1997TA2607>. The mixture of aldehydes 307 was converted to the corresponding aminals 314a, and 314b through reaction with an enantiomerically pure diaminocyclohexane derivative in near-quantitative yield and 99% ee. The resulting metallocenes were easily resolved chromatographically using silica on a preparative scale, with the enantiomerically pure aldehydes being obtained by hydrolysis; the chiral diamine was recoverable at this stage. CHO
OHC
P
P Fe
(S )-307
(S )-307
R
P Fe
Fe
Fe
308: R = NMe2 309: R = CH2NMe 2 310: R = PCy2 311: R = CH 2PPh2 312: R = CHO
P Me
Me N
Fe P Fe
N
N N
Me
Me
(R )-314a
(S )-314b
P Fe
313
P Fe
1123
1124 Phospholes Fu broadened the use of planar chiral phosphaferrocene chelate ligands in catalysis with the preparation of the mixed Cp* /phospholyl ferrocenes 315–317, which are readily resolved via chiral high-performance liquid chromatography (HPLC) <1998JOC4168, 2000OL3695>. For example, in combination with [Rh(COD)2]PF6, P,P-complexes 315 proved effective for the enantioselective hydrogenation of dehydroamino acids with ee’s in the range 80–96% (COD ¼ cyclooctadiene). Ligands 317 have been used to effect the kinetic resolutions of azomethine imines via copper-catalyzed [3þ2] cycloaddition reactions with excellent ee’s (ca. 99%), but moderate yields (typically 40%) <2005JA11244, 2006ACR853>. R P Fe
315: R = CH 2PPh 2 316: R = CH 2 COCF3 O
(R )- and (S )-317: R = N
R1
R1 = But , Pr i
An alternative methodology for the preparation of chiral phosphino-phosphaferrocenes ()-322 was outlined by Hayashi, using enantiopure chiral phospholyl ligands (Section 3.15.9, Scheme 45) <2001OM3913>. In this approach, an intermediate mesitylene complex 321 was prepared and the mesitylene exchanged for a phospholide bearing ()-menthyl substituents 319 (Scheme 106). As a consequence of its sterically encumbered nature, complex 322 can act as either a mono- or bidentate ligand on treatment with 0.5 or 0.25 equiv of [Pd(5-C3H5)Cl]2, respectively. The resulting chelated palladium(II) complexes of 322 promote asymmetric allylic alkylation of rac-1,3-diphenyl-2propenyl acetate with excellent ee’s of 77–99%, depending on reaction conditions.
R*
P
R*
Li, THF –PhLi
Ph
R*
P
R*
319
318
R* = (–)-menthyl R* i, AlCl3, Al, H 2 O mesitylene
Fe
PF 6 Fe
PPh 2
PPh2
ii, NH4PF6
320
P
319
R*
Fe
THF
PPh 2 (–)-322 31%
321 90%
Scheme 106
The inherent planar chirality of substituted phosphaferrocenes can be exploited for the diastereoselective derivatization of the heterometallocenes themselves. This is nicely illustrated by the preparation of the alcohol derivative 323 as a single diastereomer (cf. LiAlH4 reduction of 307, which affords a 1:1 mixture of diastereomers; Scheme 107) <1998CEJ2148>. Alcohol 323 was then used to prepare the enantiomerically pure P,P-diphosphorus ligand 324.
CHO
P Fe
i, MeMgI, Et 2 O
P Fe
ii, H2O (R )- 307 Scheme 107
OH
i, H +
P Fe
ii, HPPh 2
323
324
PPh2
Phospholes
Recently, Carmichael and co-workers have described the synthesis of 2-(29-methoxynaphth-19-yl)-3,4-dimethyl-5phenylphospholyl)-iron(II) 328 and -ruthenium(II) 329 complexes (Scheme 108) <2005JCD2173>. Despite crystallographic evidence suggesting that hindered rotation of the naphthyl moiety could give rise to enantioselection, NMR studies have demonstrated that equilibration takes place both for the free phosphametallocenes and for their complexes with PtCl2.
Me
Me I
Me
Me
+ Ph
P
K
Ph
MeO
diglyme
+
326
P
MeO
110 °C
325
Me
Me
Me
Me
KOBut
P
[MClCp*] Ph
diglyme 110 °C
P
THF
M
MeO
MeO
327
328: M = Fe 329: M = Ru
Scheme 108
The C2-symmetric rac ansa-diphosphaferrocene 330, which formed diastereoselectively upon reaction of the corresponding bis(phospholide) with FeCl2 (Scheme 109), has been reported <2001OM1499>. This iron complex is the first example of an ansa-metallocene possessing a phospholyl ligand. An X-ray diffraction study revealed a phospholyl–phospholyl ring tilt angle of 20 , typical of their well-known all-carbon ring analogues.
Me Me
FeCl 2 , 0.3AlCl 3 Me
P Me
P
2–
P
THF, 0–25 °C
Fe P rac- 330 30%
Scheme 109
Non-ansa-bis(phospholyl)ferrocenes have also been synthesized. For example, diphosphaferrocene 331 was prepared and its oxidation chemistry studied. Here, advantage was taken of both the electron-rich nature of the heterocycles and their steric bulk to engender enhanced stability to the resulting diphosphaferricinium salts (Scheme 110) <2003ICA182, 2003JOM120>. Reaction with elemental iodine resulted in the near-quantitative formation of the paramagnetic ferrocenium salt 332, which was characterized by an X-ray diffraction study. Comparison of the molecular structures of complexes 331 and 332 showed that the Fe–ring-centroid distances in the salt are ca. 0.7 A˚ longer than those for in its neutral counterpart, something that is consistent with the oxidation having occurred at the Fe 3d-orbitals. This agrees with results from a computational study that indicate that removal of one electron from diphosphaferrocene will tend to increase the Fe–ring-centroid distance by lowering the electron density in the Fe–C and Fe–P bonds <1989JOM61>.
1125
1126 Phospholes
Et
Et Et
Et P Fe Et
Et Et Et
I2
P Fe Et
Et Et
CH 2 Cl 2 , rt
Et
P
I3
Et
Et
Et
P
331
Et
332 90%
Scheme 110
An important recent development in phosphole chemistry is the use of these types of P-heterocyclic ring as building blocks for the preparation of extended p-conjugated systems (Section 3.15.12.4). One of the attractive features of this strategy is that the properties of the resulting materials may be tuned readily through chemical modification of the P-center. To this end, derivative 333 was prepared via lithium-promoted P–P bond cleavage of the corresponding 1,19-diphosphole 29 and reaction of the ensuing phospholide salt with [FeCl(Cp)(p-xylene]PF6 (Scheme 111) <2005OM5369>. Compared to the corresponding oligomers featuring phosphole units, the phosphaferrocene-based compound 333 exhibits both higher thermal stability and higher HOMO–LUMO separation.
S P: S
:P
i, Li, THF S
Fe
ii, [FeCl(Cp)(p-xylene)]PF6, THF S
P
S
333
S
29 Scheme 111
Although phosphaferrocenes are the most widely studied transition metal phosphametallocene complexes, other examples, including the 20-electron nickel complex 334a <2005CEJ5381>, the 19-electron cobalt/Cp* complex 335 <2003CEJ2567>, and the planar chiral ruthenocene complex 336 <2004CC1144>, have been synthesized in the last few years. Notably, ‘ring slippage’ occurs on addition of PMe3 to 334a, forming the 14-electron, halfsandwich 1-phospholyl complex 334b – a reaction that nicely exemplifies the ‘coordination flexibility’ of phospholyl ligands <2005CEJ5381>. Significantly, the formation of the phosphaferrocene 337 has been observed from the thermolysis of 1-tert-butyl-3,4-dimethyphosphole with [CpFe(CO)2]2 <2006OM2394>. The reaction was accompanied by the formation of isobutene, which is presumed to result from transfer of the tert-butyl group to iron and subsequent -H elimination from the intermediate complex [CpFe(But)(CO)2], consistent with a nonradical reaction pathway. Bu t Bu t
Bu t
P Ni
Bu t
Bu t
Ni P
P Co
R
P Ru
OH
P Fe
PMe 3 Bu t
334a
334b
335
20e–
18e–
19e–
(+)-(R)- 336a: R = H (+)-(R)- 336b: R = Ph
337
Phospholes
3.15.12.2 Phosphole Ligands for Homogeneous Catalysis 3.15.12.2.1
Coordination to metals and binding modes
The literature describing the coordination of CN 3 phospholes to metals is extremely large and diverse, covering the synthesis, characterization, and reactivity of such complexes. Until recently, one of the more important applications of metal phosphole complexes was in catalysis, an area that has continued to grow over the last decade, largely as a result of their successful use in a number of metal-meditated transformations that are of particular relevance to organic synthesis. In the last few years, however, the coordination of metals to phospholes is now being used to fine-tune the spectroelectronic properties of conjugated materials (Section 3.15.12.4) and therapeutic agents (Section 3.15.12.3). In a review such as this, it is impossible to cover such a diverse area and hence, here, emphasis will be upon the general types of phosphole-based ligand used in catalysis and the applications for which they have proved especially beneficial. General aspects of the coordination chemistry of phospholes has been covered in depth previously and is not repeated in detail <1985SBO154, 1988CRV429, 1996CHEC-II(2)757, B-1998PTCC203, 2001PCHC307>. However, it should be noted that these P-containing unsaturated heterocycles present a number of different bonding modes to metals, since they may form bonds through the P-lone pair, the cyclic diene system, or both. Consequently, phospholes not only behave as functionalized phosphine-like (PR3) -donor ligands, but also show coordination behavior that is more akin to that of unsaturated all-carbon ligands (e.g, p-coordination). This latter feature opens up the possibility of the further functionalization of the phosphole skeleton in the coordination sphere of a metal. Although the modes of metal coordination of phospholes are now well established, with few new developments in the last decade, there is one new structural motif of particular note. A symmetrically 2-bridging phosphole arrangement has been observed in Pd(I)-dimers <2001AGE228, 2003CEJ3785>. Reaction of 2,5-dipyridylphosphole 39b with [PdCl2(CH3CN)2] initially affords a new P,N-chelated complex 338, which, on reduction with H2/HC(OCH3)3, affords a new dipalladium(I) complex 31 that exhibits a single sharp resonance at þ69.9 ppm by 31P NMR spectroscopy (Scheme 112). Characterization in the solid state by X-ray diffraction revealed that the phosphole bridges the ˚ the Pd–P bond distances are two Pd-centers, which are themselves joined by a rather long Pd–Pd bond (2.7870(9) A); ˚ The occurrence of this rare 2-bridging mode of a CN 3 P-compound is believed to be 2.349(2) and 2.358(2) A. assisted by the pendant Pd-bound pyridyl moieties, which constrain the phosphole P-atom to lie close to both Pdcenters. Extended Hu¨ckel calculations reveal that the Pd–Pd and Pd–P bonding is highly delocalized and comprises largely a strong -interaction between the P-lone pair orbitals and Pd-based orbitals of the same symmetry. This rare type of coordination mode of a CN 3 P-compound has subsequently been obtained with mixed Pd(I)–Pt(I) complexes <2005AGE2190> and Cu(I) dimers, which act as versatile molecular clips for the preparation of metal cyclophanes <2006JA3520>.
[PdCl2(CH3CHN)2] P
N
N
Ph
H2(20 b)
P
N Ph
39b
Cl
N
HC(OCH3)3
P Ph N N + Pd Pd + N Ph P
N
Pd Cl SbF 6
338 94%
31 82%
Scheme 112
3.15.12.2.2
Mono- and bi-dentate ligands
A wide variety of both mono- and bidentate phosphole-containing ligands have been reported over the last 10 years. Consequently just a selection will be presented here, focusing on those that demonstrate the important features of phospholes as metal scaffolds as identified above.
1127
1128 Phospholes A study of the coordination chemistry of 1-phenyl-2,3,4,5-tetramethylphosphole with [Mo(CO)6] has been undertaken <2001JOM297>. Upon heating equimolar quantities of the carbonyl derivative and phosphole, a mixture of complexes was obtained, with each being structurally characterized following separation (Scheme 113). This study reveals that, as expected, there is little electronic delocalization within the heterocyclic core once coordinated. Moreover, studies by X-ray diffraction indicate that the complexes 339 and 340 show considerably less steric crowding compared with the same complexes of PPh3 and PCy3, something that highlights the coordination flexibility of phospholes.
L
[Mo(CO)6]
[Mo(CO)5 (L)]
Δ
+
cis -[Mo(CO)4 (L)2 ]
+
trans-[Mo(CO)4 (L)2]
339 Me L=
Me
340
Me Me
P Ph
Scheme 113
An important property of metal-bound phosphole ligands is their ability to undergo additional reactions not possible in the noncomplexed form. This is nicely illustrated by the thermally induced reactions of the palladium(II) complex of 1-phenyl-3,4-dimethylphosphole 341 <1996IC1486>. Heating complex 341 at 145 C in solution or at 140 C in the solid state led to the formation of a mixed 7-phosphanorbornene–phosphole complex 343 (Scheme 114). These intramolecular [4þ2] cycloaddition reactions are believed to proceed via the initial formation of a diallyl 1,4-biradical TS 342. Further examples of this type of reaction may be found in Section 3.15.12.1.1. Me
Me
Me Me
Me PdCl2
P Ph
Cl
Me Ph
Δ
P
P
Ph
Me
Cl
341
Cl
Pd
P Ph
Ph Me
Pd
2
P
Me
Me
Cl
343
342
Scheme 114
Another intriguing example of reactivity specific to phospholes and their complexes is given by the formation of 3,4-dimethyl-phenylphosphole in the coordination sphere of a metal as illustrated in Scheme 115 (see also Section 3.15.5.2.2) <2004JOMC4647>. Here, treatment of the phospholyl complex 344 with ButLi affords the corresponding 4-bound phosphole complex 345, which reacts with Pd(II) to generate the bimetallic 4-Mn:-Pd complex 346 that has been characterized in the solid state by X-ray diffraction. Notably, the P–Mn bite angle of 65 is typical of other dimeric Pd2Cl2 complexes. The 4-bound C4 moiety shows the expected bond localization. Bu t
Me
Mn(CO)3 Me P
344
P:
Me Bu tLi
Me
Mn(CO)3
But
–
Me
P
[PdCl 2 (COD)] Me
Pd
(CO)3 Mn
345 346 80%
Scheme 115
Cl 2
Phospholes
1-Diisopropylamino-dimethylphosphole also reacts with a source of Pd(II) to form the chloro-bridged complex 347, which on addition of further quantities of phosphole generates the corresponding monometallic system 348 (Scheme 116). In contrast to the reactivity observed for complex 341, neither complex exhibits intramolecular cycloaddition processes upon heating <2002JOM19>.
[PdCl2(CH3CN)2 ]
Cl
L
L
Pd
1/2 Cl
Me
Me
Cl
L
Pd Cl
Cl
L Pd Cl
L
347
L
348
L= P NPr i Scheme 116
Over the years the degree of aromaticity associated with the phosphole ring has been a topic of considerable debate (see Section 3.15.2.1). One way in which aromaticity can be enhanced is to incorporate bulky substituents at the P-center, which leads to a ‘flattening’ at P. Consequently, a range of such compounds have been prepared. Any planarization at P will obviously impact upon the -donor character of these phospholes, something that will in turn affect their coordination chemistry. A recent study of the coordination of bulky phospholes 11, 12, and 27 with cis-[PtCl2(PhCN)2] was undertaken according to Scheme 117 <1999IC831>. The most hindered and hence flattened phosphole 12 reacted only very slowly (weeks), with the formation of all three diphosphole complexes being comparatively slow. A marked variation in the magnitudes of 1JPtP was observed for complexes 349a–c, depending on the phosphole used: 1JPtP12 > 1JPtP27 > 1JPtP11, something that has been assumed to reflect the decrease in aromaticity across the series 12 > 27 > 11.
cis-[PtCl2(PhCN)2 ]
L
cis -[PtCl 2(L)(PhCN)]
CDCl3
L CDCl3
trans -[PtCl 2(L)2 ]
349a–c
Me
P L=
R1
R3
11: R 1 = R 2 = But ; R3 = Me 12: R 1 = R 2 = R 3 = Bu t 27: R 1 = R 2 = R 3 = Pri
R2 Scheme 117
The same and related sterically hindered phospholes 11, 12, and 27 have been screened as ligands in the rhodiumcatalyzed hydroformylation of styrene <2002JOM32, 2003JMO131>. Both high chemoselectivities and regioselectivities were achieved, with the preferential formation of 2-phenyl-propanal being observed at 40 C. These results demonstrate a distinct improvement upon those obtained using less bulky Ph– and Me–P phospholes or dibenzophospholes. See, for example, <1989JMO219>, and references therein. In a nice illustration of the impact of metal coordination upon the reactivity of phospholes, a methodology for the functionalization of these heterocycles in the -position has been described (see also Scheme 22) <2001JOM105>. Here, coordination of both the P-lone pair and the cyclic diene system was undertaken. The resulting multimetallic complex 79 was treated with lithium diisopropylamide (LDA) to afford the lithium salt 350 (Scheme 118). This readily undergoes nucleophilic substitution with a variety of electrophiles to afford the corresponding substituted phosphole complexes 351–353. The free phospholes can be isolated following decomplexation with cerium(IV) ammonium nitrate (CAN).
1129
1130 Phospholes
Fe(CO)4 CH 2 CH 3
Me MeI
P Ph
Fe(CO) 4
351 58% Fe(CO)4 Me
Me
Fe(CO)4 CH 2 Li
Me LDA, THF
P Ph
Fe(CO)4
Fe(CO) 4 CH 2SiMe 3
Me Me 3 SiCl
–78 °C, 10 min
P
P
Ph
79
Fe(CO)4
Ph
Fe(CO)4
352
350
49% Fe(CO)4 Ph2C=O
Me
Ph Ph OH
P Ph
Fe(CO)4
353 58% Scheme 118
Bidentate ligands such as diamines and diphosphines occupy a special position in coordination chemistry, providing complexes that have well-defined geometries and low CNs as a result of chelation. Furthermore, these complexes are favored entropically and hence are less labile than their bis(monodenate) ligand counterparts. Consequently, there have been numerous studies to incorporate sterically and electronically unusual phosphole fragments into bidentate ligand frameworks. For example, a range of C2-, C3- and C4-bridged bis(biphospholes) 163a–c were prepared via the Fagan–Nugent method by P/Zr exchange using different bis(dihalo)-phosphine compounds, as illustrated in Scheme 119 (see also Section 3.15.9.2) <1999OM3558, 2001JOM182>. Following coordination to PdCl2, the resulting cis-square planar complexes 354a–c were tested for activity toward CO/C2H4 copolymerization upon treatment with MeSO3H. Each complex was active, giving rise to moderate molecular weight material and no trace of products resulting from the potentially competitive alkoxy-carbonylation process. Me Me
X2 P
PX 2
Me
Me
P
P
Me
Me
Me
Cp 2 Zr
Me
Me
Me Me
Me
163a–c
= CH2CH2CH2CH2 ( a) = CH2 CH2CH2 ( b) CH2 = ( c) CH2
[PdCl 2 (COD)] MeSO3H C 2H 4, CO (10 b)
O n
MeOH
cis -[PdCl2( 163a–c)]
354a–c Scheme 119
A variety of other bidentate bis(phosphole) complexes have been prepared over the last decade, with the majority incorporating elements of chirality. These are discussed in the section on chiral bidentate ligands (Section 3.15.12.2.3).
Phospholes
An important subclass of bidentate metal scaffold are those that have two different donor sites: so-called ‘heteroditopic’ ligands. These scaffolds exploit the inequivalence of the two Lewis-basic moieties to engender both control and selectivity in reactions occurring at metal centers to which they are bound. The significant electronic and steric asymmetry that is possible has been shown to have a considerable impact on the reactivity of their metal complexes, something that has been widely exploited in homogenous catalysis. Some of the most studied heteroditopic ligands are those that combine both a CN 3 P- and an N-donor fragment, in particular phosphine–amine and phosphine– imine variants. In order to exploit the unique features of phosphole ligands, the novel P,N-phosphole-containing multidentate ligands 85 have been prepared using the Fagan–Nugent strategy (Scheme 120) <2002OM1591>. As is common for P,N-ligands, due to the difference in trans-influence between P and N, the cationic complexes 356 are formed as single diastereoisomers by halid abstraction from 355. The pyridyl complexes 356a and 356d were isolated as air-stable solids. Complexes 356b,c,e,f are active for the copolymerization of CO/norbornene, with activities that are among the highest achieved with P,N-palladium complexes. The nature of the phosphole-based scaffold has an effect on the catalysis, with the P–Cy derivatives being more effective than their phenyl counterparts. These P,Nligands are also effective for the Pd-initiated telomerization of isoprene with amines <2006JCT425> and Ni-initiated ethylene dimerization <2004JCT235>.
a : R 1 = 2-pyridyl; R2 = Ph b : R 1 = Ph; R2 = Ph c : R 1 = 2-thienyl; R 2 = Ph d : R 1 = 2-pyridyl; R 2 = Cy e : R 1 = Ph; R 2 = Cy f : R 1 = 2-thienyl; R 2 = Cy
R1
(CH 2)4 N
i, Cp2 ZrCl 2, 2BuLi ii, R2 PBr 2
+ AgSbF6
[PdCl(Me)(COD)] P N
R1
R1
P N
R2
Pd
85
Cl
R1
P
CH3CN
N
R2 Me
Pd H3CCN
355a–f
R2 Me SbF 6
356a–f
Scheme 120
Notably, complexes 355a and 355d undergo a spontaneous, stereospecific isomerisation in CH2Cl2 at ambient temperature (5 days), to afford the novel corresponding 2-phospholene 357a and 357d complexes via a [1,3]-H migration, as illustrated in Scheme 121 <2003CC1774>. In contrast, the same reaction is only observed for the 2-Ph or 2-thienyl derivatives on addition of external base (e.g., pyridine). Recently, it has been demonstrated that the 2-phospholene ligands may be decomplexed on addition of DPPE to the complex 357 <2004OM6191>. These complexes complement the limited number of known ligands that bear a 2-phospholene moiety. They are especially noteworthy since such P-donors possess a configurationally stable stereogenic, very electron-rich P-center.
H R1
P N Pd Cl
R2 Me
355a,d Scheme 121
CH2Cl 2, rt 5d
R1
P N Pd Cl
R2 Me
357a,d
1131
1132 Phospholes It has been established that both the metal and the pendant 2-pyridyl moiety (or pyridine itself) are essential for this phosphole–phospholene rearrangement. DFT calculations highlight that the free ligand 85 (R1 ¼ 2-pyridyl; R2 ¼ Cy) is indeed lower in energy than the corresponding 2-phospholene. This situation is reversed on coordination to Pd(II), with the 2-phospholene isomer being the more stable, something attributed to the presence of the extended p-system. The synthesis of the alternative P,N-ligand scaffolds pyridyl-phosphole 227, via initial formation of sodium 2,5-diphenylphospholide and subsequent trapping with 2-chloromethylpyridine, has recently been reported <2003OM1580>. The cationic complex 358 was readily prepared and proved to be an efficient homogeneous transfer hydrogenation catalyst (Scheme 122) for a variety of organocarbonyl derivatives, achieving both high turnover frequencies and numbers. Ph P
=
N
P N
Ph
227 + i, 1/2[RuCl2 ( η -C 10 H 14 )] 2 6
P N
O R
Ru
ii, AgBF4
Cl
cat. 358 R1
HO
i
KOH, Pr OH 90 °C
R
N
BF 4
P 358
H R1
Scheme 122
3.15.12.2.3
Chiral ligands
There continues to be enormous interest in metal-catalyzed enantioselective transformations and as a consequence there is a continued drive for the preparation of variously substituted chiral ligands, with bidentate variants being among the most widely used. Indeed, diphosphines that possess C2 symmetry are powerful and robust chiral auxiliaries for a range of reactions. A particular useful type of chiral biphosphole is BIPHOS (1,19-diphenyl-3,39,4,49-tetramethyl-2,29-biphosphole) 96a, which takes advantage of its potential for both axial (ring–ring vector) and central chirality (P-atoms) giving six possible stereoisomers, corresponding to three pairs of enantiomers <1986JOM271>. Balavoine and co-workers have screened the coordination chemistry of racemic BIPHOS complexes in detail with a variety of metal fragments including Ni(II), Pd(II), Pt(II), Rh(I), and Ir(I) <1997OM1008, 2001EJI2385>. Although the free ligand exists as a mixture of stereoisomers in an 88:22 ratio, the low barrier to pyramidal inversion at P allows for conversion of the minor to the major stereoisomer upon coordination; this geometric change favors coordination. Significantly, BIPHOS undergoes spontaneous resolution upon conglomerate crystallization, giving single crystals of either the S[RR] or R[SS] forms <2001AGE1076>. Enantiomerically pure PdCl2 complexes of (þ)-or ()-BIPHOS were obtained by undertaking complexation at 78 C, which showed no racemization up to 40 C. These chiral complexes catalyze the asymmetric allylic substitution reaction between 1,3-diphenylprop-2-enyl acetate and the anion of dimethyl malonate in up to 93% yield and 80% ee. Me Me
Me
Me P
P Ph Ph
BIPHOS
96a The use of the [Rh(BIPHOS)(COD)]þ complex for the hydroformylation of styrene gave excellent regioselectivity, favoring the formation of the branched aldehyde (98%) <2001EJI2385>. The same complex very effectively
Phospholes
catalyzes the hydrogenation of -acetoamidocinnamic acid under moderate conditions (20 h, 25 C, 15 atm), with essentially quantitative conversions <2001EJI2385>. In order to modulate the rotational and inversion processes associated with BIPHOS, the related P-NPri2functionalized 2,29-biphospholes 1039a and 1039b have been prepared from the corresponding aminophospoles 1029a and 1029b, albeit it in low yield, ca. 10% (Scheme 123) <2002EJO675>. In order to lock the axial chirality of the biphosphole, it proved crucial to have both the P–NPri2 and phenyl groups on the ring backbone. Unlike compound 1039a, 1039b exists as two stable diastereoisomers.
R
R
R
+
pyrH , Br 3
MCPBA P i
NPr 2
R
R P
–30 °C to rt CH2Cl 2
O
NPr i2
–20 °C to rt CH 2Cl 2
R
R
–
P4 S10
Br
Br
P O
i
NPr 2
Br
C 7H 8
R Br
P S
NPr i2
102′a,b KOH/MeOH CH2Cl 2
a : R = Me b : R = Ph R
RR
R
R
R
R
P
i
Pr 2 N
S S
P
NPr i2
THF
R
Bu n Li
CuCl 2 Br
P S
Li i
NPr 2
THF
Br
P S
Br NPr i2
i, MeSO3 Me ii, But SLi R
RR
P NPr i2
R
P NPr i2
103′a,b Scheme 123
Enantiopure 1,2-disubstituted ferrocene derivatives have received enormous interest as chiral ligands for a wide variety of applications. In this vein, a new class of planar chiral P,N-chelating ligands 244a and 244b were prepared recently according to Scheme 124 using a series of stereochemically controlled reactions (see also Scheme 81) <2003EJI2820>. Deprotonation of the acetal-functionalized ferrocene 359 followed by reaction with the 1-CN-phosphole affords a phospholylferrocene that is trapped as its sulfide 360. A deprotection/amination sequence is used to prepare the amine-phosphole sulfides 361, which afford 244a and 244b upon desulfurization. These scaffolds exploit the conformationally flexible nature of the phosphole moiety to magnify the chirality transfer. For example, in combination with [PdCl(3-C3H5)]2, ligands 244a,b catalyzed the allylic substitution reaction between 1,3-diphenylprop-2-enyl acetate and the anion of dimethyl malonate in high yields and moderate ee (ca. 67%).
3.15.12.3 Phospholes and Their Transition Metal Complexes as Therapeutic Agents The homodimeric flavoenzymes glutathione reductase (GR) and thioredoxin reductase (TrxR) are associated with many cellular processes such as antioxidant defence, redox balance, regulation of various proteins, and nucleotide metabolism. Phosphole derivatives and phosphole complexes depicted in Figure 4 have been evaluated as inhibitors of these disulfide reductases. The derivatives 40, 362, and 363 exhibit inhibitor concentration for 50% inhibition (IC50) in the lower micromolar range for human GR (hGR) and human TrxR (hTrxR) (Table 27) <2002FF803>. The palladium complexes 338a and 338b are very efficient hTrxR inhibitors with IC50 values in the nanomolar range (Table 27).
1133
1134 Phospholes
O
O
O R i, But Li
Fe
Me
H+
Me
Me
Me
360
P
S Fe P
NaBH 4 Me
Me
ii,
359
CHO S Fe P
R
S P
Fe
Me
OH
O
Me
R = CH2OMe
CN
AcCl NEt 3
iii, S8
NR12
NR12 S Fe P
P(C2H4 CN)3
Fe P Me Me
S Fe P
R12NH
Me
Me
a: R1 = Me b: R1 = Et
244a,b
OAc
Me
Me
361a,b
Scheme 124
R1 S Y
R1
S
P
P
Ph
M
Ph Cl
40: Y = S 362: Y = Se
S
N
P Ph
Cl
363
338a,b: M = Pd 364a,b: M = Pt a: R1 =
S W(CO)5
P Ph
AuCl
N
365a,b
b: R 1 = S
N Figure 4 Selected phospholes tested as hTrxR inhibitors.
Table 27 Inhibition of hGR and hTrxR by phosphole derivatives Compound
IC50 on hGR
IC50 on hTrxR
40 362 363 338a 338b
1.5 mM 2.0 mM 1.0 mM 1.4 mM 320 nM
5 mM 20 mM 6 mM 8.5 nM 10 nM
However, the most interesting inhibitors appeared to be the gold complexes 365a and 365b <2005JBC20628, 2006AGE1881>. Time-dependent kinetics on wild-type TrxR possessing a Cys–Sec pair at the flexible C-terminal part showed that gold– and platinum–phosphole complexes 365a,b and 364a,b are extremely efficient with IC50 values in the nanomolar range <2006AGE1881>. Furthermore, similar studies on hGR showed that the gold–phosphole complexes 365a and 365b are active in the low nanomolar range and are at least 2 orders of magnitude more active than the corresponding platinum complexes 364a and 364b. Gold–phosphole complexes 365a and 365b are the most potent GR and TrxR inhibitors to date. Notably, the phosphole substitution pattern (pyridyl versus thienyl) has only a marginal effect on the inhibitor efficiency. The interaction of 365a with hGR was studied by X-ray diffraction <2006AGE1881>. Half of an hGR dimer was modified by one molecule of 365a covalently bound to the surface-exposed Cys284, and one Au-atom
Phospholes
covalently bound between Cys58 and Cys63 in the active site. The presence of a (pyridylphosphole)gold fragment at Cys284 suggests that the Cl ligand is more easily displaced than the phosphole ligand. In fact, complex 365a acts as a pro-drug that undergoes a stepwise ligand displacement resulting in an S–Au–S coordination in the inactive GR product.
3.15.12.4 Phosphole-Based p-Conjugated Materials for Optoelectronic Applications p-Conjugated oligomers and polymers have emerged as promising materials for applications in flexible, lightweight, and low-cost electronic devices such as OLEDs, field-effect transistors (FETs), plastic lasers, and photovoltaic cells. One of the most powerful means of influencing and tuning the physical properties of a p-conjugated material, at the molecular level, is to vary the chemical composition of the conjugated backbone chain. Some of the most widely studied and useful materials have extended p-systems that are based upon five-membered rings such as thiophene and pyrrole. In contrast, the use of phosphorus-derived building blocks in such materials only emerged in the late 1990s, with phosphole units having been the most thoroughly investigated to date <2006CRV4681>. Indeed, phospholes are appealing building block polymers for the tailoring of p-conjugated materials due to their unique electronic properties. First, their weak aromatic character favors p-electron delocalization, since it is well established that conjugation is enhanced for macromolecules built from monomer units that exhibit low resonance energies (see Section 3.15.2.2). However, the most appealing property of the phosphole ring as a component of conjugated molecular materials is the ease with which the physical characteristics (e.g., redox potentials, absorption and emission wavelengths, etc.) can be fine-tuned by simple chemical modification (e.g., oxidation and complexation) of the P centers. Consequently, a variety of conjugated linear oligomers as well as polymeric derivatives incorporating phospholes have been synthesized and reliable structure–property relationships have been established (see Section 3.15.3.4). In particular, this type of P-building block has been used for the tailoring of NLO-phores, and for conductive and emissive materials for OLEDs. The synthesis of ,9-oligophosphole derivatives, such as quaterphosphole 19 <1990AGE655> or thienyl-capped biphosphole derivatives 366 <1991NJC545, 1994AGE1158>, was conducted prior to 1996 by Mathey et al. (Figure 5). However, since this date, the emphasis has been the preparation of conjugated phosphole-based systems that do not posssess an ,9-phosphole moiety. Some examples of ethynyl– <1996BSF33> and ethenyl–phosphole <2000J(P1)1519> derivatives having a conjugated backbone are given in Figure 5; their synthesis was described in Schemes 35 and 39 (Section 3.15.7). Since no optical or electrochemical data have been reported for these derivatives, this has precluded determination of any structure–property relationships. However, an X-ray diffraction study of the model compound 121 revealed that the C–C linkages between the P-heterocycle and the CUC moieties ˚ <1996BSF33>, suggesting that the endocyclic dienic p-system of the phosphole are rather short (1.423(3)–1.416(3) A) unit is conjugated with the two acetylenic substituents. R1 Br
R1 R1
R1 R1
R1 R1
..
..
..
..
Ph
Ph
Ph
Ph
P
R1
..
Br
P
P
P
R1
R1
P
121
Ph
19 R1 Br
R1
R1
..
..
P
Ph
140
R1
R1 Br
P
P
Ph
Ph
S
R1 R1
P
2
R1
.. P
124
Ph
R1
..
..
P
R
R1
..
R3
R1
S
R1
R
S
S
2
366 R 1 = CH 3 ; R 2 = CH3, –CH 2 –CH 2 –; R 3 = Me3 Si Figure 5 Examples of ethynyl– and ethenyl–phosphole derivatives having a conjugated backbone.
R3
1135
1136 Phospholes The first systematic investigation of phosphole-containing conjugated systems, starting with model molecules and building up to conductive polymers and materials suitable for OLED applications, has been undertaken with 2,5di(heteroaryl)phospholes. These compounds are ideally suited to such applications due to their high thermal stability (Table 28), which allows them to be readily deposited by sublimation. In this way, single layer OLEDs based on phosphole-derived conjugated systems 40, 41, and 367–371 (Figure 6) have been manufactured following deposition of the P-based materials onto semitransparent indium tin oxide (ITO) anodes. Compounds 40, 41, and 367–371 were prepared using the Fagan–Nugent method (see Section 3.15.9.2, Scheme 54), followed either by oxidation of the P-atom with elemental sulfur or coordination with an AuCl fragment <2003JA9254, 2006JA983>. Although the variation in their optical properties has been described in detail in Section 3.15.3.4, it is important to note that these P-based chromophores have significantly different physical properties depending on their molecular structure. For example, their maximum emission wavelengths (em) in the solid state range from 517 to 553 nm and both their oxidation and reduction potentials vary over the range 0.4–0.5 eV (Table 28). It is thus apparent that the ready tuning that can be achieved by variation of the phosphole framework is of interest for OLED development, since it allows the emission color of the devices to be varied and the crucial match between the LUMO and HOMO levels and the work functions of the electrodes to be achieved.
Table 28 Photophysical and electrochemical data for derivatives 40, 41, and 367–371
40 41 367 368 369 370 371
Td10a ( C )
maxb (nm)
emb (nm)
fc (%)
b (ns)
Epcd (eV)
Epad (eV)
253 218 306 210 252 251 287
435 440 410 345 410 360 397
553 550/690 520 517 545 505/630 526
6.6 0.6 3.6 0.5 4.2 11.2 0.8
1.33 0.25/1.54 0.30 0.38 0.52 0.94/5.20 0.38
1.55 1.35 1.95 1.74 1.68 1.75 1.70
þ1.08 þ1.22 þ1.04 þ1.52 þ1.31 þ1.85 þ1.45
a
TGA, 10% weight loss. In neat film. c Absolute fluorescence quantum yield in neat film. d In CH2Cl2, referenced to SCE. b
S
P
S
R
S
S
P R
ClAu
40
41
P S
S
N
.. P R
367
P R
368
S
P R
ClAu
370
369
P S
R
R
371 Figure 6 Phosphole-derived conjugated systems used to prepare single-layer OLED devices.
Phospholes
Not surprisingly, the performance of these OLED devices varies significantly depending on the exact nature of the phosphole component employed <2003JA9254, 2006JA983>. In all cases, the electroluminescence (EL) spectra of these devices match those of the solid-state PL spectra of the phospholes upon which they are based, showing that the source of the EL emission band is the P-derivative. The highest maximum brightness (Bmax ¼ 3613 cd m2) and external EL quantum efficiency (EELQ ¼ 0.16) are obtained with the thienyl-capped phosphole 40. In order to further improve device characteristics, multilayered devices in which the phosphole layer is sandwiched between a hole-transport layer (-NPD) and an electron-transport layer (Alq3) were prepared. The EELQ and brightness of the multilayer devices are dramatically superior to those of their single-layer counterparts with similar turn-on voltages. Similarly, the EL of phosphole gold complexes 41 and 370 (Figure 6) was studied in both single-layer and multilayer structures. As was observed for their thin-film PL, their EL spectra also show two broad emission bands. The EL spectrum of the single-layer device using complex 41 uniformly covers a broad spectral range of 500–800 nm due to the well-balanced dual monomer and aggregate emissions. Overall, these results show that p-conjugated oligomers containing 3- or 4-phosphole moieties, including gold complexes, can be employed as multifunctional materials in single-layer OLEDs. They form the basis for the further development of P-based materials for optoelectronic applications <2006CRV4681>. As highlighted in Section 3.15.12.2, an important property of phospholes is their ability to form transition metal complexes. Notably, the coordination of such p-chromophores to transition metals has proved to be a very powerful way to modify their characteristics and to engender novel properties. For example, 1,4-chelating 2-pyridylphosphole derivatives possess two coordination centers with different stereoelectronic character: a feature that, in accordance with Pearson’s antisymbiotic effect, can be used to control the orientation of a second chelating ligand in the coordination sphere of a square planar d8-metal center. Indeed, 1D-dipolar phospholes 45a and 45b (Scheme 125) undergo stereoselective coordination leading to a close parallel alignment of the dipoles on the square-planar d8-Pd(II) template. Thus, the trans-influence can overcome the natural anti-parallel alignment tendency of 1D-dipolar chromophores at the molecular level. The non-centrosymmetric complexes 372a and 372b exhibit fairly high NLO activities ( 1.9 mm ca. 170–180 1030 e.s.u.), something that is probably due to the onset of ligand-to-metal-to-ligand charge transfer (LMLCT), which contributes coherently to the second harmonic generation <2002CC1674>.
2+
R
..
N
P
N R
P
0.5Pd(CH 3 CN) 4 2+ N
Ph
Ph Ph
Pd
45a,b
P R
OMe or
R= S
NBu 2
372a,b
Scheme 125
Another interesting application of p-conjugated systems is their use as chemosensors. For example, a modified dithienophosphole oxide 1609 (see Scheme 49 for the synthesis of its precursor) that incorporates boryl-end caps is a very sensitive and selective sensory material for the fluoride ion (Scheme 126). Treatment of this derivative by fluoride induces a red shift of the emission maximum (160, 452 nm; 373, 485 nm) that is visible to the naked eye. This shift in the fluorescence emission can even be detected down to micromolar concentrations of fluoride ion; notably, the addition of other halides (Cl, Br, I) does not affect the fluorescence in any way <2006OL495>. To date, no homopolymers based on the phosphole motif are known, although, in contrast, several types of phosphole-containing conjugated copolymers have been reported. The first materials of this type to be prepared were the biphenyl–phosphole derivatives 166a and 166b obtained by Mao and Don Tilley using the Fagan–Nugent methodology (see Scheme 51, Section 3.15.9.1) <1997MM5566>. Phosphole–aryl polymer 180 with a regioregular backbone (2,5-linkages) was recently prepared by Tomita using the titanacyclopentadiene-containing precursor (see Scheme 57, Section 3.15.9.1) .
1137
1138 Phospholes
Me O
Me
S
B Me Me
O B O
S
O
Me Me
Me Me
Me
F–
Me Me
Me
O–F B O
F –O S B O
S
Me Me
P
P O
Me Me
Ph
O
Ph
160′
373
Scheme 126
R1
R1 0.8n
P
P
R1
0.2n
Ph
Ph
166a
R1
166b OC 6 H17
..
P
n
Ph
C6H17O
180 The first well-defined, p-conjugated polymer featuring phosphole rings was obtained by Chujo and co-workers using the Heck–Sonogashira coupling of bromo-capped 2,5-(diphenyl)phosphole 374 with the diynes 375a–c (Scheme 127) <2003MM2594>. Macromolecules 44a–c featuring free 3-phosphole moieties are isolated in moderate to low yields as soluble powders, with low degrees of polymerization, ranging from 7 for 44c to 15 for 44a. Note that polymer 377, based on a 3-dibenzophosphole moiety, was obtained by Ni-catalyzed homocoupling of derivative 376, albeit with a rather high polydispersity (Mn ¼ 5 102; Mw ¼ 6.2 103; polydispersity index (PDI) ¼ 12.4) (Scheme 128) <2003JP2003231741>. Clearly the presence of 3-P centers, which are potential donor sites for the Ni-catalyst, does not hamper the C–C bond formation.
..
Br
Br
P
Ph
374
PdCl 2 (PPh 3 )2
+ H
Ar
..
CuI, Et 3 N
Ar
P
n
Ph
H
44a–c
375a–c On-C6H13 Ar
n-C12 H25
n-C12H25
: n-C6H13 O
Scheme 127
On-C12 H 25
a
n-C12 H25 O
b
c
Phospholes
C8 H 17 O
OC8 H 17
Br
Br
..
C8H17 O cat. Ni(0)
OC8H17
..
P
n
P
Ph
Ph
376
377
Scheme 128
Today, the best-developed route to phosphole-containing polymers is the electropolymerization of thienyl-capped monomers, a process which involves the generation and coupling of radical cations. However, to date, only CN 4 phosphole-containing monomers have proved to be successful for this type of electropolymerization (Scheme 129) <2000AGE1812, 2001CEJ4222, 2003OL3467>. With 3,3-phosphole monomers, the process is not efficient, probably due to side reactions involving the nucleophilic P-atoms and the corresponding intermediate radical cations. It is noteworthy that no anodic electropolymerization process was observed with thienyl-capped 1,19-diphosphaferrocene 333 (see Scheme 111). This has been attributed to the essentially pure metal character of the HOMO, which is a feature typical of phosphaferrocenes <2005OM5369>. In general, it has proved difficult to establish the degree of polymerization and the microstructure of the materials resulting from electropolymerization due to their insolubility, which prevents GPC and standard spectroscopic analyses.
ox. S
Y
S
S
Y
S
n
40: Y = P(S)Ph 362: Y = P(Se)Ph +
378 = PMePh Scheme 129
The polymers prepared from neutral phospholes 40 and 362 exhibit p- and n-doping characteristics with fairly good reversibilities (>70%). Cationic poly378 also exhibits reversible p-doping, but its electroactivity dramatically decreases upon reduction. It is noteworthy that these doped materials have lower potentials than those of the corresponding monomers, suggesting that the electroactive materials possess much longer conjugation pathways and smaller band gaps than the monomers. This is confirmed by the fact that the values of onset for the de-doped polymers were considerably redshifted compared with those observed for the corresponding monomers <2000AGE1812, 2001CEJ4222>. A remarkable feature of these materials is that the electrochemical (doping range) and optical properties (max, onset) obtained by electropolymerization depend on the nature of the phosphorus moiety. As already mentioned, direct access to 3-phosphole-modified polythiophene 380 is impossible (39c ! 380, Scheme 130), because the 3-phosphole ring of 39c does not tolerate oxidative electropolymerization of pendant thiophene units, probably as a result of reaction between the nucleophilic P-atom with either radical cations or protons formed during the chain growth process. In order to avoid interference from the lone pair, a P-protection/ electropolymerization/P-deprotection strategy has been used effectively for the electropolymerization of thienylcapped 4-phosphole monomers. The readily accessible, P-protected 4-Au(I)-complex 41 was subjected to anodic electropolymerization 41 ! 379 (Scheme 130) <2006AGE6152>. The final step toward the target polymer 380 required the deprotection of the P-atoms of 379 by release of the Au(I) fragments (Scheme 130). This was achieved readily by washing the poly-379-coated Pt-electrode with a CH2Cl2 solution containing excess triphenylphosphine, which instantly affords the free phosphole 380 and ClAu(PPh3). The resulting polymers have been characterized by MAS 31P NMR spectroscopy. Polymer 380 (deposited on a Pt-electrode) reacts with elemental sulfur or selenium to
1139
1140 Phospholes give the corresponding 4-thiooxo- and 4-selenophosphole polymers 381a and 381a, respectively (Scheme 130). Notably, these transformations of 380 ! 381a,b induce a large positive shift of the oxidation current offset. Hence, phosphole-modified polythiophene 380 acts as a chalcogen sensor, an unprecedented property for conjugated polymers.
S
..
anodic oxidation
X
S
S
S
..
P Ph
P Ph
S8 or Se
S P
n
Ph
380
39c
n
Y
381a: Y = S 381b: Y = Se
PPh 3
(tht)AuCl
S
tht = tetrahydrothiophene
S
S
anodic oxidation
S
S P
P Ph
AuCl
41
Ph
AuCl
n
379
Scheme 130
3.15.13 Further Developments The papers listed below appeared after submission of the original manuscript. They are assigned to particular sections of the chapter, but for some there is considerable overlap with other sections. 3.15.2.2 Extended p-Conjugated Systems Based on Phospholes Study of neutral and oxidized forms of phosphole oligomers <2007JPCC4823>. 3.15.3.1 X-Ray Diffraction Analysis First X-ray diffraction study of an iridium(III) phosphole complex <2007AC(E)m1818>. 3.15.5.2.1 Phosphole oxides, sulfides, and selenides Hetero Diels–Alder reactions involving phosphole sulfides <2007TL3349>. 3.15.9.1 General Ruthenium-promoted formation of 1H-phosphindoles from phosphaalkynes <2007JA14962>. 3.15.9.2 Reaction of 1,4-Dimetallic Derivatives of Dienic Systems with Phosphorus Dihalides Synthesis and NLO properties of 2-aryl-5-styrylphospholes <2007JOCASAP>. 3.15.12.1.1 7-Phosphanorbornadenes and 7-phosphanorbornadienes Chiral metal template-promoted cycloadditions involving 3,4-dimethyl-1-phenylphosphole and its sulfonated analogue <2006JOM3083>. 3.15.12.1.4 Phospholyl complexes Preparation and characterization of 1,19-diphosphaferrocenes with linear fused six-membered carbocycles <2007JOM55>. Synthesis and reactivity of trimethylsilyl-substituted phosphametallocenes <2007EJI553>. Synthesis and reactivity of tetramethylphospholyl complexes of scandium <2007JOM4595>. 3.15.12.2.2 Mono- and bi-dentate ligands Xanthene-phosphole ligands in the palladium-catalyzed amine allylation <2007OM1846>. 3.15.12.2.3 Chiral ligands Ferrocene-bridged phosphole-phosphane ligands and their activity in palladium-catalyzed allylic substitution <2006EIJC5148>. 3.15.12.3 Phospholes and Their Transition Metal Complexes as Therapeutic Agents Synthesis of phosphole-containing peptides <2007TL2857>. 3.15.12.4 Phosphole-based p-Conjugated Materials for Optoelectronic Applications Synthesis and optical properties of mixed phosphole-diethynylbenzene copolymers <2007JPS(A)2867>. Synthesis and optical properties of conjugated copolymers based on phospholes <2007PB645>.
Phospholes
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D. Arscott, K. Fritz-Wolf, R. Re´au, C. Henrold-Mende, S. Koncaveric, M. Meyer, E. DavioudCharvet, B. P. Ballou, et al., J. Biol. Chem., 2005, 280, 20628. ´ D. Duraaczynska and J. H. Nelson, Dalton Trans., 2005, 92. D. Carmichael, L. Ricard, N. Seeboth, J. M. Brown, T. D. W. Claridge, and B. Odell, Dalton Trans., 2005, 2173. Z. Duan, B. Donnadieu, and F. Mathey, J. Organomet. Chem., 2005, 690, 450. M. Clochard, J. Grundy, B. Donnadieu, and F. Mathey, Org. Lett., 2005, 7, 4511. C. Compain, B. Donnadieu, and F. Mathey, Organometallics, 2005, 24, 1762. L. Zhang, M. Hissler, H.-B. Bu, P. Ba¨uerle, C. Lescop, and R. Re´au, Organometallics, 2005, 24, 5369. E. Robe´, C. Ortega, M. Mikina, M. Mikolajczyk, J.-C. Daran, and M. Gouygou, Organometallics, 2005, 24, 5549.
1145
1146 Phospholes
2005PCA9310 2005SM249 2005SOS1097 2005TCC127 2006AGE1881 2006ACR853 2006AGE6152 2006AXC188 2006CH395 2006CCR627 2006CEJ3759 2006CL958 2006COC61 2006COR3 2006COR43 2006CRV4681 2006EIJC5148 2006EJO650 2006HAC344 2006JA983 2006JA3520 2006JA11760 2006JA7716 2006JCD1424 2006JCC344 2006JCT425 2006JOC5792 2006JOM3083 B-2006MI59
2006OBC996 2006OL495 2006OL503 2006OM1079 2006OM2394 2006OM2585 2006OM2715 2006OM3105 2006OM3152 2006PCA5909 2006PCA10148 2006PCP862 2006STC13 2006T401 2006TA2354 2007AC(E)m1818 2007EJI553 2007JA14962 2007JOCASAP 2007JOM55 2007JOM4595 2007JPCC4823 2007JPS(A)2867 2007OM1846 2007PB645 2007TL2857 2007TL3349
T. C. Dinadayaalane, G. Gayatri, G. N. Sastry, and J. Lszczynski, J. Phys. Chem. A, 2005, 109, 9310. J. Casado, R. Re´au, V. Hernandez, and J. T. Lopez Navarrete, Synth. Met., 2005, 153, 249. P. Le Floch and F. Mathey, Sci. Synthesis, 2005, 15, 1097. M. Hissler, P. Dyer, and R. Re´au, Top. Curr. Chem., 2005, 250, 127. S. Urig, K. Fritz-Wolf, R. Re´au, C. Herold-Mende, K. Toth, E. Davioud-Charvet, and K. Becker, Angew. Chem., Int. Ed., 2006, 45, 1881. G. C. Fu, Acc. Chem. Res., 2006, 39, 853. M. Sebastien, M. Hissler, C. Fave, J. Rault-Berthelot, C. Odin, and R. Re´au, Ang. Chem., Int. Ed., 2006, 45, 6152. J. Guadalupe Lopez Cortes, S. Vincendeau, J.-C. Daran, E. Manoury, and M. Gouygou, Acta Crystallogr., Sect. C, 2006, 62, 188. S. Moeller, Z. Drzazga, Z. Pakulski, K. M. Pietrusiewicz, and H. Duddeck, Chirality, 2006, 18, 395. P. Le Floch, Coord. Chem. Rev., 2006, 250, 627. J. Casado, R. Re´au, and J. T. Lopez Navarrete, Chem. Eur. J., 2006, 12, 3759. Z. Zhang, J. Li, B. Huang, and J. Qin, Chem. Lett., 2006, 35(8), 2006, 958. J. Holz, M.-N. Gensow, O. Zayas, and A. Bo¨rner; Synthesis of chiral heterocyclic phosphines for application in asymmetric catalysis, in ‘Current Organic Chemistry’, 2006, 10, 61. N. Me´zailles and P. Le Floch, Curr. Org. Chem., 2006, 10, 3. L. D. Quin, Curr. Org. Chem., 2006, 10, 43. T. Baumgartner and R. Re´au, Chem. Rev., 2006, 106, 4681. J. Guadalupe, L. Cortes, O. Ramon, S. Vincendeau, D. Serra, F. Lamy, J.-C. Daran, E. Manoury, and M. Gouygou, Eur. J. Inorg. Chem., 2006, 5148. M. Toffano, C. Dobrota, and J.-C. Fiaud, Eur. J. Org. Chem., 2006, 650. S. Sasaki, T. Mori, and M. Yoshifuji, Heteroatom. Chem., 2006, 17, 344. H.-C. Su, O. Fadhel, C.-J. Yang, T.-Y. Cho, C. Fave, M. Hissler, C.-C. Wu, and R. Re´au, J. Am. Chem. Soc., 2006, 128, 983. B. Nohra, S. Graule, C. Lescop, and R. Re´au, J. Am. Chem. Soc., 2006, 128, 3520. Y. Matano, T. Miyajima, T. Nakabuchi, H. Imahori, N. Ochi, and S. Sakaki, J. Am. Chem. Soc., 2006, 128, 11760. J. Grundy, B. Donnadieu, and F. Mathey, J. Am. Chem.. Soc., 2006, 128, 7716. Y. Dienes, M. Eggenstein, T. Neumann, U. Englert, and T. Baumgartner, J. Chem. Soc., Dalton Trans., 2006, 1424. I. Garcia Cuesta, A. M. J. Sanchez de Meras, and P. Lazzeretti, J. Comput. Chem., 2006, 27(3), 2006, 344. F. Leca and R. Re´au, J. Catal., 2006, 238, 425. Y. Matano, T. Miyajima, T. Nakabuchi, Y. Matsutani, and H. Imahori, J. Org. Chem., 2006, 71, 5792. S. A. Pullarkat, K.-W. Tan, M. Ma, G.-K. Tan, L. L. Koh, J. J. Vittal, and P.-H. Leung, J. Organomet. Chem., 2006, 691, 3083. I. Tomita; Polymers possessing reactive metallacycles in the mainchain, in ‘Macromolecules Containing Metal and MetalLike Elements’, A. S. Abd-El-Aziz, C. E. Carraher, Jr., C. U. Pittman, Jr., and M. Zeldin, Eds.; Wiley-Interscience, Hoboken, NJ, 2006, p. 59. L. Nyulaszi, O. Holloczki, C. Lescop, M. Hissler, and R. Re´au, Org. Biolmol. Chem., 2006, 4, 996. T. Neumann, Y. Dienes, and T. Baumgartner, Org. Lett., 2006, 8, 495. T. Baumgartner and W. Wilk, Org. Lett., 2006, 8, 503. Y. J. Ahn, R. J. Rubio, T. K. Hollis, F. S. Tham, and B. Donnadieu, Organometallics, 2005, 25, 1079. J. Bitta, S. Fassbender, G. Reiss, and C. Ganter, Organometallics, 2005, 25, 2394. M. Siutkowski, F. Mercier, L. Ricard, and F. Mathey, Organometallics, 2006, 25, 2585. M. Ogasawara, A. Ito, K. Yoshida, and T. Hayashi, Organometallics, 2006, 25, 2715. Y. Matano, T. Nakabuchi, T. Miyajima, and H. Imahori, Organometallics, 2006, 25, 3105. N. H. Tran Huy, S. Hao, L. Ricard, and F. Mathey, Organometallics, 2006, 25, 3152. A. Alparone, H. Reis, and M. G. Papadopoulos, J. Phys. Chem. A, 2006, 110, 5909. D. Vijay and G. N. Sastry, J. Phys. Chem. A, 2006, 110, 10148. P. Adkine, T. Cantat, E. Deschamps, L. Ricard, N. Me´zailles, P. Le Floch, and M. Geoffroy, Phys. Chem. Chem. Phys., 2006, 8, 862. I. Alkorta, K. Zbrowski, and J. Elguero, Struct. Chem., 2006, 17, 13. M. Tereda and M. Kouchi, Tetrahedron, 2006, 62, 401. A. Galland, C. Dobrota, M. Toffano, and J.-C. Fiaud, Tetrahedron Asymmetry, 2006, 17, 2354. M. Kotera and T. Suzuki, Acta Cryst., Part E., 2007, m1818. R. Loschen, C. Loschen, W. Frank, and C. Ganter, Eur. J. Inorg. Chem., 2007, 553. J. G. Cordaro, D. Stein, and H. Gru¨tzmacher, J. Am. Chem. Soc., 2006, 128, 14962. Y. Matano, T. Miyajima, H. Imahori, and Y. Kimura, J. Org. Chem., 2007, ASAP. M. Ogasawara, T. Sakamoto, K. Nakajima, and T. Takahashi, J. Organomet. Chem., 2007, 692, 55. F.-G. Fontaine and K. A. Tupper, J. Organomet. Chem., 2007, 691, 4595. J. Casanovas and C. Aleman, J. Phys. Chem. C., 2007, 111, 4823. H.-S. Na, Y. Morisaki, Y. Aiki, and Y. Chujo, J. Polym. Sci, Polym. Chem., Part A, 2007, 45, 2867. G. Mora, B. Deschamps, S. van Zutphen, X. F. Le Goff, L. Ricard, and P. Le Floch, Organometallics, 2007, 26, 1846. H.-S. Na, Y. Morisaki, Y. Aiki, and Y. Chujo, Polymer Bulletin, 2007, 58, 645. S. van Zutphen, V. J. Margarit, G. Mora, and P. Le Floch, Tetrahedron Lett., 2007, 48, 2857. M. Segi, K. Kawaai, M. Honda, and S. Fujinami, Tetrahedron Lett., 2007, 48, 3349.
Phospholes
Biographical Sketch
Re´gis Re´au received his Ph.D. in 1988 under the supervision of Denis Neibecker at the Laboratoire de Chimie de Coordination (Toulouse, France). In 1989, he spent a postdoctoral year with Wolfgang Keim in Aachen (Germany) as an Alexander von Humboldt Fellow. During these years, he was involved in the synthesis of transition metal-based homogeneous catalysts for hydroformylation (Toulouse) and asymmetric C–C coupling reactions (Aachen). In 1990, he joined the group of Guy Bertrand at the Laboratoire de Chimie de Coordination (Toulouse, France). There he worked on the synthesis of antiaromatic heterocycles, 1,3- dipoles, and superLewis acids. In 1997, he was appointed professor at the University of Rennes 1 (France). In 2001, he became a junior member of the Institut Universitaire de France. His current main research interests are the design of conjugated materials based on organophosphorus building blocks and the supramolecular assembly of chromophores using coordination chemistry.
Philip Dyer was awarded his Ph.D. in 1993 from the University of Durham (UK) working under the supervision of Vernon Gibson and Jas Pal Badyal in the areas of metal organoimido chemistry and heterogeneous catalysis. In 1994, he moved to Toulouse, France, as a Royal Society European Science Exchange Fellow, where he worked for a period of 18 months with Guy Bertrand in the Laboratoire de Chimie de Coordination. Over the course of this postdoctoral visit, he worked in the areas of -metallo-nitrilimine and -diazo complexes and the reactivity of isolable phosphino carbenes. On returning to the UK, he held a temporary lectureship at Imperial College, London, working alongside the group of Mike Mingos. In 1996, he took up a lectureship at the University of Leicester and then in 2004 moved to Durham University. Currently his research interests include transition metal-mediated catalysis, ligand design, coordination, and organophosphorus chemistries.
1147
3.16 Arsoles, Stiboles, and Bismoles V. Milata Slovak Technical University, Bratislava, Slovakia ª 2008 Elsevier Ltd. All rights reserved. 3.16.1
Introduction
3.16.2
Theoretical Methods
3.16.2.1 3.16.2.2 3.16.3
1150 1151
Semi-Empirical Calculations
1151
Ab Initio Calculations
1152
Experimental Structural Methods
1153
3.16.3.1
X-Ray Diffraction
1153
3.16.3.2
NMR Methods
1155
3.16.3.2.1 3.16.3.2.2
1
H NMR spectroscopy C NMR spectroscopy
1157 1157
13
3.16.3.3
Mass Spectrometry
1158
3.16.3.4
Ultraviolet Spectroscopy
1158
3.16.3.5
Infrared and Raman Spectroscopy
1159
3.16.3.6
Electron Spin Resonance Spectroscopy
1159
3.16.3.7 3.16.4
Electrochemistry
1159
Thermodynamic Aspects
1159
3.16.4.1
Boiling and Melting Points
1159
3.16.4.2
Solubility and Chromatographic Behavior
1161
3.16.4.3
Aromaticity and Stability
1161
3.16.4.3.1 3.16.4.3.2
3.16.4.4
Conformations
3.16.4.4.1 3.16.4.4.2
3.16.5
Aromaticity and electron-pair delocalization Stability
1162 1163
1163
Geometry at the heteroatom and inversion barriers Conformational equilibria of trigonal bipyramid and octahedral compounds
Reactivity of Fully Conjugated Rings
1163 1165
1165
3.16.5.1
General Survey of Reactivity
1165
3.16.5.2
Unimolecular Thermal Reactions
1166
3.16.5.3
Electrophilic Attack at the Heteroatom
1166
3.16.5.3.1 3.16.5.3.2
Neutral ring systems Anionic and radical anion ring systems
1166 1166
3.16.5.4
Electrophilic and Nucleophilic Attack at Carbon
1166
3.16.5.5
Nucleophilic Attack at the Heteroatom
1167
3.16.5.6
Reactions with Radicals and Electron-Deficient Species
1167
3.16.5.7
Cyclic Transition State Reactions with a Second Molecule
1167
3.16.6
Reactivity of Nonconjugated Rings
1167
3.16.7
Reactivity of Substituents Attached to Ring Heteroatoms
1167
3.16.8
Ring Synthesis Classified by Number of Ring Atoms
1167
3.16.8.1
Synthesis of Fully Conjugated Systems
3.16.8.1.1
3.16.8.2
1167
Condensation reactions
1167
Synthesis of Dihydro Derivatives
1169
1149
1150 Arsoles, Stiboles, and Bismoles 3.16.8.3
Synthesis of Tetrahydro Derivatives
3.16.8.3.1 3.16.8.3.2
3.16.8.4
Synthesis of Derivatives with CN 4, 5, and 6
3.16.8.4.1 3.16.8.4.2 3.16.8.4.3
3.16.9
1.4-Dihalobutanes 1.4-Di-Grignard reagents CN 4 CN 5 CN 6
Ring Synthesis by Transformation of Another Ring
3.16.9.1
1170 1170 1170
1170 1170 1170 1171
1171
Interconversion at the Heteroatom
1171
3.16.9.2
Interchange of the Heteroatom
1173
3.16.10
Synthesis of Particular Classes of Compounds
1174
3.16.10.1
Synthesis of Anionic Intermediates
1174
3.16.10.2
Synthesis of 1,19-Biheterole Derivatives
1175
3.16.10.3
Synthesis of Organometallic Derivatives
1175
3.16.10.3.1 3.16.10.3.2
3.16.11 3.16.11.1
Important Compounds and Applications Application of Arsoles, Stiboles, and Bismoles in Catalysis
3.16.11.1.1
3.16.11.2 3.16.12
-Complexes p-Complexes
Thermochromism
1175 1175
1176 1176 1176
Other Applications
1176
Further Developments
1176
References
1177
3.16.1 Introduction The heterocyclic chemistry of arsenic, antimony, and bismuth has a history of ca. 100 years and originates in the medical applications of organoarsenic compounds in the treatment of syphilis. Arsenic compounds have caused health problems in Bengal, where high levels of arsenic have leached from natural sources (particularly pyrites) into village wells <2001JIC224>. Drugs having a bismuth atom (e.g; bismole) are now of particular interest for the treatment of gastric problems, such as ulcers, gastritis, etc., and interest in this area has developed since Helicobacter pylori have developed resistance against metronidazole. Progress in arsole, stibole, and bismole chemistry occurred mainly during the period 1970–90. Historical developments have been summarized in CHEC(1984) and CHEC-II(1996) <1984CHEC(1)539, 1996CHEC-II(2)857> and in a book . More than 30 years ago, the first reports on arsoles focused on inversion barriers and aromaticity <1972JA2861>. Interest in this question remained for many years, and the aromaticity of the cyclopentadienides, the corresponding phospholides, and their homologues were compared <1992JOC3694, 1983OM1008>. Twenty years later, a (TMEDA)lithium tetramethylarsolide was isolated and characterized by X-ray crystallography (TMEDA ¼ tetramethylethylenediamine) <1991CB2453>. Ring enlargement reactions of arsolides and the formation of arsabenzenes (arsinines) were reported by Ma¨rkl et al. in 1974 <1974TL303>. This chapter is a continuation of the previous chapters in CHEC(1984) and CHEC-II(1996) <1984CHEC(1)539, 1996CHEC-II(2)857> and covers the period 1995–2006. For a full coverage of the chemistry, all three editions must be consulted. Some references that were not included in the earlier editions have been included in this chapter. During the last 10 years, there have been some papers dealing with selected general aspects of the heterocyclic chemistry of nitrogen, phosphorus, arsenic, antimony, and bismuth (in general, pnictogen), for example, aromaticity, basicities <1995JMT51>, (hyper)polarizabilities <2006PCA5909>, inversion barriers <2002JPC6387> of heteroelementoles or diheteroelementaferrocenes <1995OM2689>. Related are reviews dealing with heterocyclopentadienyl complexes <2001EJI891>, cyclic aromatic systems with hypervalent centers <2001CR1247>, and the synthesis and properties of optically active organoantimony compounds <2003YZ577>. This chapter covers five-membered monoelementaheterocycles of arsenic, antimony, and bismuth and includes benzo-, dibenzo-, unsaturated, partially unsaturated species and some with a different coordination numbers (CNs).
Arsoles, Stiboles, and Bismoles
Elementoles, that is, monoelemental monocyclic five-membered heterocycles (arsole, stibole, and bismole), are also known in the literature as elementacyclopentadienes. The most commonly encountered structures are monoheteroelementoles 1, such as arsole (E ¼ As), stibole (E ¼ Sb), and bismole (E ¼ Bi), and their substituted derivatives. To this group belong also diheteroferrocenes, known also as hetero/elemantapenta-2,4-dienes 2, with both elements the same. Two different elements or monosubstitution (monoheteroferrocenes) have not been described. Other examples include the (1,19)-biheteroles 3, but having both pnictogen atoms equal.
Substituents Rn are indexed with n, where n indicates the position of the substituent on the ring. Benzo derivatives of elementoles are bicyclic systems where a benzene ring is fused to heterocyclic ring, that is, they are formally benzoelementoles. They can be benzo[b] 4 or benzo[c] fused 5. Tricyclic systems can occur as the derivatives 6 and the dibenzocondensed dibenzoelementoles 7.
n ¼ ring position of the corresponding substituent Some fused pentacyclic derivatives are known, for example, dinaphtho[2,1-b;19,29-d]elementole, especially stiboles 8b (E ¼ Sb). A few compounds with a CN different from 3 are known, especially compounds with CN 5 of the type 9 and their benzoderivatives 10.
3.16.2 Theoretical Methods 3.16.2.1 Semi-Empirical Calculations Semi-empirical NDDO methods have been used for the study of various heterocycles <1995JMT51>. A belief that highly accurate values are not essential for valid conclusions to be drawn and the time advantage of semi-empirical over ab initio methods were factors governing the choice of these procedures. In general, there is reasonable agreement between structures and energies computed and experimental or ab initio values. The semi-empirical structural data have been discussed and compared with previously determined structures (Table 1). The results of semi-empirical calculations for 1H-arsole 1a and 1H-stibole 1b can be compared with an ab initio study <1988JA4204>. The bond angles in 1H-arsole 1a do not differ by more than 1.2 , and the bond lengths are ˚ Bond lengths and angles almost identical, usually agreeing to within 0.01 A˚ and never differing by more than 0.014 A. ˚ are similarly quite close for 1H-stibole 1b, except that PM3 gives the C–Sb distance shorter by 0.029 A. For 1H-arsole 1a and 1H-stibole 1b, the heats of formation were 51.8 or 73.2 kcal mol1, respectively, using the PM3 method <1995JMT51>. Geometries were fully optimized and vibrational analysis confirmed that the geometry optimization had produced a local minimum.
1151
1152 Arsoles, Stiboles, and Bismoles Table 1 Elementacyclopentadienesa
Parameter
E–C(2)
C(2)–C(3)
C(3)–C(4)
C(5)–E–C(2)
E–C(2)–C(3)
C(2)–C(3)–C(4 )
1H-Pyrrole
1.397
1.390
1.421
109.7
107.0
108.1
1.370
1.382
1.417
109.8
107.7
107.4
1.823
1.342
1.459
90.5
109.4
114.9
1.783
1.343
1.438
90.7
1.943
1.337
1.464
86.5
109.8
116.6
1.949
1.330
1.478
85.5
111.0
116.1
2.132
1.331
1.465
80.7
110.4
119.2
2.161
1.330
1.482
80.2
110.6
119.3
1H-Phosphole
1H-Arsole, 1a
1H-Stibole, 1b
Reference Method 1995JMT51 PM3 1969JST491 Experiment 1995JMT51 PM3 1973JCD1888, 1970JA5779 Experimentb 1995JMT51 PM3 1988JA4204 Ab initio 1995JMT51 PM3 1988JA4204 Ab initio
˚ angles in ( ). Bond lengths (r) in A, Geometry of P-benzylphosphole. Adopted from D. J. Berger, P. P. Gaspar, and J. F. Liebman, J. Mol. Struct. Theochem, 1995, 338, 51. a
b
3.16.2.2 Ab Initio Calculations Using MP2/6-31G* calculations, the aromatic stabilization energy (ASE) has been obtained from the energies of isodesmic reactions (Equation 1) for many derivatives <1995JST57>. Thus, for arsole, the heat of bond separation reaction is calculated to be 16.63 kcal mol1. This is ca. 36% of the corresponding value for pyrrole. CHXYZNH þ NH3 þ XH3 þ YH3 þ ZH3 þ CH4 CH2 TZH þ CH3 –NH2 þ NH2 –ZH2 þ HXTYH þ YH2 –ZH2
ð1Þ
where X, Y, and Z denote N, P or As and CH groups. Geometries, inversion barriers, static and dynamic electronic and vibrational dipole polarizability (), and the first () and second () hyperpolarizability of the pyrrole homologues C4H4XH (X ¼ N, P, As, Sb, Bi) have been calculated by Hartree–Fock (HF), Møller–Plesset second-order perturbation theory (MP2), coupled-cluster theory accounting for single, double, and noniterative triple excitations methods (CCSD(T)), as well as density functional theory using B3LYP and PBE1PBE functionals and Sadlej’s Pol and 6-311G** basis sets <2006PCA5909>. Relativistic effects on the heavier homologues stibole and bismole have been taken into account within effective core potential (ECP) approximations. The results show that the electronic (hyper)polarizabilities monotonically increase with the atomic number of the heteroatom, being consistent with the decrease in the molecular hardness. Ring planarization reduces the carbon–carbon bond length alternation of the cis-butadienic unit, enhancing the electronic polarizability values (<e>) by 4–12% and the (hyper)polarizability values (evec and < e>) by 30–90%. Anharmonic corrections dominate the pure vibrational hyperpolarizabilities of pyrrole, while they are less important for the heavier homologues. Static and dynamic electronic response properties of the pyrrole homologues are comparable to or larger than the corresponding properties of the furan and cyclopentadiene homologue series. Calculations at the B3LYP/6-31þG(d,p)//MP2(FC)/6-31þG(d,p) level of the atoms-in-molecules (AIM) interbasin pair numbers were carried out for 14 substituted cyclopentadienyl five-membered rings (among them arsole and phosphole) and compared to the electron localization function (ELF) bond basin populations <2000CPH175>. A smooth correlation is found for the formally single C–C bond pair number with the corresponding homomolecular–homodesmic resonance energy (RE), as was previously shown for the ELF bond basin numbers (Figure 1).
Arsoles, Stiboles, and Bismoles
2.0
1.8
2F (C–C)
1.6 2F (C–C) 2F (C=C)
1.4
1.2
1.0
0.8 –60.0
–40.0
–20.0
0.0
20.0
E (H) Figure 1 Plot of the C–C and CTC pair numbers (2Fij) for the substituted cyclopentadienyl systems against the homomolecular–homodesmotic REs (E(H), in kcal mol1). From D. B. Chesnut and L. J. Bartolotti, Chem. Phys., 2000, 257, 175.
3.16.3 Experimental Structural Methods 3.16.3.1 X-Ray Diffraction The molecular structure of (TMEDA)lithium tetramethylarsolide resembled the characteristic features of the carbon analogues such as 5-coordination <1999CRV969>. The differences of molecular and crystal structures of the arsolides 11a (M ¼ alkali metal) and the stibolides 11b (M ¼ alkali metal) of the heavier alkali metals are dominated by the differences of the radii of the metal atoms and of the pnictogen atoms. In Table 2, the radii of the relevant atoms are listed <2004OM3417>.
Table 2 Radii of the heavier alkali metal cations (CN 6) and van der Waals radii of the pnictogen atoms as well as ˚ bond lengths of the metal atoms to the pnictogen atoms of the 5-bonded ligands (A) r (Mþ)
P
As
Sb
1.16 1.52 1.66 1.81
1.90 2.939 3.204 3.451 3.570
2.00 3.030 3.327 3.521 3.636
2.20 3.160 3.507b 3.668 3.776
a
r(E) Na K Rb Cs a
van der Waals radii r of the pnictogen atoms E. Taken from <2000OM2393>. From M. Westerhausen, M. W. Ossberger, P. Mayer, H. Piotrowski, and H. No¨th, Organometallics, 2004, 23, 3417. b
Characteristic bond lengths, summarized in Table 2, in molecular structures of the 2,3,4,5-tetraethylarsolides and -stibolides 11a and 11b (M ¼ alkali metal) of rubidium and cesium are similar.
1153
1154 Arsoles, Stiboles, and Bismoles Discrete molecules of dimeric (TMEDA)sodium tetraethylarsolide in the solid state are found with the sodium atoms bound in an 5-manner to one arsolide anion and having an Na–As -bond to the other. Furthermore, the coordination sphere of the sodium atom contains a bidentate TMEDA molecule. The molecular structure resembles the structure of the homologous phospholide. The heavier 2,3,4,5-tetraethylstibolide 11b (M ¼ Na) shows a totally different arrangement of the ions in the solid state. A chain structure is formed due the larger pnictogen atom. Besides the 5-coordination of the stibolide ligands, discrete Na–Sb bonds are also observed <2004OM3417>. For the potassium arsolide 11a (M ¼ K), only 5-coordination of the 2,3,4,5-tetraethylarsolide is observed. The rubidium 11a (M ¼ Rb) and cesium 11a (M ¼ Cs) analogues, as well as the homologues 2,3,4,5-tetraethylstibolides 11b (M ¼ alkali metal) and 11b (M ¼ Rb, Cs), crystallize as zigzag polymeric chains with the bending at the alkali metal atoms, which are also bonded to 1,2-dimethoxyethane (DME) molecules <2004OM3417>, and very similar to those of the corresponding 2,3,4,5-tetraethylphospholides 1 (E ¼ P, R ¼ alkali metal, R2–R5 ¼ Et) <2003ZFA2398>. Dependent on the size of the alkali metal atom, no DME co-ligands (K–PC4Et4 <2003ZFA2398>), a coordination to only a part of the alkali metal atoms (11a, 11b: M ¼ K), or a coordinative saturation of all alkali metal centers by ether co-ligands (11a, 11b: M ¼ Rb, Cs), <2004OM3417> takes place. The size of the metal and pnictogen atoms determines the degree of bending of the one-dimensional polymers. The bidentate DME co-ligand prevents an interconnection of these one-dimensional polymers. Related octaethyl heteroleptic magnesium and calcium chloride derivatives with analogous structures to 12 and 2,29,3,39,4,49,5,59-octaethyl-1,19-diheterolestrontocene 13 (crystallize as tetrahydrofuran (THF) adduct) and corresponding -barocene 14 (crystallize co-ligand free, but with a chain structure) have been described <2001ZFA1741>.
Torsional angles, distances, and dihedral angles of 7-phenyldinaphtho[2,1-b ;19,29-d ]arsole 15 have been published <1996G11>. The structure of 7-p-tolyldinaphtho[2,1-b ;19,29-d]stibole 16, which has the (S)-configuration, has been obtained by single crystal X-ray analysis <2001TL441, 2003YZ577>. The naphthalene rings are bent significantly ˚ Also away from each other, making the compound chiral: the distance between protons H-1 and H-3 is 2.406 A. apparent is that the geometry of the five-membered heterole (heteroatom P, As, Sb) rings in the dinaphtho derivatives (dinaphthoheteroles 8) is sensitive to change in the heteroatom. For instance, the values of the inner dihedral angles of the heterole rings C(6a)–C(13c)–C(13b)–C(7a) for dinaphthoheteroles increase in the order dinaphthophosphole (P: 13.6 ) < dinaphthoarsole (As: 15.3 ) < dinaphthostibole (Sb: 21.1 ) <1996G11>. This tendency implies that the planarity of the heterole ring in dinaphthoheteroles decreases as the element becomes heavier. Accompanying this alteration of the angles, the outer dihedral angles C(13a)–C(13b)–C(13c)–C13d) for dinaphthoheteroles increase in the order dinaphthophoshole (P: 24.2 ) < dinaphthoarsole (As: 26.4 ) < dinaphthostibole (Sb: 37.6 ). These regular variations of the dihedral angles are close to the difference in the covalent radii of the P, As, and Sb atoms.
Arsoles, Stiboles, and Bismoles
The molecular structure and linkage of two columns in the crystal structure of semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5-tetraethyl-1-stibolide) 17 have been studied <2000OM2393>. 5-Coordination of the stibolide anions to the potassium cations leads to the formation of columns. The C–Sb distances within a column ˚ whereas the linkage between the columns shows K–Sb -bond lengths of 3.62 A. ˚ There vary between 3.49 and 3.56 A, are three crystallographically and chemically different metal centers: K-1 lies between two parallel stibolide anions, ˚ and enforces a nonparallel orientation of the neighboring and at K-3 a THF ligand is bonded (with K(3)–O(3) 2.68 A) stibolide substituents, whereas K-2 displays close contacts to the neighboring column. The shortening of the Sb–C bond lengths compared to a single bond is less pronounced. On the other hand, these bonds are clearly longer than ˚ observed for an SbTC bond (2.06 A).
3.16.3.2 NMR Methods The influence of the alkali metals on 1H and 13C chemical shifts is far less pronounced than the variations caused by the pnictogen atoms. This is in agreement with the model of mainly ionic compounds, especially regarding the electronegativities according to Pauling (sodium has a value of 0.93, the heavier alkali metals show very similar electronegativities: potassium 0.82, rubidium 0.82, and cesium 0.79) <2004OM3417>. Nuclear magnetic resonance (NMR) parameters (proton and carbon) for 1-chloro-2,3,4,5-tetraethylheretoles 18 (E ¼ P, As, Sb), arsolid 11a and stibolid anions 11b of the corresponding magnesium, calcium, strontium, barium salts, and 2,3,4,5-tetraethyldihetereroles 19 (E ¼ P, As, Sb; R2–R5TEt) have been compared at 25 C in benzene-d6 <2001ZFA1741>.
1
H NMR spectra of 7-p-tolyldinaphtho[2,1-b ;19,29-d]stibole 16 present fluxional behavior at elevated temperatures <2001TL441, 2003YZ577>. The energy barrier (G‡) resulting from the flipping of the two naphthalene rings was estimated to be 85 1 kJ mol1 ( ¼ 9.7 Hz, Tc ¼ 393 K, DMSO-d6) and its half-life (t1=2) for racemization was determined to be 5.2 h in benzene at 20 C (DMSO ¼ dimethyl sulfoxide). At 50 C all of the corresponding signals on the two naphthalene rings are nonequivalent and appear as two sets of signals (Table 3; Figure 2). The energy barrier is larger than those reported for the corresponding phosphorus (56 kJ mol1) and arsenic (59 kJ mol1) analogues.
Table 3
1
H NMR spectra of 7-p-tolyldinaphtho[2,1-b;19,29-d]stibole 16 at 50 C (in ppm)
Chemical shift
H-2,12
H-3,11
H-1,13
50 C
7.34 7.36
7.49 7.52
7.73 7.76
1155
1156 Arsoles, Stiboles, and Bismoles
H1H13
H3 H11
H2 H12
363 K (90 °C)
383 K (110 °C)
388 K (115 °C) 393 K (120 °C) 80
7.5
7.0 δ (ppm)
Figure 2 Variable 1H NMR data of aromatic region of 7-p-tolyldinaphtho[2,1-b;19,29-d]stibole 16b in DMSO-d6. From S. Yasuike, T. Iida, K. Yamaguchi, H. Seki, and J. Kurita, Tetrahedron Lett., 2001, 42, 441 and S. Yasuike, Yakugaku Zasshi, 2003, 123, 577.
These magnetic features of naphthyl protons on dinaphthostibole are different from those of dinaphthophospholes and dinaphthoarsoles, for which all of the corresponding signals are seen to be equivalent. The results suggest the presence of some restriction on flipping between the naphthalene rings on 7-p-tolyldinaphtho[2,1-b ;19,29-d]stibole 16 at ambient temperature on the NMR timescale. 1 H and 13C NMR spectra of 2,29,5,59-tetramethyl- 20, 3,39,4,49-tetramethyl- 21 and 2,29,3,39,4,49,5,59-octamethyldiheteroferrocenes 22 (E ¼ As, Sb, Bi), 2-acetyl- 23, 2,2-diacetyl-3,39,4,49-tetramethyl- 24, and 3-acetyl-2,29,5,59tetramethyldiarsaferrocenes 25 have been tabulated <1995OM2689>.
29
Si NMR spectra of 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopenta-2,4-diene (arsole) 26a and dimeric bis[3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopentadienyl]bis(tetrahydrofuran-O)calcium chloride 12 have been described <1999OM2491>.
Arsoles, Stiboles, and Bismoles
3.16.3.2.1
1
H NMR spectroscopy
1
H NMR data of the 2,3,4,5-tetraethylarsolides 11a (M ¼ alkali metal) and -stibolides 11b (M ¼ alkali metal) of the type (L)M-EC4Et4 at 25 C are summarized in Table 4 <2004OM3417>. General comments are given earlier in this section.
Table 4 1H NMR data of the alkali metal 2,3,4,5-tetraethylarsolides 11a and -stibolides 11b (M ¼ alkali metal) of the type (L)M–EC4Et4 at 25 C
E L Solvent
Na As TMEDA C6D6
Na Sb 1/2 DME C6D6
K As 2/3 DME C6D6
Ka Sb 1/3 THF C6D6
Rb As DME THF-d8
Rb Sb DME C6D6
Cs As DME THF-d8
Cs Sb DME THF-d8
(CH3) (CH2) 3 J(H,H) (CH3) (CH2) 3 J(H,H)
1.15 2.60 7.4 1.48 2.97 7.5
1.07 2.50 6.9 1.39 2.85 6.6
0.95 2.39 6.7 1.24 2.70 7.0
1.01 2.22 Broad 1.01 2.43/2.83 Broad
1.22 2.66 7.7 1.47 2.90 7.4
1.03 2.49 7.5 1.37 2.84 7.2
1.00 2.37 7.6 1.19 2.63 7.4
1.03 2.42 7.5 1.24 2.70 7.1
a Taken from <2000OM2393>. Adopted from M. Westerhausen, M. W. Ossberger, P. Mayer, H. Piotrowski, and H. No¨th, Organometallics, 2004, 23, 3417.
1
H NMR spectra of 1-chloro-2,3,4,5-tetraethyl-1-stibole 18 (E ¼ Sb) and semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5-tetraethyl-1-stibolide) 12 <2000OM2393>, 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopenta2,4-diene 26, and dimeric bis[3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopentadienyl]bis(tetrahydrofuran-O)calcium chloride 12 <1999OM2491> have been reported.
3.16.3.2.2
13
C NMR spectroscopy
13
The C NMR shifts of the 2,5-carbon atoms bound to the pnictogen atoms show, as expected, the strongest variation toward lower field with increasing size of the pnictogen atom. The average values for the phospholides <2003ZFA2398>, arsolides, and stibolides are ¼ 145.5, 157.0, and 164.2 ppm, respectively. The data for the ring carbon atoms of the well-known potassium 2,3,4,5-tetraethylstibolide 11b (M ¼ K) form an exception to these trends. However, in all cases, bidentate co-ligands are present, whereas for the salt 11b (M ¼ K) only THF was coordinated to the alkali metal <2004OM3417>. In solution, all 2,3,4,5-tetraethylstibolide anions 11b are chemically and magnetically equivalent, whereas in the solid state this is only the case for the rubidium and cesium derivatives and the dimeric TMEDA adduct of sodium 2,3,4,5-tetraethylarsolide 11a (M ¼ Na). Exchange and dissociation reactions lead to a magnetic equivalence on the NMR timescale, which can be expected for mainly ionic compounds (Table 5) <2004OM3417>. Table 5 13C NMR data of the alkali metal 2,3,4,5-tetraethylarsolides 11a and -stibolides 11b (M ¼ alkali metal) of the type (L)M–EC4Et4 at 25 C
E L Solvent
Na As TMEDA C6D6
Na Sb 1/2 DME C6D6
K As 2/3 DME C6D6
Ka Sb 1/3 THF C6D6
Rb As DME THF-d8
Rb Sb DME C6D6
Cs As DME THF-d8
Cs Sb DME THF-d8
(CH3) (CH3) (CH2) (CH2) (C3,C4) (C2,C5)
17.3 20.3 22.0 26.0 132.4 156.3
16.5 21.0 23.8 29.2 138.8 161.8
16.7 19.4 21.7 25.6 131.4 156.9
15.2/16.1 18.9/21.2 23.1/23.7 26.5/29.1 150.2 153.3
16.4 19.0 21.6 25.5 131.1 156.8
16.0 20.8 23.7 29.0 138.2 164.6
16.3 18.7 21.6 25.3 132.1 158.1
15.9 20.4 23.7 28.7 138.4 166.2
a Taken from <2000OM2393>. Adopted from M. Westerhausen, M. W. Ossberger, P. Mayer, H. Piotrowski, and H. No¨th, Organometallics, 2004, 23, 3417.
13 C NMR spectra of 1-chloro-2,3,4,5-tetraethyl-1-stibole 18 (E ¼ Sb) and semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5-tetraethyl-1-stibolide) 17 have been reported <2000OM2393>. The ethyl groups of the latter compound are
1157
1158 Arsoles, Stiboles, and Bismoles split but whether this splitting arises from two chemically different stibolide anions or from the ethyl substituents of one anion has not been determined. No temperature dependency was observed and hindered rotation can therefore be ruled out. 13 C NMR spectra of 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopenta-2,4-diene (arsole) 26 have been reported <1999OM2491>. In the 1H NMR spectrum of bismole polymer 27, protons at ortho-positions of the benzene ring that is attached to the bismuth atom in the bismole unit appear at a characteristic low field of 8.2 ppm <2006PSA4857>.
3.16.3.3 Mass Spectrometry Mass spectra are sometimes used for confirmation of molecular mass of the prepared compounds, for example, <1995OM2689>, but no special fragmentation pathways or other studies have been reported.
3.16.3.4 Ultraviolet Spectroscopy Ultraviolet photoelectron spectroscopy combined with ab initio calculations of the five- and six-membered unsaturated rings containing phosphorus and arsenic have been studied <1995JST57>. Assigning the spectra, no defect of Koopmans’ theorem has been found in the low-ionization-energy region. Reorganization and correlation effects should be comparable and be considered free from any defects of Koopmans’ theorem. The optical properties of bismole-containing polymer 27 in dilute chloroform solution have been investigated <2006PSA4857>. The absorption spectrum and the emission spectrum of polymer 27 are shown in Figure 3. The absorption maximum was observed at max ¼ 311 nm (log " ¼ 4.11) in chloroform at room temperature ((A), Figure 3). The polymer displayed an emission peak at 440 nm in dilute chloroform solution that was excited at 310 nm in the visible bluish green region ((B), Figure 3). Emission efficiency () of polymer 27 at room temperature was found to be 0.13 in dilute chloroform solution using 9-anthracenecarboxylic acid in dilute dichloromethane solution as a standard ( ¼ 0.442).
(B)
Intensity (a.u.)
Absorbance (a.u.)
(A)
300
350
400
450
500
550
600
650
Wavelenth (nm) Figure 3 UV–Vis spectrum of polymer in CDCl3 (A); emission spectrum of polymer 27 in CDCl3 excited at 311 nm (B). From Y. Morisaki, K. Ohashi, H.-S. Na, and Y. Chujo, J. Polym. Sci., Polym. Chem., Part A, 2006, 44, 4857.
Arsoles, Stiboles, and Bismoles
3.16.3.5 Infrared and Raman Spectroscopy Infrared spectra of 1-chloro-2,3,4,5-tetraethyl-1-stibole 18 (E ¼ Sb) and semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5-tetraethyl-1-stibolide) 17 <2000OM2393>, 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopenta2,4-diene (arsole) 26, and dimeric bis[3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopentadienyl]bis(terahydrofuran-O)calcium chloride 12 <1999OM2491> have been reported.
3.16.3.6 Electron Spin Resonance Spectroscopy 2,29,5,59-Tetramethyl- and 2,29,3,39,4,49,5,59-octamethyldiheteroferrocenes 2 (E ¼ P, As, Sb, Bi) have been examined using electron peramagnetic resonance (EPR) spectroscopy <1995OM2689>. The diheteroferrocenium ions are even less stable in solution. Two trends are discernible: with increasing atomic number of the heteroatom, the g anisotropy of the diheteroferrocenium radical cations decreases and the difference between the components (gx and gy) of g? increases.
3.16.3.7 Electrochemistry Redox behavior of sets of compounds 20 (E ¼ P, As, Sb, Bi, and CH) have been explored <1995OM2689> in dimethoxyethane at 45 C using cyclic voltammetry: the two series were completely analogous (Table 6). Table 6 Cyclic voltammetry data for various redox processes for selected heterolesa Compound 2
E1/2(0/)b (V )
Epb (mV )
rc
E1/2(þ/0)b (V )
Epb (mV )
rc
Epad (V )
E ¼ As; R3,39,4,49 ¼ Me E ¼ Sb; R3,39,4,49 ¼ Me E ¼ Bi; R3,39,4,49 ¼ Me E ¼ As; R2,29,3,39,4,49,5,59 ¼ Me E ¼ Sb; R2,29,3,39,4,49,5,59 ¼ Me E ¼ Bi; R2,29,3,39,4,49,5,59 ¼ Me
2.258r 2.036r 2.004r 2.381r 2.176r 2.140r
57 51 76 57 66 58
0.79 0.82 0.83 0.74 0.86 0.87
0.578r 0.293r 0.030r 0.405r 0.141r 0.133r
56 58 75 75 76 58
1.0 1.0 1.0 1.0 1.0 1.0
1.089 0.547 0.344 1.151 0.607 0.35
In DME/(n-Bu)4NClO4 (0.1 M) at glassy carbon vs. SCE, T ¼ 40 C, v ¼ 100 mV s1. Abbreviations: r, reversible. E1/2 ¼ 1/2(Epa þ Epc); Ep ¼ Epa Epc. c t ¼ ipa/ipc. d Peak potential of an irreversible wave. Adopted from A. J. Ashe, S. Al-Ahmad, S. Pilotek, D. B. Puranik, Ch. Elschenbroich, and A. Behrendt, Organometallics, 1995, 14, 2689. a
b
The diphosphaferrocenes and the diarsaferrocenes are harder to oxidize than the corresponding substituted ferrocenes (Table 6). The distibaferrocenes have nearly the same E1/2(0/þ) as the ferrocenes, while only dibismaferrocenes are easier to oxidize. Thus, the P and As heterocyclopentadienyl groups are more effective at withdrawing electron density from Fe in 1,19-diheteroferrocenes, 3,39,4,49-tetramethyl-l,l9-diheteroferrocenes, or 2,29,3,39,4,49,5,59-octamethyl-l,l9-diheteroferrocenes 2 than are the corresponding substituted cyclopentadienyl rings of ferrocenes. Regressions of the E1/2 on the atomic ionization energies I of selected derivatives 2 of the free atoms of P, As, Sb, and Bi are shown in Figure 4.
3.16.4 Thermodynamic Aspects 3.16.4.1 Boiling and Melting Points Many of the prepared compounds are (colorless) oils but they are not distilled as the final purification method. The prepared oils are often analytically pure for further characterizations. Some compounds characterized by their melting/boiling points can be found in CHEC-II(1996) <1996CHEC-II(2)857>. In Table 7 are summarized selected compounds by their color and melting points.
1159
1160 Arsoles, Stiboles, and Bismoles
0.8 0.7 0.6
x P4
0.5 E½ (V )
x 0.4 0.3 x
0.2 P4
0.1
x
0 –0.1
7
8
9
10
11
I(X) (eV )
Figure 4 Regressions of the E1/2 (0/þ) of the 2,29,5,59-tetramethyl-1,19-diheteroferrocenes 2 (R2,29,5,59 ¼ Me, top line) and the 2,29,3,39,4,49,5,59-octamethyl-1,19-diheteroferrocenes 2 (R2,29,3,39,4,49,5,59 ¼ Me, bottom line) on the atomic ionization energies I (2) of the free atoms X ¼ P, As, Sb, and Bi. From A. J. Ashe, S. Al-Ahmad, S. Pilotek, D. B. Puranik, Ch. Elschenbroich, and A. Behrendt, Organometallics, 1995, 14, 2689.
Table 7 Physical properties of some derivatives Compound
Color
m.p. ( C )
Reference
Na(tmen)AsC4Et4 K(DME)AsC4Et4 Rb(DME)AsC4Et4 Cs(DME)AsC4Et4 Na(DME)SbC4Et4 Rb(DME)SbC4Et4 Cs(DME)SbC4Et4 (3,4-Me2C4H2Sb)2Fe, 21 (E ¼ Sb) (3,4-Me2C4H2As)2Fe, 21 (E ¼ As) (2,3,4,5-Me4C4Bi)2Fe, 21 (E ¼ Bi) 3-Acetyl-(2,5-Me2C4H2As)2Fe, 25 2-Acetyl-(3,4-Me2C4H2As)2Fe, 23 2,29-Diacetyl-(3,4-Me2C4H2As)2Fe, 24 – diastereomers
Light brown Brown Brown Brown Yellow Gray Green Red Red Shiny black Dark red Orange red Red Orange red Yellow
250 157 210 173 174 (dec.) >300 250 295 305 (dec.) >100 (dec.) 54–55 79 121 124 Decomposed without melting 165
2004OM3417 2004OM3417 2004OM3417 2004OM3417 2004OM3417 2004OM3417 2004OM3417 1995OM2689 1995OM2689 1995OM2689 1995OM2689 1995OM2689 1995OM2689
Dimeric bis[3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopentadienyl]bis(tetrahydrofuran-O)calcium chloride, 12 Semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5tetraethyl-1-stibolide), 17 1-Phenyldibenzobismole-1,1-diacetate, 49
Yellow Colorless
183
1999OM2491 2000OM2393 2000J(P1)3775
Colors of 1-chloro-tetraethylarsole and -stibole 18 (E ¼ As, Sb) and melting points of corresponding diarsoles, distiboles 19 (E ¼ As, Sb), and anionic species with metals 11 (M ¼ Mg, Ca, Sr, Ba) depending on weight ratio have been summarized <2001ZFA1741>. Complexes of racemic ()-1-phenyl-2-trimethylsilylstibindole 28 <1990AGE771> with optically active di- chlorobis{(S)-2-[1-(dimethylamino)-ethyl]phenyl-C,N}dipalladium(II) 29 were separated by chromatography on silica gel using dichloromethane/hexane/diethyl ether (10:10:1) <2000CC191>.
Arsoles, Stiboles, and Bismoles
3.16.4.2 Solubility and Chromatographic Behavior Most of the prepared heteroles are soluble in less polar solvents such as hexane(s), benzene, toluene, diethyl ether, THF, dioxane, CHCl3, CH2Cl2, etc. Generally, the target compounds are less stable in polar solvents (solvolysis) or under exposure on air. The most frequent isolation is based on extraction or precipitation of by-products or unreacted reagents (Table 8).
Table 8 Chromatographic behavior of selected compounds Compound
Stationary phase
Solvent systems
Reference
3-Acetyl-(2,5-Me2C4H2As)2Fe, 25 2-Acetyl-(3,4-Me2C4H2As)2Fe, 23 2,29-Diacetyl-(3,4-Me2C4H2As)2Fe, 24 – diastereomers
Silica gel Silica gel Silica gel
Acetonitrile/benzene (1:9 v/v) Benzene Dichloromethane/benzene 1:1 Dichloromethane/benzene 3:1
1995OM2689 1995OM2689 1995OM2689
3.16.4.3 Aromaticity and Stability Several aspects of aromaticity have been studied <2002JOC1333> using statistical analyses of quantitative definitions of aromaticity. ASEs, REs, magnetic susceptibility exaltation (), nucleus-independent chemical shift (NICS), the harmonic oscillator model of aromaticity (HOMA), (I5) and (AJ), evaluated for a set of 75 five-membered p-electron systems and a set of 30 ring-monosubstituted compounds (aromatic, nonaromatic, and antiaromatic systems) revealed statistically significant correlations between the various aromaticity criteria, provided the whole set of compounds is used. The data in Table 9 have been found for arsole (AsH) 1 (E ¼ As, R ¼ H), its anion (As), and protonated species (AsH2þ).
Table 9 Calculated ASE (in kcal mol1), , NICS, NICS 1 A˚ above the ring centers (denoted as NICS(1), in ppm) and HOMA for AsH (arsole) 1 (E ¼ As, R ¼ H), As and AsH2þ Species
ASE
NICS
NICS(1)
HOMA
As AsH, 1 AsH2þ
22.21 1.71 6.55
10.75 0.08 4.12
12.88 3.93 1.12
10.60 4.62 2.30
(0.877) (0.447) (0.010)
ˇ Adopted from M. K. Cyranski, T. M. Krygowski, A. R. Katritzky, and P. von Rague´ Schleyer, J. Org. Chem., 2002, 67, 1333.
The various measures of aromaticity are related and aromaticity can be regarded statistically as a one-dimensional phenomenon. In contrast, when comparisons are restricted to some regions, for example, aromatic compounds with ASE > 5 kcal mol1, the quality of the correlations can deteriorate or even vanish. In practical application, energetic, geometric, and magnetic descriptors of aromaticity do not agree. In this sense, the phenomenon of aromaticity is regarded as being statistically multidimensional <2002JOC1333>.
1161
1162 Arsoles, Stiboles, and Bismoles The same set has been evaluated <2003T1657> using six isodesmic reactions of which two belong to the subclass of homodesmotic reactions, which are based on cyclic and acyclic reference systems. It has been strongly recommended that only cyclic reference compounds should be used for ASE(1,2) and other aromaticity evaluations. The analysis has been based on ab initio optimized geometries at B3LYP/6-311G** . Systems with strongly positive ASE are aromatic (As), while those with strongly negative ASE are antiaromatic (AsH2þ). Resonance energies RE(4)–RE(6) are pertubed to some extent by additional effects mainly involving the changes in hybridization (Table 10). Table 10 Calculated ASE and RE for AsH 1 (E ¼ As, R ¼ H), As, and AsH2þ ASE(1) (kcal mol 1)
Species As AsH, 1 AsH2þ
ASE(2) (kcal mol 1)
RE(4 ) (kcal mol 1)
RE(5) (kcal mol 1)
RE(6) (kcal mol 1)
17.29 0.88
3.06 2.48
20.06 3.65
30.51 3.33
26.67 1.55
8.16
17.73
5.39
16.04
9.33
´ Adopted from M. K. Cyranski, P. von Rague´ Schleyer, T. M. Krygowski, H. Jiao, and G. Hohlneicher, Tetrahedron, 2003, 59, 1657.
Due to the so-called double-bond rule <1948JA2140>, until the late 1980s, PTC, AsTC double-bonded systems were considered to be unstable and not accessible . This had been concluded as due to the poor overlap between the p orbitals of the heavy atom (P, As) and carbon, prohibiting the formation of a stable double bond. The appearance of several stable systems was explained by the formation of a conjugated aromatic electronic structure or by being kinetically stabilized by bulky substituent groups <1989AIC259>. The effect of the aromaticity on the electronic structure of phosphorus and some of the related arsenic containing systems was investigated by photoelectron spectroscopy <1995JST57>. Separating antiaromaticity effects for the (CH)2EH species from the aromaticity effects in (CH)4EH species is as difficult as it was to decouple strain and antiaromaticity in the analysis above. Again the analysis is complicated by the absence of thermochemical data for the group 15 metalloles. Indeed, the only case known to the authors of experimental heat of formation data for an entire series of such compounds is for the group 16 species furan, thiophene, and selenophene, (CH)4O, (CH)4S, and (CH)4Se .
3.16.4.3.1
Aromaticity and electron-pair delocalization
The extent of delocalization of the anionic charge can be estimated by comparison of the endocyclic C–C bond lengths of the 2,3,4,5-tetraethylphospholides <2003ZFA2398>, -arsolides, and -stibolides 1 (E ¼ P, As, Sb; R2-R5 ¼ Et) (Table 11) <2004OM3417>. A lower degree of delocalization leads to a larger difference () in the bond lengths C(2)–C(3) (or C(5)–C(4)) in angstroms. ˚ of the 2,3,4,5-tetraethylphospholides, Table 11 Comparison of the endocyclic bond length differences (in A) -arsolides, and -stibolides 1 (E ¼ P, As 11a, Sb 11b; R2–R5 ¼ Et) of the heavy alkali metals (R(M) ¼ Na, K, Rb, Cs) E/R in 1 (11)
P
As
Sb
Na K Rb Cs
0.03 0.026 0.039 0.018
0.045 0.051 0.033 0.060
0.080 0.06 0.067 0.04
Adopted from M. Westerhausen, M. W. Ossberger, P. Mayer, H. Piotrowski, and H. No¨th, Organometallics, 2004, 23, 3417.
The discrepancy increases with the size of the pnictogen atom, which can be interpreted in the sense of decreasing charge delocalization and consequently decreasing aromatic character of the 6p-electron system of the cycle. This finding is in agreement with expectation because the overlap of the pnictogen-centered p orbital (which increases from phosphorus to antimony) with the carbon-centered p-system should decrease due to the increasing E–C bond lengths and an increasing misfit of the size of the pE and pC orbitals <2004OM3417>.
Arsoles, Stiboles, and Bismoles
The PM3-derived heats of hydrogenation for the formation of the saturated pyrrolidine, phospholane, arsolane, and stibolane increase in the same order, being calculated to be 39.2, 51.5, 53.0, and 59.3 kcal mol1, respectively, and also indicative for decreasing aromaticity in the corresponding unsaturated rings.
3.16.4.3.2
Stability
Differences of semi-empirical heats of formation for (CH)2EH and (CH)4EH decrease in aromaticity/antiaromaticity proceeding down a column of the periodic table in the order: 57.8, 26.2, 15.2, and 13.9 kcal mol1 for E ¼ N, P, As, and Sb in the same order <1995JMT51>.
3.16.4.4 Conformations 3.16.4.4.1
Geometry at the heteroatom and inversion barriers
The heteroatoms in arsole and stibole, like phosphole, are pyramidal, but with reduced planarization energies (inversion barriers) relative to arsines and stibines. The inversion barriers are summarized in Table 12 <1995JMT51>. The steady increase in inversion barriers points to steadily decreasing efficiency of p-bonding between carbon and the heteroatom, and probably to greater s character of the lone-pair orbital.
Table 12 Comparison of inversion barriers for Me3E and (CH)4EH <1995JMT51> Inversion barriers Compound type
Heteroatom E
(kcal mol 1)
(kJ mol 1)
Me3E
N P As Sb
7.9 35.6 42.1 83.9
33.076 149.050 176.264 351.272
(CH)4EH
N P As Sb
0.0 14.4 22.4 57.5
0.0 60.290 93.784 240.741
The electron localization function has been used to describe aromaticity in five-membered rings. For arsole it has ˚ for C–C 1.4564, CTC 1.3616, and C–As 1.9179) using MP2(FC)/6been calculated for ring bond distances (in A, 31þG(d,p) and homomolecular homodesmotic energy 4.21 kcal mol1 using BLYP/6-311G(d,p)//BLYP6-31G(d) level <2000CPH1>. Ring bond populations in number of electrons are presented in Table 13.
Table 13 Ring bond populations of arsole 1 (E ¼ As) Bond
C–C
CTC
C–X
Basin population (Ni) Population variance (i) Number of pairs (Nii)
2.25 1.06 3.94
3.31 1.21 9.11
2.03 1.07 3.24
Adopted from D. B. Chesnut and L. J. Bartolotti, Chem. Phys. 2000, 253, 1.
The inversion process of pyrrole, phosphole, arsole, stibole, and bismole has been analyzed in detail by using ab initio and density functional techniques and compared with the corresponding divinyl and diethyl compounds, HE(C2H3)2 and HE(C2H5)2, respectively (E ¼ N, P, As, Sb, and Bi) <2002JPC6387>.
1163
1164 Arsoles, Stiboles, and Bismoles The more important structural data for all minima and inversion transition states of HEC4H4, HE(C2H3)2, and HE(C2H5)2 (E ¼ N, P, As, Sb, and Bi) are listed in Tables 14 and 15. The inversion transition states of all 5-ring systems are of C2 symmetry and exhibit a perfectly planar arrangement. The tendency to nonplanarity around the C2EH unit can be expressed by the angle (Equation 2): ¼ 360 –
3 X
ai ¼ 360 – ðCEC9 þ CEH þ HEC9 Þ
ð2Þ
i¼l
Table 14 Selected molecular structure parameters (in A˚ and degrees) for the minimum structures of heteroles HEC4H4 at the MP2 and B3LYP level of theory E in HEC4H4
Method
E–C(1)
E–H
C(1)–C(2)
C(2)–C(29)
C(1)–E–C(19)
N
MP2 B3LYP
1.372 1.372
1.011 1.008
1.384 1.373
1.419 1.421
110.2 109.8
0 0
P
MP2 B3LYP
1.803 1.813
1.425 1.424
1.363 1.349
1.449 1.455
90.6 90.1
66.7 67.6
As
MP2 B3LYP
1.934 1.946
1.531 1.532
1.356 1.342
1.456 1.462
86.0 85.6
81.2 80.6
Sb
MP2 B3LYP
2.139 2.149
1.727 1.724
1.354 1.341
1.463 1.467
80.5 80.2
90.3 89.4
Bi
MP2 B3LYP
2.238 2.242
1.828 1.817
1.352 1.338
1.465 1.470
78.0 77.9
96.8 94.4
360
Adopted from S. Pelzer, K. Wichmann, R. Wesendrup, and P. Schwerdtfeger, J. Phys. Chem., 2002, 106, 6387. Table 15 Selected molecular structure parameters (in A˚ and degrees) for the inversion transition state structures of HEC4H4 (E ¼ N, P, As, Sb, and Bi) at the MP2 and B3LYP level of theory E in HEC4H4
Method
E–C(1)
E–H
C(1)–C(2)
C(2)–C(29)
C(1)–E–C(19)
N
MP2 B3LYP
1.372 1.372
1.011 1.008
1.384 1.373
1.419 1.421
110.2 109.8
P
MP2 B3LYP
1.718 1.724
1.400 1.395
1.400 1.386
1.413 1.417
99.2 98.6
As
MP2 B3LYP
1.829 1.840
1.486 1.482
1.394 1.375
1.415 1.424
95.0 94.2
Sb
MP2 B3LYP
2.034 2.049
1.672 1.664
1.388 1.366
1.420 1.434
88.0 87.0
Bi
MP2 B3LYP
2.124 2.137
1.762 1.743
1.383 1.357
1.419 1.437
85.4 84.3
Adopted from S. Pelzer, K. Wichmann, R. Wesendrup, and P. Schwerdtfeger, J. Phys. Chem., 2002, 106, 6387.
where a planar C2EH arrangement corresponds to ¼ 0 . The angle systematically increases with the nuclear charge of element E (Table 15) for heteroles 1, the divinyl and the diethyl compounds, with only minor differences between MP2 and B3LYP. This increase in is fully in line with the behavior of the group 15 hydrides and can be expected for classical inversion processes. The planar C2EH inversion structures possess shorter E–C and E–H bonds, as compared to the minimum nonplanar structures, in agreement with the fact that the group 15 element E changes formally from planar sp2 to nonplanar sp3 hybridization. The C(1)–C(2) bond distances remain almost constant throughout one series of group 15 compounds with the expected order rC–C(vinyl) < rC–C(heterole) < rC–C(alkyl). The Julg index J (which defines the degree of aromaticity by the deviations of n individual C–C bond lengths ri from the average C–C bond length r) indexes for the minima and planar transition states are shown in Figure 5 for pyrrole, phosphole, arsole, stibole, and bismole 1 (E ¼ N, P, As, Sb, Bi; R ¼ Rn ¼ H). The B3LYP method yields lower Julg indexes (or a more pronounced bond alternation) than MP2, but the qualitative features are the same for both methods. The planar transitions states are distinctly more aromatic than their corresponding bent minima with the maximum degree of aromaticity found for planar phosphole 1 (E ¼ P). The aromatic character of the rings decreases from P toward the heavier homologues, more so for the minimum structures than for the planar transition states.
Arsoles, Stiboles, and Bismoles
1 MP2 planar 0.9
0.8
B3LYP planar
J
0.7 MP2 nonplanar 0.6 B3LYP noplanar 0.5 N
P
As
Sb
Bi
Figure 5 Julg index J for the (nonplanar) minimum and (planar) transition state ring structures of HEC4H4 at the MP2 and B3LYP level of theory. From S. Pelzer, K. Wichmann, R. Wesendrup, and P. Schwerdtfeger, J. Phys. Chem., 2002, 106, 6387.
The inversion barrier (Table 16) (Ea; not corrected for zero-point vibrational energies) increases from nitrogen to bismuth for all series of compounds. As mentioned before, the angle which describes the deviation from planarity about the pnictogen atom also increases from nitrogen to bismuth. The agreement between the calculated data and the fit is demonstrated for the MP2 results. As indicated by the Julg index, the transition states for the cyclic compounds possess significant aromatic character that leads to their stabilization. Table 16 Calculated inversion barriers Ea in kJ mol1 for HEC4H4 1 for E ¼ N, P, As, Sb, and Bi E in HEC4H4
HF
MP2
B3LYP
N P As Sb Bi
0.0 106.2 158.2 210.7 280.9
0.0 60.4 110.8 154.6 218.7
0.0 76.2 127.8 169.9 225.9
Adopted from S. Pelzer, K. Wichmann, R. Wesendrup, and P. Schwerdtfeger, J. Phys. Chem., 2002, 106, 6387.
3.16.4.4.2
Conformational equilibria of trigonal bipyramid and octahedral compounds
No further studies in this field have been reported during the last decade and all results are reviewed in CHECII(1996) <1996CHEC-II(2)857>.
3.16.5 Reactivity of Fully Conjugated Rings For compatibility with CHEC-II(1996), the following subsections are included but no new work has been reported.
3.16.5.1 General Survey of Reactivity From previous chapters summarizing syntheses and reactivity of the title compounds, it is conclusive that the most frequent method for preparation of saturated rings of this type of heterocyclic compounds is condensation of appropriate dihalogeno derivatives with dimetallated species. Unsaturated analogues are prepared using transmetallation or coupling reactions. Reactivity of the ring substituents is rarely studied. Reductions of heteroles led often to
1165
1166 Arsoles, Stiboles, and Bismoles diheteroles and after that further reduction to heterolides (heterole anions) is preferred over origination of partially reduced species. Electrophilic attacks are concentrated mainly on the pnictogen atom.
3.16.5.2 Unimolecular Thermal Reactions No new studies have been reported.
3.16.5.3 Electrophilic Attack at the Heteroatom No new studies have been reported.
3.16.5.3.1
Neutral ring systems
No new studies have been reported.
3.16.5.3.2
Anionic and radical anion ring systems
The reduction of 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsacyclopenta-2,4-diene (arsole) 26 with distilled calcium gave dimeric 3,4-dimethyl-2,5-bis(trimethylsilyl)-1-arsacyclopentadienyl bis-(tetrahydrofuran-O)calcium chloride 12 (Equation 3).
ð3Þ
Anionic species derived from 2,3,4,5-tetraethylhetereroles 11a, 11b and the metals Mg, Ca, Sr, and Ba have been prepared <2001ZFA1741> from corresponding 1-chloroderivatives 18 (E ¼ As, Sb) by reaction with an excess of the appropriate metal in THF. Magnesium and calcium react under ultrasonic irradiation and heteroleptic compounds with structures analogous to 12 have been formed. Intermediates of biheterole type 3 can be isolated.
3.16.5.4 Electrophilic and Nucleophilic Attack at Carbon 3,39,4,49-Tetramethyl-1,19-diarsaferrocene 21 (E ¼ As) can be acetylated with acetyl chloride in the presence of aluminium chloride (Scheme 1) <1995OM2689>. Acetylation with 1 equiv of acetyl chloride gives the monoacetyl product 23 in 54% yield. Acetylation with an excess of acetyl chloride gives a mixture of diacetylated products 30 and 24 in the ratio of 3:5.
Scheme 1
Arsoles, Stiboles, and Bismoles
It is possible to separate the meso- and racemic products by chromatography, but their spectra do not allow a structural assignment. When the -positions are blocked (e.g., in the case of use of 2,29,5,59-tetramethyl-1,19diarsaferrocene, 20 (E ¼ As)), acetylation occurs in the -position and only the monoacetylated product 25 is formed. Acetylation of corresponding distibaferrocenes and dibismaferrocenes failed. 3,39,4,49-Tetramethyl-1,19-diheteroferrocenes 21 (E ¼ As, Sb) undergo electrophilic isotopic exchange of the ring hydrogen atoms on treatment with monodeuterotrifluoroacetic acid at rates that increase with the atomic number of the heteroatom in the -position <1995OM2689>.
3.16.5.5 Nucleophilic Attack at the Heteroatom Reduction of 1-chloro-2,3,4,5-tetraethylarsole 18 (E ¼ As) and -stibole 18 (E ¼ Sb) with alkali metals (from Na to Cs) in DME or TMEDA yielded the base-stabilized arsolides or stibolides. All form one-dimensional polymers apart from [Na(TMEDA)AsC4Et4]2 and all exhibit only 5-coordination except the sodium complexes which also show 1-coordination <2005ARA20, 2004OM3417>.
3.16.5.6 Reactions with Radicals and Electron-Deficient Species No new studies have been reported.
3.16.5.7 Cyclic Transition State Reactions with a Second Molecule No new studies have been reported.
3.16.6 Reactivity of Nonconjugated Rings No new studies have been reported and CHEC-II(1996) <1996CHEC-II(2)857> should be referred to for coverage of this topic.
3.16.7 Reactivity of Substituents Attached to Ring Heteroatoms Desilylation of 2,5-bis(trimethylsilyl)-3,4-dimethyl-1-phenylstibole 31 using Bu4NF/H2O (Equation 4) yielded the corresponding 3,4-dimethylphenylstibole 32 <1995OM2689>.
ð4Þ
3.16.8 Ring Synthesis Classified by Number of Ring Atoms In the last decade, syntheses of arsoles, stiboles, and bismoles have been based on transmetallations and reactions based on the ring closure of dilithio species.
3.16.8.1 Synthesis of Fully Conjugated Systems 3.16.8.1.1
Condensation reactions
3.16.8.1.1(i) Dilithio systems All three possible isomers of 1-phenylthienoheteroles 33–35 with a -fused heterole nucleus (Figure 6) have been prepared starting from suitably substituted iodo/bromothiophenes via the corresponding 1,4-dilithium intermediates
1167
1168 Arsoles, Stiboles, and Bismoles
Figure 6 1-Phenylthienoheteroles 33–35.
derived from (Z)-(-bromo--trimethylsilylvinyl)thiophenes by treatment with tert-butyllithium (Schemes 2–4) <1997H(45)1891>. The ring systems 33–35 (E ¼ As, Sb, Bi) fall within the scope of Chapter 10.01 of CHEC-3. However, due to the specialist nature of As, Sb, and Bi chemistry, we believe that it is useful to also include coverage here. 3-Iodothiophene 36 (X ¼ H) couples with trimethylsilylacetylene in the presence of a catalytic amount of a mixture bis(triphenylphosphine)palladium dichloride and copper(I) iodide to give the trimethylsilylethynyl thiophene 37 (X ¼ H) in ca. 80% yield. Derivative 37 (X ¼ H) is reduced by diisobutylaluminium hydride (DIBAL-H) followed by bromination with N-bromosuccinimide (NBS) to give the (Z)-3-(-bromo--trimethylsilylvinyl)thiophene 38 (X ¼ H) in 75% yield. The vinyl compound 38 (X ¼ H) was treated with tert-butyllithium in dry ether at –80 C, and then with PhECl2, resulting in ring closure forming the 2-trimethylsilylthieno[2,3-b]heteroles 40 in 45–65% yields, presumably via the key 1,4-dilithium intermediate 39. The trimethylsilyl group in products 40 was removed by treatment with tetrabutylammonium flouride (TBAF) in THF containing water to give the desired C-unsubstituted parent thieno[2,3-b]arsole or stibole 33 in 50–60% yields. The alternative starting material, 2-bromo-3-iodo-thiophene 36 (X ¼ Br), gives the dilithium intermediate in lower yields (20–40%).
Scheme 2
Scheme 3
Arsoles, Stiboles, and Bismoles
Scheme 4
The same protocols have been used for preparations of thieno[3,4-b]heteroles 34 (Scheme 3), starting from 3-bromo-4-(trimethylsilyl)ethynylthiophene 42, or for synthesis of thieno[3,2-b]heteroles 35 (Scheme 4) using 3-bromo-2-(trimethylsilyl)ethynylthiophene 42 as starting compound. 2,29-Dilithiobiphenyl 43, prepared and isolated from biphenyl as a TMEDA adduct, has been used in a modification of the method of Wittig and Hellwinkel when treated with phenylbismuth diiodide to prepare 1-phenyldibenzobismole 44 in 56% yield (Scheme 5) <2000J(P1)3775>.
Scheme 5
When (R)-(þ)-2,29-dibromo-1,19-binaphthyl 45 was treated with tert-butyllithium in dry ether at 80 C, and subsequently with dibromo-p-tolylstibane, ring closure gave the desired product, 7-p-tolyldinaphtho[2,1-b;19,29-d]stibole 16, in 35% yield (Scheme 6), via the corresponding 2,29-dilithio-1,19-binaphthyl intermediate 46. Recrystallization of the product from ether gave the racemic compound as crystals, and the desired optically active (–)-enantiomer could be obtained from the mother liquid as an oil. The optically active (–)-dinaphthostibole 16 isolated here is far more optically stable than corresponding dinaphthophosphole and dinaphthoarsole, but racemizes gradually at room temperature (t1/2 ¼ 5.2 h at 20 C in benzene), but in contrast to other analogues can be isolated as an optically active form.
Scheme 6
3.16.8.2 Synthesis of Dihydro Derivatives No new results in this area have been isolated thus far since the publication of CHEC-II(1996) <1996CHEC-II(2)857>.
1169
1170 Arsoles, Stiboles, and Bismoles
3.16.8.3 Synthesis of Tetrahydro Derivatives 3.16.8.3.1
1.4-Dihalobutanes
No new studies have been reported.
3.16.8.3.2
1.4-Di-Grignard reagents
The 1,4-di-Grignard reagent prepared from 1,4-dibromobutane was used for the preparation of 1-phenyl-tetrahydroarsole 47 by reaction with phenylarsenic dichloride (Equation 5) <2001JIC224>.
ð5Þ
3.16.8.4 Synthesis of Derivatives with CN 4, 5, and 6 3.16.8.4.1
CN 4
Resolution of the racemic 7-p-tolyldinaphtho[2,1-b ;19,29-d]stibole 16 using optically active palladium complexes (with 0.5 equiv of dimeric optically active di-m-chlorobis{(S)-2-[1-(dimethylamino)-ethyl]phenyl-C,N} dipalladium(II)) 29 is a rare example of a reaction giving a product with CN 4 (Equation 6). The diastereomeric mixture thus produced could not be separated by fractional recrystallization from a variety of solvents or by column chromatography, because the optically active 7-p-tolyldinaphtho[2,1-b ;19,29-d]stibole 16 easily racemizes in the presence of the palladium complex 48. Also the complex prepared from enantiomerically pure R-(–)-stibole 16 racemizes due to fluxionality (NMR estimated at elevated temperatures) <2001TL441, 2003YZ577>.
ð6Þ
The same approach and reagent has been used also for resolution ()-1-phenyl-2-trimethylsilylstibindole 28 <2000CC191>.
3.16.8.4.2
CN 5
1-Phenyldibenzobismole 44 on treatment with sodium perborate in acetic acid is easily transformed to 1-phenyldibenzobismole-1,1-diacetate 49 in 61% yield (Equation 7) <2000J(P1)3775>.
ð7Þ
1-Phenyldibenzobismole-1,1-diacetate 49 is a phenylation reagent with reduced reactivity and high regioselectivity in C-phenylation (under basic catalysis) with good to modest yields and in O- or N-phenylations under copper catalysis (copper diacetate), similar to triarylbismuthdiacetate (Ar3Bi(OAc)2) or 1,1,1-triphenyldibenzobismole 50 <2000J(P1)3775>.
Arsoles, Stiboles, and Bismoles
3.16.8.4.3
CN 6
No new preparations have been reported.
3.16.9 Ring Synthesis by Transformation of Another Ring Metathesis reactions and the use of dilithio compounds are the most frequently used methods for synthesis of these organometallic compounds. These reactions use almost exclusively zirconapentalenes, especially disubstituted with two cyclopentadiene rings on a zirconium atom. Ring expansions or contractions have not been reported.
3.16.9.1 Interconversion at the Heteroatom The metathesis reaction of zirconocene dichloride 51 at low temperatures with 2 equiv of n-butyllithium followed by 2 molar equiv of trimethylsilylpropyne yields 1,1-bis(cyclopentadienyl)-3,4-dimethyl-2,5-bis(trimethylsilyl)-1-zirconacyclopenta-2,4-diene 52 (Equation 8).
ð8Þ
The metathesis reaction of product 52 with AsCl3 yields 1-chloro-3,4-dimethyl-2,5-bis(trimethylsilyl)arsole 53 (Equation 9) <1999OM2491>.
ð9Þ
The first successful synthesis of a conjugated polymer containing a bismuth atom 27 in the conjugated main chain by incorporating a bismuth atom into the cyclopentadiene framework (bismole) has been published <2006PSA4857>. The starting polymer 54 was obtained by the polycondensation reaction of 1,7-octadiyne, 2-dodecyloxy-5-methoxy-1,4-diiodobenzene, and 2,5-dimethoxy-4-methyliodobenzene in the presence of a catalytic amounts of Pd(PPh3)4 and CuI in THF:Pri2NH for 72 h at room temperature. The number-average molecular weight (Mn), weight-average molecular weight (Mw), and molecular weight distribution (Mw/Mn) of polymer 54 were 4200, 12 000, and 2.9, respectively. The treatment of polymer 54 with zirconocene, which was generated by the reaction of zirconocene dichloride with BunLi, gave a deep red solution of zirconacyclopentadiene-containing polymer 55. To the reaction mixture containing polymer 55 without isolation, 1.2 equiv of Cu2Cl2 and 2.4 equiv of I2 (based on the zirconacyclopentadiene unit) were added to obtain polymer 56 in 71% yield (Scheme 7). Scheme 8 demonstrates the synthesis of bis-mole-containing polymer 27 by the polymer reaction of diiodinated polymer 56. The reaction of the diiodobutadiene units of polymer 56 with BunLi generated lithiated polymer 57. This was followed by treatment with dibromophenylbismuthine. Dibromophenylbismuthine was prepared by the addition of triphenylbismuthine to 2 equiv of bismuth tribromide and was used without isolation (Scheme 8).
1171
1172 Arsoles, Stiboles, and Bismoles
Scheme 7
Scheme 8
Arsoles, Stiboles, and Bismoles
The final polymer is composed of a cisoid-diiodobutadiene unit. Polymer 27 was found to be partially soluble in common organic solvents such as THF, toluene, and CHCl3, although the solubility was enhanced by incorporating an asymmetric dialkoxy benzene units into the polymer backbone.
3.16.9.2 Interchange of the Heteroatom 1,1-Bis(cyclopentadienyl)-2,3,4,5-tetramethyl-1-zirconacyclopenta-2,4-diene 58 has been used for adapted Fagan– Nuget heterole synthesis exploiting transmetallation of the starting compound with PhECl2 to prepare 1-phenyl2,3,4,5-tetramethylheteroles 59 (E ¼ As, Sb, Bi) (Equation 10) <1995OM2689>.
ð10Þ
Zirconocene dichloride reacts with butyllithium and hex-3-yne at 78 C in THF to give almost quantitatively red 1,1-bis(cyclopentadienyl)-2,3,4,5-tetraethyl-1-zirconacyclopenta-2,4-diene 60. Transmetallation with antimony trichloride yields the corresponding 1-chloro-2,3,4,5-tetraethyl-1-stibole (Scheme 9) <2000OM2393>.
Scheme 9
1-Phenyl-2-phosphinobenzostibole 64 was prepared starting from diphenylzirconocene 61 and alkynylphosphine. In benzene at 80 C for 6 h, phosphinozirconaindene 63 is formed, arising from insertion of the carbon–carbon triple bond into a zirconium–carbon bond of the transient benzyne zirconocene 62. An exchange reaction with phenyldichlorostibene leads to the formation of compound 64 (Scheme 10) <1997CC279>.
Scheme 10
2,29,5,59-Tetramethyl-1,19-diheteroferrocenes 20 and 2,29,3,39,4,49,5,59-octamethyl-1,19-diheteroferrocenes 22 with P-, As-, Sb-, and Bi-like heteroatoms have been prepared <1995OM2689> from the reactions of the corresponding 1-phenylheteroles 65 with lithium followed by treatment with FeCl2 (Scheme 11).
1173
1174 Arsoles, Stiboles, and Bismoles
Scheme 11
3,39,4,49-Tetramethyl-1,19-diheteroferrocenes 21 have been prepared by a modification of the McCormack reaction, based on the fact that the starting diiodide 66 could be stereospecifically desilylated with Bu4NF/H2O to afford 67 in 86% yield. Lithiation of diiodide 67 with butyllithium followed by reaction with dichlorophenylarsine or dichlorophenylstibine, respectively, yields the target compounds 68 (X ¼ As, Sb). Unfortunately, the reaction failed for the bismole derivative preparation (Scheme 12) <1995AGE295>.
Scheme 12
3.16.10 Synthesis of Particular Classes of Compounds 3.16.10.1 Synthesis of Anionic Intermediates 2,29,3,39,4,49,5,59-Octaethyl-1,19-biarsole/stibole 19 (E ¼ As, Sb) can be reduced by alkali metals such as sodium, potassium, rubidium, and cesium in DME or TMEDA yielding metal arsolides 69 (E ¼ As) or stibolides 69 (E ¼ Sb) with corresponding counterion and solvents being bidentate co-ligands (Equation 11) <2004OM3417>.
ð11Þ
Co-ligands also help in the crystallization: if TMEDA is used as solvent and the excess is removed in vacuo, the product recrystallizes from toluene. Arsolides of rubidium and cesium 69 (E ¼ As; M ¼ Rb, Cs) have thus been reported for the first time. Very similar results have been obtained with alkali earth metals (Mg, Ca, Sr, Ba) <2001ZFA1741>.
Arsoles, Stiboles, and Bismoles
1,1-Bis(cyclopentadienyl)-2,3,4,5-tetraethyl-1-zirconacyclopenta-2,4-diene 60 has been transmetallated to 1-chloro-2,3,4,5-tetraethyl-stibole 18 (E ¼ Sb), which could be reduced using potassium metal in THF to yield semi(tetrahydrofuran-O)bispotassium bis(2,3,4,5-tetraethyl-1-stibolide) 17 (Equation 12) <2000OM2393>.
ð12Þ
3.16.10.2 Synthesis of 1,19-Biheterole Derivatives The reduction of 2,3,4,5-tetraethyl-1-chloroarsole 18 (E ¼ As) or -stibole 18 (E ¼ Sb) with alkali metals such as sodium, potassium, rubidium, and cesium afforded the corresponding 2,29,3,39,4,49,5,59-octaethyl-1,19-biarsole/stibole 19 (Equation 13) <2004OM3417>.
ð13Þ
3.16.10.3 Synthesis of Organometallic Derivatives 3.16.10.3.1
-Complexes
No new studies have been reported.
3.16.10.3.2
p-Complexes
When 2,29,3,39,4,49,5,59-octaethylbiheteroles 19 are reduced with higher alkali earth metals (Sr, Ba) in THF, dioctaethylstrontocenes 13 and -barocenes 14 are formed (Equation 14) <2001ZFA1741>.
ð14Þ
Strontocene crystallizes as a THF adduct whereas the barocene precipitates co-ligand free but with a chain structure.
1175
1176 Arsoles, Stiboles, and Bismoles
3.16.11 Important Compounds and Applications Bluish green photoluminescence in solution is displayed by bismole polymer 27 <2006PSA4857>. This compound has been prepared with the aim of studying the contribution of the bismuth atom to the conjugated main chain, but mainly for application as an X-ray contrast material <2006PSA4857>.
3.16.11.1 Application of Arsoles, Stiboles, and Bismoles in Catalysis Only thermochromism has been found in the literature, see below.
3.16.11.1.1
Thermochromism
For more than 35 years, the thermochromic purple-blue 2,29,5,59-tetramethyldistibolyl 70 <1981JA207> and stibolides 1 (E ¼ Sb) <1980JOMC95, 1992OM1491> have been well known.
3.16.11.2 Other Applications 1,1-Dibromo- and 1,1-dichloro-1-phenylbenzostiboles markedly increased the lactate dehydrogenase (LDH) activity leaked into the medium from vascular endothelial cells after 24 h treatment, suggesting that these four compounds have strong cytotoxicity to vascular endothelial cells, caused leakage in vascular smooth muscle cells, and destroyed the monolayer of both endothelial and smooth muscle cell layers <2005JHS333>.
3.16.12 Further Developments Geometries, inversion barriers, static and dynamic electronic and vibrational dipole polarizability (), and first () and second () hyperpolarizability of the pyrrole homologues C4H4XH (X ¼ N, P, As, Sb, Bi) have been calculated by Hartree–Fock, Møller–Plesset second-order perturbation theory, coupled-cluster theory, accounting for singles, doubles, and noniterative triple excitations methods, as well as by density functional theory using B3LYP and PBE1PBE functionals and Sadlej’s Pol and 6-311G** basis sets. Relativistic effects on the heavier homologues stibole and bismole have been taken into account with effective core potential approximation <2006JPC5909>. Anharmonic corrections dominate the pure vibrational hyperpolarizabilities of pyrrole, while they are less important for the heavier homologues. The Einv value monotonically increases along the series (X ¼ P, As, Sb, Bi), consistent with the structural properties. The CCSD(T)/Pol Einv values are 19.3, 28.6, 35.9, and 55.9 kcal mol1 for phosphole, arsole, stibole, and bismole, respectively. The corresponding B3LYP/Pol values are 16.9, 27.7, 35.3, and 52.2 kcal mol1, respectively. The B3LYP/Pol atomization energies (D0), evaluated as the difference between the sum of the atomic energies and the ground-state molecular energy corrected for the zero-point vibrational energy, are 43.7, 40.8, 39.8, 38.9, and 38.6 eV in the same set and order. Accordingly, from the ECP-Pol results the dipole moments are in the following order:
(pyrrole) > (phosphole) > (bismole) > (arsole) > (stibole). Five increasingly sophisticated aromaticity indexes, based on nucleus-independent chemical shifts (NICS), were evaluated against a uniform set of aromatic stabilization energies (ASE) for 75 mono- and polyheterocyclic fivemembered rings <2006OL863>, among them a set of 11 with structure C4H4X, where X ¼ NH, PH, AsH, SbH, BiH.
Arsoles, Stiboles, and Bismoles
In the process of fragmentation of all four dihalogeno phenylarsanes, a halogen atom abundant halogeno phenylarsenium ions is produced in the 70 eV-EI and MIKE mass spectrometry study <2006IJMSP130>. Molecules of fluoro and chloro derivatives fragment only by loss of HF and HCl, a metastable bromo derivative exhibits losses of HBr and Br? of about equal intensity and the metastable molecular iodo ion fragments only by loss of an iodine atom. Unsymmetrical 9-chloro-9-arsafluorenes (dibenzoarsoles) have been obtained in close to quantitative yields by simple thermolysis of m-terphenyldichloroarsines. The reaction temperature is 140 C and the reaction is complete within 5 min. Alternatively, these compounds can be synthesized through an AlCl3-catalyzed Friedel–Crafts type ring-closure reaction at low temperatures, but this method suffers from difficult workup procedures <2006IC5568>.
References K. S. Pitzer, J. Am. Chem. Soc., 1948, 70, 2140. L. Nygaard, J. T. Nielsen, J. Kirchheimer, G. Maltesen, J. Rastrup-Anderson, and G. O. Sørensen, J. Mol. Struct., 1969, 3, 491. 1970JA5779 P. Coggon, J. F. Engel, A. T. McPhail, and L. D. Quin, J. Am. Chem. Soc., 1970, 92, 5779. 1972JA2861 R. H. Bowman and K. Mislow, J. Am. Chem. Soc., 1972, 94, 2861. 1973JCD1888 P. Coggon and A. T. McPhail, J. Chem. Soc., Dalton Trans., 1973, 1888. 1974TL303 G. Ma¨rkl, J. Advena, and H. Hauptmann, Tetrahedron Lett., 1974, 15, 303. 1980JOMC95 A. J. Ashe and T. R. Diephouse, J. Organomet. Chem., 1980, 202, C95. 1981JA207 A. J. Ashe, W. Butler, and T. R. Diephouse, J. Am. Chem. Soc., 1981, 103, 207. 1983OM1008 N. M. Kostic and R. F. Fenske, Organometallics, 1983, 2, 1008. 1984CHEC(1)539 R. E. Atkinson; in ‘Comprehensive Heterocyclic Chemistry I’, A. R. Katritzky and C. W. Rees, Eds.; Pergamon Press, Oxford, 1984, vol. 1, ch. 18, p. 539. B-1985MI1 W. E. Dasent; ‘Nonexisting Compounds’, Marcel Dekker, New York, 1985, ch. 4. B-1986MI1 J. B. Pedley, R. D. Naylor, and S. P. Kirby; ‘Thermochemical Data pf Organic Compounds’, 2nd edn., Chapman and Hall, London, 1986. 1988JA4204 K. K. Ba´ldridge and M. S. Gordon, J. Am. Chem. Soc., 1988, 110, 4204. 1989AIC259 R. Appel and F. Knoll, Adv. Inorg. Chem., 1989, 33, 259. 1989DPC650 V. A. Klyuchnikov, S. N. Kolabin, G. N. Shvets, P. I. Varushkin, N. A. Deryagina, N. A. Korchevin, and S. I. Tsvetnitskaya, Dokl. Phys. Chem., 1989, 307, 650. 1990AGE771 S. L. Buchwald, R. A. Fisher, and B. M. Foxman, Angew. Chem., Int. Ed. Engl., 1990, 29, 771. 1991CB2453 S. C. Sendlinger, B. S. Haggerty, A. L. Rheingold, and K. H. Theoplod, Chem. Ber., 1991, 124, 2453. 1992JOC3694 E. J. Padma Malar, J. Org. Chem., 1992, 57, 3694. 1992OM1491 A. J. Ashe, J. W. Kampf, and S. M. Al-Taweel, Organometallics, 1992, 11, 1491. B-1994MI1 S. Patai, Ed.; ‘The Chemistry of Organic Arsenic, Antimony and Bismuth Compounds’; . in ‘The Chemistry of Functional Groups’, S. Patai and Z. Rappoport, Eds.; John Wiley and Sons, Chichester, 1994. 1995AGE295 H. Gru¨tzmacher, Angew. Chem., Int. Ed. Engl., 1995, 34, 295. 1995JST57 L. Nyula´szi and T. Veszpre´mi, J. Mol. Struct., 1995, 347, 57. 1995JMT51 D. J. Berger, P. P. Gaspar, and J. F. Liebman, J. Mol. Struct. Theochem, 1995, 338, 51. 1995OM2689 A. J. Ashe, S. Al-Ahmad, S. Pilotek, D. B. Puranik, Ch. Elschenbroich, and A. Behrendt, Organometallics, 1995, 14, 2689. 1996CHEC-II(2)857 C. C. Caster; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. Scriven, Eds.; Pergamon Press, Oxford, 1996, vol. 2, ch. 16, p. 857. 1996G11 D. Fabbri, A. Dore, S. Gladiali, and O. De Lucchi, Gazz. Chim. Ital., 1996, 126, 11. 1997CC279 Y. Miquel, A. Igau, B. Donnadieu, J.-P. Majoral, L. Dupuis, N. Pirio, and P. Meunier, Chem. Commun., 1997, 279. 1997H(45)1891 S. Yasuike, J. Kurita, and T. Tsuchiya, Heterocycles, 1997, 45, 1891. 1999CRV969 P. Jutzi and N. Burford, Chem. Rev., 1999, 99, 969. 1999OM2491 M. Westerhausen, M. H. Digeser, C. Gu¨ckel, H. No¨th, J. Knizek, and W. Ponikwar, Organometallics, 1999, 18, 2491. 2000CC191 J. Kurita, F. Usuda, S. Yasuike, T. Tsuchiya, Y. Tsuda, F. Kiuchi, and S. Hosoi, Chem. Commun., 2000, 191. 2000CPH1 D. B. Chesnut and L. J. Bartolotti, Chem. Phys., 2000, 253, 1. 2000CPH175 D. B. Chesnut and L. J. Bartolotti, Chem. Phys., 2000, 257, 175. 1948JA2140 1969JST491
1177
1178 Arsoles, Stiboles, and Bismoles
2000J(P1)3775 2000OM2393 2001CR1247 2001EJI891 2001JIC224 2001TL441 2001ZFA1741 2002JOC1333 2002JPC6387 2003T1657 2003YZ577 2003ZFA2398 2004OM3417 2005ARA20 2005JHS333 2006IC5568 2006IJMSP130 2006JPC5909 2006OL863 2006PCA5909 2006PSA4857
A. Yu. Fedorov and J.-P. Finet, J. Chem. Soc., Perkin Trans. 1, 2000, 3775. M. Westerhausen, C. Gu¨ckel, M. Warchhold, and H. No¨th, Organometallics, 2000, 23, 2393. V. I. Minkin and R. M. Minyaev, Chem. Rev., 2001, 101, 1247. F. Nief, Eur. J. Inorg. Chem., 2001, 891. V. K. Jain, J. Ind. Chem. Soc., 2001, 78, 224. S. Yasuike, T. Iida, K. Yamaguchi, H. Seki, and J. Kurita, Tetrahedron Lett., 2001, 42, 441. M. Westerhausen, C. Gu¨ckel, H. Piotrowski, P. Mayer, M. Warchhold, and H. No¨th, Z. Anorg. Allg. Chem., 2001, 627, 1741. ˇ M. K. Cyranski, T. M. Krygowski, A. R. Katritzky, and P. von Rague´ Schleyer, J. Org. Chem., 2002, 67, 1333. S. Pelzer, K. Wichmann, R. Wesendrup, and P. Schwerdtfeger, J. Phys. Chem., 2002, 106, 6387. ´ M. K. Cyranski, P. von Rague´ Schleyer, T. M. Krygowski, H. Jiao, and G. Hohlneicher, Tetrahedron, 2003, 59, 1657. S. Yasuike, Yakugaku Zasshi, 2003, 123, 577. M. Westerhausen, M. W. Ossberger, A. Keilbach, C. Gu¨ckel, H. Piotrowski, M. Suter, and H. No¨th, Z. Anorg. Allg. Chem., 2003, 629, 2398. M. Westerhausen, M. W. Ossberger, P. Mayer, H. Piotrowski, and H. No¨th, Organometallics, 2004, 23, 3417. I. B. Gorrell, Annu. Rep. Prog. Chem., Sect. A, 2005, 101, 20. Y. Fujiwara, M. Mitani, S. Yasuike, J. Kurita, and T. Kaji, J. Health Sci., 2005, 51, 333. A. A. Diaz, J. D. Young, M. A. Khan, and R. J. Wehmschulte, Inorg. Chem., 2006, 45, 5568. D. Kirchhoff, H.-F. Gru¨tzmacher, and H. Gru¨tzmacher, Int. J. Mass. Spectrom., 2006, 249–250, 130. A. Alparone, H. Reis, and M. G. Papadopoulos, J. Phys. Chem., 2006, 110, 5909. H. Fallah-Bagher-Shaidaei, C. S. Wannere, C. Corminboeuf, R. Puchta, and P. v. R. Schleyer, Org. Lett., 2006, 8, 863. A. Alparone, H. Reis, and M. G. Papadopoulos, J. Phys. Chem. A, 2006, 110, 5909. Y. Morisaki, K. Ohashi, H.-S. Na, and Y. Chujo, J. Polym. Sci., Polym. Chem., Part A, 2006, 44, 4857.
Arsoles, Stiboles, and Bismoles
Biographical Sketch
Viktor Milata was born in 1957 at Bratislava. He attended the Faculty of Chemical Technology, Slovak Technical University, Bratislava, from 1976 to 1981. He obtained Ph.D. in organic chemistry in 1982 from the Faculty of Chemical Technology, Slovak Technical University, Bratislava, in ‘Utilisation of Derivatives of 3-Alkoxy-2-Propenoic Acid in Synthesis of Condensed Benzazoles’. He did postdoctoral work with Prof. E. Henry-Basch, Laboratory of Organometallic Chemistry, University Paris-Sud, Orsay, and Dr. R. Faure, University d’Aix, Marseille in 1991 (6 months); Prof. Dr. F. Sauter, Institute of Organic Chemistry, Technical University, Vienna, in 1993–94 (6 months); and Dr. I. Flemming, Department of Organic Chemistry, Cambridge University, Cambridge, in 1995 (1 month). In 1996, he became an associate professor and did study on ‘N-Substituted Aminoethylene Derivatives – Their Preparation, Structure, Properties and Utilisation in Organic Synthesis’. In 1998, he did postdoctorate with Prof. Dr. J. Fro¨hlich, Institute of Organic Chemistry, Technical University, Vienna, and in 1999–2000 (12 months), with Prof. R. Claramunt Vallespı´/Prof. J. Elguero, Department of Organic Chemistry and Biology, National University of Extramural Studies/ Spanish Academy of Sciences, Madrid. In the years 2003, 2004, and 2007 (1 month every year), he held lectureship with Prof. Dr. Andre´ Loupy and Prof. Dr. Cyril Kouklovsky at the Laboratory of Selective Reactions on Supports, Paris-South University, Orsay. He continues in the capacity of associate professor and a research group leader at the Department of Organic Chemistry, Slovak University of Technology. He has been the president of Slovak (from 2007, member 1984) and member of Czech (2001) Chemical Societies. He has been a member on the editorial board of electronic journal ARKIVOC (1999) and Molecules (1999), European Journal of Organic Chemistry (2001), Current Organic Chemistry (2004), Tetrahedron (2004), Journal of Heterocyclic Chemistry (2006), Israel Science Foundation (2006), Acta Chimica Slovenika (2007), Chemical Papers, Collection of Czechoslovak Chemical ˇ Communications, VEGA, and GACR. He has to his credit over 90 publications, 30 lectures, 15 patent applications, about 160 citations in foreign scientific sources, co-authorship of 1 scriptum, 12 reviews and monographs, and 3 audiovisual courses. His main interests include organic chemistry, heterocyclic chemistry (quinolones, dihydropyridines, benzimidazoles, benzotriazoles, benzoselenadiazoles, benzothiadiazoles, glutaric acids, enol ethers), utilization of heterocyclic compounds in the organic synthesis, and molecular spectroscopy.
1179
3.17 Siloles, Germoles, Stannoles, and Plumboles B. Wrackmeyer and O. L. Tok Universita¨t Bayreuth, Bayreuth, Germany ª 2008 Elsevier Ltd. All rights reserved. 3.17.1 3.17.2 3.17.2.1
Introduction Theoretical Methods
1182 1182
Optimization of Molecular Structure
1182
3.17.2.2 Calculation of Spectroscopic Properties 3.17.3 Physical Structural Methods
1184 1184
3.17.3.1
Direct Structural Information (X-Ray Analysis)
1184
3.17.3.2
NMR Spectroscopy
1185
3.17.3.2.1 3.17.3.2.2 3.17.3.2.3
3.17.3.3
1
H and 13C NMR spectroscopy 29 Si, 119Sn, and 207Pb NMR spectroscopy NMR Spectroscopy of other nuclei
Optical Properties
1185 1186 1188
1188
3.17.3.4 Electrochemical Properties 3.17.4 Reactivity of Fully Conjugated Rings
1189 1189
3.17.4.1
Reactions with Organolithium Reagents and Other Nucleophiles
1189
3.17.4.2
Reactions with Alkali Metals and Other Heteroatom Reactions
1190
3.17.4.3
Cycloaddition Reactions
1192
3.17.4.3.1 3.17.4.3.2
Siloles Germoles and stannoles
1192 1193
3.17.4.4 Complexes with Transition Metals 3.17.5 Reactivity of Nonconjugated Rings 3.17.5.1
1193 1194
Thermal Reactions
1194
3.17.5.2 Photochemical Reactions 3.17.6 Reactivity of Substituents Attached to Ring Carbons 3.17.7 Reactivity of Substituents Attached to Ring Heteroatoms 3.17.8 Ring Synthesis from Acyclic Compounds
1195 1195 1197 1200
3.17.8.1
1200
Formation of One Bond
3.17.8.1.1 3.17.8.1.2
Adjacent to the heteroatom to the Heteroatom
1200 1201
3.17.8.2
Formation of Two Bonds
1202
3.17.8.3
Formation of Three Bonds
1206
3.17.8.4
1,1-Organoboration of Alkyn-1-ylmetal Compounds
1207
3.17.8.4.1 3.17.8.4.2 3.17.8.4.3 3.17.8.4.4 3.17.8.4.5
General Siloles Germoles Stannoles Plumboles
1207 1209 1212 1212 1213
3.17.9 Ring Synthesis by Transformation of Another Ring 3.17.10 Important Classes and Applications 3.17.11 Further Developments References
1181
1213 1215 1215 1219
1182 Siloles, Germoles, Stannoles, and Plumboles
3.17.1 Introduction Metalloles and derivatives have been reviewed repeatedly <1990CRV215, 1990CRV265, 1996CHEC-II(2)903, B-1998MI(2)1961, B-2004MI73, 2006HAC188>. The basic structures and the IUPAC nomenclature have been introduced previously in CHEC-II(1996) <1996CHEC-II(2)903>. Parallel to the name metallole, metallacyclopenta-2,4-diene is still in use. Metalloles of the group-14 elements Si, Ge, Sn, and Pb can be considered as an attractive challenge in several ways, both for synthesis and theory. There is no straightforward route available for the synthesis of the parent compounds. The remarkable photophysical properties <1993MI339, 1996SM(82)149, 1999IC2464, 1998OM4910, 2005IC2003> of the metallole p-system are a powerful driving force in this chemistry, and have prompted the development of a large variety of synthetic routes to metallole derivatives. These require substituents other than hydrogen (in most cases) at the metal, and, in the absence of extremely bulky substituents at the heteroatom, there should be at least one or more substituents in the 2–5 positions. In short, experience in the chemistry of cyclopentadiene is hardly transferable to its heavy congeners. This is also true for monoanions of such metalloles, the heavy analogues of the cyclopentadienyl anion. In the case of the latter, aromaticity is clearly indicated as in other six-p-electron heterocycles such as pyrrole or thiophene, whereas this property is debatable for the metallole monoanions, since the surroundings of the metals are pyramidal. However, the structures of the few transition metal complexes known with silolyl or germolyl anionic ligands suggest the analogy to cyclopentadienyl complexes. The ever-increasing number of X-ray structural studies of metalloles certainly helps to improve the picture of their molecular structures in the solid state. On the other hand, the nuclear magnetic resonance (NMR) spectroscopic characterization of metalloles provides frequently instructive examples for a multinuclear approach to the bonding situation in solution, at least for M ¼ Si, Sn, Pb. Nowadays, optimized molecular gas-phase geometries of siloles or germoles can be reliably calculated and provide in turn access to calculated spectroscopic properties.
3.17.2 Theoretical Methods 3.17.2.1 Optimization of Molecular Structure Advances in computational hardware allow for reasonably fast optimization of molecular structures of molecular siloles, germoles, and derivatives using ab initio and/or density functional theory (DFT) methods at a fairly high level of theory. The agreement with crystal structure determinations, in the absence of marked solid-state effects, is satisfactory. Some calculated structural parameters of several siloles and derivatives can be found in Table 1. For consistency, these data were recalculated at the same level of theory. Figure 1 depicts the optimized structures of two complexes, where in one case the geometry of the silole ligand corresponds closely to expectations for an 4-diene ligand, in contrast to the cationic complex, where the 5-silolyl ligand (see <1998JA8245> for a Hf complex) is calculated to be planar when coordinated to the metal.
Table 1 Selected calculated structural data (RB3LYP/6-311þG(d,p) level of theory) and calculated chemical shifts 29Sia and one-bond coupling constants b of siloles and derivatives <2006UP1> 1
Compound
29
C–Si–C ( )
Si–C ( pm)
C(2)–C(3) ( pm)
C(3)–C(4) ( pm)
97.5
189.7
156.0
157.0
9.0
95.9
190.7
151.7
133.7
27.0
Si ( ppm)
J (Hz) Si–13C [29Si–1H ] 29
1
1
13
13
43.2 [175.1]
þ31.7
þ34.4
44.3 [185.9]
þ37.2
þ79.9
J (Hz) C(2)–13C(3)
J (Hz) C(3)–13C(4)
(Continued)
Siloles, Germoles, Stannoles, and Plumboles
Table 1 (Continued) 1
Compound
a 29
29Si ( ppm)
J (Hz) Si–13C [29Si–1H ]
1
1
13
13
57.8 (2) 45.8 (5) [181.5]
þ68.4
þ41.1 (3–4) þ31.7 (4–5)
38.8
60.6 [188.6]
þ67.0
þ54.2
þ9.5
61.0
þ67.3 (1–2)
þ54.0 (2–3)
145.0
43.8
17.6c [98.2]c
þ58.7
þ61.8
134.7
152.4
þ303.6
56.6 [259.3]
þ69.2
þ52.0
187.0
140.9
142.4
þ72.9
þ14.7d
þ53.0
þ70.5
87.2
193.0
134.2
150.1
þ783.0e
þ15.0d
þ66.6
þ58.3
85.8
187.1
142.7
142.7
31.2
58.5 [207.4](endo) [170.8](exo)
þ39.4
þ47.2
93.5
180.5
142.7
142.3
66.2 [311.9]
þ42.2
þ47.9
C–Si–C ( )
Si–C ( pm)
C(2)–C(3) ( pm)
C(3)–C(4) ( pm)
93.8
186.7 190.5 (4-5)
134.1
151.4 155.8 (4-5)
20.2
92.2
187.7
134.7
148.6
91.8
188.2
134.6 (1–2)
148.8 (2–3)
89.5
188.0
137.5
98.7
182.5
88.0
þ37.8
29
J (Hz) C(2)–13C(3)
J (Hz) C(3)–13C(4)
Si ¼ (SiMe4) (calcd.); with (SiMe4) ¼ 344.1. Since the gyromagnetic ratio (29Si) < 0, and (1H) > 0 and (13C) > 0, the signs of J(29Si,13C) or J(29Si,1H) are opposite to the signs of the reduced coupling constants K. c Note the small values as the result of pyramidal surroundings of the silicon atom and a largely Si-sited negative charge (‘lonepair effect’ <1989MRC409>)). d Note the inversion of the coupling sign as the result of the ‘lone-pair effect’. e Note the typical 29Si nuclear deshielding of a carbene-like silylene <1999JA9722>. b
1183
1184 Siloles, Germoles, Stannoles, and Plumboles
Figure 1 Optimized gas-phase geometries [B3LYP/6-311þG(d,p)] of the parent complexes Fe(CO)3-4-silole and [Fe(CO)35-silolyl]þ.
In connection with the electronic structure of metalloles, the question of aromaticity of metalloles, their mono- and dianions has been discussed in numerous publications and was addressed in great detail by Schleyer et al. <1996OM1755, 1997OM1543>. According to this work, aromatic character by all criteria must be attributed to the metallole dianions, in contrast with the monoanions and the metalloles themselves.
3.17.2.2 Calculation of Spectroscopic Properties In the last 15 years, the calculation of chemical shifts <1990JA8251, B-1999MI(3)1835> had considerable impact on the assignment of NMR spectra and better understanding of the basic physical principles. More recently, the calculations have been extended toward indirect nuclear spin–spin coupling constants nJ(X,Y) <1999CRV293, 2003CPL(375)452>. Examples of data for siloles and derivatives are given in Table 1. The trends found for the calculated chemical shifts 29Si and one-bond coupling constants 1J appear to be reliable, and major changes in the NMR parameters are mirrored by significant changes of the bonding situation around the silicon atom.
3.17.3 Physical Structural Methods 3.17.3.1 Direct Structural Information (X-Ray Analysis) Many group-14 metalloles (except plumboles) were characterized by X-ray analysis (see Table 2 for a direct comparison for M ¼ Si, Ge, Sn). With few exceptions <1995JOM(499)C7, 1998OM5133, 1996JOM(517)235, 2002JOM(649)232, 2003JOM(680)271>, at least two aryl groups are in the 2–5 positions <2006JMC3814, 2006AGE2578, 1998OM5796, 2004JA5336, 2005OM3081, 1997OM2230, 2003JOM(666)15, 1997OM2486, 2005EIC3770, 2005MI487>. This includes stable diradicals of siloles <2006CEJ5547, 2003OM4833>. There are many examples in which the metallole ring is condensed with one or two aromatic systems <1986JOM(312)305, 1998JOM(553)487, 2004OM5481, 2004OM5622>. Steric interactions cause nonplanarity in dinaphtho[2,1-b; 19,29-d]siloles and -germoles of the type 1 (Figure 2) <2000OM4483, 2001T10047>. There is also much structural data for anionic species (monoanions and dianions), for which a comparison of bond distances and angles is less meaningful since the bonding interactions with the respective counterion(s) depend on the ions themselves and the nature of coordinating solvents <1995JA11608, 1996JA10457, 1998JA5814, 2002JA49, 1999OM2919, 2000OM1806, 2006JA4934>. Molecular structures of transition metal complexes of siloles and germoles show that the diene system is 4-coordinated to the metal <1986OM910, 1987JOM(335)91, 1993CB1385, 2000OM4720>. Some transition metal complexes with silolyl and germolyl ligands (the heavy cyclopentadienyl congeners) were structurally characterized <1993AGE1744, 1998JA8245, 2000OM2671>. The 5-coordinated MC4-rings are essentially planar, and the surroundings of M ¼ Si 2 or M ¼ Ge (Figure 3) are slightly pyramidal, possibly for steric reasons. The pattern of the C–C bond distances is somewhat surprising, since it is opposite to that found for the anion.
Siloles, Germoles, Stannoles, and Plumboles
Table 2 Selected bond distances (pm) and angles ( ) for 2,5-dithienyl group - 14 metalloles <1998OM4910>
M(1)–C(2,5) M(1)–C(Ph) C(2)–C(3) C(3)–C(4) C(2)–M(1)–C(5) C(Ph)–M(1)–C(Ph) M(1)–C(2)–C(3) C(2)–C(3)–C(4)
M ¼ Si
M ¼ Ge
M ¼ Sn
188.7(2) 187.0(2) 135.6(3) 147.3(3) 92.99(8) 110.43(9) 105.9(1) 117.6(2)
195.9(2) 195.8(4) 135.1(4) 147.5(4) 89.9(1) 110.3(1) 106.5(2) 119.0(3)
214.8(4) 212.7(5) 137.0(6) 148.5(6) 84.6(2) 112.0(2) 106.8(3) 120.6(4)
Figure 2 Side view of the molecular structures of dinaphtho[2,1-b; 10,20-d]-metalloles.
Figure 3 5-Silolyl complex of Cp*HfCl2 and some bond distances <1998JA8245>. The sum of bond angles at the threecoordinate silicon atom is 354.7 , and the angle centroid-Hf-centroid is 135.2 .
3.17.3.2 NMR Spectroscopy 3.17.3.2.1 1
13
1
H and
13
C NMR spectroscopy
H and C NMR spectra of group-14 metalloles provide the usual important information on the composition of the compounds and their structures in solution. Although the magnitude of coupling constants J(M,13C) (M ¼ 29Si, 119Sn, 207 Pb) are of interest (see, e.g., Figure 4), these data are not always reported. In some cases, intramolecular dynamic processes of metalloles can be revealed by NMR spectroscopy. The same spirocyclic stannole as in Figure 4 was studied by solid-state Magic Angle Spinning (MAS) 13C NMR spectroscopy, and the NMR parameters for the solution and the solid state agree reasonably well <2003JOM(680)271>.
1185
1186 Siloles, Germoles, Stannoles, and Plumboles
Figure 4 62.9 MHz 13C{1H} NMR spectra in C6D6 at 23 C showing the range for the olefinic carbon atoms of a spirocyclic stannole <2003JOM(680)271>. 117/119Sn satellites (Sn) corresponding to 1J(Sn, 13C) and 2J(Sn, 13C), and 29Si satellites (Si)
In favorable cases, 13C NMR spectra can be recorded to reveal coupling constants 1J(13C, 13C) as shown in Scheme 1 for a silole 3 and its Fe(CO)3 complex 4 <2000MRC520>. The fairly small values of the coupling constants for the CTC bonds in the silole are due to the influence of the electropositive Si atom rather than to the silole system itself. The changes in the magnitude of 1J(13C, 13C) upon complexation are typical for 4-diene coordination.
Scheme 1
The compounds of type 1 (R1 ¼ Me, R2 ¼ H) (Figure 2) are examples for dynamic processes. 1H NMR spectra indicate that racemization takes place with energies of activation G# ¼ 76–77 2 (M ¼ Si) and 80 2 kJ mol1 (M ¼ Ge) <2001T10047>.
3.17.3.2.2
29
Si, 119Sn, and 29
119
207
Pb NMR spectroscopy
The chemical shifts Si, Sn, and 207Pb are sensitive to changes in the substituent pattern of the metalloles. It appears that the -bond of silicon to a transition metal causes 29Si nuclear deshielding <1987OM141>, and silyl, stannyl, or plumbyl substituents in 2,5-positions exert a deshielding effect on the metal nuclei in the ring (see Scheme 2 for M ¼ 29Si) <1993CB1107, 1993CB2221, 1986CC397>.
Siloles, Germoles, Stannoles, and Plumboles
Scheme 2
Starting from siloles or derivatives various ionic species can be prepared and characterized, in some cases at least in solution by 29Si NMR spectroscopy. This is shown (Scheme 3) for the increase in the silicon coordination number in a pentaorganosilyl anion (low-frequency shift) <1996AGE1127>, and also by reducing the coordination number as in the silolyl anions (high frequency shift) <1993JA5883, 2004JOM(689)134> and in the silole dianion <2004JOM(689)134>.
Scheme 3
The chemical shifts 29Si, 119Sn, and 207Pb change in a comparable way if the respective analogous molecules possess similar structures. This is shown for 119Sn of stannole mono- and dianions (Scheme 4) <2003CL912>, when compared with 29Si data in Scheme 3. It is noteworthy that the signs of the coupling constants 1J(119Sn, 13C) are most likely opposite to those known for ‘normal’ organotin compounds, as a result of the ‘lone pair effect’ <1989MRC409>.
Scheme 4
1187
1188 Siloles, Germoles, Stannoles, and Plumboles 3.17.3.2.3
NMR Spectroscopy of other nuclei
In addition to 1H, 13C NMR and 29Si, 119Sn or 207Pb NMR spectroscopy, other suitable nuclei may be found in the substituents of the metallole ring. Thus, 11B NMR is a convenient tool for monitoring 1,1-organoboration reactions <1995CCR125> (see Section 3.17.8.4). In the absence of suitable donors or bonding interactions with other substituents, the chemical shifts 11B prove the presence of three-coordinate boron atoms linked to three organic groups. 15N NMR spectroscopy has been used in particular for stannoles with amino groups linked to tin <2002JOM(649)232, 2003JOM(680)271>. Applications of 31P NMR include stannoles with phosphanyl substituents in 2,5-positions <1994PS(91)229>. Just one example of 57Fe NMR of a silole complex 4 (see Scheme 1) has been reported <2000MRC520>.
3.17.3.3 Optical Properties A huge variety of new metalloles, mainly siloles, and polymers have been prepared during the last decade in order to obtain materials with improved optical properties. Polyaryl-substituted siloles 5 and 6 containing bulky <2004AGE6336> or donor/acceptor <2004JA3724> substituents or oligomers of type 7 <2000AGE1695> show luminescence with high quantum efficiencies both in solution and in the solid state 8 <2005JA9071>. Polygermoles 9 with n ¼ 1900–20 000 show very efficient photoemission <2000OM3469>. Fused dithiophenosiloles 10 exhibit intense fluorescence emission in the green region and electroluminiscence devices based thereon are produced <2004OM5280>.
Siloles, Germoles, Stannoles, and Plumboles
3.17.3.4 Electrochemical Properties The behavior of several tetraphenylsiloles toward electrochemical oxidation in different conditions was examined <2004JEC(569)15>. The nature of the electrochemical oxidation products of silole 11 is strongly dependent on the conditions and the electrolyte, and both cyclic and open chain products (e.g., 12–16) are formed <2001JEC(507)49>.
Tetraphenylgermoles show at least two irreversible oxidation steps and lead to the mixtures of up to six products, similar to those prepared from siloles <2004JEC(573)139>.
3.17.4 Reactivity of Fully Conjugated Rings 3.17.4.1 Reactions with Organolithium Reagents and Other Nucleophiles One of the M–Si bonds in 1,1-bis(trimethylsilyl)metalloles 17 (M ¼ Si, Ge) is cleaved by the reaction with benzyl lithium to give the monoanions 18 which are further converted to the respective hafnocenes 2 (Figure 3) <1998JA8245>.
Treatment of the silole 19 with at least one Si–H function with KH leads first to penta-coordinated anion 20, followed by an allowed [1,5]-sigmatropic hydrogen migration (formally [1,2]-shift) to form the carbanion 21 <1994JA8428, 1999OM3813>. The latter reacts with an electrophile to give the 2,5-dihydrosilole derivative 22 as a mixture of two diastereomers.
A similar reaction is observed, when the siloles 23 (R ¼ H) are treated with sodium bis(trimethylsilyl)amide <1999OM3813, 1997OM1445>. The silicate 24 formed in the first step either eliminates NaH to give 26 or rearranges to the carbanion 25 which reacts further with MeI to the heterocycles 27.
1189
1190 Siloles, Germoles, Stannoles, and Plumboles
The Sn–Sn bond in the 1,19-bis(stannole) 28 can be cleaved at low temperature by treatment with BuLi to give the monoanion 29 <2002CC1002>.
3.17.4.2 Reactions with Alkali Metals and Other Heteroatom Reactions Reactions with alkali metals usually proceed by substitution of one or two substituents at the heteroatom of the metallole with the formation of mono- or dianionic species, respectively. Thus, 1-chlorosilole 30 reacts with Li in tetrahydrofuran (THF) at room temperature to give the monoanion 31 which can be alkylated to 32 or undergoes dimerization to the tricyclic dianion 33 <1997OM2770>.
Siloles, Germoles, Stannoles, and Plumboles
1,1-Dichlorosilole 34 gives under the same conditions the dianion 35 <1995JA11608>. Dibenzosilol 36 affords in the beginning a mixture consisting of the dimer 37 and the dianion 38. An excess of Li cleaves the Si–Si bond in 37, and after 1 h only 38 is present <2000TL6685>. Treatment of 36 with K in Et2O also gives 38 <2002JA49>. The silaindene 39 is converted to the dianion 40 by treatment with Li or Na <1998JA5814>.
Germoles and stannoles react with alkali metals in a way similar to siloles and form the dianions 41–43 <2000OM1806, 1995BSF495, 2005AGE6553, 2004PS(179)703>.
In contrast to siloles and germoles, the stannoles do not require a halogen function at the heteroatom. Thus, 43 is prepared from hexaphenylstannole <2005AGE6553> or 1-tert-butyl-pentaphenylstannole <2004PS(179)703>. Heating of the distannane 44 in boiling THF together with Li provides the dianion 43 <2002CC1002>.
Dichlorosilole 45 gives under Wurtz-reaction conditions the cyclic product 46 together with a significant amount of polymer <1999JA2937>.
1191
1192 Siloles, Germoles, Stannoles, and Plumboles
3.17.4.3 Cycloaddition Reactions 3.17.4.3.1
Siloles
Metalloles easily react with dienophiles to give [4þ2] cycloaddition products. A computational study of the cycloaddition reaction of silole with acetylene was performed <2002JMT(589)291>. It is shown that the silole has the lowest activation energy among five-membered conjugated heterocycles containing C, N, P, O, and S. If the silole bears hydrogen atoms in 2,5-positions (e.g., 48), it can undergo cycloaddition with the very weak dienophile 47 to give 7-sila-norbornadiene 49 or with itself during its formation to give 7-sila-norbornenes such as 50 <2002ZNB741>.
In the case of two different substituents at silicon, the stereochemistry of the final [4þ2] cycloaddition product depends on steric repulsion. Thus, the Diels–Alder reactions of silole 51 gives mixtures of 7-sila-norbornenes 52 and of 7-sila-norbornadienes 53, respectively, where the major isomer is that in which the SiMe group is in syn-position with respect to the C(2)–C(3) double bond <2003JOM(665)196>.
Siloles, Germoles, Stannoles, and Plumboles
Siloles 54 react with naphthalene oxide to give cycloadducts of type 55 <1998JOM(566)85>.
3.17.4.3.2
Germoles and stannoles
Germoles 56 undergo cycloaddition reaction with the wide range of dienophiles shown; the thermal and photochemical stability of the adducts were examined <2000RCB1275>.
1,1-Dimesitylgermole 57 reacts with maleic acid anhydride at room temperature to give the cycloaddition product 58 <1994JOM(482)131>.
The reaction of stannoles 59 with two different phosphaalkynes has been examined <1996JOM(520)211>. In all cases, the formation of phosphabenzenes 62 and 63 is detected as the result of dialkyltin elimination from the primary cycloadducts 60 and 61.
3.17.4.4 Complexes with Transition Metals The metallole ring is shown theoretically to be an analogue of cyclopentadiene and can form both 4- and 5-complexes with transition metals. Thus, siloles and germoles react with Fe(CO)5 or Fe2(CO)9 to give
1193
1194 Siloles, Germoles, Stannoles, and Plumboles 4-irontricarbonyl complexes 64 <1994JOM(482)131>, 65 <1999OM1717>, or 4 <2000MRC520>. The 4-Rh complex 66 is prepared from divinyl complex Cp* Rh(2-CH2TCHSiMe3)2 <1999JA4385>. The reaction of TaCl5 with 1-(trimethylsilyl)pentamethylgermole affords complex 67 which is further modified to 68–70 <2000OM4720>.
Monoanions 71 prepared from an appropriate silole or germole react with (C5Me5)HfCl3 to give the hafnocene analogues 2 (M ¼ Si, Ge) (Figure 3) in moderate yields <1998JA8245>. Complex 2 (M ¼ Ge) can be lithiated further and gives the bimetallic compound 72 upon treatment with (PMe3)4RhOTf <2000OM2671>.
The iron complex 73 is prepared from the germolyl anion and iron(II) chloride <2002OM1734>. This complex 73 can be further lithiated with MeLi to 74 and elimination of Li[Si(SiMe3)3] gives the 1,19-sila-[1]-1,19-digermaferrocenophane 75 <2002OM1734>.
3.17.5 Reactivity of Nonconjugated Rings 3.17.5.1 Thermal Reactions Many siloles and germoles are fairly stable toward heating or decompose in an uncontrolled way. However, their partly or comletely saturated derivatives are known to undergo thermal rearrangements mainly by elimination of the unit containing the heteroatom. Thus, 2,5-dihydrogermoles 76 undergo thermal cheletropic elimination to give germylenes and 2,3-dimethylbutadiene <2004AOC676>.
Siloles, Germoles, Stannoles, and Plumboles
In the conditions of flash vacuum thermolysis (FVT), germoles 77 are decomposed with the final formation of germaisonitriles such as 78 <1999OM5322> which are characterized in the gas phase by photoelectron spectroscopy.
3.17.5.2 Photochemical Reactions The photochemical behavior of saturated metallole derivatives is reminiscent of the thermal behavior. Laser flash photolysis of germoles 76 (R ¼ H, Me, Ph, Mes) causes extrusion of divalent germanium species together with 2,3dimethylbutadiene <2004JA16105>. UV irradiation of 79 (M ¼ Si, Ge) in a CsI or sapphire matrix generates silylene and germylene 80, respectively <1996OM4714>. The analysis of ultraviolet (UV) spectra of the products indicates the presence of isomers 80–83 which are in equilibrium by photochemically allowed [1,3]-H sigmatropic shifts.
3.17.6 Reactivity of Substituents Attached to Ring Carbons The modification of substituents at the carbon atoms of metallole rings is becoming more important in recent years. The 2,5-dilithiosiloles (see Section 3.17.8.1.2) give an access to a huge variety of different substituents at the 2,5positions of the silole ring. Thus, the reaction of 84 with ZnCl2 gives novel organozinc reagents 85 (M ¼ ZnCl, R ¼ Me, Ph) <2003OM4833, 2004OM6205>. The treatment of 84 with Bu3SnCl affords the 2,5-distannyl derivative 85 (M ¼ SnBu3, R ¼ n-C6H13) <1994JA11715>. Compound 84 can also be silylated to 85 (M ¼ SiMe3, R ¼ Me) and selenolated with PhSeCl to give 85 (M ¼ SePh, R ¼ Me) <1994JA11715>. A 2,5-diborylated derivative 85 (M ¼ B(NEt2)2, R ¼ Bu) is accessible from the reaction of 84 with (Et2N)2BCl at 70 C, which upon hydrolysis leads to the synthetically useful boronic acid 85 (M ¼ B(OH)2, R ¼ Bu) <2000AGE1695>.
1195
1196 Siloles, Germoles, Stannoles, and Plumboles
Bromination of 84 provides dibromosiloles 85 (M ¼ Br, R ¼ Me, Et, Pri, n-C6H13) <1994JA11715> which can be converted into the 2-lithio-5-bromosiloles when treated with BuLi at 78 C. Chlorination of 86 with N-chloro-3-methyl-2,6-diphenylpiperidin-4-one (NCP) gives the unsymmetrical silole 87 which after further iodination with I2 affords the synthetically useful 2-chloro-5-iodosilole 88 <2004JA3724>.
Trimethylsilyl groups as substituents in metalloles can also be substituted by halogens. Reaction of compounds 89 with PyHBr3 or with ICl/AgBF4 affords 2,5-dibromo- and 2,5-diiodosiloles 90, respectively <1998OM5133>.
The organometallic-substituted 85 (M ¼ a derivative of B, Zn, Sn) and halogeno-substituted siloles 85 (M ¼ Cl, Br, I) are suitable starting compounds for cross-coupling reactions. Pd-catalyzed coupling of 91 (R ¼ Me, Ph) with 4-amino- and 4-heteroaryl-bromobenzenes affords the siloles 92 in high yield <2004OM6205>.
Siloles, Germoles, Stannoles, and Plumboles
1,1-Diallylsilole 93 is treated with Bu3SnH/AIBN (AIBN – 2,29-azobisisobutyronitrile) in benzene to give the tricyclic compound 94 (42%) <1998T10699> along with a partially cyclized derivative (33%) via hydrostannation followed by elimination of Bu3SnI.
3.17.7 Reactivity of Substituents Attached to Ring Heteroatoms In Sections 3.17.4.3 and 3.17.4.4, the reactions of metalloles with alkali metals and other nucleophiles were discussed, leading to the formation of mono- and dianions. These reagents allow modification of the substituents at the heteroatom of metalloles, when the anions are treated with a variety of electrophiles. Silole 95 (M ¼ Si, R ¼ Me, SiMe3, R1 ¼ Me, Ph) <1995JOM(499)C7, 1997OM2770>, germoles 95 (M ¼ Ge, R ¼ Me, SiHMe2, SiMe3, R1 ¼ Et, Ph) <1999OM2919, 1995BSF495>, 96 <2000OM1806>, 97 <2002JA12174>, and stannoles 95 (M ¼ Sn, R ¼ Me, Ph, R1 ¼ Ph) <2002CC1002> are prepared in this way.
The controlled oxidation of the dianion 98 followed by methanolysis leads to the digermane 99 <2002JA12174>.
The treatment of metalloles bearing halogen function(s) in the 1-position with nucleophiles allows the preparation of metalloles with different substituents at the heteroatom. The monochloride 100 gives alkyne derivatives 101, the hydride 102, and hydroxysilole 103 by treatment with alkynyllithium (magnesium) reagents, LiAlH4 or NH4OH, respectively <2003CM1535>. Dichlorides 104 give dihydrogermoles 105 or 106 on treatment with organomagnesium reagents in THF <2004JA16105>.
1197
1198 Siloles, Germoles, Stannoles, and Plumboles
The reaction of 1,1-dilithio-tetraphenylsilole(germole) 107 (M ¼ Si, Ge) with R2SiCl2 gives metallolsilane copolymers 108 (M ¼ Si, Ge). Silole-germole copolymers 111 are prepared in the reaction of 109 and dichlorogermole 110, followed by reaction with MeOH <2003JA3821>.
Similarly, tri- 112 (n ¼ 1, 83%) and tetrasilole 112 (n ¼ 2, 20%) are prepared by treatment of 1,1-dichloro-2,5dimethyl-3,4-diphenylsilole with Na and then reaction with 1-chloro-1,2,5-trimethyl-3,4-diphenylsilole <1997OM2486>. The 1,1-dichlorogermole 110 gives cyclic trimers 113 under conditions of hydrolysis <2001MGM823>.
Siloles, Germoles, Stannoles, and Plumboles
The dianion 107 reacts with 2-adamantanone to give 5-silapentafulvene 114 <2004JA5336>.
Hydrogen attached to the heteroatom of metalloles can also be substituted by another group. Thus, the germole 115 and the 2,5-dihydrogermole 117 react with Me3SnNEt2 to give 1,1-bis(trimethyltin)derivatives 116 and 118 <1996IZV2764>.
Oligomers 119 (M ¼ Si, Ge) with MW ¼ 3500–6500 Dalton are prepared by catalytic dehydrocoupling (Pt, Pd, or Rh catalysts) of tetraphenylsilole or germole by heating in boiling toluene or by using microwaves <2005OM3081>. The reduction of tetraphenylsilole with Red-Al in THF also leads to the oligomers 119 (M ¼ Si, n ¼ 10–15) <2002OM2796>.
Halogenation of hexaphenylstannole with Br2 or I2 leads to the opening of the heterocycle with the formation of tin-containing butadienes 120 and 121 instead of substitution of at least one of the phenyl groups at the tin atom <2001HAC349>.
1199
1200 Siloles, Germoles, Stannoles, and Plumboles
3.17.8 Ring Synthesis from Acyclic Compounds 3.17.8.1 Formation of One Bond 3.17.8.1.1
Adjacent to the heteroatom
Intramolecular hydrosilylation of the alkynes 122 and 124 catalyzed with AlCl3 proceeds at low temperature and gives after 1 h the silole derivatives 123 and 125 in moderate yields <2000JOC8919>.
The reaction of the arylsilane 126 with MeLi gives the pentaorganosilyl anion 127 which can be further converted to the dibenzosilole 128 <1996AGE1127>.
1-Bromo-4-trimethylsilyl-1,2,3,4-tetraethyl-1,3-butadiene 129 gives 1,1-dimethyltetraethylsilole 130 in 88% yield by treatment with 2 equiv of ButLi at 50 C <2005TL499>.
A similar reaction of the butadienylstannane 131 in Et2O leads to 1,19-bis(pentaphenylstannole) (82%) 132, and in THF the yield drops to 58% with formation of 7% of 1-t-butylpentaphenylstannole 133 <2005EIC3750>. When 1-bromo-4-(tribromostannyl)tetraphenylbutadiene 134 is treated with various alkyl- or aryllithium reagents, different product distributions are observed: 1 equiv of MeLi gives only the trimethylstannylbutadiene 137 (15%), whereas 3 equiv of MeLi lead to 62% of 135 (R ¼ Me) and 27% of the stannole 136 (R ¼ Me) <2005EIC3750>; t-BuLi and s-BuLi gave bisstannoles 135 (R ¼ But, 55%) and 135 (R ¼ Bus, 40%) <2005EIC3750>; with PhLi the stannole 136 (R ¼ Ph, 33%) is a major product together with 135 (R ¼ Ph, 12%) <2005EIC3750>.
Siloles, Germoles, Stannoles, and Plumboles
The 2,2-bis(silyl)tolanes 138 are converted to the fused bis(siloles) 139 by treatment with naphthalene lithium in THF at room temperature, followed by oxidation with I2 <2003JA13662>. The analogous reaction of the diyne 140 affords 141 in high yield.
3.17.8.1.2
to the Heteroatom
The treatment of bis(phenylethynyl)silanes 142 with naphthalene lithium in THF at room temperature induces reductive ring closure to give 2,5-dilithio-3,4-diarylsiloles 143 <2004OM6205, 2004JA3724, 2003OM4833, 2000AGE1695, 1994JA11715> .
Divinyl and diallylsiloles 145 are prepared by similar reaction starting from appropriate silanes 144 <1998T10699>.
1201
1202 Siloles, Germoles, Stannoles, and Plumboles
The 1,2-hydrostannylation of (2-iodobenzyl)vinylsilanes 146 with tributylstannane induced with AIBN followed by elimination of tributyltin iodide provides 2,5-dihydro-benzo[c]siloles 147 (R1 ¼ R2 ¼ Me, R1 ¼ R2 ¼ vinyl, R1 ¼ R2 ¼ allyl, R1 ¼ Me, R2 ¼ allyl) together with minor amounts of benzosilacyclohexenes 148 or benzosilacycloheptene 149 <2002JOC8906>.
2-Vinylidene-2,5-dihydro-benzo[c]silole 151 is prepared by the same reaction sequence from disilylacetylene 150 <2002JOC8906>.
3.17.8.2 Formation of Two Bonds The [1þ4] cycloaddition of silylenes and germylenes to 1,3-dienes is a well-documented method leading to 2,5dihydrosiloles and -germoles. Carbene-like intermediates can be generated chemically, thermally, or by photoirradiation. Thus, the germylene, formed from (trimethylsilylmethyl)tribromogermanium 152 and Mg in THF, reacts with isoprene to give 2,5-dihydro-3-methylgermol 153 in moderate yield <1997OM4956>.
Dichlorosilylene and dichlorogermylene are formed in the gas phase at 500–550 C and can be trapped with 1,3butadienes with the formation of substituted 1,1-dichloro-2,5-dihydrometalloles 154 <2001RJC1438>.
Siloles, Germoles, Stannoles, and Plumboles
M–M bonds in polysilanes and polygermanes as well as silylgermanes are readily cleaved by photolysis to generate reactive silylenes and germylenes which are trapped with butadienes affording the cyclic products 155 and 156 <2000OM3232, 2002JOM(649)25>. In the case of 156, the replacement of Ar by less bulky substituents leads to small yields and the cycloaddition is accompanied by the formation of many side products.
Double and triple M–M bonds are a source of carbene- and carbyne-like intermediates which can easily undergo cycloaddition reactions to give dihydrometalloles. Thus, digermene 157 gives 71% of 158 at 50 C <2005OM3309>, and the alkyne analogue 159 reacts with 2,3-dimethylbutadiene in toluene at room temperature with the formation of 160 <2002CC1312>.
Three-membered heterocycles of type 161 or 163 can also be used for germylene formation and for the synthesis of germole derivatives <1999JA8811, 1994JOM(482)131>.
1203
1204 Siloles, Germoles, Stannoles, and Plumboles
The reaction of butadiene with Si atoms in argon at 10 K leads finally to the parent silole 165 <2003EOC478>, of which the structure was proposed on the basis of isotopic labeling and comparison of experimental and calculated infrared (IR) spectra.
The reaction between 1,4-dilithiobutadienes or 2,29-dilithiodiphenyl is a well-known and successful route to metalloles, although the choice of substituents in the 2–5 positions is somewhat limited. However, various substituents can be introduced at the metal. Thus, dilithiated butadienes 166 and 168 react with halo- or methoxyderivatives of Si and Ge to give siloles 167 and germoles 169 in high yield <2000JCD1049, 1998JOM(559)73>.
The analogous reaction with trichloro(phenylethynyl)silane affords the silole 171. On the other hand, trichlorovinylsilane reacts with dilithioderivative 170 in the ratio 2:1 forming silacycloheptadiene 172 <2000CC697>.
Siloles, Germoles, Stannoles, and Plumboles
Dibenzometalloles are prepared by the reaction of dialkyl- or diarylmetal dihalides (M ¼ Si, Ge, Sn) with 2,29dilithiodiaryls (easily available from appropriate dibromides and BuLi). Thus, binaphthyl derivative 173 gives dinaphthosiloles 1 (see also Figure 2) <2000OM4483>. Dilithiodiphenyl 174 reacts with SiCl4 to give spirosiloles 8 <2005JA9071>. At 95 C, the similar reaction leads to the 1,1-dichlorodibenzometalloles 175 (M ¼ Si, Ge) <2002JA12174>. Bis(benzothiophene) 176 (X ¼ S) and bisindole 176 (X ¼ NMe) provide the corresponding diphenylsiloles 177 <2004OM5622>.
Another useful method leading to metalloles takes advantage of the exchange of the Cp2Zr fragment in zirconoles with suitable electrophiles containing Si, Ge, or Sn. The zirconocene derivatives 178 react with GeBr4 at room temperature to give the dibromogermoles 179 in 92% yield <2000OM3469>. The reactions of the corresponding thienyl-substituted zirconole 180 with Et2GeCl2 or Me2SnBr2 afford, after heating in boiling toluene for 3 days, the germole 181 and the stannole 182, respectively, in 23% and 32% yield <1998OM4910>.
1205
1206 Siloles, Germoles, Stannoles, and Plumboles
3.17.8.3 Formation of Three Bonds Reactions of metalylenes with 2 equiv of alkynes lead to metalloles in high yield. Dimesitylgermylene (generated from cyclotrigermane 163) reacts with ethyne in the presence of Pd(PPh3)4 or PdCl2(PPh3)2 to give the germole 183 in 85% yield together with 1,4-digermacyclohexadiene 184 <1994JOM(482)131>. Similarly, the reaction of compound 185 with phenylacetylene as a solvent at 105 C provides diphenylgermole 186 in 21% yield in mixture with the four- and six-membered heterocycles 187 and 188 <1999OM2206>. When toluene is used as a solvent only traces of 186 are observed.
Weakly associated or monomeric dialkylstannanes, such as 189, react with ethyne under mild conditions in the presence of 1–3% Pd catalyst to give the stannoles 190 in high yield <1996JA804>. The mechanistic aspects of the stannole formation are considered by MO calculations <2000OM5661, 2002OM2662>.
Siloles, Germoles, Stannoles, and Plumboles
In the presence of an excess of trimethyl(vinyl)silane, the olefinic Rh complex 191 slowly undergoes rearrangement to the complex 66, containing an 4-coordinated silole ligand <1999JA4385>.
Ni-catalyzed cleavage of the Si–Si bond in the pseudo-pentacoordinated silane 192 leads to a short-lived silylene species which is trapped by an excess of tolane to give the silole 193 <1996JOM(521)325>.
3.17.8.4 1,1-Organoboration of Alkyn-1-ylmetal Compounds 3.17.8.4.1
General
One of the most versatile routes to siloles, germoles, stannoles, and eventually to plumboles of type 194, allowing for a great variety of substituents in all positions, is provided by 1,1-organoboration of the respective alkyn-1-ylmetal compounds <1995CCR125, 2006HAC188>. The sequence of reactions involved does not fit into the concept of bond formations (Sections 3.17.8.1–3.17.8.3) outlined so far and therefore it is dealt with separately.
The activation of the polar M–CU bond by the electron-deficient boron atom in triorganoboranes helps to explain the mechanistic principles behind 1,1-organoboration. This bond activation can be considered to take place either intermolecularly or intramolecularly. The intermolecular 1,1-organoboration proceeds via activation of the M–CU bond in 195, leading to cleavage of this bond and formation of the alkyn-1-ylborate-like zwitterionic intermediate 196. The formation of the new M–C bond is accompanied by the 1,2-shift of one organyl group from boron to the neighboring alkynyl carbon atom. Since this reaction is stereoselective in most cases, alkenes 197 are formed, in which the boryl group and the MLn fragment are in cis-positions. Depending on the substituents at the CTC bond, the 1,1-organoboration can be reversible. The conversion of the intermediates 196 into the alkenes 197 is reminiscent of the reaction of alkali metal alkyn-1-ylborates with electrophiles <1977PAC765, 1976JOM(108)281, 1982CSR191, 1982ACR178> which also leads, sometimes stereospecifically and in high yield, to alkenes of type 197.
1207
1208 Siloles, Germoles, Stannoles, and Plumboles
If one or more of the groups L in the MLn metal fragment are alkynyl groups, the cis-positions of BR2 and MLn moieties will strongly favor further reactions via intramolecular M–CU bond activation, opening the way to the formation of heterocycles such as metalloles <1995CCR125>. This is shown in Scheme 5 for dialkyn-1-yl(dimethyl)metal compounds, when the intermolecular 1,1-organoboration has already proceeded in the first step to give the alkenes 198. Intramolecular M–CU bond activation leads to the zwitterionic intermediates 199 which finally rearrange via intramolecular 1,1-vinylboration into the metalloles 200 <1977JOM(132)213, 1993CB1361, 1994CB333>.
Scheme 5
Alternatively, the intermediates of type 199 can rearrange into the 1-metalla-4-bora-cyclohexa-2,5-dienes 201 via intramolecular 1.1-alkylboration for R ¼ alkyl (mainly for M ¼ Sn <1978JOM(153)153>, Pb <1989AGE1500>, R1 ¼ Me and R ¼ Pri, C5H9). If the intramolecular 1,1-organoboration proceeds slowly, a second intermolecular 1,1organoboration may become competitive, leading to the dialkenylmetal derivatives 202 which are known to rearrange into the 1-metalla-cyclopent-3-enes 203 (mainly for M ¼ Sn <1978JOM(153)153, 1990ZNB437>, Pb <1990ZNB437>; R1 ¼ Me; and R ¼ Me, Et). The zwitterionic intermediates of type 199 are frequently detected by NMR spectroscopy (see Section 3.17.3.2) in the reaction solutions at low temperature for M ¼ Sn, Pb. Their rearrangement can be monitored, again by using NMR spectroscopy <1993CB1361, 1994CB333, 2006EJI101>. In several cases, these intermediates have been characterized by X-ray crystallography <1993CB1361, 1994CB333, 1989AGE1500, 1991AGE1370> showing the side-on coordination of the metal-containing fragment to the CUC bond. In the cases of M ¼ Si, Ge, the intermediates 199 are too short-lived to be detected under the reaction conditions. However, the substitution pattern of the five-membered rings and potentially stepwise routes <1993CB2221> provide unambiguous evidence for the analogous reaction mechanism.
Siloles, Germoles, Stannoles, and Plumboles
The ease of cleaving the M–CU bond depends on the bond polarity which increases from M ¼ Si to M ¼ Pb. Thus, rather mild reaction conditions (below 20 C) are typical for M ¼ Sn, Pb, whereas reactions for M ¼ Ge take place slowly at room temperature or after short heating at 60 C, and rather harsh reaction conditions (heating up to several days at 100 C) are required for M ¼ Si. Bulky groups L, R1 or R, linked to the metal, the CUC bond or to boron, respectively, expectedly hamper 1,1-organoboration reactions.
3.17.8.4.2
Siloles
Owing to the low reactivity of the Si–CU bonds toward triorganoboranes, most 1,1-organoboration reactions of alkyn1-ylsilanes require heating of the reaction mixtures at 100–110 C for several days, sometimes even weeks. Thermal stability is not a problem with most alkyn-1-ylsilanes. In contrast, numerous triorganoboranes decompose at elevated temperatures by 1,2-dehydroboration to give boron hydrides <1955JA5016, 1963AG1978, 1965LA21>. The latter are reagents for 1,2-hydroboration and therefore react with alkyn-1-ylsilanes giving rise to complex mixtures of products <1988CC1624>. Triethylborane, BEt3, is well suited for these 1,1-organoborations, since 1,1-dehydroboration usually does not take place below 150 C, and BEt3 can be used as a convenient solvent (bp 96 C). More reactive triorganoboranes such as 1-boraadamantane, triallylborane, or trivinylborane can also be considered for 1,1-organoboration. Some siloles possess fairly limited stability, since it is well known that siloles can readily undergo [4þ2] cycloadditions to give dimers or even more complex systems (see Section 3.17.4.3.1). Diethynyl(dimethyl)silane, Me2Si(CUC–H)2 47, reacts slowly at 80–90 C with BEt3 to give the silole 48 which, however, undergoes fast various [4þ2] cycloadditions (see Section 3.17.4.3.1) <2002ZNB741>.
Apparently, at least one substituent other than hydrogen in 2,5-positions is needed for kinetic stabilization of these siloles. This is shown by 1,1-ethylboration of Me2Si(CUC–H)CUC–R1 (R1 ¼ Bu, But, C5Hi11), where the siloles 204 and 205 (as mixtures of isomers) can be detected prior to [4þ2] cycloaddition reactions involving the starting alkyne. The bulkiness of R1 ¼ But prevents this [4þ2] cycloaddition, and the isomer 205 is formed almost exclusively, proving the much lower reactivity of the Si–CUC–But unit compared with that of the Si–CUC–H unit toward the initial intermolecular 1,1-ethylboration <2002ZNB741>.
Dialkyn-1-yl(dimethyl)silanes Me2Si(CUC–R1)2 with R1 ¼ alkyl, Ph, SiMe3 <1993CB1107>, SnMe3 <1986JOM(310)151> react with BEt3 to give selectively the siloles 206. Except for R1 ¼ SnMe3 prolonged heating at about 100 C is required. In the case of R1 ¼ SiMe3, there are three Si–CU bonds which can be attacked by BEt3, and the stereochemistry of the initial intermolecular 1,1-ethylboration is not predictable. However, the equilibrium between 1,1-ethylboration and 1,1-deethylboration is finally shifted by irreversible ring closure toward the intermediates analogous to 198 and 199. For R1 ¼ SnMe3, the mild reaction conditions <1986JOM(310)151> leave no doubt that one of the Sn–CU bonds is cleaved in the beginning by 1,1-ethylboration. Again the equilibrium between 1,1-ethylboration and 1,1-deethylboration is shifted to the intermediate with desired stereochemistry for the final irreversible ring closure.
1209
1210 Siloles, Germoles, Stannoles, and Plumboles
Among dialkyn-1-yl(dimethyl)silanes those with different alkynyl groups are attractive, considering the variation of substituents at the silole ring. If one alkynyl group is the trimethylstannylethynyl group as in Me2Si(CUC–R1)CUC–SnMe3, the high reactivity of the Sn–CU bond toward triorganoboranes invites 1,1-organoboration reactions under mild conditions (78 C to room temperature). The intramolecular Si–CU bond activation is straightforward, and the siloles 207 are formed in essentially quantitative yield <1993CB2221>.
1-Boraadamantane (Bad) <1996CHEC-II(8)889> is known as the most reactive trialkylborane, being much more reactive than BEt3. Thus, 1,1-organoboration reactions of alkyn-1-ylsilanes take place readily at room temperature <2001JOM(620)51, 2002CEJ1537>, and this is also true for dialkyn-1-yl(dimethyl)silanes Me2Si(CUC–R1)2 (R1 ¼ Me, But, SiMe3) which, upon treatment with Bad, afford the tetracyclic siloles 208 <2001CEJ775> (Scheme 6). For R1 ¼ Me, this 1,1-organoboration is nonselective, since a 7-sila-2,5-diboranorbornane derivative 209 is also obtained <2001CEJ775>. Because of the enormous reactivity of Bad, both Si–CU bonds can be attacked by Bad, and the compound 209 is formed by rearrangement of the intermediate dialkenylsilane; the molecular structure of a tin derivative related to 209 has been determined by X-ray analysis <2001CEJ775>.
Scheme 6
Triallylborane <1988PAC895, 1992JOM(424)127>, B(CH2-CHTCH2)3, B(allyl)3, reacts after gentle heating at 50–60 C with alkyn-1-ylsilanes <1999AGE124, 1999JOM(580)234, 2004AOC43>. 1,2-Allylboration <1988PAC895> can compete with 1,1-allylboration <1999AGE124, 1999JOM(580)234, 2004AOC43>. With R1 ¼ SiMe3, the silole 210 is formed selectively <2002JOM(657)146>. In contrast, for R1 ¼ Me the heterocycle 211 results first and rearranges finally into the bicyclic derivative 212. The formation of 211 requires consecutive 1,1-allylboration and 1,2-allylboration reactions <2002JOM(657)146>.
Siloles, Germoles, Stannoles, and Plumboles
Although trivinylborane appears to be slightly more reactive than triethylborane in 1,1-organoboration reactions, its reaction with Me2Si(CUC–But)2 still requires heating at 100–110 C for 2 h to give the silole 213. These conditions cause partial decomposition of trivinylborane. The fairly insoluble decomposition products can be filtered off to leave the pure silole 213 <2002CCC822>.
The 1,1-organoboration reactions described so far also work with dialkyn-1-ylsilanes Me(H)Si(CUC–R1)2 (R1 ¼ Bu, But, SiMe3) bearing an Si–H function <2002CCC822, 2004ICA(357)1103, 2005ZNB251>. Tetraalkyn-1-ylsilanes Si(CUC–R1)4 react in boiling toluene in the presence of a large excess of triethylborane to give spirosilanes (1,19-spirobisoles) such as 214 (R1 ¼ Me or Ph) <1993CB1385>. Protodeborylation leads to 215 (R1 ¼ Me or Ph), the former of which upon reaction with Fe(CO)5 affords the diastereomeric Fe(CO)3 complexes 216 (R1 ¼ Me), and the meso-isomer was characterized by X-ray structural analysis (see Section 3.17.3.1).
Condensed silole derivatives such as 217 (1,6-dihydro-1,6-disilapentalenes) can be prepared by 1,1-ethylboration of disilatriynes with terminal groups R1 ¼ SiMe3, SnMe3 <1998JOM(562)207, 1999JOM(577)82>.
1211
1212 Siloles, Germoles, Stannoles, and Plumboles
3.17.8.4.3
Germoles
1,1-Ethylboration of dialkyn-1-yl(dimethyl)germanes Me2Ge(CUC–R1)2 (R1 ¼ Me, Ph, SiMe3, SnMe3) affords the germoles 218 in the same way as the siloles, although under milder reaction conditions <1986JOM(310)151, 1995CCR125, 2001MGM603, 2006HAC188>. Similarly, the 1,1-spiro-bigermoles 219 can be prepared by 1,1ethylboration of tetraalkyn-1-ylgermanes Ge(CUC–R1)4 (R1 ¼ Me, Ph) <1993CB1385>.
3.17.8.4.4
Stannoles
Numerous stannoles are readily available by 1,1-organoboration of dialkyn-1-yl(diorgano)stannanes <1995CCR125; 2006HAC188> in the same way as described for siloles and germoles. Examples are 220 <1977JOM(132)213> and 221 <1996JOM(517)235> of which the molecular structures have been determined by X-ray analysis. The reactions proceed under mild conditions, and, with few exceptions, the formation of the stannoles is quantitative and complete after warming the mixtures to room temperature. Such stannoles with different substituents in 2,5-positions can be obtained by stepwise reactions <1978JOM(148)137, 1995JOM(503)289>. The 1,1-organoboration of trialkyn-1ylstannanes MeSn(CUC–R1)3 (R1 ¼ Bu, But, SiMe3) leads to stannoles in which an exocyclic alkyn-1-yl group is present. This alkyn-1-yl group can also undergo 1,1-organoboration <1994ICA(220)161>. Furthermore, functional groups can be present at the tin atom. Bulky amino groups appear to be suitable as shown for 222 <1994ICA(216)51, 1999ICA(296)26>, 223 <2002JOM(649)232>, and 224 <2003JOM(680)271>, with X-ray structural analyses for the latter two compounds. The 1,1-dihalogenostannoles 225 were found to be unstable with respect to elimination of SnX2 and complex decomposition <2002JOM(646)125>.
Siloles, Germoles, Stannoles, and Plumboles
Tetraalkyn-1-ylstannanes Sn(CUC–R1)4 react with various triorganoboranes by 1,1-organoboration, and numerous intermediates have been identified <1991AGE1370, 1993CB1385, 1992CB1597>, providing useful insight into the mechanism of these reactions. In some cases, the selective formation of 1,1-spiro-bistannoles 226 is observed, in particular for R1 ¼ SiMe3 <1992CB643>.
3.17.8.4.5
Plumboles
Few attempts have been made to prepare plumboles via 1,1-organoboration. The reaction of dialkyn-1-yl(dimethyl)plumbane Me2Pb(CUC–Me)2 with triisopropylborane affords a 1-plumba-4-bora-cyclohexa-2,5-diene instead of a plumbole. Zwitterionic intermediates, for example, 227, in this and similar reactions were identified and structurally characterized which gave decisive mechanistic information <1989AGE1500, 1990MRC465>. The 1,1-ethylboration gives the plumbol-3-ene 228 instead of a plumbole <1990ZNB437>. It proved necessary to use R1 ¼ SiMe3 in order to observe the formation of the plumbole 229 which is reasonably stable in solution <1990JOM(399)1>.
3.17.9 Ring Synthesis by Transformation of Another Ring Three-membered rings containing silicon are enlarged in the Pd-catalyzed reaction with alkynes. trans-Silirane (trans230) reacts with terminal acetylenes to give in all cases siloles 231 <1997OM1097>. The cis-isomer (cis-230) under similar conditions leads to a mixture of silole 231 together with up to 30% of the dihydrosiloles 232. The same behavior is observed when 230 reacts with disubstituted alkynes. Only cis-234 is formed in reasonable amount (21%) <2001OM3691>. The yield of trans-234 does not exceed 2%. The unsymmetrical activated alkyne 235 reacts with trans-230 to give two isomeric siloles 236 and 237 in the ratio c. 4:1.
1213
1214 Siloles, Germoles, Stannoles, and Plumboles
The silirenes 238 and 239 react with phenylacetylene by insertion to give the siloles 240 <2001OM3691> and 241 <1997OM4824>.
Irradiation of disilacyclohexadiene 242 in the presence of methylene blue as a sensitizer affords siloles 243 in high (R ¼ H) and moderate (R ¼ Ph) yields <1997TL3525>. An analogous ring contraction takes place by oxidation of 242 with (p-BrC6H4)3NþSbCI 6.
1,2-Digermacyclohexadienes 244 give germoles 245 as sole products by irradiation in benzene <1998OM1782>. When silagermacyclohexadiene 246 is treated in the same way, the formation of two metalloles is possible, but germole 247 is formed as a major product (84%) compared with silole 248 (9%).
2,5-Dihydrogermoles 250 are prepared by ring rearrangement and insertion starting from the bicyclic compound 249, when it is heated with tolane in benzene <2001OM3364>.
Siloles, Germoles, Stannoles, and Plumboles
3.17.10 Important Classes and Applications The unique photophysical properties of metalloles (mainly siloles and germoles) forced the development of new preparation methods of these compounds, some of which will be addressed here again. Thus, the reductive cyclization of dialkyn-1-ylsilanes 142 gives first 2,5-dilithiosiloles 143 which possess an enormous synthetic potential, also opening the way to different 2,5-(bisaryl)metalloles (via cross-coupling reactions), known to show outstanding optical properties.
Another attractive and promising aspect in metallole chemistry is the access to fused systems such as 139, 141, and 217.
1,1-Organoboration reactions (8.4) give the possibility to obtain metalloles with up to six different substituents, starting from readily available alkynes (Scheme 7).
Scheme 7
3.17.11 Further Developments The reactivity in Diels–Alder reactions of some mono- and polycyclic metalloles containing silicon, germanium and tin was calculated <2006NJC1149>. Optical properties were investigated for dendrimeric polyarylsiloles <2007JOM(692)5053, 2006MI103706, 2006OM766>, aminoarylsubstituted siloles <2007CPL124, 2006MI084907>, silole based dendrimers bearing globotriaose moieties <2007TL4365>, 2,5-bis(perfluoroaryl)siloles <2006CM3261>, polyarylsubstituted mono- <2007MI9543>, and
1215
1216 Siloles, Germoles, Stannoles, and Plumboles spirobisiloles <2006MI681>, fused dithienosiloles <2006OM1511>. The effect of the substituents in 2,5-positions in silole based chromophores on electrogenerated chemoluminescence was examined <2006JA10163>. An unexpected cycloaddition was observed for dilithiosilole 35 to give the spirocompounds 252 and 253 <2006AGE2578>.
The reaction of dichlorosilole 34 with dilithiobutadiene 170 gives ca. 60% of naphthylsubstituted silole 254 instead of expected octaphenylspirobisilole <2007MI239>.
1,1-Dichlorotetraethylgermole reacts with two equivalents of maleic anhydride or maleimide by a cycloaddition mechanism to give the corresponding tetracyclic compounds 255 and 256 with high yield <2007MI46>.
The treatment of hexaphenylstannane with 3 equiv of lithium in THF at room temperature selectively leads the formation of the pentaphenylstannole anion <2007EJI1297>. The reversible redox behavior between tetraphenylstannole dianion and octaphenylbistannole 1,2-dianion was investigated by 1H NMR spectroscopy <2006JA4934>. Subsequent treatment of a solution of compound 256 in THF with 1 equiv of Cp2Zr(H2CTCH2) (Takahashi’s reagent) at –35 C for 14 h, followed by hydrolysis of the reaction mixtures with 3 N aqueous HCl, resulted in the formation of sila-spirene 257 as crystalline solid in yield of 26% <2007CEJ7204>.
A series of spirosiloles 258 was prepared by one-pot reactions of dilithiobutadiene 170 with the corresponding cyclic dichlorosilenes. They were characterized by X-ray diffraction and their optical properties were examined <2007OM519>. For silole 258 (n ¼ 1) DFT calculations were carried out <2006JMAC3814>.
Siloles, Germoles, Stannoles, and Plumboles
Several silole bridged nitroxyl biradicals were prepared and characterized by X-ray diffraction, and their magnetic properties were investigated both experimentally and theoretically <2006MI386, 2006MI1319, 2006CEJ5547>. The dilithiobutadienes 259 undergo a novel type of skeletal rearrangement to give the otherwise hardly accessible 2-lithiosiloles 260 with high yield <2007JA3094>.
The reaction of dimethyldivinyltin 261 with various triorganoboranes proceeds by a 1,1-organoboration mechanism and affords stannolanes 262, which can undergo 1,2-dehydroboration to give stannolenes 263 <2007APOC531>.
Upon treatment of benzosilacyclobutanes 264 and 265 with CpCo(CO)2 in toluene the tricyclic compounds 266 and 267 each containing a silacyclopentane moiety were obtained in 56% and 29% yield, respectively <2007OM819>.
The combination of 1,2-hydroboration of double bond and 1,1-organoboration of triple bond of the corresponding vinyl(alkinyl)silanes 268 with 9-borabicyclo[3.3.1]nonane (9-BBN) affords in high yield the 1-silacyclopent-2-enes 269 <2006APOC99>.
1217
1218 Siloles, Germoles, Stannoles, and Plumboles
2,5-Ferrocenyl-substituted stannoles 270, 271, and 272 were obtained in the reactions of dimethylbis(ferrocenylethynyl)tin or tetra(ferrocenylethynyl)tin with triethylborane <2006EJI101>.
Ni-Catalyzed hydrosilylation of 1,6-diynes of type 273 gives dendrimeric 2,5-disubstituted siloles 274 with remarkable photophysical properties (emission at about 500 nm) <2007JOM(692)5053>.
Ru-catalyzed double hydrosilylation of 1,3-butadiynes in mild conditions gives access to 2,5-diphenylsiloles 275 with moderate yields <2007CC2627>.
Siloles, Germoles, Stannoles, and Plumboles
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1222 Siloles, Germoles, Stannoles, and Plumboles
2006JMC3814 2006MI386 2006MI681 2006MI1319 2006MI084907 2006MI103706 2006NJC1149 2006OM766 2006OM1511 2006UP1 2007APOC531 2007CC2627 2007CEJ7204 2007CPL124 2007EJI1297 2007JA3094 2007JOM(692)5053 2007MI46 2007MI239 2007MI9543 2007OM519 2007OM819 2007TL4365
X. Zhan, C. Risko, A. Korlyukov, F. Sena, T. V. Timofeeva, M. Yu. Antipin, S. Barlow, J.-L. Bredas, and S. R. Marder, J. Mater. Chem., 2006, 16, 3814. N. Roques, P. Gerbier, I. Imaz, P. Guionneau, and J.-P. Sutter, Acta Crystallographica Section C: Crystal Structure Communication, 2006, C62, m386. J. Lee, Y.-Y. Yuan, Y. Kang, W.-L. Jia, Z.-H. Lu, and S. Wang, Adv. Funct. Mater., 2006, 16, 681. N. Roques, P. Gerbier, Y. Teki, S. Choua, P. Lesniakova´, J.-P. Sutter, P. Guionneau, and C. Gue´rin, New Journal of Chemistry, 2006, 30, 1319. N. Huby, L. Hirsch, G. Wantz, L. Vignau, A. S. Barrie`re, J. P. Parneix, L. Aubouy, and P. Gerbier, J. Appl. Phys., 2006, 99, 084907. N. J. Watkins, A. J. Ma¨kinen, Y. Gao, M. Uchida, and Z. H. Kafafi, J. Appl. Phys., 2006, 100, 103706. D. Margetic0 and M. Eckert-Maksi´c, New J. Chem., 2006, 30, 1149. H.-J. Son, W.-S. Han, H. Kim, C. Kim, J. Ko, C. Lee, and S. O. Kang, Organometallics, 2006, 25, 766. D.-H. Kim, J. Ohshita, K.-H. Lee, Y. Kunugi, and A. Kunai, Organometallics, 2006, 25, 1511. B. Wrackmeyer, 2006 Unpublished results. B. Wrackmeyer and O. L. Tok, Appl. Organometal. Chem., 2007, 21, 531. T. Matsuda, S. Kadowaki, and M. Murakami, J. Chem. Soc., Chem. Commun., 2007, 25, 2627. Yan, J. Mohsseni-Ala, N. Auner, M. Bolte, and J. W. Bats, Chem. Eur. J., 2007, 13, 7204. Y. Dong, J. W. Y. Lam, A. Qin, Z. Li, J. Liu, J. Sun, Y. Dong, and B. Zhong Tang, Chem. Phys. Lett., 2007, 446, 124. R. Haga, M. Saito, and M. Yoshioka, Eur. J. Inorg. Chem., 2007, 1297. C. Wang, Q. Luo, H. Sun, X. Guo, and Z. Xi, J. Am. Chem. Soc., 2007, 129, 3094. T. Sanji, T. Kanzawa, and M. Tanaka, J. Organomet. Chem., 2007, 692, 5053. M. Westerhausen, B. Stein, M. W. Ossberger, H. Go¨rls, J. C. G. Ruiz, H. No¨th, and P. Mayer, ARKIVOC, 2007, 46. V. I. Timokhin, I. A. Guzei, and R. West, Silicon Chemistry, 2007, 3, 239. I. L. Karle, R. J. Butcher, M. A. Wolak, D. A. da Silva Filho, M. Uchida, J.-L. Bre`das, and Z. H. Kafafi, J. Phys. Chem. C, 2007, 111, 9543. H.-J. Son, W.-S. Han, J.-Y. Chun, C.-J. Lee, J.-I. Han, J. Ko, and S. O. Kang, Organometallics, 2007, 26, 519. N. Agenet, J.-H. Mirebeau, M. Petit, R. Thouvenot, V. Gandon, M. Malacria, and C. Aubert, Organometallics, 2007, 26, 819. K. Hatano, H. Aizawa, H. Yokota, A. Yamada, Y. Esumi, K. Yasuaki, K. Koshino, T. Koyama, K. Matsuoka, and D. Terunuma, Tetrahedron Lett., 2007, 48, 4365.
Siloles, Germoles, Stannoles, and Plumboles
Biographical Sketch
Bernd Wrackmeyer received his Diploma in Chemistry from the University of Munich in 1971 and his Ph.D. from the same University with Heinrich No¨th in 1973. He performed postdoctoral studies at John Cass College of Science and Technology in London with William McFarlane in 1974 and moved back to the University of Munich in 1975, where he finished his habilitation in 1979. He became a Heisenberg-Fellow in 1983 and moved to the University of Bayreuth in 1986. His work focuses on the application of multinuclear magnetic resonance spectroscopy (NMR), on the chemistry of organoboranes, carboranes, Group 14 metal chemistry and on metal amides.
Oleg L. Tok has graduated from D. I. Mendeleev Moscow Institute of Chemical Technology in 1987 (Diploma in Chemistry). After that he has been working in Moscow Institute of Organic Dyes as a researcher. From 1993 he was a researcher in A. N. Nesmeyanov Institut of Organoelement Compounds of Russian Academy of Science, where he completed his Ph.D. thesis in 1998 under the supervision of Yu. N. Bubnov. In 1998 and 2000 he worked at the University of Bayreuth as a postdoctoral fellow, and continued from 2001 until now. His scientific interests are focused on the reactivity of organoboranes, their application in organic synthesis, chemistry of unsaturated derivatives of Group 14 metal, and multinuclear magnetic resonance spectroscopy (NMR).
1223
3.18 Boroles G. Varvounis University of Ioannina, Ioannina, Greece ª 2008 Elsevier Ltd. All rights reserved. 3.18.1
Introduction
1225
3.18.2
Theoretical Methods
1226
3.18.3
Experimental Structural Methods
1227
3.18.3.1
Molecular Structure
1227
3.18.3.2
NMR Spectroscopy
1228
3.18.3.3
Mass Spectrometry
1228
3.18.3.4
Ultraviolet and Fluorescence Spectroscopy
1229
3.18.4
Thermodynamic Aspects
1229
3.18.5
Reactivity of Fully Conjugated Rings
1229
3.18.5.1
General Survey of Reactivity
3.18.5.1.1 3.18.5.1.2 3.18.5.1.3 3.18.5.1.4 3.18.5.1.5
1229
Thermal and photochemical reactions Nucleophilic addition on boron Reduction Ring expansion Nucleophilic substitution on boron
1230 1230 1230 1231 1232
3.18.6
Reactivity of Nonconjugated Rings
1233
3.18.7
Ring Synthesis
1233
3.18.7.1
Introduction
1233
3.18.7.2
Formation of One Bond
1234
3.18.7.3
Formation of Two Bonds
1235
Transformation of Existing Heterocycles
1238
3.18.7.4 3.18.8
Further Developments
1239
References
1239
3.18.1 Introduction Simple boroles are highly reactive antiaromatic molecules since their five-membered rings have four p-electrons with an empty boron p orbital. The first stable monomeric borole to be reported was 1,2,3,4,5-pentaphenylborole 1 (Ar ¼ Ph), a deeply colored solid which was synthesized from 1,4-dithio-1,2,3,4-tetraphenylbutadiene and dibromophenylborane <1961JA4406>. In CHEC(1984), a very brief account, mainly of the chemistry of pentaphenylborole 1 (Ar ¼ Ph) and its dipotassium pentaphenylborole dianion 2, was given <1984CHEC(1)629>. In CHEC-II(1996) <1996CHEC-II(2)919>, an attempt was made to cover all aspects of borole chemistry up to 1994. In the present updated account, the author found a decline in the chemistry of boroles although the interest in borole complexes with metals aimed at finding new Ziegler– Natta olefin polymerization catalysts has been on the increase. So far research on boroles has been centered on ammonia or dialkoxide borole adducts of general formula 3, 2,3-dihydroboroles 4, 2,5-dihydroboroles 5, borolanes 6, benzo[b]borolanes 7, and dibenzoboroles (or 9-borafluorenes) 8. A new ring system, dithienoborole 9, was described.
1225
1226 Boroles
Although no review article on the chemistry of boroles has appeared since 1995, organometallic compounds of borole and other heterocyclic rings have been reviewed <2001AHC(79)115>.
3.18.2 Theoretical Methods The strong antiaromatic nature of the borole molecule has been shown by the large negative value of the ‘resonance stabilization energy’, or otherwise called ‘aromatic stabilization energy’ of 0.98 and 0.97 eV obtained at the MP2(fc)/6-311þG(d,p) <2002JOC1333> and BLYP/6-311G(d,p)//BLYP/6-31G(d) levels respectively, in contrast with the large positive values for thiophene (0.81 eV) and furan (0.64 and 0.67 eV, respectively) <2000JCP1>. A theoretical evaluation of several chiral vinylborolanes as potential enantioselective Diels–Alder dienophiles has predicted that 2,5-diphenyl-1-vinylborolane 10 stands out to be a promising reagent for this purpose. These [4þ2] cycloadditions were studied both with highly reactive cyclopentadiene and isoprene and can lead to four diastereoisomeric borolanes which arise from the attack of the diene from either face of the dienophile (Re and Si) and with endo- or exo-stereochemistry. The geometries of the reactants were optimized, the transition structures were located, and the activation energies calculated using Jaguar with the B3LYP functional and the 6-31G* basis set. The transition structures were located using the standard nonquadratic synchronous transit (non-QST) method following the lowest Hessian eigenvector. The initial geometries were obtained by manual distortion of the product geometries toward the starting material geometries by stretching the C(1)–C(6) and C(2)–C(3) bonds to 2.2 A˚ <2004MI209>.
In order to obtain the characteristic features of the extended conjugated electronic structure of dithienoborole derivative 11, molecular orbital calculations were performed with the B3LYP/3-21G* functional. It turned out that the highest occupied molecular orbital (HOMO) is delocalized over the p-conjugated systems via the boron vacant p orbital. On the other hand, the lowest unoccupied molecular orbital (LUMO) is localized on a boron with a dithienyl unit. Examination of the HOMO and LUMO of 11 indicates that photoexcitation results in a net charge transfer from the conjugated p-electron system to the borole ring <2004CC68>.
Boroles
The intensive research that has been taking place in conjugated polymers is associated with the chemist’s dream of finding the novel conjugated conducting polymer with a small band gap, Eg, and thus obtaining the truly synthetic metal. To this end, the geometrical structures and electronic properties of borole/thiophene cooligomers 12–14 and copolymers 15 and 16 were studied employing the density functional theory with B3LYP functional. The borolecontaining oligomers have been suggested to have the quinoid structure and distinct biradical character. The introduction of thiophene rings into the oligoborole is predicted to retard the appearance of the quinoid structure and consequently stabilize the borole-containing oligomers. Electronic structures of polyborole and borole/thiophene copolymers were investigated by the periodic boundary condition (PBC) and the cyclic oligomer model. Both the PBC and cyclic models predict the quinoid structure of borole/thiophene copolymer. The PBC calculations give estimations of band gaps around 2.21 eV for the borole/thiophene (1:1) copolymer, which are different from those (0.00 eV) obtained by the oligomer extrapolation schemes <2005MM1123>.
3.18.3 Experimental Structural Methods 3.18.3.1 Molecular Structure 2,5-Dihydro-1H-boroles may have a classical structure 17 with a planar ring skeleton <1994CB1401> or alternatively a nonclassical structure 18 with a folded ring skeleton and an interaction between the empty p orbital of the boron and the p-orbital of the olefinic double bond <1994JA1880>. Amino substituents at position 1 of the dihydroborole ring stabilize the classical structure 17 while the nonclassical structure 18 has been found in bicyclic systems where the bicyclic structure strongly favors the folding of the dihydroborole ring. The X-ray structure determination of cis-1tert-butyl-2,5-dihydro-1H-borole 19 reveals that the molecule is essentially planar with a small folding of 8(1) . This is rather surprising since the virtually planar structure of the molecule is not significantly perturbed by the intramolecular repulsion between the two cis phenyl groups <1995JOM67>. The molecular structure of tritetrahydrofuran lithium dihydrodibenzoborole 20 is of interest since the Li center is pentacoordinated by three oxygen atoms of the tetrahydrofuran (THF) molecules and the two hydrogen atoms bonded to the boron atom. An unexpected feature of this structure is the bending of the H2B unit with respect to the LiH2 plane by 16 . This bending was postulated to be due to packing effects since the interaction between the solvated Li cation and the dihydrobenzoborole anion is primarily determined by electrostatic forces. As expected, the dibenzoborole unit was found to be planar, the largest ˚ Bislithium dibenzoborolyl dianion 21 is one of several dibenzobordeviation from the mean plane being only 0.04 A. ole derivatives that have been structurally characterized by X-ray crystallography <1996JA7981, 2001OM844, 2003OM1266>.
Several borollide complexes and cluster complexes have been prepared and structurally characterized by X-ray crystallography. These include borollide–tantalum complexes <1995JA2671, 1995POL93, 1996JA10317, 1998JA7791>, 1-aminoborole complexes of zirconium and hafnium <1997JOM65, 1998JOM1324>, 1-pentafluorophenylborole complexes of zirconium <1998JA6816, 2001OM4080>, mono-, di-, and trinuclear complexes of 1-phenylborole with rhodium <1997OM4292, 1997OM4800, 1998OM519, 2005EJI1737, 2006JOM3251,
1227
1228 Boroles 2006JOM3646> and, the mixed-metal 1-phenylborole complexes <1998OM2177, 1999JCD2807, 1999JOM66> and a cluster complex <1995AGE1010>. X-Ray crystallography has also been used to characterize borole salt 65 and diborate salt 66 (Scheme 6) <1996JA7981>, adduct 89 (Scheme 10) <2001OM844>, and dibenzoborole 97 (Equation 12) <2004JCD1245>.
3.18.3.2 NMR Spectroscopy 11
B and13C nuclear magnetic resonance (NMR) spectroscopy has been used to monitor the progress of the reaction of 1,19-spirobistannole 22 with boron tribromide, where 2,5-dihydro-1H-borole 23 was identified as an intermediate that rearranges to 1,6-dibromo-3,4-diethyl-2,5-dipropyl-2,3,4,5-tetracarba-nido-hexaborane(6) 24. In the 11B NMR spectrum of compound 23, the boron signal is a broad singlet at @ 67.7 ppm (Scheme 1) <1995JOM87> which is in the vicinity of other 2,5-dihydro-1H-boroles such as 25 @ 11B ¼ 49 ppm and 26 @ 11B ¼ 90 ppm <1995JOM67>. 1-Chloroand 1-methoxy-trans-2,5-diphenylborolanes 27 and 28 give values of @ 11B ¼ 77 and 54.6 ppm respectively <1997TL8487>. In the NMR spectra of 5-chloro-, 5-ethyl, and 5-phenyldibenzoboroles 8, @ 11B is between 53 and 64 ppm <2004JOM58>, but in pyridine adducts of 8 boron is considerably shielded and gives a peak around @ 4.2 ppm <2001OM844>. An even stronger shielding of the boron atom occurs in metal dihydrodibenzoborole adducts such as 20 where it appears at around @ 22.40 ppm, the type of metal (sodium or lithium) influencing the chemical shift only slightly <2000JOM168, 2003OM1266, 2004JOM58>. Furthermore, the boron signal in the 11B NMR spectrum of these adducts is not seriously influenced by the solvent used. For example, in the spectrum of potassium dibenzoborole salt 29, @ 11B ¼ 15.4 ppm taken in d8-THF and @ 11B ¼ 16.1 ppm taken in C6D6 <1996JA7981>. On the other hand, in the 11B NMR spectrum of the simple bislithium 1-phenyldibenzoborolyl dianion in C6D6, the shielding is less, the sharp boron signal appearing at @ 6.2 ppm <2003OM1266>, close to values reported for related compounds such as 21 with @ 11B ¼ 14.3 ppm in the same solvent <1996JA7981, 2001OM844>. 11B NMR spectra of dibenzoboroles 43 (Equation 6) and 97 (Equation 12) <2004JCD1245> and complexes 80 (Scheme 9), have also been reported.
Br Pr n Et Et 2 B
Pr n
BEt 2 +
Sn Pr n n Pr
Et
Et
Br
Et
Pr n
22
B
Et
Et
BBr3
B
BBr 3
B
Et
Pr n
Pr n
B
Br
Br
23
24
Pr n
Scheme 1
Ph
B
Ph
Ph
B
Ph
R
R
25: R = NMe2, NEt2, or NPri2 26: R = But
27: R = Cl 28: R = MeO
B K 2THF
Me
H
29
3.18.3.3 Mass Spectrometry Boroles have been routinely analyzed by mass spectrometry but only as far as to deduce their molecular mass. Electron impact, chemical ionization, and electron spray ionization methods have been used. No reports on the fragmentation patterns of boroles have been published to date.
Boroles
3.18.3.4 Ultraviolet and Fluorescence Spectroscopy The ultraviolet–visible (UV–Vis) absorption spectra of only a few dibenzoborole derivatives have been reported <1967LA197, 2000JA12911>, and more recently the fluorescence properties of these compounds were found to be distinct from those of the carbon and nitrogen analogues, fluorene and carbazole <2002JA8816>. Thus, the UV–Vis spectrum of 5-(2,4,6-triisopropylphenyl)dibenzoborole shows a characteristic weak shoulder band at 410 nm (log " ¼ 2.39) and exhibits a green fluorescence at 514 nm with a low quantum yield of 0.009. The large Stokes shift (100 nm) and the considerably longer emission maximum (max ¼ 160–200 nm) compared to those of fluorene (max ¼ 314 nm) and carbazole (max ¼ 349 nm) suggest the significant contribution of the boron vacant p orbital to the photophysical properties. The shoulder band of 5-(2,4,6-triisopropylphenyl)dibenzoborole in the absorption spectrum was attributed to transition from the HOMO delocalized over the biphenyl moiety to the LUMO delocalized over the dibenzoborole skeleton through the pp–p* conjugation <2002JA8816>. Dithienoborole 11 displays a bright green fluorescence at 534 nm in THF, an absorption band at 369 nm attributed to the p–p* transition of the p-electron unit, and an intense band at 438 nm. The positions of the absorption and fluorescence bands in 11 are independent of solvents such as dimethylformamide (DMF) and hexane. The Stokes shift (100 nm) supports an earlier correlation given between boron vacant p orbital and photophysical properties <2004CC68>.
3.18.4 Thermodynamic Aspects The 4p-electron antiaromatic system in monomeric boroles is destabilizing and reactions that remove the 2p orbital on boron from conjugation such as Lewis complexation, reduction to the dianion with metals, interaction with electron-rich metal centers, or borole ring-opening reactions such as Diels–Alder addition, oxidation, and photodeboration, result in more stable compounds. Benzo[b]boroles are also antiaromatic due to their 8p-electron systems and so are dibenzoboroles due to their 12p-electron systems. Of the three ring types, dibenzoboroles are the most stable because the 6p-electrons of either benzene ring are less prone to conjugate with the 2p orbital on boron.
3.18.5 Reactivity of Fully Conjugated Rings 3.18.5.1 General Survey of Reactivity The five-membered 4p-electron antiaromatic ring of borole with an empty p orbital on the sp2 boron atom is a strong Lewis acid. The inherent pp–p* conjugation of each p-electron pair through the vacant p orbital of the boron atom is ‘turned off’ by the binding of a neutral or charged nucleophile. The addition of neutral nucleophiles leads to stable adducts (Equation 1), reduction by metals forms dianion salts (Equation 2), while the addition of charged nucleophiles bearing a leaving group induces 1,2-migrations (Scheme 2).
B R
Scheme 2
Nu
:
+
B R
+
ð1Þ
B R
M B R
Nu
2M
ð2Þ
1229
1230 Boroles Free boroles 30 are isoelectronic with the cyclopentadienyl cation 31 and with cyclobutadiene 32 whereas the 6pelectron borollide dianion 33 is the closest structural relative to the cyclopentadienide anion 34. Dianions 33 have been used as 6p-electron ligands to form complexes with metals. These complexes have similar electronic and structural characteristics with the corresponding cyclopentadienide monoanion metal complexes but different molecular charge. The isolobal analogy between borollide dianion 33 and cyclopentadienide ion 34 is useful in comparing the reactivity and bonding capacities of organometallic reagents that can be used to tune the selectivity of metal– metal and metal–ligand interactions, which play an essential role in synthetic chemistry.
3.18.5.1.1
Thermal and photochemical reactions
The use of high-temperature (200 C) thermal reactions for the synthesis of dibenzoboroles from 2-biphenyldialkylboranes was first realized by Ko¨ster and Benedikt <1963AG419>. It was later shown that the pyridine adduct of 2-biphenylborane could also be converted by thermolysis to the corresponding pyridine adduct of dibenzoborole <1973JOM33>. In the recent literature, there have been no reports on the use of thermal and photochemical methods to prepare borole derivatives.
3.18.5.1.2
Nucleophilic addition on boron
The idea behind adding fluoride ion to the boron atom of dibenzoborole derivatives 35 was to provide adducts 36 in which pp–p* conjugation through the vacant p orbital of the boron atom is turned off. This caused a remarkable hypsochromic shift in the absorption and fluorescence maxima of compounds 36 attributed to a change in the pp–p* conjugation in the LUMO that significantly increased the HOMO–LUMO gap. Therefore addition of Bun4NF to dibenzoboroles 35 caused their emission bands around 561 nm to weaken and the intensity of the fluorescent bands around 419 nm to significantly increase (Equation 3) <2002JA8816>.
ð3Þ
3.18.5.1.3
Reduction
Boroles are readily reduced to the respective dianions owing in part to the empty p orbital on the boron atom. The reduction of 6-(4-tert-butylphenyl)-3-tert-butyl-5-(bis-2,6-(4-tert-butylphenyl)phenyl)dibenzoborole 37 with excess lithium powder in diethyl ether suspension at 10 C led to deep red crystalline dianionic bis(diethylether)dilithium salt 38. An attempt to obtain transition metal complexes by metathesis reactions of transition metal halides SnCl4,
Boroles
C5H5ZrCl3, FeCl2, FeBr2, or Cu(MeCN)4PF6 with dianionic salt 38 led only to the reduction of the metal halide salts, and the neutral species 37 could in each case be retrieved by simple workup (Equation 4) <2001OM844>.
ð4Þ
The reduction of 5-phenyldibenzoborole 39 was achieved by using excess of lithium powder in THF suspension at 78 C. The dilithium salt 40 was isolated as a THF solvate with a variable number of THF molecules depending on experimental conditions (Equation 5) <2003OM1266>.
ð5Þ
3.18.5.1.4
Ring expansion
Ring expansion of 5-chlorodibenzoborole 41 to 2,29-bisboranylbiphenyl 42 was possible by reaction with sodium borohydride in THF. It is proposed that the complicated mechanism initially involves a ligand exchange reaction to give the unsubstituted dibenzoborole together with in situ-formed borane, followed by five-membered ring expansion and coupling cyclization with borane (Scheme 3) <2004JOM58>. In the reaction between 5-chlorodibenzoborole 41 and sodium triethylborohydride, two ligand reactions occurred with hydrogen and ethyl groups. In situ 11B NMR spectra revealed the immediate H and Cl ligand exchange to form dibenzoborole ( ¼ 53.85 ppm) and BEt3 ( ¼ 83.65 ppm). These sharp peaks gradually gave way to two new peaks at 19.28 and 72.30 ppm corresponding to 5-ethyldibenzoborole 43 and 2,29-bis-ethylboranylbiphenyl 44 (Equation 6) <2004JOM58>.
Scheme 3
ð6Þ
1231
1232 Boroles 3.18.5.1.5
Nucleophilic substitution on boron
The chlorine atom of 5-chlorodibenzoborole 41 has previously been displaced by a variety of nucleophiles including hydride ion from sodium triethylborohydride <1996CHEC-II(2)919>. However, the reaction of 41 with excess lithium hydride in THF goes a step further to give lithium dihydrodibenzoborole 20. It is postulated that the reaction occurs by addition of hydride ion to 41, loss of lithium chloride from lithium salt 45, and addition of hydride ion to unsubstituted dibenzoborole (Scheme 4) <2000JOM168>.
LiH, THF B Cl
41
pentane
–LiCl H
LiH B
B Cl Li
20
H
45
Scheme 4
The structural similarity between the cyclopentadienide monoanion 34 and the borollide dianion 33, a 6p-electron ligand, has attracted several workers into synthesizing and characterizing numerous borollide–metal complexes. The dianionic borollide ligands provide a change in the ligand–metal relationship without deviating too far from wellcharacterized cyclopentadienyl–metal complexes. Borollide metallocenes not only provide innovative catalytic possibilities in terms of polymerization and heterolytic bond activation reactions, but also serve as new templates for the study of basic metal-mediated transformations. Aminoborollide ligand 46, known as Herberich’s reagent, is conveniently prepared in multigram quantities and provides suitable starting material for borollide-supported organotransition metal chemistry <1990AGE317>. For example, reaction of Me3TaCl2 with 46 in diethyl ether produces the extremely deficient (24-electron) triple-decker complex 47 (Equation 7) <1995POL93>. Complexes of tantalum, zirconium, and hafnium containing both cyclopentadienyl and a diisopropylaminoborollide ligand such as C5H5[5-C4H4B-N(CHMe2)2]TaMe2 48 <1995JA2671, 1996JA10317> and C5H5[5-C4H4B-N(CHMe2)2]M(3-C3H5) 49 (M ¼ Zr or Hf) <1997JOM65, 1998JOM1324> were prepared. A versatile complex, [C4H4B-N(CHMe2)2]TaCl3 51, was prepared in 47% yield by adding Li2[C4H4B-N(CHMe2)2]THF 50 to a benzene slurry of AlCl3 followed by addition of a suspension of TaCl5 in benzene. Complex 51 provided entry into other tantalum borollide complexes by reaction with MeMgCl, LiCH(SiMe2)2, 2,6-Pri2C6H3NH2, or acetone <1998JA7791>.
ð7Þ
Bercaw and co-workers showed that pentamethylcyclopentadienyl–aminoborole complexes of hafnium and zirconium 52 react with allyl magnesium bromide in diethyl ether to yield the allyl complexes 53 (Equation 8) <1997JOM65>.
ð8Þ
Boroles
A large number of transition metal complexes of borollide dianion (C4H4BPh)2 have been synthesized as structural analogues of the well-established uninegative 6p-electron cyclopentadienide ion. The ultimate goal was to produce compounds with similar activity but with beneficial reduced Lewis acidity, a desirable feature in homogeneous Ziegler–Natta olefin polymerization metallocene-type catalysis. Herberich et al. have done pioneering work in this area of chemistry. Triple-decker complexes 54 described in the early 1980s <1983AG(E)996> have since been <1997OM4292> oxidatively degraded to heterocubane 55 and the bis(borole)iodorhodium compound 56. The heterocubane 55 is readily attacked by excess pyridine at ambient temperature to give complex 57 and labile borole– pyridine adduct 58 <1997OM4800>.
Further work on (1-phenylborole)rhodium complexes is described by Herberich et al. <1998OM519>, Kudinov and co-workers <2005EJI1737>, and by both of these authors <2006JOM3251>. The first heterometallic (1-phenylborole) complexes of iron and gold appeared in the late 1990s <1998OM2177, 1999JOM66>. The borole-containing carbonyl metallates [(-C4H4BPh)Re(CO)3] and [(-C4H4BPh)Re(CO2)H] have been used as convenient precursors to incorporate a borole ligand in heterobimetallic systems <1995AGE1010, 1999JCD2807>. Borole complexes containing a zirconium metal have shown interesting reactivity with nitriles and isocyanides <2001OM4080>.
3.18.6 Reactivity of Nonconjugated Rings The addition of excess methanol to 1-chloro-trans-2,5-diphenylborolane 27 yielded the boronic ester 28 in 57% yield together with boronic and borate esters in 30% and 12% yield, respectively. On the other hand, oxidation of 1-chloroborolane 27 with 3 equiv of sodium perborate gave the water-soluble 1,4-diphenyl-trans-1,4-butanediol 59 in 55% yield (Scheme 5) <1997TL8487>.
OH Ph
Ph OH
59
NaBO3
MeOH Ph
B
Ph
Ph
B
Cl
OMe
27
28
Ph
Scheme 5
3.18.7 Ring Synthesis 3.18.7.1 Introduction The inherent high reactivity of monomeric antiaromatic boroles has continued to be an obstacle in the development of new synthetic routes and consequently the study of their chemical and physical properties. However, borole
1233
1234 Boroles dianions have been synthesized as complexes from zirconium-coordinated dienes, while zirconium to boron transmetallation was used in the synthesis of a 2,5-dihydroborolane. There has been no mention of any synthesis of the unstable benzo[b]borole ring, whereas there are several reports on the synthesis of dibenzoboroles. Apparently, the 12p-electron system of dibenzoboroles does not conjugate readily with the 2p orbital of boron and therefore these compounds are the most stable benzo-fused derivatives. A new dithienoborole ring system was recently introduced in which borole is part of an extended fully conjugated p-electron-rich system.
3.18.7.2 Formation of One Bond A new synthesis of dibenzoboroles by reductive cyclization of arylboron dibromides opens up access to several derivatives of this ring system (Scheme 6) <1996JA7981>. Monoarylboron dibromides 61 and 62 were prepared by reaction of the appropriate aryl lithium compound 60 with boron tribromide in hexane. Reductive cyclization of arylboron dibromide 61 with an excess of lithium metal in diethyl ether gave bislithium dibenzoborole complex 63. At the time of writing, compound 63 was the first dibenzoborole dianion to be structurally characterized by X-ray
Scheme 6
Boroles
crystallography. A characteristic feature of this molecule is that both lithium ions are solvated by diethyl ether and are also 5-coordinated to the five-membered borole ring. Similar reduction of 61 with lithium metal led to the dimer 64 whose structure was also established by X-ray crystallography and found to be analogous to that of 63, except that there are two types of lithium ion coordination spheres in the structure. Two of the four lithium atoms are each solvated by diethyl ether and are 5-coordinated to the five-membered borole ring, whereas the remaining two lithiums are each solvated with differing -coordination, by both dibenzoborole rings. Aryl boron dibromide 61 reductively cyclized to potassium dibenzoborole salt 65 with KC8 in THF and was characterized by X-ray crystallography. In dimer 65, two THF molecules solvate each potassium ion and also interact with the 5-H and 5-Me groups of the dibenzoborole ring. When arylboron dibromide 62 was reacted with 3 equiv of KC8 in diethyl ether, reduction occurred to the diborate 66. The structure of this compound was also established by X-ray crystallography. The formation of compounds 63–66 was rationalized by assuming that they have been formed via similar boranediyl intermediates 67 or 68 (Scheme 7). The intramolecular insertion of such a boranediyl fragment into an o-Me substituent C–C bond leads to dibenzoboroles 68 or 70. Further reduction of the five-membered borole ring of intermediate 68 with lithium leads to products 63 or 64. The appearance of the extra hydrogen atom (presumably from solvent) leads to the dibenzoborole salt 65. It is however unclear why the electrophilic boranediyl fragment does not intramolecularly add to an o-Me substituent C–H bond to give dihydro-9-boraphenanthrenes. On the other hand, formation of 66 from 69 may be rationalized by either the insertion of the boranediyl moiety into the aryl–methine (isopropyl) bond with subsequent loss of propane or by attack of the ortho-carbon of a 2,4,6-triisopropylbenzo group followed by elimination of propene. Dimerization of the resulting radical, formed by one-electron reduction, leads to compound 66.
Ar Ar
:
H H
B
68
K
–H 2 C=CHMe
H
64
Me
67
Ar
63
B
..
B Me
Me H
69
Ar
B H
70
Ar
B. H
K
71
66 Scheme 7
3.18.7.3 Formation of Two Bonds In CHEC-II(1996), the synthesis of the relatively stable diethyl ether adducts of 1,2,3,4,5-pentaarylboroles was described. Since then, the direct synthesis of the highly reactive borole monomer still remains unachieved. The construction of a borole ring that is part of a metal complex from zirconium-coordinated 1,3-dienes and tris(pentafluorophenyl)borane has been recently introduced. Tris(pentafluoro-phenyl)borane is widely used as an activator of metallocene-based polymerization catalysts; because of its resistance to aryl-transfer reactions, it acts as the boron source. The reaction utilizes the zwitterionic 14-electron bis(allyl)zirconium complexes 72 and 73 which are converted to the corresponding complexes 74 and 75 via activation of one of the C–H bonds of the B–CH2 moiety
1235
1236 Boroles and elimination of butene. The formation of these complexes is associated with the catalyst deactivation. Complexes 74 and 75 lose HC6F5 upon heating with concomitant five-membered borole ring formation to give the corresponding zirconium half-sandwich compounds 76 and 77 (Scheme 8) <1998JA6816>. The complexes contain the pentafluorophenyl substituted ligands [C4H4BC6F5]2 and [3-MeC4H3BC6F5]2, respectively.
Me 3Si F Me 3 Si (C6 F5 )3 B
SiMe 3
H H
SiMe 3
F
F
F
–C3H5R1 Zr
C6F5 F
R1
Zr
B C6F5
R
74: R = H 75: R = Me
R R1
72: R = H; = Me 73: R = Me; R1 = H
–HC 6F5
Me3Si SiMe 3 Zr
C6F5
R B C6F5
76: R = H 77: R = Me Scheme 8
The reaction of tris(pentafluorophenyl)borane with zirconium diene complexes, carrying smaller cyclopentadienyl ligands or at slightly elevated temperatures, takes a remarkably different course. The reaction of CpRZr(3-crotyl)(4butadiene) 78 in toluene at room temperature or warming at 50 C does not lead to mononuclear borole complexes vide infra but generates the borole-bridged triple-decker complexes 80 in near-quantitative yield. The reaction proceeds via the boryldiene compounds 79 as intermediates. Two molecules of 79 react with redistribution of the C6F5 substituents of their –B(C6F5)2 moieties to give borole and a borate. One C–H activation step is involved which leads to the formation of 1 equiv of pentafluorobenzene. As a result of these rearrangements, one of the original B(C6F5)3 molecules has lost all of its C6F5 substituents. The 11B NMR spectra of compounds 80 consist of a sharp signal at 12 to 13 for the borate and a broad signal around @0 to 3 for the borole ligand (Scheme 9) <2003PAC1183>. 1-(Substituted)-2,5-dihydro-2,5-diphenyl-1H-boroles 83a–c were obtained as mixtures of cis–trans-isomers by treatment of the magnesium–butadiene reagent 81 with dichloro(dialkyl-amino)borolanes 82a–c. The reactions took place in hexane or pentane at 78 C and were monitored by 11B NMR spectroscopy. The products were obtained in near-quantitative yields and NMR spectroscopic analysis was used to distinguish the cis- from the transisomers and establish their ratios which were as follows: cis-83a:trans-83a ¼ 2.2:1, cis-83b:trans-83b ¼ 1.1:1 and cis83c:trans-83c ¼ 2.4:1. In the case of compound 83c a single crystallization from hexane afforded crystals of pure cis83c. When magnesium reagent 81 was treated with tert-butylborondifluoride 84 in hexane at 78 C, the reaction produced (E,E)-1,4-diphenyl-1,3-butadiene 85 together with 1-tert-butylborole mixture cis-19 and trans-19. Fractional crystallization from hexane removed the diene and afforded pure cis-19. The structure of cis-19 was unambiguously assigned by X-ray crystallography (Equations 9 and 10) <1995JOM67>.
Boroles
Scheme 9
ð9Þ
ð10Þ
As described in CHEC-II(1996), a general approach for the synthesis of 5-alkyl(or aryl)dibenzoboroles is thermal ring closure of appropriate 2-biphenyl(dialkyl or diaryl)boranes. A different approach has been introduced that could work for 5-aryldibenzoboroles. So far, however, only 6-(4-tert-butylphenyl)-3-tert-butyl-5-{bis-[2,6-(4-tert-butylphenyl)]phenyl}dibenzoborolepyridine 89 has been synthesized. Thus reaction of 2,6-(4-tert-butylphenyl)phenyl bromide 86 with n-butyllithium in hexanes at 78 C formed the lithium salt 87. Addition of borane salt 88 to the latter afforded the product 89, which was detected in the crude reaction mixture by 1H NMR spectroscopy. The isolation of 89 was prevented due to its high solubility in common solvents. The addition of a large excess of pyridine however caused large colorless crystals of the adduct of 89 to form. The structure of the adduct of 89 was determined by X-ray crystallography. The mechanism of formation of the adduct of 89 is not yet understood (Scheme 10) <2001OM844, 2003OM83>. The synthesis of bis{2-[4-(bis(9,9-dimethylfluorenyl)aminophenyl]-5-thienyl}dithienoborole 11 as an extended conjugated electron-rich p-system was accomplished through metallation of 3,39-dibromodithieno compound 90 first by reaction with n-butyllithium in THF to give an intermediate 3,39-dilithiodithieno complex and then addition of 2,4,6-triisopropylphenyldimethoxyborane (Equation 11) <2004CC68>.
1237
1238 Boroles
Scheme 10
ð11Þ
3.18.7.4 Transformation of Existing Heterocycles Transmetallation is a useful method of changing one metal for another in organometallic compounds since it combines the attributes of both metals. The transmetallation of trans-2,5-diphenylzirconacyclopentane 93 to 1-chloro-trans-2,5-diphenylborolane 27 by boron trichloride proceeds with retention of stereochemistry (98%). Complex 93 was prepared in two steps from zirconocene dichloride 91 by alkylating with 1 equiv of tert-butyllithium at 78 C, allowing the tert-butyl group to isomerize at room temperature, adding another equivalent of tert-butyllithium at 78 C to the bis(cyclopentadienyl)zirconium complex 92 and finally treating this with 2 equiv of styrene. Complex 93 was not isolated; boron trichloride was added directly to the reaction solution containing 93. The conversion to borolane 27 was in excess of 85%, as measured by the ratio of boron species in the 11B NMR spectrum (Scheme 11) <1997TL8487>. Addition of 2 equiv of n-butyllithium to 2,29-dibromobiphenyl 94 and subsequent quenching with Me2SnCl2 afforded 5,5-dimethyl-5H-dibenzostannole 95 in near-quantitative yield. The stannole was reacted with dichlorophenylborane to yield 5-phenyldibenzoborole 39 and Me2SnCl2. The latter was removed by sublimation to leave pure 39 which was obtained in near-quantitative yield (Scheme 12) <2003OM1266>. Gabbai and co-workers reported that the anionic boron peri-bridged naphthalene derivative, dimesityl-1,8-naphthalenediylborate 96, reacts with 5-chlorodibenzoborole 41 to form diborane 97. The 11B NMR spectrum of 97 shows two resonances at 57 and 71 ppm confirming the presence of two different boron centers. The structure of 97 has been unambiguously assigned by X-ray single crystal analysis. The cyclic voltammagram of 97 in THF shows two distinct reversible reduction waves at E1/2 214 and 2.56 V. The first reduction wave most likely indicates the formation of a radical anion in which the unpaired electron pair is -delocalized over the two boron centers (Equation 12) <2004JCD1245>.
Boroles
Scheme 11
Scheme 12
ð12Þ
3.18.8 Further Developments New material since writing and proofreading this manuscript includes three articles on metal complexes with boroles <2006DT2950, 2006IC5852, 2006RCB1581> and one theoretical study on dibenzoboroles <2006JPC2434>.
References 1961JA4406 1963AG419 1967LA197 1973JOM33 1983AG(E)996 1984CHEC(1)629
E. H. Braye, W. Hu¨bel, and I. Caplier, J. Am. Chem. Soc., 1961, 83, 4406. R. Ko¨ster and G. Benedikt, Angew. Chem., 1963, 75, 419. R. Ko¨ster, G. Benedikt, W. Fenzl, and K. Reinert, Liebigs Ann. Chem., 1967, 702, 197. R. V. Veen and F. Bickelhaupt, J. Organomet. Chem., 1973, 47, 33. G. E. Herberich, B. Hessner, W. Boveleth, H. Luthe, R. Saive, and L. Zelenka, Angew. Chem. Int. Ed. Engl., 1983, 22, 996. I. Ander; in ‘Comprehensive Heterocyclic Chemistry I’, A. R. Katritzky and C. W. Rees, Eds.; Pergamon, Oxford, 1984, vol. 1, p. 629.
1239
1240 Boroles
1990AGE317 1994CB1401 1994JA1880 1995AGE1010 1995JA2671 1995JOM67 1995JOM87 1995POL93 1996CHEC-II(2)919 1996JA7981 1996JA10317 1997JOM65 1997OM4292 1997OM4800 1997TL8487 1998JA6816 1998JA7791 1998OM519 1998OM2177 1998JOM1324 1999JCD2807 1999JOM66 2000JA12911 2000JCP1 2000JOM168 2001AHC(79)115 2001OM844 2001OM4080 2002JA8816 2002JOC1333 2003OM83 2003OM1266 2003PAC1183 2004CC68 2004JCD1254 2004JOM58 2004MI209 2005EJI1737 2005MM1123 2006DT2950 2006IC5852 2006JOM3251 2006JOM3646 2006JPC2434 2006RCB1581
G. E. Herberich, M. Hostalek, R. Laven, and R. Boese, Angew. Chem., Int. Ed. Engl., 1990, 23, 317. G. E. Herberich, T. P. Spaniol, and U. Steffan, Chem. Ber., 1994, 127, 1401. P. J. Fagan, W. A. Nugent, and J. C. Calabrese, J. Am. Chem. Soc., 1994, 116, 1880. P. Braunstein, U. Englert, G. E. Herberich, and M. Neuschu¨tz, Angew. Chem., Int. Ed. Engl., 1995, 34, 1010. G. C. Bazan, S. J. Donnelly, and G. Rodriguez, J. Am. Chem. Soc., 1995, 117, 2671. G. E. Herberich, T. Wagner, and H.-W. Marx, J. Organomet. Chem., 1995, 502, 67. B. Wrackmeyer and G. Kehr, J. Organomet. Chem., 1995, 501, 87. G. C. Bazan and G. Rodriguez, Polyhedron, 1995, 14, 93. G. Varvounis; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 2, p. 919. W. J. Grigsby and P. P. Power, J. Am. Chem. Soc., 1996, 118, 7981. C. M. Kowal and G. C. Bazan, J. Am. Chem. Soc., 1996, 118, 10317. A. Pastor, A. F. Kiely, L. M. Henling, M. W. Day, and J. E. Bercaw, J. Organomet. Chem., 1997, 528, 65. G. E. Herberich, H. J. Eckenrath, and U. Englert, Organometallics, 1997, 16, 4292. G. E. Herberich, H. J. Eckenrath, and U. Englert, Organometallics, 1997, 16, 4800. T. E. Cole and T. Gonza´lez, Tetrahedron Lett., 1997, 49, 8487. G. J. Pindado, S. J. Lancaster, M. Thornton-Pett, and M. Bochmann, J. Am. Chem. Soc., 1998, 120, 6816. C. K. Sperry, W. D. Cotter, R. A. Lee, R. J. Lachicotte, and G. C. Bazan, J. Am. Chem. Soc., 1998, 120, 7791. G. E. Herberich, H. J. Eckenrath, and U. Englert, Organometallics, 1998, 11, 519. P. Braunstein, G. E. Herberich, M. Neuschu¨tz, M. U. Schmidt, U. Englert, P. Lecante, and A. Mosset, Organometallics, 1998, 17, 2177. A. F. Kiely, C. M. Nelson, A. Pastor, L. M. Henling, M. W. Day, and J. E. Bercaw, J. Organomet. Chem., 1998, 17, 1324. P. Braunstein, U. Englert, G. E. Herberich, M. Neuschu¨tz, and M. U. Schmidt, J. Chem. Soc., Dalton Trans., 1999, 2907. P. Braunstein, G. E. Herberich, M. Neuschu¨tz, and M. U. Schmidt, J. Organomet. Chem., 1999, 580, 66. P. A. Chase, W. E. Piers, and B. O. Partrick, J. Am. Chem. Soc., 2000, 122, 12911. D. B. Chestnut and L. Bartolotti, J. Chem. Phys., 2000, 253, 1. J. Knizek and H. No¨th, J. Organomet. Chem., 2000, 614, 168. A. P. Sadimenko, Adv. Heterocycl. Chem., 2001, 79, 115. R. J. Wehmschulte, M. A. Khan, B. Twamley, and B. Schiemenz, Organometallics, 2001, 20, 844. T. J. Woodman, M. Thornton-Pett, D. L. Hughes, and M. Bochmann, Organometallics, 2001, 20, 4080. S. Yamaguchi, T. Shirasaka, S. Akiyama, and K. Tamao, J. Am. Chem. Soc., 2002, 124, 8816. ˜ M. K. Cryanski, T. M. Krygowski, A. R. Katritzky, and P. R. Schleyer, J. Org. Chem., 2002, 67, 1333. R. J. Wehmschulte, A. A. Diaz, and M. A. Khan, Organometallics, 2003, 22, 83. P. E. Romero, W. E. Piers, S. A. Decker, D. Chau, T. K. Woo, and M. Parvez, Organometallics, 2003, 22, 1266. M. Bochmann, S. J. Lancaster, M. D. Hannant, A. Rodriguez, M. Schormann, D. A. Walker, and T. J. Woodman, Pure Appl. Chem., 2003, 75, 1183. S. Kim, K.-hyung Song, S. O. Kang, and J. Ko, Chem. Commun., 2004, 68. J. D. Hoefelmeyer, S. Sole, and F. P. J. Gabbai, J. Chem. Soc., Dalton Trans., 2004, 1254. H. Hong and T. C. Chung, J. Organomet. Chem., 2004, 689, 58. S. C. Pellegrinet, M. A. Silva, and J. M. Goodman, J. Comput.-Aid. Mol. Des., 2004, 18, 209. D. A. Loginov, D. V. Muratov, P. V. Petrovskii, Z. A. Starikova, M. Corsini, F. Laschi, F. B. Fabrizi, P. Zanello, and A. R. Kudinov, Eur. J. Inorg. Chem., 2005, 1737. H. Cao, J. Ma, G. Zhang, and Y. Jiang, Macromolecules, 2005, 38, 1123. N. Auvray, T. S. B. Baul, P. Braunstein, P. Croizat, U. Englert, G. E. Herberich, and R. Welter, Dalton Trans., 2006, 2950. P. Croizat, N. Auvray, P. Braunstein, and R. Welter, Inorg. Chem., 2006, 45, 5852. D. V. Muratov, P. V. Petrovskii, Z. A. Starikova, G. E. Herberich, and A. R. Kudinov, J. Organomet. Chem., 2006, 691, 3251. D. A. Loginov, D. V. Muratov, Z. A. Starikova, P. V. Petrovskii, and A. R. Kudinov, J. Organomet. Chem., 2006, 691, 3646. K. S. Thanthiriwatte and S. R. Gwaltney, J. Phys. Chem. A, 2006, 110, 2434. D. A. Loginov, D. V. Muratov, Z. A. Starikova, P. V. Petrovskii, and A. R. Kudinov, Russ. Chem. Bull., Int. Ed., 2006, 55, 1581.
Boroles
Biographical Sketch
George Varvounis was born in Alexandria, Egypt, in 1953. He received his B.Sc. (Honors) degree in chemistry and biochemistry in 1977 at the Polytechnic of Central London, UK, and his M.Sc. degree in applied heterocyclic chemistry in 1979 and Ph.D. degree in organic chemistry in 1982 at the University of Salford, UK. He became a lecturer at the University of Ioannina, Greece, in 1982, an assistant professor in 1990, and an associate professor in 2001. He spent several short periods on sabbatical leave working with Dr. G. W. H. Cheeseman at Queen Elizabeth College, University of London in 1983–87, with Professor H. Suschitzky and Dr. B. J. Wakefield at the University of Salford, and with Professor J. A. S. Smith and Dr. C. W. Bird at King’s College London, University of London, in 1988–94. His research interests include the synthesis and properties of heterocyclic compounds, especially benzo- and naphtho-fused tricycles containing nitrogen, nitrogen and oxygen, or nitrogen and sulfur atoms.
1241
3.19 Five-membered Rings with Other Elements A. P. Sadimenko University of Fort Hare, Alice, South Africa ª 2008 Elsevier Ltd. All rights reserved. 3.19.1
Introduction
1244
3.19.2
Theoretical Methods
1244
3.19.3
Experimental Structural Methods
1245
3.19.4
Thermodynamic Aspects
1245
3.19.5
Reactivity of Fully Conjugated Rings
1245
3.19.5.1
General Remarks
1245
3.19.5.2
Complexation
1246
3.19.5.3
Reactions with Lewis Acids
1247
3.19.5.4
C–C Bond-Forming Reactions by Zirconacycles – Acyclic Products
1249
3.19.5.5
Tandem Inter–Intra-Molecular Cyclizations of Zirconacycles
1251
3.19.5.6
Carbonylation Reactions of Titana- and Zirconacycles
1251
3.19.5.7
Cyclotrimerization and Other Coupling Reactions of Titana- and Zirconacycles on the Way to Carbocycles
1252
3.19.5.8
Coupling of Zirconacycles Leading to Fundamental Heterocycles
1253
3.19.5.9
Cycloaddition Reactions of Zirconaindenes
1255
3.19.5.10
Insertion Reactions of Metallacycles
1256
3.19.5.11
Intermolecular Coupling of Various Metallacycles
1256
3.19.5.12
Oxidative-Addition Reactions of Metallacycles
1259
3.19.5.13
Reactions of Zirconacycles with Phosphines
1260
3.19.6
Reactivity of Nonconjugated Rings
1261
3.19.6.1
Reactions with Lewis Acids
1261
3.19.6.2
Scope of Reactivity of Aluminacycles
1261
3.19.6.3
C–C Bond-Forming Reactions by Zirconacycles – Acyclic Products
1262
3.19.6.4
Tandem Inter–Intra-Molecular Cyclizations of Zirconacycles
1262
3.19.6.5
Carbonylation Reactions of Titana- and Zirconacycles
1263
3.19.6.6
Cyclotrimerization and Other Coupling Reactions of Titana- and Zirconacycles on the Way to Carbocycles
1263
3.19.6.7
Coupling of Zirconacycles Leading to Fundamental Heterocycles
1263
3.19.6.8
Insertion Reactions of Metallacycles
1263
3.19.6.9
Oxidative Addition Reactions of Metallacycles
1265
3.19.6.10
Reactions of Zirconacycles with Phosphines
1266
3.19.6.11
Decomposition and Rearrangement
1267
3.19.7
Reactivity of Substituents Attached to Ring Carbon Atoms
1267
3.19.8
Reactivity of Substituents Attached to Ring Heteroatoms
1267
3.19.9
Ring Synthesis from Acyclic Carbons Classified by Number of Ring Atoms Contributed by Each Component
3.19.9.1
1267
Intermolecular Coupling
3.19.9.1.1
1267
Magnesa- and aluminacycles
1267
1243
1244 Five-membered Rings with Other Elements 3.19.9.1.2 3.19.9.1.3 3.19.9.1.4 3.19.9.1.5
Titana-, zircona-, and hafnacycles Ferra-, ruthena-, and osmacycles Cobalta-, rhoda-, and iridacycles Nickela-, pallada-, and platinacycles
1268 1276 1281 1283
3.19.9.2
Reduction
1285
3.19.10
Ring Synthesis by Transformation of Another Ring
1285
3.19.10.1 3.19.10.2 3.19.11
Nucleophilic Attack on Coordinated Ligands
1285
Insertion
1286
Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available
3.19.11.1 3.19.11.2
Transmetalation Reaction Cyclometalation
1287 1287 1287
3.19.12
Important Compounds and Applications
1288
3.19.13
Further Developments
1290
References
1291
3.19.1 Introduction For the period since publication of CHEC-II(1996) <1996CHEC-II(2)933>, synthesis and reactivity of the heterocycles containing nontransition metals (magnesium, aluminium) and transition metal elements (groups IV–VIII) has very much developed, especially from the viewpoint of new synthetic methods and the appearance of a variety of new compounds. There have appeared attempts to classify synthetic methods, although the main method remains oxidative coupling. The major feature of the period is the extensive study of titana- and zirconacyclocumulenes from the synthetic, theoretical, chemical, and catalytic point of view. Such studies are ongoing. As before, metallafive-membered heterocycles remain attractive reagents for organic synthesis of numerous classes of organic compounds, including fundamental heterocycles, as well as attractive catalysts for organic transformations. Such compounds are quite often regarded as the models of intermediates of catalytic transformations mediated by transition metal complexes. There are rare but interesting examples of application of the compounds under consideration in modern materials chemistry, specifically as valuable inorganic polymers. Taking into account the modern state of affairs in the field of five-membered rings of other elements, we present in the following sections various synthetic methods, trends in reactivity, and catalytic applications. In the reactivity part, we give only a limited number of reaction equations and schemes because this work was covered thoroughly in CHEC-II(1996) <1996CHEC-II(2)933>. However, emphasis is given to new, and sometimes old, representatives of this family of heterocycles that were not described in CHEC(1984) or CHEC-II(1996). The following abbreviations for cyclopentadienyl derivatives have been used throughout the chapter: Cp (cyclopentadienyl), Cp* (pentamethylcyclopentadienyl), and Cp9 (variously substituted cyclopentadienyls).
3.19.2 Theoretical Methods A series of computations mainly using density functional theory (DFT) methods of 1-metallacyclopenta-2,3,4-trienes and 1-metallacyclopent-3-ynes are focused on consideration of the resonance forms as depicted in Equations (1) and (2), where M ¼ Ti, Zr and Cp9 ¼ variously substituted cyclopentadienes <1997AGE606, 1988JA125, 1998JA6952, 2001JOM(635)204, 2002OM2254, 2003OM3466, 2003OM4958, 2004JOC6357>. Open diyne and cumulene forms explain the enhanced stability of titana- and zirconacyclocumulenes and -alkynes. Computations point to rather strong p-interactions between metal center and double or triple bonds within a cycle and considerable p-delocalization within a cycle even in the case of metallacyclopentynes compared to the corresponding carbocycles.
ð1Þ
Five-membered Rings with Other Elements
ð2Þ
DFT methods have been applied to the reactions schematically shown in Equation (3) where L2M ¼ Cp2Zr, (MeO)2Zr, (Ph3P)Ni, and (Ph3P)Pt <2005OM2129>. The zirconium complexes enter this reaction readily and the driving force is the charge-transfer interaction between Zr(d p* ) and p* (CHUCH) orbitals. Due to the higher energy of d orbitals, nickel and platinum complexes react with difficulty overcoming a certain activation barrier, and the driving force of the C–C bond formation in this case is the charge-transfer interaction of the type: d(M)–p* –p* bonding couple of the two acetylene molecules. ð3Þ Cyclotrimerization of alkynes mediated by the cationic complex [(5-Cp)Ru(acetonitrile)3](PF6) was shown by the DFT methods to proceed via the ruthenacyclopentadiene intermediates in accord with experimental findings <2003JOM(682)204>. One illustration for the transformation of such an intermediate into the final product is illustrated in Equation (4).
ð4Þ
Electronic, geometric, energetic, and magnetic conventional criteria of aromaticity when applied to cobalta- and iridacyclopentadiene showed that these heterocycles are 6p-electronic and aromatic <2004JOM(689)1050>. However, there is controversy in the literature concerning the existence and extent of p-delocalization in metallacyclopentadienes, -trienes, and metallacyclopentynes, and more systematic theoretical computations are needed.
3.19.3 Experimental Structural Methods X-Ray structural determinations and nuclear magnetic resonance (NMR) studies have become versatile tools in the elucidation of the structure of the five-membered metallacycles. Structural and NMR patterns are comprehensively outlined in CHEC-II(1996) <1996CHEC-II(2)933>. Herein we occasionally refer when necessary to the results of structural studies in the reactivity and synthetic sections.
3.19.4 Thermodynamic Aspects Kinetic and mechanistic aspects prevail in the field. However, to the best of our knowledge, no systematic thermodynamic studies appeared during the period under review.
3.19.5 Reactivity of Fully Conjugated Rings 3.19.5.1 General Remarks Titana- <2000CRV2835> and zirconacycles <1999BCJ2591> including metallacyclopentanes, -pentenes, and pentadienes are useful reagents and catalysts in synthetic organic chemistry. Zirconacycles are used for the synthesis of carbocyclic and heterocyclic compounds <1986JOC4080, 1991JA165, 1991JA4685, 1994JOC7164, 1995JA2693, 1995T4291, 1998T7057, 1999JA8706>, in particular nitrogen <1994JOC5633, 1994JOC5643, 1998S552, 1998S557> and silicon <1997SL1371> heterocycles. Zirconacycles enter oxygenation, halogenation, and metathesis with SCl2, SOCl2, SiCl4, SnCl4, BRCl2, PRCl2, BiRCl2, or SbRCl2. They are also able to undergo carbonylation to yield cyclopentenones or
1245
1246 Five-membered Rings with Other Elements cyclopentadienones, tandem reactions including insertion of isocyanides and further reaction with alkenes or alkynes to alkenylcyclopentane or -cyclopentadiene amines, 1,1- and 1,2-additions to alkynes in the presence of copper(I) chloride to yield polysubstituted derivatives of cyclohexane or benzene, 1,1-addition reactions to acid chlorides, addition to 1,1-, 1,3-, or 1,4-dihalides, monohalogenation using Ph2PCl or R3SnCl, dihalogenation, addition of acid chlorides, enones, and allyl, aryl, or alkynyl halides in the presence of copper(I) chloride, insertion of lithium chloroallylides and then electrophilic reaction with aldehydes and ketones to yield various alkenols.
3.19.5.2 Complexation Nickelacyclopropene 1 on interaction with titano- and zirconocene derivatives form the nickel(0) 2-coordinated complexes 2 (MLn ¼ Ni(PPh3)2, R1 ¼ R2 ¼ But, Ph, M9 ¼ Ti, Zr) <1996AGE1112>. Less stable complexes can be prepared for metallacyclocumulenes 3 (R1 ¼ R2 ¼ Me3Si, M ¼ Ti, Zr, Cp9 ¼ Cp; R1 ¼ Ph, R2 ¼ Me3Si, M ¼ Ti, Zr, Cp9 ¼ Cp) <1995OM2961>. Titanacyclocumulenes 3 (M ¼ Ti, R1 ¼ R2 ¼ But, Ph, Cp9 ¼ Cp) can react with additional titanocene derivative to yield binuclear species 2 (MLn ¼ TiCp, M9 ¼ Ti, R1 ¼ R2 ¼ But, Ph), 4 (R1 ¼ R2 ¼ But, Ph) and subsequently 5 (R1 ¼ R2 ¼ But, Ph) <1992JOM(439)C36, 1995OM2961, 1996AGE1112>. Two titanacyclocumulenes, 3 (R1 ¼ R2 ¼ SiMe3, Cp9 ¼ Cp, M ¼ Ti) and 3 (R1 ¼ R2 ¼ But, Cp9 ¼ Cp, M ¼ Ti), undergo photocatalytic metathesis, forming 4 (M ¼ Ti, R1 ¼ SiMe3, R2 ¼ But) as the final product <1998AGE1915>. Bis(acetylides) of titanium and zirconium [(5-Cp2)M(CUCPh)2] (M ¼ Ti, Zr) react with vanadocene to yield the -2,4-complexes 2 (MLn ¼ VCp2, M9 ¼ Ti, R1 ¼ R2 ¼ Ph) <1998CEJ1100, 1999ACR494, 2000OM1901>. Bis(alkynyl)phosphines [RP(–CUCPh)2] react with derivatives of zirconocene to yield the products 6 <1997OM3086>. [(5-Cp)2ZrPh2] on reaction with 1,4-diphenyl1,3-butadiyne gives complex 7 via the zirconacyclopropene derivative 8 and then the zirconacyclopentadiene 9 <2000OM4463>. Zirconocene derivatives mediate the intermolecular coupling of the alkynyl groups in bis(alkynyl)silanes to yield 10 and then the bicyclic derivative 11 <1995JA2665, 1997JA12842>. Similar products have been prepared using tetrakis(alkynyl)silanes <2000OM1198> and tetraynes <1997AGE2615>. Some other similar compounds have been described <1997JOM(536)93, 2002CL1174, 2005OM20>.
Five-membered Rings with Other Elements
Titanacyclocumulene 3 (R1 ¼ R2 ¼ Ph, Cp9 ¼ Cp, M ¼ Ti), prepared from [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] and diphenylacetylene, on standing in toluene forms dinuclear complexes 12 (R ¼ Ph) and 13 <1999JOM(578)125>. The reaction of [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] with MeCUCCUCMe does not lead to an isolable titanacyclocumulene 3 (R1 ¼ R2 ¼ Me, Cp9 ¼ Cp, M ¼ Ti). The products are the dinuclear complex 4 (R1 ¼ R2 ¼ Me, M ¼ Ti), fused titanacyclopentene–titanacyclopentadiene complex 12 (R ¼ Me), and titanacyclopentadiene 14.
1-Zirconacyclopent-3-yne 15 (R ¼ H, M ¼ Zr, Cp9 ¼ Cp) reacts with [(5-Cp)2Zr(1-butene)(PMe3)] to yield the dinuclear complex 16 <2004JA60>. A similar complex exists with [Ni(PCy3)2] <2005OM456>. 1-Zirconacyclopent3-yne 15 (R ¼ H, M ¼ Zr, Cp9 ¼ Cp) with [L2Ni(2-C2H4)] (L ¼ PPh3, PCy3) in tetrahydrofuran (THF) forms the binuclear complexes 17 (L ¼ PPh3, PCy3) <2005OM3047>. 1-Zirconacyclopent-3-yne 15 (R ¼ H, M ¼ Zr, Cp9 ¼ Cp), when reacted with [(5-Cp)2ZrCl2] in THF in the presence of magnesium, or with [(5-Cp)2Zr(2CH2C(H)TEt)] in THF, thus in the absence of a stabilizing phosphine ligand, forms the bicyclic binuclear complex 18 (M ¼ Zr). 1-Titanacyclopent-3-yne 15 (R ¼ H, M ¼ Ti, Cp9 ¼ Cp) with [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] gives binuclear bicyclic complex 18 (M ¼ Ti) <2004CC2074>.
Sandwiches based on metallacyclopentadienes attract the attention of researchers and include sandwiches of the 18-valence electron species 19 (Cp9 ¼ Cp, R ¼ H, M ¼ Fe), 19-valence electron species 19 (Cp9 ¼ Cp, M ¼ Co, R ¼ H) <1986AJC1187, 1988JA4246, 1989OM1576, 1990JOM(391)247, 1990OM1106, 1991OM1002, 1993JCD487, 1994OM1129, 1994OM4214, 1995OM3817, 1997JOM(541)207, 1997OM2016, 2002CEJ1591>, and 16-electron species 19 (M ¼ Cr, Cp9 ¼ Cp* , R ¼ Me) <1992ICA(198)741>. Nickelocene, when reacted with 19 (M ¼ Fe, Cp9 ¼ Cp, R ¼ H), gives sandwich 20 <1985OM1594>. Nickelocene also reacts with phenyllithium and diphenylacetylene to yield 21 <1998JOM(566)217, 2000JOM(613)37>. Nickelocene when reduced with lithium in the presence of trans1,2-diphenylpropene in THF gives compound 22 (R ¼ Me), among other products <2005JOM(690)1523>. Reduction of nickelocene with sodium in the presence of triphenylethene forms 22 (R ¼ Ph).
3.19.5.3 Reactions with Lewis Acids Zirconacycle 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, M ¼ Zr, Cp9 ¼ Cp) reacts with B(C6F5)3 to yield the zwitterionic complex 24 via complex 25 <1996AGE80>. Zirconacycle 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, M ¼ Zr, Cp9 ¼ Cp) with HB(C6F5)2 reacts similarly to yield 26 through the step of 27 <2004JOM(689)1402>.
1247
1248 Five-membered Rings with Other Elements
Zirconacyclocumulenes 3 (R1 ¼ R2 ¼ SiMe3, Me, Ph, Cp9 ¼ Cp* , M ¼ Zr) enter CTC bond cleavage with Lewis acids <1992JOM(439)C36, 1993JA10394, 1994OM2903, 1995OM2961, 1997CCC331>. Zirconacyclocumulene 3 (R1 ¼ R2 ¼ SiMe3, M ¼ Zr, Cp9 ¼ Cp* ) with B(C6F5)3 undergoes cleavage of the central CTC bond to yield [(5Cp* )2Zr(–CUCSiMe3)2] <1997JOM(536)293, 1999JOM(578)125, 2000CC241, 2000JOM(598)243, 2001OM4072, 2003AGE1414, 2003JOM(670)84, 2004OM5188>. When R1 ¼ R2 ¼ Me, the reaction is completely different; the Lewis acid attacks the -carbon atom preserving the C4 moiety and forming the zwitterionic product 28. When R1 ¼ R2 ¼ Ph, attack occurs on the -carbon atom and the product in this case is 29 <2004OM4391, 2004OM5188>. In case of R1 ¼ R2 ¼ SiMe3, when But2AlH was used as the Lewis acid, the cycle is again cleaved to yield 30 <2004OM4160>. For R ¼ Me, the zirconacyclopentadiene complexes 31 and 32 are formed. Complex formation in the case of R1 ¼ R2 ¼ Ph is far more complicated and occurs in two steps forming first 33 and then 34.
Five-membered Rings with Other Elements
1-Titanacyclopent-3-yne 15 (R ¼ H, M ¼ Ti, Cp9 ¼ Cp) <2004CC2074, 2005OM791> with B(C6F5)3 forms zwitterionic complex 35 <2005OM5916>. 1-Zirconacyclopent-3-yne 36 reacts with B(C6F5)3 to yield zwitterionic complex 37. 1-Titanacyclopent-3-yne on interaction with BH3?SiMe2 forms 2,29-dititanabicyclo[2.2.0]hex-1(4)-ene 4 (M ¼ Ti, R1 ¼ R2 ¼ H). Titanacyclocumulene 3 (M ¼ Ti, R1 ¼ R2 ¼ But, Cp9 ¼ Cp) and B(C6FG5)3 also form the bicyclic complex 4 (M ¼ Ti, R1 ¼ R2 ¼ But).
3.19.5.4 C–C Bond-Forming Reactions by Zirconacycles – Acyclic Products Halogenolysis of zirconacycles leads to C4HnX2, organic dihalides (e.g., Equation 5) <1994ICA(220)319, 1994JA11797, 1996ICA(252)91, 1997TL4099, 1998CL517>. [NiX2(PPh3)2]- (X ¼ Cl, Br) and CuCl-mediated additions of enones, aryl, alkyl, and alkynyl halides gives rise to numerous acyclic hydrocarbons <1999AGE349, 1999BCJ2591, 2002T1107>. Reaction of zirconacyclopentadienes with molecular iodine, N-chloro- or N-bromosuccinimide results in oxidative cleavage of the zirconium–carbon bond <1997TL4099, 1998CC1931, 1998CL517, 1998T715>. Addition of a second equivalent of the halogenating agent gives dihalobutadienes and acidification gives monohalobutadienes: using copper(I) chloride tricyclic cyclobutadienes are formed, and using RCUCI dienenynes are formed. Zirconacyclopentadiene when reacted with 2 equiv of molecular iodine in the presence of copper(I) chloride gives the diiodinated diene compound (Equation 6) <2004ICC245>. This reaction can be interrupted at an earlier stage whereupon the monoiodinated cleaved zirconium-containing product is isolated.
ð5Þ
ð6Þ
With organic halides, dialkylation and formation of two new C–C bonds <1998CC1931, 2003SL183> or monoalkylation and formation of one new C–C bond <1995CC109, 1995T4407, 1997CC1599, 1997CL825, 1998T715> may occur. Thus, reaction of zirconacyclopentadienes 23 (R1 ¼ R2 ¼ Et, R3 ¼ R4 ¼ Ph, Cp9 ¼ Cp, M ¼ Zr; R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, Ph, Cp9 ¼ Cp, M ¼ Zr) and 38 (R ¼ n-C6H14, M ¼ Zr) with a variety of allyl halides, CH2TCHX–CH2Y (X ¼ Y ¼ Br; X ¼ COOEt, Y ¼ Br; X ¼ H, Y ¼ Cl), in the presence of copper(I) chloride gives monoallylation products 39 (X ¼ Br, R1 ¼ R2 ¼ Et, R3 ¼ R4 ¼ Ph; X ¼ Br, R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, Ph; X ¼ COOEt, H, R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, Ph; X ¼ Br, R1 ¼ R4 ¼ n-C6H13, R2 \ R3 ¼ (CH2)4) <2003SL183>. In the presence of lithium chloride, however, reaction of 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, Cp9 ¼ Cp, M ¼ Zr) leads to the diallylation product 40 <2004TL595>.
1249
1250 Five-membered Rings with Other Elements
Zirconacyclopentadienes with iodobenzenes form monophenylated dienes in a C–C bond-formation reaction <1996JA5154, 1997TL447>. Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Prn, M ¼ Zr, Cp9 ¼ Cp) react with various aryl iodides in the presence of copper(I) chloride and N,N9-dimethylpropyleneurea (DMPU) with subsequent (1) hydrolysis to give monoarylated dienes, (2) iodination to give iododiene derivatives, and (3) interaction with iodohexyne to yield dienyne derivatives (Equation 7). With 2-thienyl iodide, zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Prn, M ¼ Zr, Cp9 ¼ Cp) in the presence of CuCl and DMPU give thienyl-iododienes along with thienyldienes (Equation 8). In the presence of copper(I) chloride and N,N-dimethyl-n-propylurea, zirconacyclopentadienes are subjected to double alkynylation by alkynyl iodides <1997TL4103>. If only copper(I) chloride mediates the reaction, monoalkynylation occurs to yield iododiene derivatives <1998T715>.
ð7Þ
ð8Þ
Methyllithium treatment enhances the nucleophilicity of zirconacyclopentadienes <2004TL5159>. Thus, when zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Cp9 ¼ Cp, M ¼ Zr) reacts with benzaldehyde in the presence of methyllithium in an acidic medium, the product is PhOHCHC(Et)TC(Et)C(Et)TC(Et)H <2004TL9041>. A similar reaction occurs with methyl methacrylate in the presence of n-butyllithium in acidic medium and the product is MeOOCCHMeCH2C(Et)TC(Et)C(Et)TC(Et)H. When the electrophile is 1-bromobutyne, MeCUCCH2C(Et)TC(Et)C(Et)TC(Et)H is obtained. This methodology is illustrated in Equation (9).
ð9Þ
Five-membered Rings with Other Elements
3.19.5.5 Tandem Inter–Intra-Molecular Cyclizations of Zirconacycles Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Ph; R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ Bun, Ph; M ¼ Zr, Cp9 ¼ Cp), 38 (R ¼ Ph, M ¼ Zr), and others with ICHTCCOOR in the presence of CuCl give a series of pentasubstituted cyclopentadienes (Equation 10) <1998TL4321>. Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Ph; R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ Ph; M ¼ Zr, Cp9 ¼ Cp) with R5ICTCHCOOR/CuCl produce hexasubstituted cyclopentadienes. These reactions are thought to be a sequence of Zr/Cu transmetalation with ring opening and then crosscoupling–conjugate addition with cyclization.
ð10Þ
Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Prn, Bun, M ¼ Zr, Cp9 ¼ Cp) react with 1,4-dibromo-2butyne in the presence of CuCl via a tandem inter–intra-molecular cyclization to yield 2,3,4,5-tetrasubstituted styrenes (Equation 11) <2002T1107>. 3-Chloro-(2-chloromethyl)propene reacts with the same set of zirconacyclopentadienes in the presence of CuCl to yield tetrasubstituted methylene cycloheptadienes. Reaction with 3,4dichlorobutene under identical conditions yields vinylcyclohexadienes. In both cases, tandem inter–intra-molecular allylation occurs.
ð11Þ
3.19.5.6 Carbonylation Reactions of Titana- and Zirconacycles Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Bun, M ¼ Zr, Cp9 ¼ Cp) react with carbon monoxide and, after acidification, give a mixture of mainly cyclopentenones and cyclopentadienones <2003JOM(682)108>. In the same way, the reaction proceeds for zirconacycle 38 (R ¼ Et, M ¼ Zr) and zirconaindene (Equation 12). In the latter case, indanones and indenones are formed. Bicyclic titanacyclopentadienes on reaction with aldehydes give dialkenyl derivatives of cyclopentane. Reaction of zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, M ¼ Zr, Cp9 ¼ Cp) with butyraldehyde does not take place, but in the presence of aluminium chloride penta-n-propylcyclopentadiene is formed (Equation 13) <1999BCJ2591>. In this reaction, AlCl3, AlBr3, AlEtCl2, BF3, and Sc(OTf)3 can be used as the Lewis acid <2002CEJ4292>. Zirconacyclopentadienes react with diethyl ketomalonate in the presence of bismuth(III) chloride to yield oxacyclohexadienes <2002JA1144>. Use of a variety of aldehydes in this type of reaction allows the preparation of thienyl-tetra-n-butyl- and thienyl-tetra-n-propylcyclopentadienes and also phenyltetramethylcyclopentadiene <2000AGE2950, 2002CEJ4292>. Reaction of zirconatetrahydroindenes (Equation 14; R ¼ Prn, Ph, C4H3S) with aldehydes (R1 ¼ 2-C4H3S, Ph, 4-MeOC6H4, 4-ClC6H4, 4-MeC6H4) leads to a variety of tetrahydroindene derivatives, provided AlCl3 or BF3 are used as the mediators. A similar strategy was applied to the synthesis of a series of indenes.
ð12Þ
ð13Þ
1251
1252 Five-membered Rings with Other Elements
ð14Þ
3.19.5.7 Cyclotrimerization and Other Coupling Reactions of Titana- and Zirconacycles on the Way to Carbocycles Zirconacyclopentadienes of the type 23 in the presence of copper(I) chloride are able to react with a third alkyne containing an electron-withdrawing group R3, for example COOMe, and the cyclotrimerization product is the hexasubstituted benzene derivative (Equation 15) <1995CC361, 1998JA1672, 1999JA1119, 2001PAC271>. This type of reaction appears to be more general when, instead of copper(I) chloride, [NiX2(PPh3)2] (X ¼ Cl, Br) were used <1999JA11093, 2000JA12876, 2002JA5059>. In this situation, the nature of R1, R2, and R3 is not important. A series of hexasubstituted benzenes, including those with R1 ¼ Ph, R2 ¼ Me, R3 ¼ Prn; R1 ¼ Bun, R2 ¼ Me, R3 ¼ Et; R1 ¼ Prn, R2 ¼ Me, R3 ¼ Et, were prepared. Zirconacyclopentadienes with alkynyl halides in the presence of [NiCl2(PPh3)2] give polysubstituted arylalkynes <2000CL1410>. Titanacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, Et, Prn, M ¼ Ti, Cp9 ¼ Cp) react with MeO2CCUCCO2Me in the presence of copper(I) chloride under acidic conditions to yield linear trienes (Equation 16) <2001JOM(633)18>, which is in sharp contrast to zirconium analogues which form derivatives of benzene (Equation 17) <1998JA1672>. Zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, M ¼ Zr, Cp9 ¼ Cp) with 1-octynyllithium in THF after quenching the product mixture with hydrochloric acid gives 1-(n-hexyl)-2,3,4,5-tetraethylbenzene. A similar reaction of 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph) with diphenylacetylene is slower and along with 1-(nhexyl)-2,3,4,5-tetraphenybenzene, 1,2,3,4-tetraphenyl-1,3,5-dodecatriene is produced <2004T1345>. Zirconacyclic compound 23 (R1 ¼ Bun, R2 ¼ Me, R3 ¼ H, R4 ¼ SiMe3, M ¼ Zr, Cp9 ¼ Cp) was reacted with n-C6H13CUCLi to yield 1-trimethylsilyl-2-methyl-4-n-butyl-6-n-hexylbenzene.
ð15Þ
ð16Þ
ð17Þ
Several copper-mediated or copper-catalyzed reactions of zirconacyclopentadienes are known. Coupling with dihaloaromatic compounds allows preparation of fused aromatics <1996JA5154>. Intermolecular coupling of trisubstituted alkenes, alkynes, and isocyanates gives cyclopentenones <2001OM595> and cyclotetraenes <1999CC1543, 1999CC1595>. Tandem inter- and then intramolecular allylation leads to vinylcyclopentadienes and methylenecyclopentadienes <1997TL8355>. Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et; R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Et; R1 ¼ R4 ¼ Me3Si, R2 ¼ R3 ¼ Me; R1 ¼ R4 ¼ Et, Ph, R2 \ R3 ¼ (CH2)4; R1 ¼ R2 ¼ Et, R3 \ R4 ¼ CHTCHCHTCH) react with CH2TCHCHCl–CH2–CH2Cl or ClCH2CHTCHCH2Cl in the presence of CuCl to yield vinylcyclohexadienes (Equation 18) and with CH2TC(CH2Cl)CH2Cl to afford methylene cycloheptatrienes (Equation 19) <1997TL8355>. Both reactions are tandem intermolecular allylations of zirconacyclopentadienes. Intermolecular [4þ4] and [4þ5] coupling with bis(halomethyl)aromatic compounds gives rise to eight- and nine-membered
Five-membered Rings with Other Elements
derivatized cycles <1998OM3841>. Zirconacyclopentadienes react with various 3-iodopropenoates in the presence of copper(I) chloride via Michael addition and coupling to yield penta- and hexadienes, and, in the case of 3-iodocycloenones, spirocyclic cyclopentadienes <2000JOC945>. Reaction with 1,1-dihalo compounds and enones gives cyclopentadienes, spirocycles <2000JOC945>, and benzocycloheptenes <2000OL1197>. Zirconacyclopentadienes react with propargyl halides in the presence of copper(I) chloride to yield derivatives of benzene <1999CCC1119>. Zirconacyclopentadiene 39 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Cp9 ¼ Cp, M ¼ Zr) with 3-chloro-1lithioprop-1-yne in an acidic medium gives 1-methyl-2,3,4,5-tetraethylbenzene <1997CC1321>. Pentasubstituted benzenes are formed from tetrasubstituted zirconacyclopentadienes and LiCUCR in acidic medium <2000CL218, B-2002MI86, 2004T1345, 2004TL9041>.
ð18Þ
ð19Þ
Cyclopentadienes can be prepared by double Michael addition of zirconacyclopentadienes with propynoates <1997CC2069> or nucleophilic attack of zirconacyclopentadienes on acyl halides mediated by copper(I) chloride and accompanied by elimination <1995CC1503, 1996TL7521>. Tetraethylzirconacyclopentadiene with benzal chloride in THF in the presence of copper(I) chloride and DMPU yield 1,2,3,4-tetraethyl-5-phenylcyclopenta-1,3diene <2000TL7471>. A series of other similar compounds were prepared from tetra-n-propylzirconacyclopentadiene and ,-dichlorotoluene, tetra-n-butylzirconacyclopentadiene and ,-dichlorotoluene or ,-dibromotoluene, as well as some other combinations. Tetraethylzirconacyclopentadiene reacts with 1,1-dibromo-1-alkene-3-ynes under the same conditions (copper(I) chloride and DMPU) to yield alkynylfulvenes.
3.19.5.8 Coupling of Zirconacycles Leading to Fundamental Heterocycles Interaction of zirconacycles with ACl2 (A ¼ S, SO, Se, PR, BiR, SbR, SnCl2, SnR2, SiCl2, GeCl2, BR, AlR, GaCl, InCl) is a metathesis reaction leading to five-membered heterocycles <1998CCR(178)145, 1998JOM(564)61, 1998TL2787, 1999CL1127, 1999JA9744, 1999OM4205, 2000AGE314, 2000JOM(595)261, 2000OM3469, 2000T121, 2001CEJ4222>. Siloles are made from zirconacyclopentadienes and silicon dihalides <1999CL1127>, in particular with RHSiCl2, germoles, and stannoles (by reaction of zirconacyclopentadienes with R2GeCl2 and R2SnCl2) <1998TL2787, 2000H(52)1171>. Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Me; M ¼ Zr, Cp9 ¼ Cp) react with R2SnCl2 (R ¼ Me, Ph) in the presence of CuCl in THF to yield the corresponding stannoles (e.g., Equation 20) <1998TL2787>. The CuCl-catalyzed reaction of zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, M ¼ Zr, Cp9 ¼ Cp) with tin tetrachloride gives a spiro stannacyclopentadiene (Equation 21). A macrocyclic zirconacyclopentadiene when reacted with S2Cl2 gives the corresponding trithiophene (Equation 22) <2003JOM(666)15>. Reaction of the same macrocycle with germanium tetrachloride gives trigermoles.
ð20Þ
1253
1254 Five-membered Rings with Other Elements
ð21Þ
ð22Þ
In a sequence of reactions, iodination of zirconacyclopentadienes to yield open-chain diiododienes, then lithiation with n-BuLi to afford dilithiodienes, and finally reaction with R2SiCl2 gives silacyclopentadienes <1994OM4067, 1995JOM(499)C7, 1996JA10457>. The synthetic difficulty of formation of monoiododienes along with the desired diiododienes can be overcome by applying copper(I) chloride as the catalyst of the corresponding preparative step <1997TL4099> and using ICl instead of I2. Thus zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph; R1 \ R2 ¼ CHTCHCHTCH, R3 ¼ R4 ¼ Me) after a complete cycle produce siloles 41 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph; R1 \ R2 ¼ CHTCHCHTCH, R3 ¼ R4 ¼ Me) with Me2SiCl2 at the final stage, and 23 (R1 \ R2 ¼ CHTCHCHTCH, R3 ¼ R4 ¼ Me) with MCl4 (M ¼ Si, Ge) gives spirocompounds 42 (M ¼ Si, Ge).
Zirconacyclopentadienes enter coupling reactions with 2,3-dihalopyridines to yield 5,6,7,8-tetrasubstituted derivatives of quinoline, while 3,4-dihalopyridines give 5,6,7,8-tetrasubstituted isoquinolines <2000JA4994, 2002JA576, 2004JOC4559>. 1,2-Di(2-hexynyl)-3,4,5,6-tetra-n-propyl benzene enters into a zirconacyclopentadiene-mediated reaction with PCl3 to yield a P-chlorophosphole from which the corresponding 1,19-diphosphaferrocene can be prepared <2007JOM(692)55>. Sulfur dioxide reacts with various zirconacyclopentadienes to yield thiophene 1-oxides <1999JA9744, 2000AGE2870>. Nitrosobenzene undergoes a Zr–C insertion reaction with zirconacyclopentadienes affording pyrroles via intermediates 43 <2000OL2283, 2001JA2074>, for example, R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me <2001OM5515>. The derivative with R1 ¼ R4 ¼ Me3Si, R2 ¼ R3 ¼ H <1991JOM(409)179> does not undergo this reaction <2001OM5515>. However, annulated zirconacyclopentadienes produce annulated pyrroles. For compound 44 (R ¼ Me), the insertion route is the same and the product is a tetrahydroisoindole derivative. In the case of 38 (M ¼ Zr, R ¼ Me), the route is different, and occurs via 45 to produce the indole derivative 46.
Five-membered Rings with Other Elements
Pyridine derivatives are obtained by the successive interaction of an alkyne to give zirconacyclopentadiene, then with benzonitrile azazirconacyclopentadiene follows. After transmetalation using [NiCl2(PPh3)2], azanickelacyclopentadiene is formed which reacts with another alkyne to yield pyridine derivatives <2002JA5059>.
3.19.5.9 Cycloaddition Reactions of Zirconaindenes 2-Phosphino-1-zirconaindene 47 (R ¼ Ph) <1997CC279> reacts with dimethyl acetylenedicarboxylate, methyl propiolate, and 3-butyn-2-one to yield zwitterionic complexes 48 (R ¼ OMe, R1 ¼ COOMe, H) <1998JA3504, 2000OM54>. With a variety of heterocumulenes (CO2, CS2, CyNTCTNCy, RNTCTS (R ¼ Ph, But), RNTCTO (R ¼ Ph, Me)), it yields the zwitterionic products 49 (X ¼ Y ¼ O; X ¼ Y ¼ S; X ¼ Y ¼ NCy; X ¼ NR (R ¼ Ph, But), Y ¼ O; X ¼ NR (R ¼ Ph, Me), Y ¼ S) via nucleophilic attack by the phosphine group with subsequent cyclization <1999OM1882>. Cycloaddition of phenyl isothiocyanate on compound 50 <1996OM5436> proceeds similarly to give the zwitterionic product 51, while with carbon disulfide the dimer 52 results <1999OM1882>. A similar pattern is known for the reactions of 47 (R ¼ Ph) with aldehydes <1999OM1580>. 2-Phosphino-1-zirconaindene enters [3þ2] cycloaddition with various aldehydes RCHO to yield the zwitterionic complexes 53 (R ¼ Ph, o-PPh2C6H4, HCTCH(Me), Fc, and other complex substituents). With polyaldehydes, dendrimers and multidendrimers form. With PhCUCC(O)H, the product is complex 54 <2000OM54>, and with EtOCUCH the species 55 is formed. Zirconacycloindenes 47 (R ¼ Ph, Et) with R2PCUCH (R ¼ Ph, Et) gives the products 56 (R ¼ Et, Ph). The main product of interaction of 47 (R ¼ Ph) with Ph2P(S)CUCH is 57 and with Ph2PCUCH it is 58. With heterosubstituted propargyl derivatives HCUCCH2X (X ¼ OMe, OCH2CUCH, NMe2), the products are 59 (X ¼ OMe, OCH2CUCH, NMe2).
1255
1256 Five-membered Rings with Other Elements
3.19.5.10 Insertion Reactions of Metallacycles Zirconacyclopentadienes with PhNO in the presence of Lewis acids give N-phenylpyrroles <2001OM5515>. Isonitriles <1988CRV1047, 1988TL1631, 2001OM4122> and PhNO <2001OM5515> insert into the Zr–C bond of zirconacyclopentadienes to yield seven-membered zirconacycles. Isocyanides insert into the Zr–C bond of zirconacyclopentadienes to afford cyclic imines <1997JA11086>. Insertion of isonitriles along with alkynes followed by acidification gives alkenylaminocyclopentanes, -pentenes, or -pentadienes <1995TL4113>. Zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph, M ¼ Zr, Cp9 ¼ Cp) inserts carbon monoxide to yield 60 <1997JCD3087>. Zirconacyclopentadienes when reacted with carbon monoxide in the presence of n-butyllithium form cyclopentadienyloxazirconocene anionic derivatives 61 <1999JA1094, B-2002MI50>.
Ring expansion of zirconacyclopentadienes to zirconacyclohexadienes has been described <2000CL218, 2000T2113>. Reaction of zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, Prn, M ¼ Zr, Cp9 ¼ Cp) with chloro(trimethylsilyl)methyllithium leads to zirconacyclohexadienes (Equation 23). The latter with PCl3 give phosphinines via a metathesis route (Equation 23) <2004TL7633>. Zirconacyclopentadiene 23 (R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Me, M ¼ Zr, Cp9 ¼ Cp) inserts chloro(trimethylsilyl)methyllithium into the side adjacent to the methyl group and the resultant cyclohexadiene reacts with PCl3 to yield the corresponding phosphinine.
ð23Þ
3.19.5.11 Intermolecular Coupling of Various Metallacycles Titanacyclocumulenes 3 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, Ph, Cp9 ¼ Cp, M ¼ Ti; R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph, Cp9 ¼ MeC5H4, M ¼ Ti) form an equilibrium mixture with titanacyclopropenes 62 <1997JOM(536)293, 1999JA8313, 1999JOM(578)125, 2000CEJ81, 2000JA6317>. These coexisting species tend to intermolecularly couple with each other in two ways, either via insertion of the internal double bond of a titanacyclopentadiene into a Ti–C bond of 62 to yield the annulated species 12, or by dimerization to form 13. The interaction of the same two species (R ¼ Ph, Cp9 ¼ Cp) but in the presence of acetone or water leads to products 63 and 64, respectively <1997JOM(536)293>, while the zirconium couple (R ¼ Ph, Cp9 ¼ Cp, M ¼ Zr) in the presence of PhCUCLi gives the anionic species 65 <2000CC1511>. Another coupling reaction is the reaction of half-sandwiches 66 (R ¼ But, SiMe3) with carbon dioxide to give product 67 <2002OM1512>. Zirconacyclocumulene 3 (R1 ¼ R2 ¼ SiMe3, Cp9 ¼ Cp* , M ¼ Zr) inserts 2 equiv of carbon dioxide to yield product 68, while compound 3 (R1 ¼ R2 ¼ SiMe2But) adds 1 equiv to yield product 69 <1999JA8313>.
Five-membered Rings with Other Elements
Iridacyclopentadienes react with terminal alkynes <1989JA4129, 1990JA9013, 1992TL7119, 1994JOM(468)257, 1994OM1165, 1995CC1209, 1995CC1495, 1995JA8861, 1997OM816>. Thus complex 70 reacts with 3-butyn-1-ol to give the carbene 71 <1987JA7578>. Iridacyclopentadiene 72 reacts with 3-butyn-1-ol to yield the p-allyl species 73 <1997JA3631>. Iridacyclopentadiene 74 reacts with bis(2-diphenylphosphinomethyl)phenylphosphine to give 75 <2001OM1482>. Species 75 when treated with silver tetrafluoroborate in methylene chloride gives the cationic complex 76 (S ¼ CH2Cl2). Under carbon monoxide, complex 77 is formed. With 3-butyn-1-ol, in contrast to the reaction with 72, the oxapentylidene carbene complex 78 forms.
1257
1258 Five-membered Rings with Other Elements
Iridacyclopentadienes 79 (R ¼ Ph, p-Tol, H, Me) on reaction with alkynes in the presence of a protonating agent in acetonitrile produce iridabenzenes by a C–C bond-forming reaction <2004CEJ4518>. (2-Acetato)iridacyclopentadiene 80 reacts with alkynes RCUCH (R ¼ Ph, p-Tol) to produce a variety of iridabenzenes via cis-(alkynyl)(but-1,3-dien-1yl)iridiums, which are protonated <2005OM4849>.
Iridacyclopentadienes tend to be the intermediates of [2þ2þ1] cyclotrimerization of alkynes leading finally to iridabenzenes <2004CEJ4518>. Iridacyclopentadienes 81 (R ¼ COOMe) <2004JA1610> and 81 (R ¼ H)
Five-membered Rings with Other Elements
<2006AGE474> react with ethane to yield allyl complexes 82 (R ¼ H, COOMe) by insertion into the Ir–C bond. Propene inserts into an Ir–C bond of compound 81 (R ¼ COOMe) in deuterochloroform at room temperature to yield 83, whereas in methylene chloride at elevated temperatures iridabenzene 84 (R ¼ COOMe, R1 ¼ Et, R2 ¼ H) is the product. This process may involve isomerizations of propene to propylidene followed by insertion and -hydride elimination. Compound 81 (R ¼ H) reacts differently and forms iridabenzene 84 (R ¼ H, R1 ¼ Me) in methylene chloride both at room and moderate temperatures. The process additionally might involve migration of the alkenyl carbon.
Osmacyclopentatriene 85 on reaction with ButNH2 gives rise to an osmahexatriene complex by 1,2-hydrogen shift within one of two carbene moieties <1992JA7609>.
3.19.5.12 Oxidative-Addition Reactions of Metallacycles Palladacyclopentadienes containing bis(nitrogen) ligands 86 oxidatively add organic halides to give 87 (R ¼ Me, Et; X ¼ Br, I) and as a result of reductive elimination form 1,3-dienyl complexes with formation of a new C–C bond <1991JMO(65)L13, 1992OM1999, 1993CC1203, 1994JA977, 1994T323, 1999AGE3715>. Palladacyclopentadienes
1259
1260 Five-membered Rings with Other Elements 88–90 <1997AGE1743, 1998OM1812> when reacted with halogens (Cl2, Br2, I2) give rise to 1,4-dihalo-1,2,3,4tetrakis(carbomethoxy)-1,3-butadienes <2003OM722>.
3.19.5.13 Reactions of Zirconacycles with Phosphines Zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, Cp9 ¼ Cp, M ¼ Zr) does not react with chlorodiphenylphosphine <2002OM1383>. However, in the presence of copper(I) chloride, the reaction of 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, Ph, Cp9 ¼ Cp, M ¼ Zr) proceeds through the stage of transmetalated complex 91 to give valuable diphosphine ligands, such as 1,4-bis-(diphenylphosphino)-1,2,3,4-tetraphenyl (or -methyl)-1,3-butadiene. The annulated zirconacyclopentadienes 92 (R ¼ Et, Ph) interact with copper(I) chloride/chlorodiphenylphosphine to yield through the transmetalation stage 1,2-bis(1-(diphenylphosphino)benzylidene)cyclohexane and 1,2-bis(1-(diphenylphosphino)prop-1-ylidene)cyclohexane. Zirconacyclocumulenes 3 (R1 ¼ R2 ¼ Me, Ph, M ¼ Zr, Cp9 ¼ Cp) react with PCl3 in THF to give the addition products 93 (R ¼ Me, Ph, n ¼ 0) <2005OM4742>. With PhPCl2, species 93 (R ¼ Me, Ph, n ¼ 1) result, and with Ph2PCl compounds 93 (R ¼ Me, Ph, n ¼ 2) are the products. Other addition reactions to zirconacyclocumulene complexes are known <1997JOM(536)293, 2001OM2859>.
1,4-Diphosphino-1,3-butadienes follow from the reaction of zirconacyclopentadienes with Ph2PCl in the presence of copper(I) chloride <2001JA5110>. Phospholes follow from zirconacyclopentadienes and PhPCl2 <1998CCR(178)145>. A one-pot synthesis of symmetrical phospholes from zirconacyclopentadienes and RPCl2 has been elaborated <1997MM5566, 1999CC345, 1999OM3558>. Zirconacyclopentadienes 23 (R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Me, Et, Prn, M ¼ Zr, Cp9 ¼ Cp) on reaction with PhPCl2 produce unsymmetrical phospholes <2000JOM(595)261>.
Five-membered Rings with Other Elements
3.19.6 Reactivity of Nonconjugated Rings 3.19.6.1 Reactions with Lewis Acids Zirconacyclopentenes with B(C6F5)3 give zwitterionic complexes of the type 94 <1997JA11165, 2001ACR309, 2004JOM(689)4305>. Zirconacyclopentanes also form zwitterionic complexes <1999OM3094>.
3.19.6.2 Scope of Reactivity of Aluminacycles Aluminacyclopentanes and aluminacyclopentenes have been employed in the synthesis of cyclobutanes <1989BAU1981, 1994RCB252>, cyclopropenes (Equation 24; R ¼ Bun, n-C6H13, n-C9H19) <1990BAU1071, 2000RCB1086, 2001JOM(636)76, 2001RCB1465>, thiophanes and selenophanes <1989BAU1324, 1994RCB255>. Aluminacyclopentanes react with carboxylic esters in the presence of copper(I) chloride to yield cyclopentanols (Equation 25; R ¼ Bun, n-C6H13, Cy, CH2Ph; R1 ¼ H, Me, Et; R2 ¼ Alk) <2004T1281>. Aluminacyclopentanes with R ¼ Bun, n-C6H13 react with methyl formate in the presence of CuCl to give differently substituted cyclopentanols. Aluminacyclopentanes with thionyl chloride give 3-alkyltetrahydrothiophenes (Equation 26; R ¼ Bun, n-C6H13, Cy, CH2Ph). Aluminacyclopentanes interact with thionyl chloride to afford 3,4-dialkyltetrahydrothiophenes (Equation 27; R ¼ Me2CH(CH2)2, PhCH2, Cy), with dichlorophenylphosphine to yield phospholanes, and with dichloromethylvinylsilane to form silacyclopentanes. Reaction of aluminacyclopentenes with CO2 or ClCOOEt gives cyclopentenones: with BunLi and paraformaldehyde followed by protonolysis they give alkenols, and with BunLi and BrCH2OMe they give alkenylcyclopropanes (Equation 28; R ¼ R1 ¼ Bun, Prn; R ¼ Me, R1 ¼ Ph) <1998TL2503>. Aluminacyclopentadienes react with aldehydes by the route of deoxygenation of carbonyl groups from the latter and formation of multisubstituted cyclopentadienes <2003T3779>.
ð24Þ
ð25Þ
ð26Þ
1261
1262 Five-membered Rings with Other Elements
ð27Þ
ð28Þ
3.19.6.3 C–C Bond-Forming Reactions by Zirconacycles – Acyclic Products Zirconacyclopentenes 95 (R1 ¼ ButMe2Si, H, R2 ¼ SiMe3) are intermediates on the way to homoallylic ethers or alcohols. Zirconacyclopentene 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Zr) with 2 equiv of an aldehyde in the presence of AlCl3 gives homoallylketones and alcohols <2002CC142, 2003JOC4355>.
3.19.6.4 Tandem Inter–Intra-Molecular Cyclizations of Zirconacycles Bromination of zirconacycle 97 gives 1,2-bromomethylcyclopentane <1994JA9457>. Protonolysis of zirconacyclopentenes 95 (R1 ¼ ButMe2Si, R2 ¼ SiMe3, SMe; R1 ¼ H, R2 ¼ SiMe3) with acetic acid leads to alkylidene cyclohexanes <1995T4421>. Zirconacyclopentenes 98 (R ¼ ButMe2SiO, OH, CONEt2, CH2NEt2) are intermediates on the way to alkylidene cyclopentanes.
Zirconacyclopentenes 96 (R1 ¼ R2 ¼ Prn, Ph, R3 ¼ R4 ¼ H, M ¼ Zr) with 3,4-dichlorobutene in the presence of CuCl give 1,2-disubstituted-4-vinylcyclohexenes. Zirconacyclopentanes 99 (R ¼ H, Me) give vinylated bicyclic compounds, that is, 3,4-diethyl-8-vinylbicyclo[4.4.0]deca-3-enes.
Five-membered Rings with Other Elements
3.19.6.5 Carbonylation Reactions of Titana- and Zirconacycles Zirconacycle 100 on carbonylation with CO/acetic acid and then carbomethoxylation with methyl carbonate/NaH gives the bicyclic ketone 2-methoxycarbonylcycloindan-1-one <1997JA22>. Carbonylation of zirconacyclopentadienes leads to the five-membered carbocyclic ketones or alcohols <1997CEJ1324, 1997T9123, 1999JA1094>. Carbon monoxide reacts with metallacyclic compounds by insertion and results in a variety of cyclic ketones <1988CRV1081>. Insertion of carbon monoxide to titana- and zirconacyclopentenes gives bicyclic cyclopentenones <1988CRV1047, 1991JA7424, 1992TL1543>. Insertion of carbon monoxide into titanacyclopentene 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Ti) gives monocyclic ,-disubstituted cyclopentenones. In the case of a similar reaction of zirconacyclopentenes, additional treatment of the reaction mixture with I2 is a necessary condition <1987JA2544>. Bicyclic titanacyclopentanes upon hydrolysis give cyclopentane derivatives <1995TL4261, 1999PAC1511>.
3.19.6.6 Cyclotrimerization and Other Coupling Reactions of Titana- and Zirconacycles on the Way to Carbocycles The reaction of zirconacyclopentenes 96 (R1 ¼ R2 ¼ Me, Et, Prn, R3 ¼ R4 ¼ H, M ¼ Zr) with LiCUCR3 (R3 ¼ Et, Ph) is a migratory insertion yielding species 101 (R ¼ Cp, alkynyl, R1 ¼ R2 ¼ Me, Et, Prn, R3 ¼ Et, Ph) <1999JA11223>.
3.19.6.7 Coupling of Zirconacycles Leading to Fundamental Heterocycles Zirconacyclopentene 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Zr) with 2 equiv of an aldehyde in the presence of copper chloride gives THF derivatives (Equation 29; R ¼ Ph, 2,4,6-Me3C6H2) <2003TL6895, 2004T1417>.
ð29Þ
3.19.6.8 Insertion Reactions of Metallacycles Zirconacyclopent-3-ene reacts with nitriles (R–CUN; R ¼ But, CH2Ph) in stages, first forming the product of insertion 102 (R ¼ But, CH2Ph) and then the ring-expansion product 103 (R ¼ But, CH2Ph) <1993JOC6771, 1993OM1921>. Boron and aluminium agents lead to similar products <1992OM4174, 1994CB805, 1995AGE1755>. Zirconacyclopentenes 96 (R1 ¼ R2 ¼ Et, Prn, Ph, R3 ¼ R4 ¼ H, M ¼ Zr) react with isocyanates R1–NTCTO (R1 ¼ Ph, CH2Ph, Bun) to give oxa- and azazirconacyclopentenes. On addition of I2, N-bromo-, N-chlorosuccinimide (NCS), or NCS in the presence of copper(I) chloride, haloimidation of alkynes takes place to yield amides of haloalkenoic acids <2004T1393>. Zirconacyclopentadiene 104 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, M ¼ Zr) with PhNTCTO gives the product of cyclotrimerization, that is, triphenylisocyanurate.
1263
1264 Five-membered Rings with Other Elements
Insertion of the carbenoids Li(Cl)CTC(R1)(R2) or LiCARCl (A ¼ OR, SR, SiR3, P(O)(OR)2, CN, Ar, CUCR, Alk) is a ring-expansion reaction leading to various derivatized zirconacyclohexanes <1997CC1045, 1997CC1321, 1997PAC633>. Another reaction is catalytic cyclomagnesiation of zirconacyclopentanes <1994JOC4542, 1995H(40)551>. Zirconacycle 105 (R ¼ H) inserts lithium chloroallylide into the zirconium–carbon bond. Further reaction with benzaldehyde gives insertion products: 5-(2-methylenecyclopentyl)-1-phenyl-3-penten-1-ol and 5-(2methylcyclopentylidene)-1-phenyl-3-penten-1-ol. Insertion of lithium chloromethallide and further protonation using glacial acetic acid gives 3-ethyl-1,1-bis(methoxymethyl)-4-(3-methyl-2-butenylidene) cyclopentane <2000T2113, 2004T1269>. Insertion into zirconacycles 106 <1994JOC4993> and 107 gives 1-benzyl-3-methyl-4-(2-methyl-1propenyl)-octahydro-1H-indole and 1,1-bis(methoxymethyl)-3-(methyloctahydro-1H-inden-4-yl)-1-phenyl-3-buten-1-ol, respectively <2000T2113>. Zirconacycles can insert the carbenoids ALiCl (A ¼ H, Alk, SiR3, OEt, SPh, CN, P(O)(OEt)2, SO2Ph) to yield six-membered zirconacycles with the substituent A adjacent to the zirconium heteroatom . Ring expansion of zirconacyclopentadienes to zirconacyclohexadienes has been reported <2000CL218, 2000T2113>. Zirconacyclopentane 108 (R ¼ H) with PCl3, after some manipulations, gives the corresponding phosphinine.
Zirconacyclopentane 108 (R ¼ H) inserts LiCH2Cl in THF solution to yield the cyclopentyl iodide <2004T1401> followed by the ring opening, which is not a new process for the reaction of zirconacyclopentanes with alkyllithium species <1996CC963>. Compound 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Zr) on reaction with LiCH2Cl undergoes ring expansion to yield zirconacyclohexane 109, which is further converted by NaHCO3 into methylethylcyclopentane and dimethylcyclopentane <2004T1401>. Zirconacyclopentene 105 (R ¼ Bun) undergoes insertion of Me3SiCH2Cl in the presence of lithium diisopropylamide (LDA) followed by MeOH/NaHCO3 to give alkenylcyclopentadiene; insertion proceeds into the zirconium–alkyl bond. Insertion of lithium chloroallylides followed by an electrophilic reaction with aldehydes and ketones yields various alkenols <1995SL77, 1995TL4109, 1996TL7661, 1998TL123>.
Small unsaturated molecules often insert into the M–C bonds and cause expansion of metallacycles. The mechanism of the process is often described as migratory insertion when the reagent is first coordinated by the metal center and then enters further intramolecular reactions <1994JA12117, 1995RTC73, 1996CCR(155)209>.
Five-membered Rings with Other Elements
Thus, insertion of CO into complex 110 proceeds through the intermediate 111 and results in fused cyclopentenones <1994OM1728>. Nickelacyclopentene 110 with acetylenes RCUCR1 (R ¼ R1 ¼ H, Ph, p-C6H4Me, COOMe; R ¼ H, R1 ¼ CH2CH2OH, CH(OH)Et, Ph, But, COOMe; R ¼ Me, R1 ¼ CH2OH, Ph, COOMe; R ¼ CH2OH, R1 ¼ Ph) and benzyne produces dihydronaphthalenes and phenanthrene <1993OM4032>. Compound 110 inserts CS2 to yield the 1,1-dithiolate complex <1983IC415>. Insertion of sulfur dioxide into 112 gives product 113 <1994JOM(484)53>. Dinitrogen monoxide (N2O) reacts with nickelacyclopentane 114 and the oxygen atom inserts into the Ni–C bond accompanied by ring expansion and formation of the nickelacycle 115 <1998OM2924>. Nickelacyclopentene 116 reacts with [(Me3P)ClNi(3-xylyl)] carbene complex via the route of -hydrogen abstraction through the stage of an alkylidene-bridged dinuclear complex 117, which with trimethylphosphine is transformed to the phosphonium cation 118 <1991CC149, 1993OM4431, 1994G341>. Carbon monoxide may insert from the side of the sp3-carbon of nickelacyclopentene to yield oxanickelacycloheptene, which hydrolyzes to carboxylic acids and carboxylation products <2005TL5173, 2006T7589>.
3.19.6.9 Oxidative Addition Reactions of Metallacycles Electrophilic attack on metallacycles is exemplified by the oxidative addition of molecular iodine on platinacyclopentanes 119 and 120 (L2 ¼ bis(diphenylphosphino)methene (dppm), 2,29-bipyridine (bpy)). It gives platinum(IV) complexes 121 and 122 (L2 ¼ dppm, R ¼ Me; L2 ¼ bpy, R ¼ Et) <1997CRV1735, 1998JOM(568)53>. Palladium metallacycle 123 adds various organyl halides to yield 124 (R ¼ Me, X ¼ I; R ¼ CH2TCHCH2, X ¼ Br; R ¼ O2NC6H4CH2, X ¼ Br) <1988JOM(346)C27, 1990JOM(390)251, 1993JOM(458)C12>. A similar reaction of palladacyclopentanes 125 gives a series of derivatives 126 (R ¼ PhCH2, PhCOCH2, PhCHTCHCH2, CH2TCHCH2, X ¼ Br; R ¼ Me, Et, CF3, X ¼ I) <1998OM2046>. Palladacyclopentane based on pyrazol-1-yl borate ligand 127 reacts with: (1) halogens (Br2, I2) or PhCICl2 to yield 128 (X ¼ Cl, Br, I); (2) RX to yield 128 (X ¼ Me, Et, PhCH2, CH2CHTCH2); and (3) H2O to yield 128 (X ¼ OH) <1995JOM(490)C18, 1995OM199, 1996OM5713, 1997OM5331>. The reaction of palladacyclopentene 129 (L ¼ PY3, Y ¼ Me, Ph) with alkyl halides goes via -C–C cleavage to yield the doubly alkylated products 130 (L ¼ PY3, Y ¼ Me, Ph, X ¼ Br, I, R ¼ Me, Et) <1994AGE2421>. Interaction of the perfluorocyclopentane derivative of nickel 131 with boron trifluoride proceeds in two stages and gives first 132 and then 133 <1988OM1642>.
1265
1266 Five-membered Rings with Other Elements
3.19.6.10 Reactions of Zirconacycles with Phosphines Zirconacyclopentanes and -pentenes <1989TL3495, 1993TL687> react with chlorodiphenylphosphine by activation of the Zr–C bond to yield alkylphosphines and homoallylic phosphines, respectively <1996ICA(252)91, 1996TL3109, 1998JOM(564)61>.
Five-membered Rings with Other Elements
The alkynylphosphine BunCUCPPh2 with [(5-Cp)2ZrEt2] gives the zirconacyclopentene 134 (R ¼ Bun), which on acidification gives the alkenyl (diphenyl) phosphine <2004TL2427>. Species 134 (R ¼ Bun), when treated with 1 equiv of iodine, followed by acidification, gives a mixture of alkenylphosphine and monoiodinated alkenylphosphine oxide. With 2 equiv of iodine under the same conditions, only the iodoalkenylphosphine oxide is formed. With 4 equiv of I2, iodo- and diiodophosphine oxides are formed in a mixture. With 6 equiv of I2, only the diiodo product is formed, which is also the case for 2 equiv of molecular iodine in the presence of copper(I) chloride. Zirconacyclopentenes 134 (R ¼ Bun, Ph) when treated with RCUCR1 (R ¼ Bun, R1 ¼ Et, Bun; R ¼ Ph, R1 ¼ Et, Prn, Ph) yield zirconacyclopentadienes 135 (R ¼ Bun, R1 ¼ Et, Bun; R ¼ Ph, R1 ¼ Et, Prn, Ph), which on acidification produce trans-1,3-butadienyl diphenylphosphines. Zirconacyclopentadiene 135 (R ¼ Bun, R1 ¼ Et) was reacted with various amounts of iodine and the resultant mixture was acidified. With 1 equiv, dienylphosphine oxide and iododiphenylphosphine oxide resulted, but with 2 and 4 equiv only the monoiodinated compound was produced. With 2 equiv but in the presence of copper(I) chloride, the diiodo dienylphosphine oxide formed.
3.19.6.11 Decomposition and Rearrangement Pallada(IV)cyclopentanes decompose into alkanes and alkenes via Pd(II)–n-alkyl intermediates by -elimination <1994OM3517, 1995JOM(500)337>.
3.19.7 Reactivity of Substituents Attached to Ring Carbon Atoms There are no indications that such types of studies have been undertaken during the period under review.
3.19.8 Reactivity of Substituents Attached to Ring Heteroatoms Specific features of the heterocycles under review are due to the fact that customary reactivity of substituents attached to ring heteroatoms cannot be undertaken.
3.19.9 Ring Synthesis from Acyclic Carbons Classified by Number of Ring Atoms Contributed by Each Component 3.19.9.1 Intermolecular Coupling 3.19.9.1.1
Magnesa- and aluminacycles
Magnesacyclopentanes are widely known <1995JOM(491)1, 1995T4541, 1998ICA(280)8>. Allenes (CH2TCHTCHR; R ¼ n-C5H11, n-C7H15, CH2Ph) react with diethylmagnesium in the presence of [(5-Cp)ZrCl2] to yield magnesacyclopentanes 136 (R1 ¼ TCHR, R2 ¼ H; R1 ¼ R, R2 ¼ TCH2; R1 ¼ TCH2, R2 ¼ R; R ¼ n-C5H11, n-C7H15, CH2Ph) <2004T1287>. Aluminacyclopentanes are generated in situ as a result of the Zr-mediated cycloalumination of alkenes <1992MC28, 1992MC135, 1994JOM(466)1, 1995JA10771, 1995T4333, 1996JA1577, 1998RCB786, 2000RCB2051, 2000RCR121>. For example, alkenes CH2TCHR (R ¼ Bun, n-C6H13, Cy, CH2Ph) with AlEt3 in the presence of [(5Cp)ZrCl2] form aluminacyclopentanes 137 (R ¼ Bun, n-C6H13, Cy, CH2Ph) <2004T1281>. Reaction of allyl phenyl sulfide or 4-phenyl-1-butene with triethylaluminium proceeds via aluminacyclopentanes 137 (R ¼ CH2SPh, CH2CH2Ph) <1997TL2335>. Alkenes CH2TCHR (R ¼ Bun, n-C6H13) with Al(CH2CH2CH2R)3 in the presence of [(5-Cp)ZrCl2] form aluminacyclopentanes 138 (R ¼ Bun, n-C6H13) <1991BAU1022>. Alkenes (CH2TCHR; R ¼ Me2CH(CH2)2, PhCH2, Cy) with EtAlCl2 in the presence of [(5-Cp)2ZrCl2] and magnesium give aluminacyclopentanes 139 (R ¼ Me2CH(CH2)2, PhCH2, Cy) <1991BAU1425, 1992MC26>. [(5-Cp)2ZrCl2]-catalyzed reaction of triethylaluminium with RCUCR1 (R ¼ R1 ¼ Bun, Prn; R ¼ Me, R1 ¼ Ph) gives aluminacyclopentenes 140 (R ¼ R1 ¼ Bun, Prn; R ¼ Me,
1267
1268 Five-membered Rings with Other Elements R1 ¼ Ph) <1998TL2503>. If the enynes CH2TCHCH2(CH2)nCH2CUCSiMe3 (n ¼ 1, 2) are used in this reaction, the products are aluminacyclopentanes 141 (n ¼ 1, 2). Zirconium-catalyzed carboalumination of enynes proceeds via aluminacyclopentenes, for example 142, which are transformed to cyclopentenones under carbon monoxide. Aluminacyclopentadienes are also of interest <1996JA9577>. 1,4-Dilithio-1,3-dienes [LiC(R)TC(R)C(R)TC(R)Li] react with aluminium chloride to yield compounds 143 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, Bun; R1 ¼ R3 ¼ Bun, R2 ¼ R4 ¼ Ph) and 144 <2003T3779>.
3.19.9.1.2
Titana-, zircona-, and hafnacycles
Zirconacyclopentanes, -pentenes, and -pentadienes are prepared from zirconocene derivatives and alkenes or alkynes by inter- or intramolecular cyclization <1995COMC-II(12)771>. Various five-membered zirconacycles may be prepared by (1) co-cyclization of dienes (zirconacyclopentanes), enynes (zirconacyclopentenes), or diynes (zirconacyclopentadienes) with a derivative of zirconocene; (2) trapping of a zirconocene incorporated into a zirconacyclopropene moiety with alkenes (zirconacyclopentenes) or alkynes (zirconacyclopentadienes); or (3) trapping of a zirconocene incorporated into a zirconacyclopropane moiety with alkenes (zirconacyclopentanes) or alkynes (zirconacyclopentenes) <1988CRV1047, B-1991MI(5)1163, 1993SCI1696, 1994ACR124, 2004JOM(689)3873>. 1-Titana- and 1-zirconacyclopentanes 104 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, Alk, M ¼ Ti, Zr) are formed by oxidative coupling of two alkane molecules in the presence of a metallocene derivative <1996CL241, 1996CL357>. Saturated titanacycles are unstable. Zirconacyclopentane 104 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ H; M ¼ Zr) is prepared from [(5-Cp)2Zr(2-C2H4)(PMe3)] and ethylene <2006CCR(250)2>. [(5-Cp)2Zr(Bun)2] enters intermolecular co-cyclization with the 1,6-heptadiene CH2TCHCHC(CH2OMe)2CH2CHTCH2 to yield the condensed zirconacyclopentane 145 (R ¼ H) <2004T1401>. 4,49-Bis(methoxymethyl)-6-octen-1-yne reacts with [(5-Cp)2ZrCl2] and magnesium to yield 145 (R ¼ Me) <1996TL9059, 2000T2113>. Alternatively, [(5-Cp)2Zr(Bun)2] enters co-cyclization with 4,4-bis(methoxymethyl)hepta1,6-diene to yield zirconacyclopentane 145 (R ¼ H) <2004TL7633>. 1,6-Heptadiene reacts with [(5-Cp)2ZrCl2] in the presence of n-butyllithium to yield zirconacycle 97 <1994JA9457>. 1,8-Octadiene reacts with [(5-Cp)2ZrCl2] in the presence of n-butyllithium to yield zirconacyclopentane 100 <1997JA22>. A similar reaction in which the diene is CH2TC(Me)CH2CH2CH{CMe2(PhCH2O)}CHTCH2 gives compound 146 <1995TL6639, 2000COR809>, which is used to prepare diols by oxygenation. Carbomagnesation of alkenes catalyzed by [(5-Cp)2ZrEt2] proceeds via formation of zirconacycles 104 (R1 ¼ R2 ¼ Alk, R3 ¼ R4 ¼ H, M ¼ Zr) <1991CL1579, 1991JA5079, 1991TL6797, 1998BCJ755>. The coupling reaction of [(5-Cp)2Zr(2-C2H4)(THF)] with norbornene leads to isolation of zirconacyclopentane 147 (Cp9 ¼ Cp) <2000OM2532>. [(5-Me3SiC5H4)2ZrCl2], ethylmagnesium chloride, and norbornene yield 147 (Cp9 ¼ Me3SiC5H4). Numerous X-ray studies of zirconacyclopentanes exist <1994JA1845, 1994JA9457, 1996CL357, 1997OM2886>. The 1,6-diene CH2TCHCH2C(PhCH2OCH2)2CH2CHTCH2 undergoes a cyclization reaction with [(2-propene)Ti(OPri)2] to yield the bicyclic titanacyclopentane 148 <1995TL4261, 1999PAC1511>. Reductive coupling of zirconium(IV) benzamidinate [{PhC(NSiMe3)2}2ZrCl2] with ethylene in the presence of sodium amalgam gives zirconacyclopentane 149 <1994OM4670, 1997JCD3087>.
Five-membered Rings with Other Elements
The titanaallene compound [(5-Cp* )2TiTCTCH2] reacts with cyclohexylisonitrile to give titanacycle 150 <2001OM1354>. With 2,6-Me2C6H3NC, product 151 (Ar ¼ 2,6-Me2C6H3) is formed. One of the products of interaction of [(5-Cp)2Ti(PMe3)2] with 3-methyl-1,2-butadiene is titanacyclopentane 152 <2000POL879>.
Zirconacyclopentene 96 (R1 ¼ R2 ¼ Alk, Ar, H, Me, R3 ¼ R4 ¼ H, M ¼ Zr) is prepared from [(5-Cp)2Zr(2C2H4)(PMe3)] and R1CUCR2 (R1 and R2 ¼ Alk or Ar, R1 ¼ R2 ¼ H, Me) <2006CCR(250)2>. Zirconacyclopentene 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Zr) is formed from [(5-Cp)2ZrEt2] and dimethylacetylene <2004T1417>. [(5Cp)2ZrCl2] with ethylmagnesium bromide gives [(5-Cp)2ZrEt2], and on reaction with an alkyne RCUCR (R ¼ Et, Prn, Ph) it gives zirconacyclopentenes 96 (R ¼ Et, Prn, Ph, M ¼ Zr) <2004T1393>. [(5-Cp)2ZrCl2] reacts with ethylmagnesium bromide to give [(5-Cp)2Zr(2-CH2TCH2)], which with dimethylacetylene gives zirconacyclopentene 96 (R1 ¼ R2 ¼ Me, R3 ¼ R4 ¼ H, M ¼ Zr) <1997T9123>. Similarly, reaction of [(5-Cp)2ZrCl2] with n-butyllithium gives [(5-Cp)2Zr(2-EtCHTCH2)], and further interaction of this complex with excess dimethylacetylene gives zirconacyclopentadiene 96 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, M ¼ Zr) <1998BCJ755>. In a similar fashion, [(5-Cp)2HfCl2] and EtMgBr have been used to prepare hafnacyclopentenes, and [(5-Cp)2HfCl2] and n-butyllithium give hafnacyclopentadienes <1997JOM(547)209>. Titanacyclopentenes 96 (R1 ¼ R2 ¼ Ph, Bun, Prn; R1 ¼ Ph, R2 ¼ Bun, Me; R3 ¼ R4 ¼ H, M ¼ Ti) are formed from [(5-Cp)2TiCl2], EtMgBr, and further R1CUCR2 <2001JOM(633)18>. Titanacyclopentadienes 96 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Me, Et, Prn; R1 ¼ R3 ¼ Ph, R2 ¼ R4 ¼ Me, Bun) follow from [(5-Cp)2TiCl2] and excess RCUCR. [(5-Cp)2Zr(2-C2H4)] reacts with 1,6-heptenyne to yield zirconacycle 105 (R ¼ H) <1998S552>. [(5-Cp)2ZrBun2] enters intermolecular co-cyclization with enyne BunCUC(CH2)3CHTCH2 to yield the condensed zirconacyclopentene 105 (R ¼ Bun) <2004T1401>. [(5-Cp)2ZrCl2] in THF reacts with n-butyllithium and then with the enyne substrates CH2TCH(CH2)3CH(OR1)CUCR2 (R1 ¼ ButMe2Si, R2 ¼ SiMe3, SMe; R1 ¼ H, R2 ¼ SiMe3) to yield zirconacyclopentenes 95 (R1 ¼ ButMe2Si, R2 ¼ SiMe3, SMe; R1 ¼ H, R2 ¼ SiMe3) <1995T4421>. Cyclization of 1-octene-7-ynes CH2CHCH(OR)(CH2)3CUCSiMe3 in the same manner proceeds via the zirconacyclopentene 95 (R1 ¼ ButMe2Si, H, R2 ¼ SiMe3). Cyclization of the allylic enynes CH2TCHCH(R)(CH2)2CUCSiMe3 (R ¼ ButMe2SiO, OH, CONEt2, CH2NEt2) gives zirconacyclopentenes 98 (R ¼ ButMe2SiO, OH, CONEt2, CH2NEt2). Zirconacyclopentene 153 (M ¼ Zr) follows from zirconocene generated in situ and butadiene <2004JOM(689)4305>. Metallacyclopent-3-enes of titanium and zirconium 153 (M ¼ Ti, Zr) can be prepared by formation of a complex of 1,3-butadienes with the derivatives of metallocenes <1987AGE723, 2004AOC109> or by the reductive elimination of two vinyl moieties of the corresponding metallocene complexes <1984JOM(268)C7, 1989ZFA195, 1994ZFA1455>.
1269
1270 Five-membered Rings with Other Elements
1,6-Enyne Me3SiCUCCH2C(PhCH2OCH2)CHCHTCH2 in an identical reaction gives bicyclic titanacyclopentene 154 <1996JOC6756, 1999JA1245>. Me3SiCUCCH2C(PhCH2OCH2)2CH2CHTCHCHTCH2 gives titanacyclopentene 155 containing an allyl moiety <1996TL1253, 1998CC271, 2000MI211>. Me3SiCUC(CH2)3CHTCHTCH(SiMe2Ph) gives titanacyclopentene 156 <1997JA11295>, Me3SiCUCC(CH2)3CHTCHTCH(SiMe3) gives compound 157, Me3SiCUC(CH2)2CHTCHTCMe2 gives product 158, n-C5H11CUCCH2CH2(OSiMe2But)CHTCHTCH(CH2OMe) gives product 159 <1998TL7333>, and Me3SiCUC(CH2)3CHTCH(COOR) (R ¼ Et, But) gives compound 160 <1996JA8729, 1997JA10014>. A series of titanacyclopentenes have been prepared in a similar fashion <2000TL7773>.
The major product of the reaction of [(5-Cp)2TiMe2] with dimethylacetylene is the titanacyclopentene 161 (R ¼ Me) <2000POL879>. With diethylacetylene metallacycle, 161 (R ¼ Et) is formed. Thermolysis of bis(methylcyclohexenyl)zirconocene in the presence of trimethylphosphine and further reaction with diphenylacetylene gives 162. Allene complex 163 reacts with 2-butyne or diphenylacetylene to yield the titanacyclopentenes 164 (R ¼ Me, Ph).
Five-membered Rings with Other Elements
Complex 165 enters insertion reactions with alkynes RCUCH (R ¼ SiMe3, Ph) and PhCUCPh to yield complexes 166 (R1 ¼ SiMe3, Ph, R2 ¼ H; R1 ¼ R2 ¼ Ph) <2002OM5685>.
The main route to metallacyclopent-2,4-dienes of titanium and zirconium 23 (M ¼ Ti, Zr) is the oxidative coupling of two alkyne molecules or a diyne molecule in the presence of reduced metallocene derivatives <1983CC435, 1983JOM(241)15, 1985PAC1809, 1987CL623, 1989TL3495, 1995JOC4444, 1996CL1004, 2000JA10345, 2001JOM(633)18, 2002JA388, 2003SOS(2)739>. They are often used in situ. Reductive coupling of phenylacetylene in the presence of [(5Cp)2Ti(PMe3)2] gives titanacyclopentadiene 23 (R1 ¼ R4 ¼ Ph, R2 ¼ R3 ¼ H, Cp9 ¼ Cp, M ¼ Ti) <1985JA3717>. Photochemical reaction of [(5-Cp)2MMe2] (M ¼ Ti, Zr, Hf) with diphenylacetylene in pentane gives metallacyclopentadienes 23 (M ¼ Ti, Zr, Hf, R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph, Cp9 ¼ Cp) <2006CCR(250)2>. Zirconacyclopentadienes are generally made by coupling of diphenylacetylene and a derivative of zirconocene in the ratio 2:1 <1995JOC4444>. Coupling of two different alkynes (R1CUCR1 and R2CUCR2) with a derivative of zirconocene gives zirconacyclopentadienes of the type 23. [(5-Cp)2Zr(Bun)2] when reacted with diphenylacetylene gives zirconacyclopentadiene 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Prn, M ¼ Zr, Cp9 ¼ Cp) <2000AGE2950>. Reaction of [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] with Me3SiCUCR (R ¼ Ph, C5H4N) gives a mixture of titanacyclopentadienes 23 (R1 ¼ R4 ¼ SiMe3, R2 ¼ R3 ¼ Ph, C5H4N, Cp9 ¼ Cp, M ¼ Ti) and 23 (R1 ¼ R3 ¼ SiMe3, R2 ¼ R4 ¼ Ph, C5H4N, Cp9 ¼ Cp) <1995JOM(503)221>. The reaction of [(5-Cp)2Zr(H)Cl] with HCUCBun gives [(5-Cp)2Zr(1-CHTCHBun)Cl]. The product further reacts with methyllithium and then Me3SiCUCMe to yield a mixture of zirconacyclopentadienes 23 (R1 ¼ Bun, R3 ¼ Me, R4 ¼ SiMe3, Cp9 ¼ Cp, M ¼ Zr) and 23 (R1 ¼ H, R2 ¼ Bun, R2 ¼ H, R3 ¼ Me, R4 ¼ SiMe3) <2004T1345>. Reduction of [(5-Cp)2ZrCl2] with n-butyllithium and further reaction with 4-methylaminopyridine (L) gives [(5-Cp)2ZrL2] <2000JOM(595)261>. The product reacts with diphenylacetylene and other alkynes (R1CUCR1; R1 ¼ Me, Et, Prn) to give zirconacyclopentadienes 23 (R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Me, Et, Prn, Cp9 ¼ Cp, M ¼ Zr). Reaction of [(5-Cp)2Zr(Bun)2] with 4-octyne or 2-hexyne gives zirconacyclopentadienes 23 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Et, n Pr , Cp9 ¼ Cp, M ¼ Zr) <2004TL7633>. [(5-Cp)2Zr(4-dimethylaminopyridine)2] with 2-butyne gives 23 (R1 ¼ R2 ¼ Ph, R3 ¼ R4 ¼ Me, Cp9 ¼ Cp, M ¼ Zr) <1989TL3495>. Zirconatetrahydroindenes 44 (R ¼ Prn, Ph) have been prepared from diynes of the type RCUC(CH2)4CUCR (R ¼ Prn, Ph) on reaction with [5-Cp)2Zr(Bun)2] <2002CEJ4292>. Zirconaindenes 167 (R ¼ Prn, Ph) may be prepared by a similar route <1986JA7411, 2002CEJ4292>. 1,8-Diphenyloctadiyne and 3,9-dodecadiyne with [(5-Cp)2ZrCl2] give the annulated zirconacyclopentadiene 92 (R ¼ Et, Ph) <2002OM1383>. [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] reacts with RCUC(CH2)nCUCR to yield titanacyclopentadienes 168 (R ¼ Me, Bun, n ¼ 2), 38 (R ¼ Et, n ¼ 4, M ¼ Ti), and 169 (R ¼ Me, n ¼ 5) <1996JOM(520)187>. The 1,6-diyne Me3SiCUCCH2C(PhCH2OCH2)2CH2CUCSiMe3 gives bicyclic titanacyclopentadiene 170 <1999PAC1511>. [(5-Cp)2ZrCl2] reacts with n-butyllithium in THF and then with diynes RCUC(CH2)4CUCR (R ¼ But, SiMe3, SnMe3, Me) to yield zirconacyclopentadienes 38 (R ¼ But, SiMe3, SnMe3, Me, M ¼ Zr) <1996JOM(516)111>.
Reduction of [(5-Cp)Ti(OC6HPh4-2,3,5,6)Cl2] with sodium amalgam in the presence of excess 3,3-dimethyl-1butyne leads to titanacyclopentadiene 171 <2003OM1546>. Upon heating of the product, rearrangement to 172
1271
1272 Five-membered Rings with Other Elements takes place. [(2,6-Ph2C6H3O)2TiCl2] can be reduced by sodium amalgam in the presence of 3,3-dimethyl-1-butyne to yield 173 <1997JA7685>. The same isomer 174 is obtained upon sodium amalgam reduction of [(5-Cp)2TiCl2] in the presence of HCUCBut. Two alkyne units undergo coupling at the tungsten bis(aryloxide) moiety to yield tungstacyclopentadiene <1988JA8235, 1993OM2051>.
Bis(1-alkynyl)titanium complexes 175 (R ¼ Me, Ph) undergo 1,1-alkylboration with triethylborane to yield titana2,4-cyclopentadienes 176 (R ¼ Me, Ph) <2002JOM(649)225>. Complex 177 with triethylborane or tri-n-propylborane affords 178 (R ¼ Et, Prn). A preparation of titana-2,4-cyclopentadienes is based on reduction of [(5-Cp)2TiCl2] in the presence of alkynes <1986JOM(310)311, 1992MGM269>. Another method is based on [(5-Cp)2Ti(2Me3SiCUCSiMe3)] <1995JOM(503)221, 1998EJI419>. Reduction of [{(5-C5H4)SiMe2(5-C5H4)}TiCl2] with magnesium in the presence of PhCUCPh gives titanacyclopentadiene 179 <1998EJI419>. 1,1-Bis(amino)titana2,4-cyclopentadienes need to be stabilized by ancillary 2,6-diaminopyridine functionalities containing bulky aryl groups <1997OM1491>. Reduction of [(PriO)2TiCl2] with alkynes gives alkyloxotitana-2,4-cyclopentadienes <1998JOC10060, 1999JA1245>. Bonding in titanacyclopentadienes involves pp–dp interactions between the butadiene moiety and the titanium center <1992OM3691>.
Five-membered Rings with Other Elements
Zirconium(IV) benzamidinate [{PhC(NSiMe3)2}2ZrCl2] undergoes reductive coupling with diphenylacetylene in the presence of sodium amalgam to yield zirconacyclopentadiene 56 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph) <1994OM4670, 1997JCD3087>. Another zirconacyclopentadiene 180 (R1 ¼ R3 ¼ H, R2 ¼ R4 ¼ SiMe3) follows from the same starting zirconium(IV) complex and trimethylsilylacetylene in the presence of sodium amalgam.
[(5-C4Me4P)2ZrCl2] can be reduced by magnesium in THF and further with 2-butyne to yield the zirconacyclopentadiene 181 <2002OM259>. Zirconacyclopentadiene 182 has been prepared as an intermediate in the reaction of bis(1-phenylboratabenzene)bis(trimethylphosphine) zirconium(II) with acetylene <1997AGE2014>. A similar reaction has been noted for a titanocene derivative <1998ZFA919>.
Thermolysis of [(5-C5H4R)2ZrPh2] (R ¼ H, But) in the presence of Ph2PCUCR1 (R1 ¼ H, Ph) gives 2-phosphino1-zirconaindenes 183 (R ¼ H, But; R1 ¼ H, Ph) <1997CC279>. 3-Alkynylphosphino-1-zirconaindenes 184 (R ¼ H, But, R1 ¼ But, Ph; R ¼ H, R1 ¼ NPri2) are among the products of the reaction between [(5-C5H4R)2ZrPh2] (R ¼ H, But) and bis(alkynyl)phosphanes R1P(CUCPh)2 (R1 ¼ But, Ph, NPri2) <2004T1317>. The cyclometalated complex 185 reacts with ButP(CUCPh)2 to yield 186 as the only product. Thermolysis of species 186 in benzene gives products 187 and 188. Treatment of 186 with hydrochloric acid causes the cleavage of the Zr–C bond and gives (alkenyl)(alkynyl)phosphane. Complex 184 (R ¼ H, R1 ¼ Ph) is one of the products of the reaction of [(5-Cp)2ZrPh2] with PhP(CUCPh)2. Treatment of this complex with PhSbCl2 gives 3-(alkynyl)phosphinostibaindene.
1273
1274 Five-membered Rings with Other Elements Nonconjugated diyne Me3SiCUCCH2CUCSiMe3 reacts with the zirconocene precursors to give binuclear zirconacyclopentadiene 189 <1995T4359>. Coupling of the zirconocene derivatives with two alkyne molecules has been used to prepare zirconacyclopentadiene units in macrocycles, for example 190 (n ¼ 1–3) <1995JA5365, 1995JA7031, 1998JA1193, 1998JA3271, 1998JOC3673, 2000JA10345, 2001AGE2142, 2001JA10183, 2002CEJ74>.
Derivatives of zirconocene react with 1,2,3-butatrienes RCTCTCTCR (R ¼ SiMe3, But, H) to yield 1-zirconacyclopent-3-ynes 15 (Cp9 ¼ Cp, R ¼ H; But, SiMe3; Cp9¼ C5H4But, R ¼ H; M ¼ Zr) <2002SCI660, 2004JA60, 2005OM791, 2005OM2065, 2005OM3047>. Reaction of [(5-Cp)2TiCl2] with 1,4-bis(trimethylsilyl)-1,2,3-butatriene gives 67 (Cp9 ¼ Cp, R ¼ SiMe3, M ¼ Ti) <2004CL1488, 2006JOM(691)1175> and with 1,4-dichlorobut-2-yne in THF in the presence of magnesium to give 15 (Cp9 ¼ Cp, R ¼ H, M ¼ Ti). X-Ray data for the latter product suggest the predominance of a contribution of the 4-p,p-coordination mode 191 compared to that of the 2-,-mode 15, which is in contrast to the situation for the zirconium analogue. [(5-C5H4Me)2ZrCl2] with 1,4-bis(trimethylsilyl)-1,3butadiene in the presence of BunMgCl in THF gives 15 (Cp9 ¼ C5H4Me, R ¼ SiMe3, M ¼ Zr). Similarly, [(5Cp)2HfCl2] with the same butatriene but in the presence of Mg/HgCl2 gives 67 (Cp9 ¼ Cp, R ¼ Me3Si, M ¼ Hf). Metallacyclopent-3-ynes of titanium and zirconium are stable systems <1996AGE210, 2002SCI660, 2004CC2074, 2004JA60>. 1-Titanacyclopent-3-yne was first mentioned as an intermediate of the reaction between the butatriene Me2CTCTCTCTCMe2 and a derivative of titanocene <1996AGE210>. Derivatives of zirconocene on reaction with RHCTCTCTCTCHR (R ¼ Me3Si, But) <2002SCI660> or ClCH2CUCH2Cl and magnesium give 15 (R ¼ H, Me3Si, But, M ¼ Zr, Cp9 ¼ Cp) <2004CL1488, 2004JA60>. [(5-Cp)2Ti(2-Me3SiCUCSiMe3)] with 1,4dichlorobut-3-yne give 67 (R ¼ H, M ¼ Ti, Cp9 ¼ Cp) <2004AGE3882, 2004CC2074>.
The CTC–CTC moiety in titana- and zirconacyclocumulenes is much stabilized <1999JA10638, 2003AGE1794, 2003JOM(683)261, 2004AGE3882, B-2004MI139>, and has been analyzed by theoretical computations <1997AGE606, 1988JA125, 1998JA6952, 2001JOM(635)204, 2002OM2254, 2003OM3466, 2003OM4958, 2004JOC6357, 2005OM456>. In the process of activation of C–C single bonds of titanocene and zirconocene derivatives, metallacyclocumulenes may be formed <1993AGE1193, 1994JOM(476)197, 1996SL111, 2000ACR119, B-2002MI355, 2003JOM(670)84, 2003OM884>. Interaction of [(5-Cp)2Zr(1-CUCMe)2] with catalytic amounts of B(C6F5)3 as a result of the C–C coupling reaction of the alkynyl groups gives [(5-Cp)2Zr(4-MeC4Me)] <1989OM911, 1994AGE1480, 1997JOM(527)191, 1997OM1440, 1999JOM(578)115>. Similar C–C bond coupling reactions may occur in the absence of a borane but under ultraviolet (UV) irradiation of the related -alkyne complexes. Using this route, metallacyclopentacumulenes 3 (R1 ¼ R2 ¼ H, M ¼ Ti, Cp9 ¼ Cp; R1 ¼ R2 ¼ SiMe3, Me, Ph, M ¼ Zr, Cp9 ¼ Cp* ) can be prepared <1996AGE1112, 1999JA8313, 2000CEJ81>. 1-Metallacyclopent-2,3,4-trienes of titanium and zirconium can be prepared by two main routes: (1) formation of a complex of 1,3-butadiynes with metallocenes and (2) reductive elimination of two anionic acetylide groups of the dialkyne moiety in the presence of the metallocene derivatives <1994AGE1480, 1997JOM(527)191, 2004OM4391>. The list of known metallacyclocumulenes includes 3 (R1 ¼ R2 ¼ But, Cp9 ¼ Cp, M ¼ Zr, Ti) <1994AGE1605, 1994JOM(468)C4, 1995CB967, 2004JOM(689)4592>; (R1 ¼ R2 ¼ Ph, Cp9 ¼ Cp, M ¼ Ti) <1997JOM(536)293, 1999JOM(578)125>; (R1 ¼ R2 ¼ SiMe3, Ph, ButMe2Si, Cp9 ¼ Cp* , M ¼ Zr) <1999JA8313>; (R1 ¼ R2 ¼ Me, Cp9 ¼ Cp* , M ¼ Zr)
Five-membered Rings with Other Elements
<2000CEJ81>; (R1 ¼ But, R2 ¼ CUCBut, Cp9 ¼ Cp* , M ¼ Zr) <2000JA6317>; (R1 ¼ R2 ¼ Ph, Et, Cp9 ¼ 6-C5H5BX, X ¼ Pri2N, Ph, M ¼ Zr) <1999OM4234>); and 192 (R ¼ But, SiMe3) <2002OM1512>. Another representative of the series has the composition [{(5-Cp)Zr}3{1,3,5-(4-ButC4)3C6H3}] and can be depicted as 193 <1999OM2906>. Complex 3 (R1 ¼ R2 ¼ But, Cp9 ¼ Cp, M ¼ Zr) is the product of the reaction of 194 and 1,3-butadiyne <1994AGE1605>. Sevenmembered zirconacyclocumulenes are present among the products <1993JA10394, 1995ZK707>. Titanium analogues 3 (R1 ¼ R2 ¼ But, Ph, Cp9 ¼ Cp, M ¼ Ti) follow from 195 and 1,3-diynes RCUCCUCR (R ¼ But, Ph). However, titanacyclocumulenes are difficult to isolate because they are rapidly converted to the complex containing a bridging 1,3-butadiyne ligand, for example, 196 <1996AGE1112>. Complexes 3 (R1 ¼ R2 ¼ Me3Si, Me, Ph, Cp9 ¼ Cp* , M ¼ Zr) can be prepared in two ways <1999JA8313>. In the first route, [(5-Cp* )2ZrCl2] is reacted with RCUCLi (R ¼ Me3Si, Me, Ph) to yield [(5Cp* )2Zr(–CUCR)2] (R ¼ Me3Si, Me, Ph) and under direct sunlight C–C coupling of the alkynyl groups occurred. Another route is the reduction of [(5-Cp* )2ZrCl2] with magnesium in the presence of RCUCCUCR (R ¼ Me3Si, Me, Ph). Complexes 3 (R1 ¼ CUCBut, R2 ¼ But, M ¼ Zr, Cp9 ¼ Cp) were also prepared by reduction with magnesium in the presence of ButCUCCUCCUCBut <2000JA6317>. Attempts to isolate the titanium analogues led to the symmetrical titanacyclopropene derivative. Half-sandwiches of titanacyclocumulenes 192 (R ¼ But, SiMe3) are also the result of magnesium reduction of [(5:1-C5Me4SiMe2NBut)TiCl2] in the presence of 1,3-butadiynes RCUCCUCR (R ¼ But, SiMe3). A tris(zirconacyclocumulene) derivative [{(5-Cp)Zr}3{1,3,5-(4-ButC4)3C6H3}] is the product of reaction of [(5Cp)2Zr(THF)(2-Me3SiCUCSiMe3)], from which [(5-Cp)2Zr] was generated in situ, and 1,3,5-(ButCUCCUC)3C6H3 <1999OM2906>. Titana- and zirconacyclocumulenes are nearly planar and the central CTC bond is typically elongated due to the mutual coordination.
[(5-Cp)2Ti(2-Me3SiCUCSiMe3)] with PhCUCCUCMe in n-hexane gives titanacyclocumulene 3 (R1 ¼ R2 ¼ Ph, M ¼ Ti, Cp9 ¼ Cp) <1997JOM(536)293>. On standing in toluene solution, the product forms the dinuclear complex 197. With acetone complex 3 (R1 ¼ R2 ¼ Ph, M ¼ Ti, Cp9 ¼ Cp) yields titanadihydrofuran, and with water it forms titanoxane. Bis(1-X-boratabenzene)bis(trimethylphosphine) zirconium(II) (X ¼ Ph, NPri2) reacts with 1,4-disubstituted1,3-butadiynes (R ¼ Et, Ph) in hexane at room temperature to yield zirconacumulene the adducts 198 (R ¼ Ph, X ¼ Ph, NPri2; R ¼ Et, X ¼ Ph) <1999OM4234>.
1275
1276 Five-membered Rings with Other Elements Tantallacyclopentane is the product of reaction between [(But3SiO)2(C4H8N)Ta(2-C2H4)] and ethylene <2003ICA(345)173>. Complex [(5-Et2C2B4H4)(5-Cp)TaPh2] reacts with alkynes R1CUCR2 at elevated temperatures to yield tantalacyclopentadiene 199 <1998OM3865>.
3.19.9.1.3
Ferra-, ruthena-, and osmacycles
The ruthenacyclopentane cycle 200 is formed in the course of interaction of the thioether [(5-Cp)Fe(5C5H4CUCSCUCSiMe3)] with [Ru3(CO)12] <2004OM5115>. A similar reaction between EtSCUCR with [Fe3(CO)12] gives isomers of ferracyclopentane, that is, [Fe2(CO)6{C(SEt)C(R)C(R)C(SEt)}], [Fe2(CO)6{C(SEt)C(R)C(SEt)C(R)}], and [Fe2(CO)6{C(R)C(SEt)C(SEt)C(R)}] <1993ICA(212)323>.
Coupling reactions of alkenes and alkynes mediated by transition metal complexes often proceed through a metallacyclopentene intermediate 201 <1990JA7809, 1992JA5476, 1993JA8831, 1994CC2551, 1995JA615, 1996OM1176, 1997CL1273, 1997JA836>. This can be exemplified by the reaction of [(4-COD)Ru(Tp)Cl] with terminal alkynes (COD ¼ cyclooctadiene) <1998JA6175> and [(5-Cp)Ru(1(P),2-PPh2CH2CH2CH¼CH2)(AN)](PF6) with HCUCPh <1999OM1011>, when the reaction goes through the intermediate 202.
The ortho-metalated iron hydride complexes [HFe(CO)2{P(OPh)3}{(PhO)2POC6H4}] with R1CUCR2 (R1 ¼ Ph, R ¼ Me; R1 ¼ R2 ¼ Me; R1 ¼ Me, R2 ¼ CH(OEt)2; R1 ¼ Me, R2 ¼ CH2OH; R1 ¼ R2 ¼ CH2OH) in the presence of hydrated zinc chloride give a series of ferracyclopentendione complexes 203 <2000JOM(612)61>. With phenylacetylene under similar conditions, the ferrole-type species 204 is formed with structural parameters similar to those 2
Five-membered Rings with Other Elements
described <1991OM3759, 1998JOM(555)113>. Among the products of the reaction of [NEt4][MeCOFe(CO)4] with methyl iodide in acetone and then diphenylacetylene, there is the ferracyclopentendione complex 205 <2002JOM(642)107>. Such an intermediate might occur in a similar reaction of [HFe(CO)4] with methyl iodide and alkynes in the presence of CuCl2?2H2O <1998JOC4930, 2000OM2400, 2000TL2719>.
One of the pathways of the ring-opening metathesis polymerization of cyclic alkenes by [RuCl2(TCTCH2)(PR3)] (R ¼ Pri, Cy) was postulated to proceed through a ruthenacyclopentadiene 206 <2000JOM(606)16> possessing biscarbenoid character <1999CC1437, 1999OM4681>.
A ruthenacyclopentadiene ring coordinated to the Ru(CO)3 moiety is contained in the complex [Ru3(CO)9{32,4,3-Me3SiCUC(C2Fc)CSCUCSiMe3}] <2004OM5115>. Interaction of FcCUCSCUCFc with [Ru3(CO)12] gives the main product 207 (L ¼ CO) as well as complex 208, along with some other products <2006ICC139>. Complex 207 (L ¼ CO) enters a number of ligand-substitution reactions <2006JOM(691)3596>, in particular with Me3NO in toluene to yield 207 (L ¼ NMe3). Complex 207 (L ¼ NMe3) with PPh2H gives 207 (L ¼ PPh2H). The latter with [Au(PR3)Cl] (R ¼ Ph, Pri) and TlBF4 gives 207 (L ¼ PPh2AuPR3, R ¼ Ph, Pri). Complex 207 (L ¼ NMe3) with [Au(SR)(PPh3)] (R ¼ Et, Ph) gives 207 (L ¼ SRAuPR3, R ¼ Et, Ph). A related cluster has the composition [Ru4Ni(CO)12(-PPh2)(4-1,1,2,4-t-BuCUCC4CUCBut)] <1997CC483>.
One of the products of the reaction of [Ru3(CO)12] with ferrocenyl(formyl)acetylene in refluxing cyclohexane is cluster 209 containing a ruthenacyclopentadiene ring coordinated to an Ru(CO)2 moiety <1999JOM(588)113>. Group VIII metallacyclopentadienes in the same environment are known <1992IC1505, 1995OM2167> and examples include the ruthenacycles 210–212 <1991MC126, 1994JOM(464)197, 1996RCB1200, 1999JOM(580)36, 2002CCR(230)79>.
1277
1278 Five-membered Rings with Other Elements
Ferrocenylacetylene on reaction with [Fe(CO)5] in benzene forms ferracyclopentadiene 213 with a coordinated Fe(CO)3 unit <2005OM4793>. [Ru3(CO)12] with 2-pentinal-2-ethylacetal, among other products, gives the ferrolelike species 214 <2005JOM(690)3730>. One of the products of interaction of [Fe3(CO)12] with 1,4-butyndiol and 1,4-dichlorobut-2-yne is the ferrole-like complex 215 (R ¼ H) <1999JOM(573)139, 1999JOM(580)36, 2005JOM(690)3755>. With propargyl alcohol in the presence of potassium hydroxide in methanol, one of the products is 215 (R ¼ CH2OMe). The iron complex -N-(2-oxo-2-methylethanaminato)--N-(dimethylamino)– Fe2(CO)5 with diphenylacetylene gives 216 (R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph), with phenylacetylene gives 216 (R1 ¼ R3 ¼ H, R2 ¼ R4 ¼ Ph) and 216 (R1 ¼ R4 ¼ Ph, R2 ¼ R3 ¼ H), and with 1-phenyl-1-hexyne-3-one gives 216 (R1 ¼ R3 ¼ Ph, R2 ¼ R4 ¼ COPrn) <2000JOM(613)132>. The reaction of [(5-Cp* )RuCl(tmeda)] with 1-hexyne gives ruthenacyclopentadiene 217 <1997M1189>. Ruthenacyclopentadienes 218 and 219 are among the products of interaction of [(OC)2(5-Cp9)FeCUCCUCH)] and [Ru3(CO)12] in benzene <2003JOM(670)2>.
Ruthenacyclopentadienes 220 (R ¼ CUCPh, Ph), 221, and 222 are among the products of the reaction between [Ru3(-dppm)(CO)10] and PhCUCCUCPh in THF in the presence of Me3NO <1997JOM(536)93>. Thermolysis of [Ru3(3-PhCUCCUCPh)(-CO)(CO)9] in xylene gives the species 223 and 224 <1995AXC1819>. 1,19Bis(phenylethynyl)ferrocene reacts with [Ru3(CO)12] under reflux in benzene to yield product 225 <1994CL2279, 1999JOM(578)31>. Complexes 226 and 227 are the result of interaction of [Fe3(CO)9(3-2-EtCUCEt)] and N-benzyl-N-methylpropargylamine <1998JOM(555)113>.
Five-membered Rings with Other Elements
Osmacyclopentadiene in the cluster 228 can be prepared by the reaction of Os3(CO)12 with diphenylacetylene in acetonitrile via the intermediate [Os3(CO)9(MeCN)(PhCUCPh)] <1998ICA(274)82>. With P(OCH2)3CEt and P(OPh)3 the monosubstituted complexes result, where only one of the carbonyl ligands of the Os(CO)4 moiety is substituted by a phosphine ligand.
Interaction of [(5-Cp)Ru(PCy3)(MeCN)2] with deca-2,8-diyne gives the ruthenacyclopentatriene complex 229 <2001CC1996>. [(5-Cp* )(OC)2Ru(-CO)Co(CO)2] reacts with HCUCTol-p in the presence of Me3NO?2H2O in THF to yield ruthenacyclopentadiene 230 coordinated by the Co(CO)2 moiety <2000JOM(596)121>. The metallacycle is not planar and the Ru–Co bond is retained in the process of coordination.
Among the products of interaction of the ruthenium cyclopentadienyl complexes with alkynes, ruthenacycopentadienes and ruthenacyclopentatrienes occur quite often <1991JCD1589, 1997M1189, 1998CRV2599, 1998CRV2797,
1279
1280 Five-membered Rings with Other Elements 1998M221, 2000JA4310, 2000JCD2279>. [(5-Cp* )RuCl(4-COD)] reacts with p-bromophenylacetylene in methylene chloride to give the dicarbene ruthenacyclopentatriene complex 231 (R ¼ Br) <2001JOM(627)249>. [(5Cp* )RuCl(4-COD)] with phenylacetylene gives 231 (R ¼ H) <1999JPR801>. Upon treatment of 231 (R ¼ Br) with PMe3 or P(OMe)3, the acyclic cationic ruthenium carbene complexes are formed. This is also a feature of tungstacyclopentane conversion to acyclic carbenes photochemically <1998JA823> and molybdacyclopentenes converting into cyclic carbynes upon warming <1997OM5195>. [(5-Cp* )Ru(PPh3)2Cl] reacts with acetylene to yield chlorophosphine–cyclopentadienyl–ruthenacyclopentadiene <1998OM1257>. Metallacyclopentatriene cationic species <1992JA2712> are highly electrophilic and readily undergo further rearrangements. Thus, interaction of [(5-Cp)Ru(AN)2(SbR3)]þ (R ¼ Ph, Bun) with 2,8-decadiyne gives ruthenacyclopentatriene cationic species 232 (R ¼ Ph, Bun), which rearrange to the butadienyl carbenes <1999OM3843, 2001CC1996, 2001OM3851, 2002CEJ3948, 2003OM2123, 2003OM3164>.
The cluster [RhOs(CO)3(-1:1-C(COOMe)TC(COOMe)CH2)(dppm)2](OTf) with diazomethane forms product 233 containing the rhodacyclopentene unit and not containing an Rh–Os bond as in the precursor <2005OM6398>. Complexes [RhOs(CO)3(-C(COOMe)TC(COOMe))(dppm)2](OTf) or [RhOs(CO)2(-1:1CH2C(COOMe)TC(COOMe))(dppm)2](OTf) with diazomethane, in contrast, give the product 234 with an Rh– Os bond but containing an osmacyclopentene moiety and agostic interaction of the rhodium site with the methylene group of metallacycle. Complex 234 has a structure similar to that of [RhOs(CO)3(1:1-C4H8((dppm)2)]þ <1999JA2613, 2004JA8046>. On standing, complex 234 transforms to 235 where agostic interaction is absent <2005OM6398>.
Five-membered Rings with Other Elements
3.19.9.1.4
Cobalta-, rhoda-, and iridacycles
Cobaltacyclopentadienes 114 are formed in the process of cyclotrimerization of alkynes by [(5-Cp)2CoL2] (L ¼ CO, PR3, alkene) <1983OM726, 1984AGE539, B-1986MI(1)358, 1993PAC153>. Further interaction of 236 with various ligands yields 237; in particular, alkynes afford 238. [(5-Cp)2Co(PPh3)2] reacts with diphenylarenes to yield poly(arene cobaltacyclopentadienes) <1993AM752, 1993CL271>. [(5-n-C6H14-C5H4)2Co(PPh3)2] reacts with ethynylbenzene to give two isomers of cobaltacyclopentadiene 239 (R1 ¼ R3 ¼ Ph, R2 ¼ R4 ¼ H; R1 ¼ R4 ¼ Ph, R2 ¼ R3 ¼ H) <1995SM(69)559>. With p-diethynylbenzene, oligomeric and polymeric products are formed.
The dianion of [Me2Si(Cp)(C5HMe4)] reacts with [CoCl(PPh3)3] in the presence of diphenylacetylene to give the cobaltacyclopentadiene complex 240 <2001JOM(634)109>. On reflux in toluene solution, complex 240 transforms into 241. The reaction of [(5-Cp)Co(PPh3)2] with diynes leads to the organocobalt polymers 242 <1993PB179, 1997MM5205>. The resultant polymers enter various reactions with isocyanates, nitriles, sulfur, and other reagents to yield useful polymers with a variety of main-chain structures <1995MM3042, 1997CRV637, 1997PB415, 1998MM5916>. The other opportunity for new polymeric materials is related to the ability of cobaltacyclopentadiene-based polymers to transform to cyclopentadiene–cobalt polymeric compounds <1994MM7009, 1996MM1934>. Complex 243 reacts with t-butylisocyanide to yield 244 and not the cyclobutadiene derivatives <1998CL121, 2000JOM(611)570>. The reaction between [(5-Cp)Co(PPh3)2] and PhCUCPPh2 affording the cyclobutadienyl complex proceeds via the cobaltacyclopentadiene 245 <2006JOM(691)5831>. With HCUCPPh2, the reaction gives the isolable cobaltacyclopentadiene 246, which on oxidation gives first 247 and then 248.
1281
1282 Five-membered Rings with Other Elements Rhodacyclopentadienes are often postulated as intermediates in the catalytic cyclotrimerization of alkynes <2000OM4289, 2002CC2984, 2002OL745, 2003IC7701, 2003JA784, 2003JMO(204)333, 2003JOM(678)10, 2003OL4697>. They are normally formed from rhodium complexes and internal alkynes <1999JA12035, 2001CC2626, 2002OM2572>, but are sometimes isolated from rhodium-catalyzed processes <1991JA5127, 1991OM645>. In particular, in the course of the reaction of [(4-COD)Rh(Ph2PCH2CH2NTs)] with HCUCCOOEt, the rhodacycle 249 was isolated <2006JOM(691)1945>. Complex [IrCl(N2)(PPh3)2] with MeO2CCUCCO2Me gives iridacyclopentadiene 250 <2006JOM(691)2839> whose crystal structure has been reported <2003ZK115>. Reaction of the complex 251 with phenylacetylene yields the annulated iridacyclopentadiene derivative 252 <2003OM1787>.
One of the products of the ortho-metalation reaction of [IrCl(PPh3)2(CS)] with [Hg(CHTCPh2)2] is iridaindene 253 (X ¼ Cl) <2005JOM(690)972>. Treatment of the product with sodium iodide gives 253 (X ¼ I) <2006JOM(691)3846>. Reflux of 253 (X ¼ I) with excess methyl propiolate in dichloromethane leads to ring opening and with HX (X ¼ Cl, I) 2-iridafurans are formed. (2-Acetato)bis(triphenylphosphine) iridacyclopentadiene in the reaction with alkynes also experiences ring opening to yield but-1,3-dien-1-yl iridium(III) complexes <2005OM4849>. Similar reactions are known <1991OM3967>. Iridacyclopentadiene 254 enters a ligand-substitution reaction of isonitrile in the reaction with m,m-C6H3(CUCH)3 in the presence of triethylamine to yield the product 255 <1997OM816, 1999OM2210>, releasing the polyenyne on acidification <2002OM4785>. A oxidative coupling reaction of [Ir(AN)(CO)(PPh3)2]þ with alkynes (RCUCH, R ¼ H, (CH2)4CUCH) gives iridacyclopentadienes 256 and 257 <1995CC1495, 2005MI1386>. Further reaction of the products with alkynes leads to alkyne trimerization compounds, dienynes, and alkyne cyclotrimerization compounds. Similar processes with substituted alkynes are known <1999AGE3043, 2001OM3710>.
The complexes [(OC)3Co(-RCUCR)Co(CO)3] on further reaction with alkynes give cobaltacyclopentadienes 258 (R ¼ H, Me) and then the additional products of coupling with alkynes, indicating their role in the processes of cyclotrimerization. Such complexes have been structurally characterized for cyclooctyne and tetramethyldipropargyl-N-methylamine <1992JOM(423)129>. Complex [(5-Cp)Co(,2-C4H4)(PPh3)] on reaction with [Co2(CO)8] in benzene gives the dinuclear cobaltacyclopentadiene <1983OM726>. Reaction of Fe2(CO)9 and phenylacetylene with [Co(CO)4]/trifluoroacetic acid gives among the products [Co2(CO)5(2,4-CPhCHCHCPh)] <1995JOM(489)C65>. Reaction of [Fe2(CO)9] with phenylacetylene and [Co(CO)4]/trifluoroacetic acid gives cobaltacyclopentadiene 259 coordinated to the Co(CO)3 moiety.
Five-membered Rings with Other Elements
The complexes [(OC)3Co(-R1CUCR2)Co(CO)3], when reacted with another or the same alkyne in the presence of an N-oxide, produce the 4-coordinated cobaltacyclopentadienes 260 (R1 \ R2 and R3 \ R4 ¼ (CH2)6; R1 ¼ R4 ¼ H, R2 \ R3 ¼ CMe2N(Me)CMe2; R1 ¼ R4 ¼ SF5, Ph, COOMe, n-C5H11, CH2OMe, H, R2 ¼ R3 ¼ H; R1 ¼ R2 ¼ R3 ¼ R4 ¼ COOMe; R1 ¼ R3 ¼ COOMe, COOEt, R2 ¼ R4 ¼ Me; R1 ¼ R3 ¼ CH2OMe, R2 ¼ R4 ¼ H; R1 ¼ Ph, COOMe, R2 ¼ H, R3 ¼ R4 ¼ COOMe; R1 ¼ Ph, R2 ¼ H, R3 ¼ R4 ¼ Me; R1 ¼ R3 ¼ COOMe, R2 ¼ R4 ¼ Ph; R1 ¼ R2 ¼ R3 ¼ R4 ¼ H) <1999OM197, 1999OM206>. Complex 260 (R1 ¼ R4 ¼ H, R2 \ R3 ¼ CMe2N(Me)CMe2) was prepared using N,N-dipropargylmethylamine <1992JOM(423)129> and 260 (R1 ¼ R4 ¼ SF5, R2 ¼ R3 ¼ H) using HCUCSF5 <1986CB453, 1995JOM(501)1>. The reaction of the phosphine adducts 261 (R1 ¼ Ph, R2 ¼ COOMe; R1 ¼ COOMe, R2 ¼ Ph) with [Co2(CO)8] gives complex 262 <1983OM726>. Complex 260 (R1 ¼ R4 ¼ Ph, R2 ¼ R3 ¼ H) follows from ethynylbenzene, [Fe2(CO)9], [Co(CO)4], and trifluoroacetic acid <1995JOM(489)C65>. Another known synthesis is based on HCUCMe2OH <1995ICA(228)139>.
Reactions of [HIr4(CO)9(3-2-Ph2PCUCPh)(-PPh2)] or [Ir4(CO)8(3-2-HCUCPh)(-PPh2)] with HCUCPh give two isomers, 263 and 264, containing the coordinated iridacyclopentadiene moiety <2004JOM(689)3533>.
3.19.9.1.5
Nickela-, pallada-, and platinacycles
The donor-stabilized nickelacyclopentadienes 265 (R ¼ Ph, CF3) are the result of the reductive coupling of 266 (R ¼ Ph, CF3) and RCUCPh (R ¼ Ph, CF3) in the process of cyclotrimerization of alkynes <2002OM1975)>. Nickelacycle 267 <1989JA2883> is of interest due to its reactivity and ability to transform to various organic compounds <1989PAC1701, 1994SL465>.
A group of oxidative addition reactions of C–C bonds allows the preparation of metallacycles in various ways. The first route can be termed oxidative homocoupling <1999CCR(193)207>. Oxidative cycloaddition of two unsaturated hydrocarbons to the transition metal compounds where a transition metal is low valent gives metallacyclopentanes, -pentenes, or -pentadienes, which can insert carbon dioxide leading to useful products <1983JOM(255)263, 1983S574, 1984JOM(276)C69, 1985BSB671, 1986CB991, 1986JOM(309)215, 1987AGE571, 1988JA3207, 1988JOM(345)117, 1991JOM(406)C25, 2002JA10008, 2004JA5956>. ,!-Enynes react with nickel(0) complexes to yield nickelacyclopentenes <1988JA1286, 1992SL539, 1996JA2099, 1996JOC4498, 1996TL6839, 1997JA4911, 1997T16449, 1998AGE3144, 1998T1131, 1999JA476, 1999JA11139, 2000JA6775, 2001OM370, 2002JA12060, 2003JA13481, 2003OL3771, 2004JA10331, 2004OM4636>. An illustration is the reaction of the diazadiene complexes of nickel(0) with acetylene
1283
1284 Five-membered Rings with Other Elements to produce nickela(II) cyclopentadienes 268 (R ¼ Me, H, Ar ¼ 2,6-Pri2C6H4, 2,6-Me2C6H4) coordinated to the nickel(0)(diazadiene) moiety in a p-(4-fashion) <1990JOM(390)237, 1990JOM(397)255, 1992JOM(426)131>. The reaction of a nickel(0) complex with Pri2PCH2CH2PPri2 and acetylene gives a binuclear complex containing a nickelacyclopentadiene moiety and a bridging HCUCH molecule <1987AGE1288>. Phenylacetylene with [Pt(0)(Me2C2B9H9)] gives the binuclear complex 269 <1994OM1666>. Cycloaddition of allenes to platinum(0) and nickel(0) gives platina- 270 <1994JOM(468)273> and nickela- 271 <1985OM1386> cycles. Reaction of [(5-Cp)2Ni] with LiCH2CH2CMe2CMe2CH2Li yields the nickelacyclopentane compound 272 <1995JOM(491)41>.
[Pd(DBA)2] reacts with bpy, tetramethylethylenediamine, or 1,10-phenanthroline (phen) in the presence of methyl phenylpropynoate to yield complexes 273–275 (DBA ¼ dibenzylideneacetone) <2006ICA(359)1773>. Pallada2,3,4,5-tetrakis(carbomethoxy)cyclopentadienes are known <2003ICA(350)592>.
Oxidative homocoupling of activated substrates may be illustrated by the reaction of diazabutadienes with [M(DBA)2] (M ¼ Pd, Pt) in the presence of RCUCR yielding 276 (M ¼ Pd, R ¼ COOMe, COOEt, COOPri, R1 ¼ 2,6-Me2C6H4, 2,6-Pri2C6H4, R2 ¼ H, Me; M ¼ Pt, R ¼ COOMe, COOEt, same sets of R1 and R2). Palladium starting complex [Pd(DBA)2] and diazabutadiene ligands with EtOOCCUCH gives 277 <1990JOM(384)243, 1993JMO(81)313>. Bromocycloheptatriene reacts with ButOK and further with [Pt(PPh3)2] to yield 278 <1985OM1894>. Palladacyclopentadienes containing pyridyl thioether as an ancillary ligand are formed by the oxidative coupling of the palladium(0) alkene complexes with RCUCR (R ¼ COOMe, COOEt, COOBut) <2005OM5537, 2006ICC388>.
In the oxidative heterocoupling group, an example is the reaction of the complex [(Ph3P)2Ni(2CH2TCHCOOMe)] with 1,1-dimethylcyclopropene giving nickelacyclopentane derivative 279 <1987OM1130>.
Five-membered Rings with Other Elements
The benzyne complex of nickel 280 reacts with tetrafluoroethylene to yield the nickelacyclopentene derivative 281 <1995OM2091, 1997JCD3105>. With ethylene the product is 282 and with MeO2CCUCCO2Me it is 283 <1985OM1992>. Cycloalkyne platinum complex 284 with tetracyanoethylene gives the fused platinacyclopentane 285 <1995OM2892>. The reactions between nickel-benzyne derivatives and carbon monoxide give nonisolable nickelacyclopentenones 286 (X ¼ H, F) <1996OM928>. Oxidative addition between [(4-COD)Ni(bpy)] or [(4COD)Ni(phen)] and 1,4-dialkanes gives nickelacyclopentanes 287 and 288 and benzo[c]nickelacyclopentene 289 (phen ¼ 1,10-phenanthroline) <1993JA2075, 1995POL175>.
3.19.9.2 Reduction Reduction of ansa-zircono- and hafnocene dichlorides using sodium amalgam gives metallacyclopentanes <2000OM127>. Compounds [(5-C5Me4R)2TiCl2] (R ¼ CH(Me)CHTCH2, (CH2)2CHTCH2, (CH2)3CHTCH2) can be reduced by magnesium to yield titanacyclopentanes 290–292 <2000CEJ2397, 2002JOM(642)148, 2003JOM(667)154, 2004JOM(689)1919>. Complex [(5-C5Me4SiMe2CH2CHTCH2)2TiCl2] on reduction using magnesium in THF gives titanacyclopentane 293 <2002OM2639>. Aryloxytitanacyclopentenes and -cyclopentadienes can be prepared using (ArO)2TiCl2/Na <1995OM656, 1995T4463, 1997JA7685, 1997JA8630>. Alkoxytitanacyclopentenes and -cyclopentadienes are formed from [Ti(OPri)4]–PriMgCl <1995CC659, 1997OM1491, 2000SL753>.
3.19.10 Ring Synthesis by Transformation of Another Ring 3.19.10.1 Nucleophilic Attack on Coordinated Ligands Complex 294 with methyllithium in THF gives the lithium salt 295 and then, via the cobaltacyclic intermediate 296, is converted into the complex 297, or with trimethylphosphine to the cobaltacyclopentadiene 298 <2004JOC2516>.
1285
1286 Five-membered Rings with Other Elements
3.19.10.2 Insertion Zirconacyclobutene–silacyclobutene-fused compounds react via a zirconacyclopentadiene, for example, 299 <2003TL677>. [(5-Cp)V(CH2CMe2R)2(PMe3)] on reaction with trimethylphosphine gives the annulated vanadacyclopentene derivative 300 <1993OM2268>. [Os(CO)4(2-C2H2)] with PBut3 gives the product of double carbonyl insertion 301 <1999OM2331>.
[(5-Cp* )ClIr(-Cl)2IrCl(5-Cp* )] causes decarbonylation of sodium fluorenone ketyl in THF to yield species 302 <1998CC669, 1999OM1979>. The same product is formed if treated with sodium and fluorenone in THF. Complex 302 occurs among the products of interaction of [(5-Cp* )Ir(NBut)] with aromatic pinacols.
[(5-Cp* )Ni(acac)] with 2,29-dilithiobiphenyl in ether gives the nickelafluorenyl complex 303 (acac ¼ acetylacetonate) <2006JOM(691)4080>. The coordination mode of NiCp* , as evaluated from the structural data, is intermediate between 3 and 5. [(5-Cp* )Ni(acac)] with 1-lithio-1-phenyl-2-(2-lithiophenyl)ethane in ether gives the nickelaindenyl complex 304 with coordination mode resembling that in complex 303. Similar metallafluorenyl complexes have been described <2004AGE3711>. Reaction of nickelocene with sodium in the presence of trans-methylstilbene gives (5-cyclopentadienyl)(5-1-(5-cyclopentadienyl)-2-phenyl-3-methyl-1-nickelaindenyl) nickel <2005JOM(690)1523>. The ethyl analogue of this compound 305 is formed from 1-lithio-1-phenyl-2-(29-lithiophenyl)ethane complex with tetramethylethylenediamine with nickelocene <2006ICC375>. X-Ray data are indicative of 5-coordination and sandwich complex formation <2002CCR(233)157>.
Biphenylene 306 reveals the ability to insert metal-containing moieties into the strained C–C bond to yield annulated metallacyclopentadienes 307 ([M] ¼ Ni(PEt3)2, Pt(PEt3)2, and others) <1985OM224, 1994JA3647, 1995OM1168, 1997OM2016, 1998JA2843, 1998OM4784, 1999AGE870>. Preliminary coordination of biphenylene 306 by the Mn(CO)3 framework 308 allows the preparation of a range of annulated metallacyclopentadiene products. Reaction of 308 with [Pt(PPh3)3] or [Pt(PPh3)2(C2H4)] gives 309 <1999OM4887>.
Five-membered Rings with Other Elements
The complex [(2-cyclohexyne)Pt(PPh3)2] inserts electrophilic or strained alkenes (CH2TCHR; R ¼ COMe, CHO, COOMe, CN) into the platinum–cycloalkyne bond to yield platinacyclopentenes 310 <1997CB1029, 2000JOM(600)37>.
3.19.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available Oxidative coupling of organometallic precursors with alkenes, alkynes, conjugated and nonconjugated polyenes and polyalkynes remains the main method of synthesizing various classes of five-membered rings with other elements. However, some alternative methods do exist.
3.19.11.1 Transmetalation Reaction Metallacyclopentanes can be formed from ,!-dilithium and dimagnesium derivatives M(CH2)4M (M ¼ Li, MgCl) and [MCl2L2] (M ¼ Ni, Pd, Pt) <1999CCR(193)207>. Platinacyclopentene 311 is formed from [PtI2(4-COD)] and [o-C6H4(CH2)2Mg(THF)2]3 <1989IS144>. Palladacycle 312 is the result of interaction of [PdCl2(PMe3)2] and [o-C6H4(CH2)2(MgCl)2] <1998ICA(269)191>. Nickelacyclopentadienes 313 are formed from [NiBr2L2] (L2 ¼ bis(diphenylphosphino)ethane (DPPE), (PEt3)2) and Li–C(Ph)TC(Ph)–C(Ph)TC(Ph)–Li <1985ZNB624>. Dibenzoplatinacyclopentadienes 314 are formed from dibenzostannoles and [PtCl2L2] (L2 ¼ bpy, 2,29-bipyrimidine (bpym), (PPh3)2) <1988JOM(350)109, 1991JOM(410)265>. Bicyclic derivatives of nickel <1992JOM(430)133, 1995JOM(491)41>, palladium <1993JOM(456)7>, and platinum <1993AGE387, 1994JOM(471)23, 1995JOM(503)135> result from halide-free 1,4-Li(CH2)4Li, and in the case of nickel from K[Ni(NPh2)3]. The reaction of [PtCl2(THT)2] and Li(m-RC6H4–C6H4R-m)Li (R ¼ F, CF3) gives the bicyclic derivative 315 (THT ¼ tetrahydrothiophene) <1991JOM(412)237, 1991JOM(412)243>. In a similar manner, some chroma- and tungstacyclopentanes have been synthesized <1997OM1511, 1998OM2628, 2003SOS(2)8>.
3.19.11.2 Cyclometalation Thermolysis of [Pt(CH2CMe2Ph2)L2] (L ¼ COD, bpy, phen, (PPh3)2, (PEt3)2, DPPE) gives the annulated platinacyclopentenes 316 (M ¼ Pt) <1983POL1095, 1986OM875>. Dialkylation of [NiCl2L2] (L ¼ PMe3, PMe2Ph) with
1287
1288 Five-membered Rings with Other Elements Mg(CH2CMe2Ph)Cl in the presence of iodine as catalyst gives products 316 (M ¼ Ni) <1989POL1069>, and benzo[b]nickelacyclopentene complexes. Interaction of palladium complexes 317 (R ¼ OH, H, NO2) with potassium phenolate results in palladacyclopentene 318 <1992JOM(425)151>. p-Arene complex 319 is readily cyclometalated by sodium hydroxide in the presence of triphenylphosphine to yield the fused palladacyclopentene 320 <1994OM18>. Complex [Pd(CH2CMe2Ph)ClL2] (L ¼ COD, PMe3) undergoes base-induced cyclometalation with sodium hydroxide or NaN(SiMe3)2 to yield 316 (M ¼ Pd) <1999AGE147>. Complex 321 under sodium methylate/ methanol gives the pallada-3-cyclopentenone species 322 <1995JCD3093>.
3.19.12 Important Compounds and Applications Metallacyclopentadienes are often postulated as intermediates in the alkyne-based synthesis of various organic compounds like cyclotrimerization of alkynes to yield derivatives of benzene or in the synthesis of quinines and tropones <1994MI211, 1995ICA(230)215, 1995COMC-II(12)741, 1996JOM(511)263, 1999JOM(573)139, 1999OM215, 2000IZV1, 2003OM2564, 2004JMO(213)129, 2004UK563>. There are indications <1994JPC3882, 1995SUS473, 2002JMO(184)301> that titanacyclopentadiene intermediates are formed in the process of cyclotrimerization of simple alkynes on the reduced TiO2 surface. Many transition metal-mediated reactions proceed through intermediate formation of metallacyclopentanes, -pentenes, and -pentadienes <1987ACR65, 1995T4519, 1997MI117, 1998JOC6802, 1998MI515, 2004JMO(214)227>. Chromacyclopentane is an intermediate of the catalytic trimerization of ethene to 1-hexene <1989CC674, 1997OM1511, 2000AC29>. A similar mechanism has been proposed for the TaMe2Cl3-mediated trimerization of ethene <2001JA7423>. Several catalytic C–C coupling reactions by Ti(II)/Ti(IV) involve titanacyclopentane <1997JA8630, 1999JA9111, 2000PAC1715> or -pentene intermediates <1998TL7695, 2000CRV2789, 2001ASC759, 2003JA6074, 2006TL8319>. Trimerization of ethene to 1-hexene catalyzed by mono(cyclopentadienyl– arene)titanium complexes involves the 16-electron cationic titanacyclopentane intermediate 323 <2002OM5122>. Titanacyclopentane is also implicated in the co-trimerization of ethene and styrene catalyzed by [Cp9TiMe2]þ species <2000MM2807>. Titanacyclopentene-3 is postulated as an intermediate in [(5-Cp)2TiCl2]-catalyzed coupling of vinylmagnesium chloride and chlorosilanes to yield 1,4-bis(silyl)-2-butenes <2001OL1733, 2005TL8869>. Titanacyclopentenes-2 are possible intermediates in the cyclization of 2,7- and 2,8-enyn-1-ol derivatives <1997AGE851, 1997TL8351, 1999JA3559, 2001TL4147, 2002TL6511, 2003TL653>.
Five-membered Rings with Other Elements
Titanacyclopentadienes 23 (R1 ¼ R4 ¼ SiMe3, R2 ¼ R3 ¼ Bun, Ph; R1 ¼ R2 ¼ R3 ¼ R4 ¼ Ph; Cp9 ¼ Cp, M ¼ Ti) <1995JOM(501)179> and 168 (R ¼ Me, Bun) <1996JOM(520)187> catalyze hydrosilylation of aldimines and ketimines <1997TL1533> as well as head-to-tail dimerization of alkynes <1996JOM(509)235>. Titanacyclopentadiene 324 is a catalyst for cyclotrimerization of tri-t-butylacetylene into 1,3,5-tri(t-butyl)benzene and of LiCUCBut into 1,3,5-tri(t-butyl)fulvene <1995OM656>. The latter reaction is better catalyzed by [(RO)2TiCl2] (R ¼ 2,6-Ph2C6H3, 2,6-Me2C6H3) via the intermediate 325 <1997JA11086>. [(5-Cp)2Zr]-, [(MeO)2Zr]-, and [M(PPh3)]- (M ¼ Ni, Pt) mediated cyclotrimerization of alkynes proceeding through the metallacyclopentadiene stage has been studied using theoretical methods <1994JA1845, 2005OM2129>. The reaction of propargylic ethers (R1CUCCH(R2)(OSiMe2But); R1 ¼ Bun, R2 ¼ Prn; R1 ¼ R2 ¼ Ph; R1 ¼ Ph, R2 ¼ o-BrC6H4; R1 ¼ Bun, R2 ¼ C4H3S; R1 ¼ SiMe3, R2 ¼ Ph) with [(5-Cp)2ZrEt2] gives ethylallenes [R1(Et)CTC–CHR2] through the zirconacyclopentene intermediate 326 <1997TL8723, 2000ICA(300)741>.
Chroma- or molybdacyclopentanes are implicated as intermediates in the homogeneous <2004JMO(213)21, 2004JMO(221)9, 2004JOM(689)3641> and Cr/SiO2-catalyzed polymerization of ethylene in the form of surface complex 327 <2005CRV115, 2006JCT172>, as well as [Cr{N(SiMe3)2}3]/i-butylalumoxane/SiO2-catalyzed ethylene trimerization through the stage of chromacyclopentane 328 <2002JMO(187)135>. Electrochemical oxidation of ferracyclopentane 329 leads to butene-1 <2002JOM(653)11>. Treatment of FeCl2 and FeCl3 with zinc powder in the presence of imidazol-2-ylidene or bidentate nitrogen ligands provides catalysts of intramolecular cycloisomerization of triynes to annulated benzenes <2005OL3065, 2006JOM(691)3129>.The process occurs via ferracyclopentadienes, for example, 330 (R ¼ H, Ph, Bun, SiMe3).
Ruthenacyclopentane 331 has been postulated as an intermediate in the ruthenium-catalyzed cycloisomerization of lactones <2003TL2157>. Cycloisomerization of phenylsulfonylallenes to the cyclohexane derivatives catalyzed by a ruthenium benzylidene complex might proceed through the ruthenacyclopentane intermediate 332 <2006TL3971>. The [(5-Cp* )RuCl(4-COD)]-catalyzed cyclotrimerization of 1-octyne with dimethyl acetylenedicarboxylate proceeds via a ruthenacyclopentadiene <2004JMO(209)35>.
In the process of conversion of cyclopentadienyl cobalt cyclobutadienes to cyclopentadienones under carbon monoxide, cobaltacyclopentadienes 333 (R ¼ Me, Prn, But, Ph) and then 334 (R ¼ Me, Prn, But, Ph) are intermediates <2005OM2106, 2005OM4316>. The same applies to 333 (R ¼ Me, Prn, But, Ph) and 335 (R ¼ Me, Prn, But, Ph) when cyclobutadiene complexes are transformed into arenes using alkynes <1990AGE276>.
1289
1290 Five-membered Rings with Other Elements
[(4-COD)2Ni]-catalyzed reaction between methylenecyclopropane and acrylates proceeds via nickelacyclopentanes 336 (R ¼ Me, Et) to yield cyclopentanes <1983CB2920>. Palladacyclopentadiene catalysts modified by diazabutadiene ligands are applicable to co-trimerization of dimethyl acetylenedicarboxylate with alkynes <1987JOM(326)C1>, alkenes <1993JOM(452)223>, and allenes <1988JA1286>. Ni(0)-catalyzed cyclization of enynes with isocyanides to yield cyclopentenone imines involves nickelacyclopentene complexes <1992SL539, 1996JOC4498>. Palladium-catalyzed cyclizations often proceed through palladacycles, for example, 337 ([Pd] ¼ Pd(py)2, Y ¼ H, Me, Cl) <1985G685, 1985JOM(296)C11>, since palladium complexes are prone to cyclometalation. Nickelacyclopentadienes 338 (R1 ¼ H, Me, R2 ¼ Me, Et) are the intermediates of the [(4-COD)2Ni]catalyzed synthesis of substituted phenols from cyclobutanes and alkynes <1991JA2771>. Pallada(II)cycles, for example, 339 ([Pd] ¼ Pd(py)2, Pd(bipy)), often catalyze the intramolecular ene reaction of enynes when a palladium(IV) intermediate exemplified by 340 (L ¼ pyridine (py)) is formed <1987JA4753, 1988JA1636, 1991JA1850, 1991TL3647, 1993AGE1085>. Cyclooligomerization of aryl halides <1996S769> is Pd(0)-catalyzed and proceeds via an annulated palladacyclopentene 341 ([Pd] ¼ PdL, L ¼ py, PPh3) <1994AGE103>. Catalytic transformations based on Pd(II) often include oxidative addition of organic halides to intermediate palladacyclopentanes <1997AGE119>. Palladacyclopentadienes <1998OM1812> occur in Pd(0)-catalyzed cyclotrimerization of alkynes <1990JOM(384)243>, carbostannylation of alkynes <2001BCJ637>, and transformation of alkynes to conjugated dienes <1997AGE1743>.
3.19.13 Further Developments Cyclomagnesation of ,!-diallenes is still under intensive study <2007RJOC961>. Cross-coupling reactions of 2,5-dialkylidenemagnesacyclopentanes with organic halides have been reported <2007RJOC681>. Aluminacyclopentanes have been applied in the synthesis of ethyl 1-hydroxycyclopentanecarboxylates <2007RJOC347>.
Five-membered Rings with Other Elements
Reductive coupling of alkenes and alkynes leading to metallacycles of early transition metals is the subject of the review <2007TCC209>. A reaction of titanacyclopentene leading to a titanium–alkenyl complex and the reverse transformation of a hafnium–alkenyl complex to hafnacyclopentane are considered in a review <2007CCR1294>. Rearrangement reactions of titanacyclopentadienes have been reviewed <2007JOM4424>. The reactivity of 1,1-bis(cyclopentadienyl)-2,3,4,5-tetraphenyltitanacyclopentadiene was studied <2007EJI39>. Nucleophilic carbon–carbon bond-forming reactions of 1-zirconacyclopent-3-ynes with aldehydes are the subject of a publication <2007JOM5317>. Chromacyclopentanes as components of a catalytic cycle have been reviewed <2007CCR1294>. A series of the tungstacyclopentane complexes have been synthesized <2007OM1279>. The problem of formation of ruthenacyclopentadiene and other ruthenacyclic frameworks in ruthenium clusters was studied <2007OM1349>. A wide range of substituted ruthenacyclopentadienes and annulated derivatives was prepared <2007OM1325>. Ruthenacycles are implicated in the catalytic dimerization of acrylonitrile <2007JMOC9>, dimerization of styrenes <2007AG(E)5958>, heterodimerization of alkenes <2007AG(E)7544>, and ring-closing metathesis reactions <2007CRD238>. Cobaltacyclopentadienes traditionally are implicated in the cobalt-catalyzed cyclotrimerization of alkynes <2007ARK(xii)7>, which convincingly follows from the results of theoretical computation <2007JA8860>. Formation of rhodacyclopentadienes in oxidative addition reactions was reported <2007JOM481>. Rhoda- and iridacyclopentadienes are regarded as participants of the catalytic reaction of intramolecular asymmetric [4þ2] cycloaddition of alkyne-1,3-dienes <2007AG(E)7277>, C–C bond forming reactions <2007TCC77>, coupling of ethylene and alkynes <2007CEJ5160>, as well as cyclotrimerization of 1,6-diynes with monoynes <2007ARK(xi)145>. Oxanickelacyclopentene can be prepared from the reaction of oxanickelacyclopropane with a terminal alkyne <2007EJO4981>. Substituted platinacyclopentane was prepared using a ring-expansion reaction, involving insertion into the platinum–carbon bonds <2007OM1044>.
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Five-membered Rings with Other Elements
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1296 Five-membered Rings with Other Elements
1996TL3109 1996TL6839 1996TL7521 1996TL7661 1996TL9059 1997AGE119 1997AGE606 1997AGE851 1997AGE1743 1997AGE2014 1997AGE2615 1997CB1029 1997CC279 1997CC483 1997CC1045 1997CC1321 1997CC1599 1997CC2069 1997CCC331 1997CEJ1324 1997CL825 1997CL1273 1997CRV637 1997CRV1735 1997JA22 1997JA836 1997JA3631 1997JA4911 1997JA7685 1997JA8630 1997JA10014 1997JA11086 1997JA11165 1997JA11295 1997JA12842 1997JCD3087 1997JCD3105 1997JOM(527)191 1997JOM(536)93 1997JOM(536)293 1997JOM(541)207 1997JOM(547)209 1997M1189 1997MI117 1997MM5205 1997MM5566 1997OM816 1997OM1440 1997OM1491 1997OM1511 1997OM2016 1997OM2886 1997OM3086 1997OM5195 1997OM5331 1997PAC633 1997PB415 1997SL1371 1997T9123 1997T16449 1997TL447 1997TL1533 1997TL2335
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Five-membered Rings with Other Elements
1997TL4099 1997TL4103 1997TL8351 1997TL8355 1997TL8723 1998AGE1915 1998AGE3144 1998BCJ755 1998CC271 1998CC669 1998CC1931 1998CCR(178)145 1998CEJ1100 1998CL121 1998CL517 1998CRV2599 1998CRV2797 1998EJI419 1998ICA(269)191 1998ICA(274)82 1998ICA(280)8 1998JA823 1998JA1193 1998JA1672 1998JA2843 1998JA3271 1998JA3504 1998JA6175 1998JA6952 1998JOC3673 1998JOC4930 1998JOC6802 1998JOC10060 1998JOM(555)113 1998JOM(564)61 1998JOM(566)217 1998JOM(568)53 1998M221 1998MI515 1998MM5916 1998OM1257 1998OM1812 1998OM2046 1998OM2628 1998OM2924 1998OM3841 1998OM3865 1998OM4784 1998RCB786 1998S552 1998S557 1998T715 1998T1131 1998T7057 1998TL123 1998TL2503 1998TL2787 1998TL4321 1998TL7333 1998TL7695 1998ZFA919 1999ACR494 1999AGE147 1999AGE349 1999AGE870 1999AGE3043
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1297
1298 Five-membered Rings with Other Elements
1999AGE3715 1999BCJ2591 1999CC345 1999CC1437 1999CC1543 1999CC1595 1999CCC1119 1999CCR(193)207 1999CL1127 1999JA476 1999JA1094 1999JA1119 1999JA1245 1999JA2613 1999JA3559 1999JA8313 1999JA8706 1999JA9111 1999JA9744 1999JA10638 1999JA11093 1999JA11223 1999JA11139 1999JA12035 1999JOM(573)139 1999JOM(578)31 1999JOM(578)115 1999JOM(578)125 1999JOM(580)36 1999JOM(588)113 1999JPR801 1999OM197 1999OM206 1999OM215 1999OM1011 1999OM1580 1999OM1882 1999OM1979 1999OM2210 1999OM2331 1999OM2906 1999OM3094 1999OM3558 1999OM3843 1999OM4205 1999OM4234 1999OM4681 1999OM4887 1999PAC1511 2000AC29 2000ACR119 2000AGE314 2000AGE2870 2000AGE2950 2000CC241 2000CC1511 2000CEJ81 2000CEJ2397 2000CL218 2000CL1410
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Five-membered Rings with Other Elements
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1301
1302 Five-membered Rings with Other Elements
2004OM4160 2004OM4391 2004OM4636 2004OM5115 2004OM5188 2004T1269 2004T1281 2004T1287 2004T1317 2004T1345 2004T1393 2004T1401 2004T1417 2004TL595 2004TL2427 2004TL5159 2004TL7633 2004TL9041 2004UK563 2005CRV115 2005JOM(690)972 2005JOM(690)1523 2005JOM(690)3730 2005JOM(690)3755 2005MI1386 2005OL3065 2005OM20 2005OM456 2005OM791 2005OM2065 2005OM2106 2005OM2129 2005OM3047 2005OM4316 2005OM4742 2005OM4793 2005OM4849 2005OM5537 2005OM5916 2005OM6398 2005TL5173 2005TL8869 2006AGE474 2006CCR(250)2 2006ICA(359)1773 2006ICC139 2006ICC375 2006ICC388 2006JCT172 2006JOM(691)1175 2006JOM(691)1945 2006JOM(691)2839 2006JOM(691)3129 2006JOM(691)3596 2006JOM(691)3846 2006JOM(691)4080 2006JOM(691)5831 2006T7589 2006TL3971 2006TL8319 2007JOM(692)55 2007AG(E)5958 2007AG(E)7277
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Five-membered Rings with Other Elements
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1303
1304 Five-membered Rings with Other Elements Biographical Sketch
Alexander P. Sadimenko was born at Rostov-on-Don in 1951. He studied at Rostov State University, where he obtained his M.Sc. in 1973 and Ph.D. in 1976 under the guidance of Professor O. A. Osipov. During 1976–87 he worked as lecturer, senior lecturer, and associate professor at Rostov State University, 1987–91 as associate professor at Addis Ababa University, 1991–94 as associate professor and professor at National University of Lesotho, and 1994 until the present as professor, Head of the Department, and head of Directorate of physical and earth sciences at the University of Fort Hare. His specific interests include all aspects of organometallic chemistry of the heteroaromatic ligands, in particular, materials chemistry aspects.
