Related Titles of Interest Published by Elsevier Books CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry, 2nd edition FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBÉ: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions, 2nd edition KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY, RAMSDEN, JOULE & ZHDANKIN: Handbook of Heterocyclic Chemistry, 3rd Edition KURTI & CZAKO: Strategic Applications of Named Reactions in Organic Synthesis LEVY & TANG: The Chemistry of C-Glycosides LI & GRIBBLE: Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, 2nd Edition MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain McKILLOP: Advanced Problems in Organic Reaction Mechanisms OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works LIU & MANDER: Comprehensive Natural Products II: Chemistry and Biology KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I (CD-Rom) KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, RAMSDEN, SCRIVEN & TAYLOR: Comprehensive Heterocyclic Chemistry III KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations KATRITZKY, TAYLOR: Comprehensive Organic Functional Group Transformations II TROST & FLEMING: Comprehensive Organic Synthesis Our reference works are also available online via www.sciencedirect.com Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY PHYTOCHEMISTRY LETTERS TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier publications: see www.elsevier.com
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Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2010 - 2011 PROFESSOR R.J.K. TAYLOR (CHAIRMAN) University of York, UK
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CHAPTER
1
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids Justin M. Lopchuk Dartmouth College, Department of Chemistry, Hanover, NH 03755, USA
[email protected]
1.1. INTRODUCTION Aspidosperma alkaloids are a subset of the naturally occurring monoterpenoid indole alkaloids that are derived from the fusion of tryptamine and a terpene unit (generally either 9 or 10 carbons). More than 250 different compounds are known and many are of synthetic or biological interest hB-09MI311i. In addition to the significant interest from an organic synthesis perspective, a variety of studies designed toward a better understanding of the biosynthesis of these molecules have become increasingly prevalent in the literature hB-10MI977i. N D E C B A CO2Me N H Aspidosperma skeleton
Aspidosperma terpene unit OH
N
N
N H
H N H R2
R1 1 aspidospermidine (R1 = R2 = H) 2 aspidospermine (R1 = OMe; R2 = Ac)
H N H N H
CO2Me
OH
3 tabersonine
O
4 limaspermine
The synthesis of Aspidosperma alkaloids was previously reviewed in 1998 by Saxton hB-98MI2, B-98MI343i, and a short review of the total syntheses of haplophytine has also been recently published h09AG(I)7480i. This review is not intended to be comprehensive but instead will highlight various strategies for the construction of these complex molecules reported from 2000 to early 2011.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00001-2
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2011 Elsevier Ltd. All rights reserved.
1
2
J.M. Lopchuk
1.2. ASPIDOSPERMINE AND ASPIDOSPERMIDINE Aspidospermine and aspidospermidine (along with tabersonine) are the archetypical members of the Aspidosperma alkaloids. As they comprise the basic core system of the more functional group dense and stereochemically complex members of this family of natural products, they are a popular target and ideal proving ground for new synthetic methods. Heathcock and Toczko reported a racemic synthesis of aspidospermidine in which the key complexity-generating step was the TFA-mediated intramolecular cascade cyclization of precursor 6 to give tetracyclic intermediate 7 in high yield h00JOC2642i. To effect the final ring closure, chloroacetamide 8 was converted to the corresponding iodide. Treatment with silver triflate yielded pentacycle 9 which gave (þ/)-aspidospermidine upon reduction with LiAlH4. O N
NHBoc
O MeO2C
OHC
Et
H N
Et O
i
Cl H
Cl O
6
5
7 O
O
N
ii
H
v
H
H
N H
8
N
N
iii, iv
Cl
N H H
N
9
N Boc
1 aspidospermidine
Reagents: (i) 0.5 M TFA in CH2Cl2, 76%; (ii) TFA:CH2Cl2 (1:1), 88%; ( iii) NaI, acetone; (iv) silver triflate, 86%; LiAlH4, 82%
Marino and coworkers reported an enantioselective synthesis of (þ)-aspidospermidine h02JA13398i in which Boc-protected aniline 10 was converted to intermediate 11 in five steps. Lactone 11 was ring-opened with pyrrolidine to give aldehyde 12 which subsequently underwent an intramolecular aldol reaction followed by conversion to chloroamide 13. When key intermediate 13 was treated with NaH, tricycle 14 was formed via a tandem conjugate addition/intramolecular alkylation cascade. The enone was installed with a modified Saegusa reaction; treatment of 15 with 3 M HCl facilitated deprotection of the aniline which underwent immediate conjugate addition to yield tetracycle 16. The synthesis of (þ)-aspidospermidine was completed by Wolff–Kishner reduction of the ketone and LiAlH4 reduction of the amide carbonyl.
3
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
O
O
i NBoc2
NBoc2
11 p-TolS
10
O
Boc2N 13
Cl
Boc2N 15
N H
iv Boc2N
O
14
O
O N H
O
N
O
O
H N
ii, iii
NBoc2
H 12
O
O
N
vi
O
v
O
N H
O
N H H
16
vii, viii
H N H H 1 (+)-aspidospermidine
Reagents: (i) pyrrolidine, benzene, rt, 86%; (ii) pyrrolidine, 2-propanol, 33% aq. AcOH; (iii) i-BuOCOCl, Et3N, 3-chloropropylamine hydrochloride, THF, 64% (over two steps); (iv) NaH, DMF, 86%; (v) KHMDS, TMSCl, THF, then Pd(OAc)2/O2, DMSO, 80%; (vi) 3M HCl, 2-propanol, reflux, 90%; (vii) H2NNH2–H2O/Na/HOCH2CH2OH, 75%; (viii) LiAlH4, THF, reflux, 90%
An intramolecular Schmidt reaction was utilized by Aube et al. to convert intermediate azide 17 to tricyclic amide 18 with TiCl4 h05JOC10645i. The enantioselective synthesis of aspidospermidine was completed after seven more steps in an overall yield of 1.1% (longest linear sequence, 22 steps). O
O
N3
N TiCl4
H
82% O 17
N
H
H O 18
H N H H 1 (+)-aspidospermidine
Sharp and Zard reported a radial cyclization approach to tricyclic amine 23 which served as a key intermediate in the racemic synthesis of aspidospermidine h06OL831i.
4
J.M. Lopchuk
i, ii
MeO
O
O
CO2Me
O
iii, iv
CO2Me
H N
HO Cl
19
MeO2C O
v
N
MeO2C O
N H
Cl
OH
22
21
20
O OBz
23
Reagents: (i) Li,NH3, t-BuOH, BrCO2t-Bu, THF; (ii) HCl, THF, 90% (over two steps); (iii) a) isobutylchloroformate, Et3N, b) hydroxylamine 21; (iv) BzCl, Et3N, CH2Cl2, 67% (over two steps); (v) Bu3SnH, 1,1¢-azobis(cyclohexanecarbonitrile) [ACCN], 53%
The route to amine 23 began with the Birch reduction of anisole derivative 19 followed by cyclization to yield lactol 20. Radical precursor 22 was treated with ACCN and tributyltin hydride to afford tricyclic amine 23. This radical cyclization was also successfully applied to the Stemona alkaloid core and could see future applications in the synthesis of pyrrolizidine and indolizidine alkaloids. H
O
Cbz N
Me O N Et Me
24
N CO2H
O
H
25
H N
O
ii HN
i
Cbz N
Et 26
H Cbz N
Et
27
Reagents: (i) t-BuLi, LiCl, THF, 67%; (ii) TsOH or Cu(OTf)2, MeCN, 74–91%
Waser recently reported a unique approach that utilized the catalytic cyclization of aminocyclopropanes to generate complex tetracyclic indole scaffolds h10AG(I) 5767i. Indole derivative 24 was coupled with aminocyclopropane 25 to give cyclization precursor 26. Upon treatment with either TsOH or Cu(OTf)2, 26 underwent cyclization to tetracycle 27. In addition to completing a formal synthesis of aspidospermidine, this methodology was used in the total synthesis of goniomitine. Shishido and coworkers utilized a diastereoselective ring-closing metathesis reaction to synthesize ()-aspidospermidine h03OL749i and ()-limaspermine h04H(62)787i.
1.3. ASPIDOFRACTININE Aspidofractinine was initially isolated in 1963 and first synthesized in 1976 by Ban and coworkers. This highly strained molecule has received comparably little recent attention from the synthetic community despite the challenging carbon skeleton. The most recent synthesis of (þ)-aspidofractinine was reported by Gagnon and Spino in 2009 h09JOC6035i. Advanced intermediate 28 was prepared from indole and utilized a ring-closing metathesis as one of the key steps to form the tricycle. The a-bromoketone was converted to a-diazoketone 29 with (TsNH)2 and DBU. Upon treatment with CuOTf, 29 underwent chemoselective cyclopropanation to
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
5
yield 30 in 76% yield. Exposure of 30 to NaI in acetone gave the corresponding iodide which was then treated with AIBN and tributyltin hydride to affect radical cyclization which completed the core pentacyclic structure. O
O
Br
O
N2
N
N
N
Cl N PhO2S
iii, iv
ii
i
Cl
Cl N PhO2S
28 O
N PhO2S
29
O
O N
N
v
30
N
vi, vii SO2Ph
N PhO2S
N
N H
32
31
33
O O
N
N H PhO2S
34
N
N
viii N H
ix N H
35
36 (+)-aspidofractinine
Reagents: (i) (TsNH)2, DBU, THF, 92%; (ii) CuOTf, CH2Cl2, 76%; (iii) NaI, acetone; (iv) AIBN, Bu3SnH, benzene, reflux, 92% (over two steps); (v) anthracene, Na, dimethoxyethane, 96%; (vi) PhSe(O)OH, THF/pyridine (6:1), reflux, 61%; (vii) benzene, heat, 55%; (viii) Rainey nickel, isopropanol, reflux, 67%; (ix) LiAlH4, THF, reflux, 70%
Imine 32 was generated by allowing 31 to react with sodium and anthracene which both removed the protecting group and ring-opened the cyclopropane. Oxidation with phenylseleninic acid installed the double bond in conjugation with the imine, which tautomerized upon heating to reveal a diene fortuitously setup for a Diels–Alder reaction with phenylvinylsulfone. Cycloaddition adduct 34 was desulfurized with Raney nickel in 67% yield; reduction with LiAlH4 completed the synthesis of (þ)-aspidofractinine.
1.4. TABERSONINE Tabersonine was first isolated in 1954 and is believed to be the biosynthetic precursor to most of the Aspidosperma alkaloids including vindoline (and thus also vinblastine and vincristine). Tabersonine is somewhat more complicated than aspidospermidine but necessarily contains the same core structure and so can be accessed by similar methods. A gram-scale asymmetric synthesis of (þ)-tabersonine was reported by Rawal and coworkers in 2002 h02JA4628i. An endo-selective Diels–Alder reaction of aminosiloxydiene 37 and vinyl aldehyde 38 gave cyclohexene 39 in excellent yield. Wittig olefination yielded intermediate 40 which was subjected to ring-closing
6
J.M. Lopchuk
metathesis conditions to generate bicycle 41. An ortho-nitrophenyl group was installed using (ortho-nitrophenyl)phenyliodonium fluoride (NPIF) as the arylating reagent. MeO2C
MeO2C
N
MeO2C
N
i
N
ii
CHO
+ TBSO
CHO
37
TBSO
TBSO
39
38
MeO2C
40
MeO2C N
iii
N
iv
I O2N
TBSO
41
NO2 O
F
43 NPIF
42
Reagents: (i) toluene, 85 °C, 97%; (ii) Ph3PCH3Br, n-BuLi, THF, –78 °C, 85%; (iii) Schrock molybdenum catalyst, benzene, 88%; (iv) NPIF, DMSO/THF, 94%
The indole synthesis was completed by reducing 42 to the intermediate aniline with TiCl3 and NH4OAc which then underwent spontaneous cyclization in 89% yield. The newly generated indole was deprotected with TMSI followed by reaction with 2-bromoethanol to give 45. Attempted conversion of the alcohol to the corresponding mesylate surprisingly gave chloride 46 which smoothly underwent base-promoted cyclization to tetracycle 47. The synthesis of (þ)-tabersonine was completed by deprotonation with LDA and quenching with Mander’s reagent. This proved to be a softer acylating reagent which favored the desired C-acylated product over the N-acylated regioisomer. MeO2C
MeO2C
N
O2N
HO
N
N H
O
42 Cl
N H
44
N
iv
N vi N H
N
46
45
N v
N H
N
ii, iii
i
47
CO2Me
3 (+/-)-tabersonine
Reagents: (i) TiCl3, NH4OAc, THF/H2O, 89%; (ii) TMSI, CH2Cl2, MeOH, 90%; (iii) 2-bromoethanol, Na2CO3, EtOH, 100%; (iv) MsCl, Et3N, CH2Cl2, 90%; (v) t-BuOK, THF, 87%; (vi) LDA, NCCO2Me, –70 °C, 70–80%
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
7
1.5. SUBINCANADINES The subincanadines are a unique subset of the Aspidosperma alkaloids isolated from 2002 to 2005 which have a rearranged pentacyclic skeleton. These molecules have received a considerable amount of attention from synthetic chemists due to their novel skeletons, sparse functionality, and interesting biological activity. Zhai and coworkers reported a synthesis of the pentacyclic core of subincanadine B; the key tetracyclic intermediate was formed in seven steps via a sequence of Michael addition, Pictet–Spengler cyclization, and Dieckmann condensation h06OL115i. The first asymmetric total syntheses of ()-subincanadines A and B were reported in 2006 by Takayama and Suzuki h06OL4605i. Tryptamine 48 and alcohol 49 (derived from (S)-malic acid) were coupled with carbonyldiimidazole to yield hemiaminoacetal 50 which then underwent a TMSCl-promoted intramolecular Pictet–Spengler reaction. Recrystallization gave a single diastereomer in 99% ee. Advanced intermediate 52 was treated with NiCl2 and CrCl2 in DMSO to affect a Nozaki–Hiyama–Kishi reaction which provided two tetracyclic diastereomers 53 and 54. Both diastereomers were deprotected with TMSCl/NaI and converted to the corresponding mesylates which underwent spontaneous cyclization to complete the total synthesis of ()-subincanadines A and B. NH2 48
N H
+
O HO
i
O
O
ii, iii N Me H
N Me H
OH
50
PivO
49
O N
N
51
OPiv
PivO
O
N
N
N N H O
52
iv
Me I OMEM
N Me H HO
+
53
OMEM v, vi
N
N Me H HO
54
OMEM
v, vi
Cl
N
Cl
N Me H HO
N Me H HO
55 (-)-subincanadine A
56 (-)-subincanadine B
Reagents: (i) 1,1⬘-carbonyldiimidazole, CH2Cl2, rt, 83%; (ii) TMSCl, CH2Cl2, –78 °C, quant., d.r. 9:1; (iii) recrystallization, 47%, 99% ee; (iv) NiCl2, CrCl2, DMSO, rt, 53 (35%) and 54 (53%); (v)TMSCl, NaI, MeCN, –30 °C, 82% (vi) MsCl, aq. NaHCO3, CH2Cl2, rt, 58%
8
J.M. Lopchuk
The first total synthesis of subincanadine F was reported by Zhai and coworkers in 2006 h06JOC9495i. This short synthesis began with the cycloaddition of tryptamine 57 and ketoester 58 to yield tetracycle 59 in a single step. Treatment with SmI2 fostered a ring-opening to yield intermediate 60 which was mixed with aqueous formaldehyde to give the homologated ring-closed tetracycle 61. The exocyclic double bond was installed via an aldol condensation with LDA and acetaldehyde (followed by treatment with TFAA, DMAP, and DBU to facilitate the dehydration). Deprotection and decarboxylation with either HCl or AlCl3 then HCl completed the racemic synthesis of subincanadine F. NH2 57 N PMB
N
i
+ O CO2t-Bu
Cl 58
HN
ii
N R PMB O
N R PMB O
59
60
iii
O
N
N
N vi, vii
iv, v N R O PMB
N R O PMB
or vii only
O
63 subincanadine F
62
61
N H
Reagents: (i) MeCN, rt, 75%; (ii) SmI2, THF, 86%; (iii) formalin, HCl, EtOH, 83%; (iv) LDA, MeCHO, THF; (v) TFAA, DMAP, DBU, 94% (over two steps); (vi) AlCl3, benzene, 53%; (vii) HCl, 10% (28% from 62); R = CO2t-Bu
In 2010, Waters and coworkers disclosed their own concise racemic synthesis of subincanadine F h10JOC7026i. This approach is highlighted by the Ti-mediated cyclization of 64 to give Boc-protected tetracycle 65. Deprotection with TFA reveals subincanadine F. N
N Me
N Boc
O
64
OMe
N ii
i N Boc
65
O
N H
O
63 subincanadine F
Reagents: (i) Ti(Oi-Pr)4, i-PrMgCl, Et2O, –78 to 0 °C, 47%; (ii) TFA:CH2Cl2 (1:1), rt, 92%
Other approaches to subincanadine F include a Heck cyclization to the tetracyclic core h10SL944i, a racemic protecting group free synthesis utilizing a Dieckmann condensation h09JOC7533i, and the first asymmetric synthesis of (þ)-subincanadine F which took advantage of a chemoselective radical cyclization to form the core system h10CC8436i.
9
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
1.6. MELOSCINE Meloscine is a structurally rearranged alkaloid closely related to the Aspidosperma family. The structure of meloscine was elucidated in 1969 and first synthesized by Overman in racemic form. No new syntheses of this compound were reported until 2008 when Bach and Selig disclosed the first enantioselective total synthesis of (þ)-meloscine h08AG(I)5082, 09CEJ3509i. Cyclobutane derivative 68 was generated from the regioselective and stereoselective photocyclization of amine 66 and silyl enol ether 67 with chiral complexing agent 70. Intermediate 68 underwent base-promoted rearrangement to give tricycle 69. Bn
N
Boc
CO2Me OTMS
Bn
Boc N O
OMe OTMS
67
66
Boc N O
OH
ii i
N H
Bn
O
68
N H
H NO O
H
H O
69
N H
O
N
70
Reagents: (i) hn (370 nm), chiral additive 70, silyl enol ether 67, toluene, –60 °C, 76%; (ii) K2CO3, MeOH, 20 °C, 98%
After acylation, compound 71 was deprotected with TFA and exposed to hydrogenation conditions which diastereoselectively reduced the enol double bond and induced cyclization of the amine (which was then reprotected with Boc2O) to yield tetracycle 72. Alcohol 73 was generated by a sequence of acetate hydrolysis, oxidation with IBX, Wittig olefination, and DIBAL-H reduction in 60% yield over the four steps. Boc N O Bn
Boc N H OAc
OAc i–iii
71
72
N H
CO2Me
N H
N H
O
H O
73
OH
N xi–xiii
N H
H O
N xiv–xvi
H
74
viii–x
iv–vii
H O
N H
OH
Boc N H
75
N H
H O
H N O H 76 (+)-meloscine
Reagents: (i) TFA, CH2Cl2; (ii) H2, Pd(OH)2/C, MeOH; (iii) Boc2O, Et3N, CH2Cl2, 78% (over three steps); (iv) K2CO3, MeOH, 94%; (v) IBX, DMSO, 94%; (vi) Ph3PCHCO2Et, THF, reflux, 84%; (vii) DIBAL-H, CH2Cl2, 81%; (viii) MeC(OMe)3, hydroquinone, 85% (d.r. 70:30); (ix) TFA, CH2Cl2; (x) allyl bromide, K2CO3, MeCN, 65% (over two steps); (xi) Grubbs II catalyst, toluene, 95%; (xii) DIBAL-H, CH2Cl2; (xiii) NaBH4, EtOH, 70% (over two steps); (xiv) TsCl, Et3N, CH2Cl2, 70%;(xv) 2-nitrophenylselenocyanate, NaBH4, EtOH, 98%; (xvi) TFA, 75% m-CPBA, CH2Cl2, 86%
10
J.M. Lopchuk
Intermediate alcohol 73 was converted to the methyl ester with trimethyl orthoacetate and hydroquinone in 85% yield. The amine was deprotected with TFA and converted to diene 74 with allyl bromide. Exposure to Grubbs II catalyst affected ring-closing metathesis which gave the core skeleton in near quantitative yield. The methyl ester was reduced in a two-step sequence with DIBAL-H and NaBH4 to yield intermediate 75. The resulting alcohol was eliminated to complete the enantioselective synthesis of (þ)-meloscine in 15 steps and 7% overall yield.
N CO Me 2
CO2Me O N
N CO Me 2 ii
i
76
NH NH2
78 O
77
N
79 H
O
Reagents: (i) propiolic acid, EDC–HCl, CH2Cl2, 83%; (ii) Co2(CO)8, MeCN, then trimethylamine N-oxide, 56%
A racemic synthesis of meloscine was reported by Mukai and coworkers which coupled aniline derivative 77 with propiolic acid using EDC h11OL1778i. Intermediate 78 was treated with Co2(CO)8 to facilitate the intramolecular Pauson–Khand reaction which generated tetracycle 79 in one step. This intermediate was further elaborated to give (þ/)-meloscine.
1.7. MISCELLANEOUS APPROACHES TO THE GENERAL ASPIDOSPERMA CORE Owing to the congested pentacyclic core structure of the Aspidosperma alkaloids, general approaches to this family of natural products are frequently reported in the literature. A few of these methods are outlined below. R N
t-BuOK, THF, 80 °C
R N Strychnos, Aspidosperma, and Iboga alkaloids
R = Bn, PMB, DMB N H
CHO 80
N H CHO H 81
Vanderwal and Martin reported a general approach to the core structure of the Aspidosperma, Strychnos, and Iboga alkaloids h09JA3472i in which tethered diene 80 underwent intramolecular Diels–Alder reaction with the indole double bond to yield tetracycle 81. The double bond migrated under the basic reaction conditions to remain in conjugation with the aldehyde. This method was utilized successfully in the total synthesis of norfluorocurarine. In 2008, Ishikawa, Saito, and coworkers reported the base-promoted condensation of substituted ketones and vinyl esters to yield a variety of cyclic ketones with quaternary carbon centers (82 and 83) h08JOC7498i. This approach proved exceedingly flexible and was utilized in the total synthesis of (þ)-aspidospermidine, (þ/)-galanthamine, (þ/)-lycoramine, and (þ/)-mesembrine.
11
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
+
O
O
R
i
N
ii
O
H R
R
O
Et
83
82
N H
Ph
N H H 1 (+)-aspidospermidine
Reagents: (i) t-BuOK, t-BuOH, THF; (ii) Zn(OTf)2, (S)-1-phenylethylamine, MeCN, 99%; R = CO2t-Bu
Coldham and coworkers reported an efficient synthesis of tricyclic amines that are useful intermediates in the synthesis of a variety of alkaloids h07AG(I)6159, 09JOC2290i. Simple ketone 84 was converted into cascade precursor 85 in just four steps. With the addition of glycine and camphorsulfonic acid (CSA) to 85, a cyclization/cycloaddition cascade proceeded to give tricyclic amine 86 after deprotection with HCl. This versatile approach was used to successfully synthesize aspidospermine, aspidospermidine, and quebrachamine. O
O
O
O
H
i, ii CHO Br
H
Br
N
Cl
84
86
85
Reagents: (i) H2NCH2CO2H, toluene, camphorsulfonicacid, heat, 79%; (ii) 5%aq.HCl, THF, 89%
Various other approaches have been reported, including the use of chiral cyclopentanoids as starting materials h09H(77)855i, 1,3-dipolar cycloadditions of diazo imides with tethered indole h09TL3675i, intramolecular imino Diels–Alder reactions h10OL2012i, intramolecular Heck reactions h07OL3101, 08CPB1567i, Ullmann cross-coupling reactions h05OBC213, 05AJC722i, reductive radical cyclizations h04T3273i, and palladium-catalyzed oxidative amination cascades h07OL3913i.
1.8. VINDOLINE, VINBLASTINE, AND VINCRISTINE The significant synthetic interest in vinblastine and vincristine is due to both their clinical use and structural complexity. Vindoline comprises the more complex half of vinblastine and is a popular target for researchers. OH N N MeO
H OH N Me
Et OAc
CO2Me
87 vindoline
N H MeO2C MeO
N OH N R
Et
OAc CO2Me
88 vinblastine (R = Me) 89 vincristine (R = CHO)
12
J.M. Lopchuk
Murphy and coworkers reported a formal synthesis of vindoline h02OL443i which relies on a tandem radical cyclization to produce the key tetracyclic intermediate (the same group has also published a total synthesis of (þ/)-aspidospermine using radical chemistry h99JCS(P1)995i). In 2007, Fukuyama reported the synthesis of ()-vindoline h00SL883i. They expanded upon this work with their total synthesis of (þ)-vinblastine and generated a number of analogs which were evaluated for biological activity h07OL4737i. Much of the work toward the total synthesis of these alkaloids has been completed by the Boger group who have developed a tandem [4 þ 2]/[3 þ 2] cycloaddition of a 1,3,4-oxadiazole as the key complexity building step h05OL4539, 06JA10596i. Key intermediate 92 in Boger’s synthesis of vindoline was generated by the coupling of indole 90 and acid 91 with EDC and DMAP in high yield. The tandem cyclization proceeded smoothly first with a Inverse Electron Demand Diels–Alder reaction, loss of N2 to generate the carbonyl ylide 94, followed by the 1,3-dipolar cycloaddition to yield the advanced pentacycle 95. O NH
MeO
HO2C
N
O N Me
N Me BnO
O
H
N Me
MeO
CO2Me 91
90
N N BnO CO2Me
H
92
O
O
N
N
ii MeO
N O N Et N Me OBn CO2Me
[4+2] cycloaddition
MeO
– N2
N Me
O
iii O
MeO
iv–vi
Et OBn
O N Me
CO2Me 95
O
CO2Me 97
CO2Me
OTIPS
N Et OAc
Et OBn
96
OTIPS
N MeO
OTIPS
N
MeO N Me
Et OBn CO2Me
O
N
[3+2] cycloaddition
O
94
93
N Me
Me
i
+
N
vii
MeO
viii, ix OH N Me
Et OAc
88
CO2Me 98
Reagents: (i) EDC–DMAP, 96%; (ii) triisopropylbenzene, 230 °C, 20 h; (iii) LDA, (TMSO)2, TIPSOTf, 64%; (iv) Lawesson reagent, 70%; (v) Rainey nickel, 91%; (vi) Ac2O, 97%; (vii) 45psiH2, PtO2, MeOH–EtOAc, 98%; (viii) TBAF, 89%; (ix) PPh3, DEAD, THF, 75%
This impressive sequence forms four new carbon–carbon bonds, three rings, and six stereocenters all in a single step. Compound 95 was further elaborated by installation of an OTIPS group at C7, sulfurization, and desulfurization to remove the
13
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
carbonyl group. The concise synthesis of (þ) and () vindoline was completed by reductive cleavage of the bridging oxygen and Mitsunobu elimination to install the final double bond. A similar synthetic plan was also utilized in the total synthesis of ()- and (þ)-4-desacetoxy-5-desethylvindoline h07H(72)95i, minovine h05OL741i, and aspidoalbidine h10JA3009i. Boger and coworkers later reported an improved asymmetric total synthesis of vindoline which took advantage of a shortened tether to significantly improve the key cycloaddition cascade h10JA3685, 10JA13533i. MOMO O H
Et
O [4+2]/[3+2] cycloaddition cascade
OBn
N N N N Me CO2Me O
MeO
OH N Me
O xylene 150 °C,10 h
MeO
55% two steps
99
OMOM N Et
OBn CO2Me 101
OMOM N
NaBH3CN i 20% HOAc- PrOH
MeO Et
O N Me
OBn CO2Me
100
Other improvements in the synthesis included a ring-expansion/Kornblum oxidation sequence to generate pentacycle 104 from bridged intermediate 103. O
OH
OMOM
MeO
MeO M
MeO OH N Me
Et
OAc CO2Me
102
OH
N
N
N
O N Me
103
OH
Et
OAc CO2Me
N Me
Et
OAc CO2Me
104
The total synthesis of vinblastine by the direct coupling of catharanthine 105 and vindoline has been explored by a number of research groups over the past 35 years. Most synthetic routes required numerous steps or yielded either multiple diastereomers or a reduced version of vinblastine. Boger and coworkers were able to develop a one-pot direct coupling of catharanthine 105 and vindoline 87 to give (þ) and ()-vinblastine 88 h08JA420, 09JA4904i. The reaction proceeded in 66% overall yield giving a 2:1 mixture of diastereomers (b-OH was the major diastereomer).
14
J.M. Lopchuk
N MeO Et OAc CO2Me
OH N Me
OH
2:1
N 1) FeCl3, rt, 2 h 2) Fe2(ox)3–NaBH4 air, 0 ⬚C, lutidine
87 Vindoline
H N H MeO2C MeO
66% overall yield (2:1 mixture)
+
N Et OAc CO2Me
OH N Me
N N H
88 Vinblastine CO2Me Et
105 Catharanthine
1.9. ASPIDOPHYTINE AND HAPLOPHYTINE Aspidophytine and haplophytine are two of the constituents of a traditional insecticidal powder used in various parts of Mexico and Central Mexico. However, it was not until the 1960s that the structures were finally elucidated and took until 1999 for the first total synthesis of aspidophytine to be reported by Corey h99JA6771i. This remarkable synthesis relies on the coupling of tryptamine derivative 108 and dialdehyde 109 and subsequent cascade which constructs three new rings and three stereocenters, including a quaternary center in one step.
N
O O
MeO
HO
O
N H OMe Me
Me N N
N O
MeO
106 Aspidophytine
N H OMe Me
107 Haplophytine CHO
NH2
MeO
N OMe Me
108
OHC
Me3Si
O
O
O N H
O
109
O
O MeO
N H OMe Me
110
Reagents: aldehyde 109, MeCN, 23 ⬚C, then TFAA, 0 °C, then NaBH3CN, 23 ⬚C, 66%
15
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
Fukuyama and coworkers disclosed their own enantioselective total synthesis of aspidophytine which utilized a Sonogashira coupling to join iodoindole 111 with chiral acetylene 112 h03OL1891, 03T8571i. The chiral acetylene was made in 11 steps starting from cyclopentenone. OAc
OAc OTBDPS EtO2C
I MeO OMe
OTBDPS
CH(OMe)2
112
N H
MeO
Pd(PPh3)4, CuI, Et3N, 70 ⬚C 78%
111
OMe
N H
CH(OMe)2 EtO2C
113
Advanced intermediate 113 was further elaborated by a cis-selective reduction of the triple bond and a key step which involved an intramolecular Mitsunobu reaction of the o-nosyl protected amine and pendant alcohol to yield macrocycle 115. An intramolecular Mannich reaction and lactonization completed the synthesis of 116. NsHN
MeO OMe
Ns
OH R
N
CO2Et
N Boc
N R
i
CO2Et MeO OMe
114
N Boc
CO2Et
ii, iii, iv
H N
MeO OMe
116
115
Reagents: (i) PPh3, DEAD, PhH, rt, 92%; (ii) TMSBr, CH2Cl2, –78 ⬚C, 92%; (iii) PhSH, Cs2CO3, MeCN, 55 ⬚C; (iii) TFA, Me2S, CH2Cl2, rt, then pH 7.8 buffer, 56% (over 2 steps); R = CH(OMe)2; Ns = nitrophenylsulfonyl
Marino and Cao utilized chemistry developed during their work on aspidospermidine which allowed them to take functionalized intermediate 117 to the pentacyclic core 119 of aspidophytine in just three steps including a tandem conjugate addition/intramolecular alkylation followed by a modified Saegusa reaction h06TL7711i. MeO
O
MeO
O
N
Cl
i, ii Boc2N
O H
iii
HN OBn O
OBn H
OBn MeO
117
N
MeO
NBoc2
O
118
MeO
N H OMe CHO
Reagents: (i) NaH, DMF, 0 ⬚C, 88%; (ii) KHMDS, TMSCl, THF, then Pd(OAc)2/O2, DMSO, 60 ⬚C, 85%; (iii) HCO2H, rt, 90%
O
119
16
J.M. Lopchuk
Further functional group manipulation and lactonization completed the synthesis of aspidophytine. Padwa and coworkers took advantage of a different strategy that utilized their well-developed Rh(II)-catalyzed cyclization/dipolar cycloaddition chemistry h06OL3275, 06TL8387, 08HCA285i. Indole acetic acid derivative 120 and diazo compound 121 were joined with (COCl)2 (via the acid chloride) to yield key precursor 122. Upon treatment with Rh2(OAc)4, intermediate 122 underwent decomposition of the diazo group and cyclization to form carbonyl ylide 123. A facile intramolecular [3 þ 2]-dipolar cycloaddition of the carbonyl ylide with the indole double bond proceeded smoothly and was followed by treatment with BF3–OEt2 to effect lactonization which completed the construction of the core ring system. The synthesis was finished in eight more steps by installing the C-ring double bond and removal of the E-ring carbonyl. O CO2H
HN
+ MeO
N OMe Me
CO2t-Bu
N
O N2
O MeO
CO2Me
120
121
O
O N
CO2t-Bu
i
CO2t-Bu
N
N OMe Me
O N2
122
O CO2Me
O
CO2t-Bu O
O
iii
N OMe Me
O CO2Me
123
MeO
N H CO2Me OMe Me
124
N
O O OH N H CO2Me OMe Me O
O MeO
ii
MeO
125
Reagents: (i) (COCl)2, CH2Cl2, then 121, DMAP, THF, 73%; (ii) Rh(OAc)2, PhH, reflux, 97%; (iii) BF3–OEt2, CH2Cl2, 94%
The most recent asymmetric total synthesis reported by Nicolaou et al. accessed intermediate 128 by Suzuki coupling of known indole boronic acid 126 with vinyl iodide 127 h08JA14942i. Treatment of 128 with Tf2O induced a 6-exo-trig-cyclization followed by reduction of the isolable iminium 129 gave tetracyclic compound 130. The primary alcohol was deprotected and converted to xanthate 131, which, upon exposure to n-Bu3SnH and AIBN, underwent radical cyclization to yield pentacycle 132 as a single diastereomer in 58% yield. The synthesis of aspidophytine was completed by TBAF-mediated hydrolysis and oxidative lactonization with K3Fe (CN)6 in a single pot.
17
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
TBSO TBSO B(OH)2 MeO
N OMe Me
O
i
+
O I
CO2TMSE CO2TMSE
126
TBSO
N
N H
CO2TMSE
ii MeO
N OMe Me
MeO
127
TBSO
N
N
N OMe Me
MeO
129
128
CO2TMSE
N OMe Me
130
S MeS
O
N
N H
iii, iv
CO2TMSE
N OMe Me
MeO
CO2TMSE
v
H MeO
131
N H OMe Me
132
Reagents: (i) PdCl2(dppf), Cs2CO3, DMF/H2O (10:1), 25 °C, 12 h, 86%; (ii) Tf2O, DTBMP, CH2Cl2, 25 °C, then NaBH4, MeOH, 0 °C, 88%, >95:5 d.r.; (iii) HF-pyridine, THF, 25 °C; (iv) NaH, CS2, THF, –78 °C to rt, then MeI, 83%(over two steps); (v) n-Bu3SnH, AIBN (cat.), PhH, 85 °C, 58%; TMSE = trimethylsilylethyl; DTBMP = 2,6-di-tert-butyl-4-methylpyridine
Due to the precedent of direct coupling between vindoline and catharanthine, it is not unreasonable to expect that aspidophytine and the left-hand domain of haplophytine could be coupled together as well. Toward this end, Corey and coworkers examined model systems designed to probe this problem h06OL3117i. Unfortunately, this biomimetic route remains a significant unsolved challenge. Haplophytine has long been known to undergo HBr-mediated rearrangement to give 133; researchers working toward the total synthesis of haplophytine used this rearrangement to great effect when constructing the left-hand portion of the molecule.
O HO
Me N N
N O
O
O
aq. HBr aq. NaHCO3
MeO
N H OMe Me
107 Haplophytine
O HO
N
Me N OH
MeO
133
N CO2H
N H OMe Me
18
J.M. Lopchuk
Despite the first total synthesis of aspidophytine being achieved in 1999, it remained another decade before the first total synthesis of haplophytine was reported in 2009 by Fukuyama and Tokuyama nearly 60 years after it was initially isolated h07SL3137, 09AG(I)7600i. OH NsHN O
CO2Et
Ns N OHC
OH i–iii
10 steps
O
O CO2Et
O
134
N iv, v H CO2Et
O
O
CO2Me
136
135
137
Reagents: (i) MesSO2Cl, CH2Cl2/pyridine, 0 °C; (ii) PCC, CH2Cl2, 79%; (iii) Cs2CO3, MeCN, 70 °C, 87%; (iv) 1M HCl, THF, 50 °C; (v) PhSH, Cs2CO3, MeCN, 50 °C, then silica gel, CH2Cl2, then TMSCHN2, NH4Cl, MeOH, 83%; Mes = 2,4,6-trimethylphenyl; Ns = ortho-nitrophenylsulfonyl
Tricyclic ketone 137 was prepared from diol 135 (itself prepared in 10 steps from commercially available ketone 134) by a regioselective sulfonylation of the less sterically hindered alcohol followed by PCC oxidation of the other alcohol. The intermediate was treated with Cs2CO3 which promoted intramolecular N-alkylation to give amine 136. Deprotection of the ketone and ethyl ester was achieved by treatment with 1 M HCl. The nosyl group was removed with PhSH, which set the stage for the intramolecular Mannich reaction. The cyclization proceeded upon treatment of the amine with silica gel followed by the addition of trimethylsilyldiazomethane to give tricyclic ketone 137. The second part of the synthesis commenced with 7-benzyloxyindole which was converted to tetrahydro-b-carboline 139 over 10 steps. A further six steps gave key intermediate 140 which was treated with m-CPBA to trigger a skeletal rearrangement in 84% yield. FmocHN 10 steps
H NCbz CO2Me
N H
OMe OMe
Six steps
NCbz
N H
OBn
OMs
138
N
139
i
140
OMs O
FmocHN
OMe
FmocHN
OMe
Cbz N
O
OMe
OMe
O NCbz
O NCbz
N O
142
143
MsO
N OMs O
N
141
OMs O
NHFmoc
MeO
Reagents: (i) m-CPBA, NaHCO3, CH2Cl2, rt, 84%
OMe
19
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
Key intermediate 144 was deprotected and condensed with tricyclic ketone 137 to ultimately yield Fischer indole product 145 in 47% yield. Treatment of 145 with phenylselenyl anhydride installed the desired C-ring double bond in compound X; removal of the Cbz group was achieved with BBr3. Imine reduction and reductive methylation were achieved with formaldehyde, NaBH3CN, and AcOH, while basic hydrolysis removed the mesyl and methyl ester groups. Cbz
Cbz N
O
N
N O
MsO
MeO
144
NHNH2
MsO
N
N O
MsO
CO2Me H
H O
CO2Me
N CO2Me
N
MeO OMe
Me N
O H
146
145
OMe
Cbz N N O
N
MeO
137
OMe
O
iii
i, ii
+
N
O
iv–vii
HO
N
N O
O MeO
O
N H OMe Me
107 haplophytine
Reagents: (i) 50% aq. H2SO4, dioxane, 0 °C, 80%; (ii) p-TsOH, t-BuOH, 80 °C, 47%; (iii) (PhSe)2O, THF, reflux, 61%; (iv) BBr3, pentamethylbenzene, CH2Cl2, 67%; (v) 37% HCHO, NaBH3CN, AcOH, CH2Cl2/MeOH, 55%; (vi) 1M NaOH, MeOH, 60 °C; (vii) K3[Fe(CN)6], NaHCO3, t-BuOH/H2O, 70% (over two steps)
Finally, the lactone ring was closed with potassium ferricyanide to yield (þ)-haplophytine. In 2007, Nicolaou and coworkers reported a synthesis of the “left domain” of haplophytine h07AG(I)4715i. This work, along with their prior synthesis of aspidophytine, was utilized to provide the second total synthesis of (þ)-haplophytine h09AG(I)7616i. A second generation formal synthesis was reported in 2011 by Chen and coworkers h11EJO1027i.
20
J.M. Lopchuk
N CO2Me OH N Cbz CO2Me N H
i
+
HO OH
OAc
147
N Cbz CO2Me
148
N H OAc
N
CO2Me
ii
O
N CO2Me
149
CO2Me N OMe
CO2Me N OMe
OMe OMe
iii–v
O
OAc
N
N OBn
150
BnO
x
153
N OMe CO2Me
BnO
O
152
Cbz N
O
N O
MeO
OBn
151
Cbz N
O
ix
N Cbz
N Cbz CO2Me
N Cbz CO2Me N H
OMe
vi–viii
N O
MeO
154
N OMe CO2Me
Reagents: (i) phenyliodine-bis-trifluoroacetate, MeCN, 11.5%; (ii) Cs2CO3, MeI, DMF, 76%; (iii) K2CO3, MeOH; (iv) Cs2CO3, BnBr, DMF, 70% (over two steps); (v) Cs2CO3, MeI, DMF, 65%; (vi) 2 M aq. LiCl, EtOH; (vii) (COCl)2, DMF, benzene; (viii) Hunig's base, benzene, 60% (over three steps); (ix) m-CPBA, NaHCO3, CH2Cl2, 78%; (x) DDQ, benzene, 63%
Tetrahydro-b-carboline 147 (accessed from 7-benzyloxyindole in nine steps) was treated with indoline 148 and phenyliodine-bis-trifluoroacetate in acetonitrile to yield intermediate 149 in 11.5% yield (based on the consumption of 148). Methylation of the phenol gave 150 which underwent hydrolysis of the acetyl group, reprotection with a benzyl group, and finally cleavage of the N,O-acetal with Cs2CO3 and a large excess of methyl iodide to give intermediate 151. Lactam 152 was generated by a sequence of ester hydrolysis, acid chloride formation, and cyclization. Upon treatment with m-CPBA, the skeletal rearrangement proceeded smoothly in 78% yield; the indole double bond was introduced with DDQ to give compound 154.
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
N Cbz N
O BnO
TBSO
N O
OTBS
O I
127
MeO
155
CO2TMSE
O BnO
i
BPin N OMe CO2Me
21
Cbz N
N
N O
O CO2TMSE
N OMe H
MeO
156 Cbz N
O
N
N
BnO
O
H
CO2TMSE
107
N OMe Me
MeO
157
Reagents: (i) [Pd(dppf)Cl2], Ph3As, TlOEt, DMSO, 67%; pin = 2,3-dimethylbutane-2,3-diolate
Boronic ester 155 was coupled with vinyl iodide 127 to produce advanced intermediate 156. The remainder of the synthesis is similar to the chemistry discussed for the total synthesis of aspidophytine; a radical cyclization generated core structure 157 which was taken over six steps to (þ)-haplophytine.
1.10. CONOPHYLLINE AND CONOPHYLLIDINE Conophylline and conophyllidine are bis-indole alkaloids which possess two pentacyclic Aspidosperma core units. They were first isolated in 1992 and have shown both anticancer activity as well as some antidiabetic effects. This biological activity, along with their challenging complex structures, certainly merits attention from the synthetic community. CO2Me
O H N
H N
NH
HO
O N
H OH
N H
NH
HO
O N
MeO MeO
CO2Me
MeO
OH
MeO CO2Me
158 (-)-conophylline
H
N H
CO2Me
159 (-)-conophyllidine
Two of the core indole units of conophylline were synthesized by Otsuka and coworkers from simple benzene derivatives h08JHC1803i. The first total synthesis of ()-conophylline and ()-conophyllidine was completed in 2011 by Fukuyama
22
J.M. Lopchuk
and coworkers which utilized a Polonovski–Potier reaction as a key step to join the two main pentacyclic units h11AG(I)4884i. OH HO
CO2Me
MsO
MeO
CO2Et
MeO
MsO
NC
OH
OMe
160
161
MeO OMe
N CO2Me Boc
162
The synthesis of ()-conophylline commenced from benzene derivative 160 which was converted to isocyanide 161 in 11 steps. Treatment of 161 with n-Bu3SnH, AIBN, and I2 promoted a radical cyclization to form the indole ring system which was further elaborated to yield 162. OH MsO
+
O
N H
163
MeO
Et
N Boc
CO2Me
164
162
OH
DNs N
MsO
ii
O
MeO
i
Et
N CO2Me OMe Boc
MeO
DNs N
MsO DNs
O
MsO OH
MeO
N MeO
Et
MeO
Et
N H
MeO CO2Me
165
N H
166
MsO MeO N H
167
H
N
iv–vi
MeO MeO
CO2Me
CO2Me
MsO
OH N
MeO
iii
N Troc
H
O
CO2Me
168
Reagents: (i) PPh3, DEAD, benzene, 76%; (ii) TFA, Me2S, CH2Cl2; (iii) pyrrolidine, MeOH/MeCN (5:1), 65% (over two steps); (iv) PPh3, CCl4, 2-methyl-2-butene, MeCN, 35%; (v) TrocCl, t-BuOK, DMAP, THF; (vi) m-CPBA, aq. HClO4, MeOH, 42% (over two steps); Troc = 2,2,2-trichloroethoxycarbonyl
Functionalized indole 162 was coupled with dihydrofuran 163 under Mitsunobu conditions to give 164 in 76% yield; the product was exposed to TFA which both deprotected the indole and hydrated the enol ether. Intermediate 165 was treated with pyrrolidine to cleave the 2,4-dinitrobenzenesulfonyl (DNs) group and initiate a cyclization cascade (enamine formation, Michael addition, and Mannich reaction) to furnish advanced pentacycle 167. After indole 167 was reprotected with TrocCl and DMAP, a regioselective dehydration and stereoselective epoxidation were
23
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
achieved in one-pot with m-CPBA and aq. HClO4. The structure of 168 was confirmed by a global deprotection that gave ()-taberhanine, a known indole alkaloid. MsO MeO MeO
O N
MsO N
N Troc
H
O
i
MeO MeO
169
CO2Me
170
CO2Me H N
N MeO
H
O
CO2Me
CO2Me
O H N
NH
NH
iv
iii OAllyl
O
ii
CO2Me
O
NH
MsO
H
N H
N Troc
168
H N
AllylO
O
+
CO2Me
O
N H
MsO
HO
O N
MeO
O N
H
MeO
H
OH MeO
N Troc
MeO CO2Me
171
N Troc
OH MeO
CO2Me
172
N H
CO2Me
158 (-)-conophylline
Reagents: (i) m-CPBA, CH2Cl2; (ii) TFAA, CH2Cl2, 50% (over two steps); (iii) [Pd(PPh3)4], pyrrolidine, CH2Cl2, 76%; (iv) LDA, THF, 72%
Oxidation with m-CPBA converted 168 to the corresponding N-oxide 169. A similar synthetic route was utilized to generate pentacycle 170. With both halves of conophylline in hand, the key step, a Polonovski–Potier reaction, could be investigated. Upon exposure to trifluoroacetic anhydride, the electron-rich arene in 170 intercepted the newly generated iminium ion in 169 to give coupled product 171 as a single diastereomer in 50% yield. The ring-closing reaction was achieved by treatment with [Pd(PPh3)4], and exposure to LDA removed both the mesyl and Troc groups to complete the synthesis of ()-conophylline.
REFERENCES B-98MI343 B-98MI2 B-09MI311 B-10MI977 99JA6771 99JCS(P1)995 00JOC2642 00SL883
J.E. Saxton, Synthesis of the aspidosperma alkaloids. (Ed: G.A. Cordell), Vol. 50, p. 343. Academic Press, San Diego, 1998. J.E. Saxton, Alkaloids of the aspidospermine group. (Ed: G.A. Cordell), Vol. 51, p. 2. Academic Press, San Diego, 1998. P.M. Dewick, Alkaloids. in Medicinal Natural Products: A Biosynthetic Approach (Ed: P.M. Dewick), 3rd Edition,. p. 311. John Wiley & Sons, Ltd., New York, 2009. S.E. O’Connor, Alkaloids. (Eds: L. Mander and H.-W. Liu), Vol. 1, p. 977. Elsevier, Ltd., Kidlington, 2010. F. He, Y. Bo, J.D. Altom, E.J. Corey, J. Am. Chem. Soc. 1999, 121, 6771. O. Callaghan, C. Lampard, A.R. Kennedy, J.A. Murphy, J. Chem. Soc., Perkin Trans. 1999, 1, 995. M.A. Toczko, C.H. Heathcock, J. Org. Chem. 2000, 65, 2642. S. Kobayashi, Y. Ueda, T. Fukuyama, Synlett 2000, 6, 883.
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J.M. Lopchuk
02JA4628 02JA13398 02OL443 03OL749 03OL1891 03T8571 04H(62)787 04T3273 05AJC722 05JOC10645 05OBC213 05OL741 05OL4539 06JA10596 06JOC9495 06OL115 06OL831 06OL3117 06OL3275 06OL4605 06TL7711 06TL8387 07AG(I)4715 07AG(I)6159 07H(72)95 07OL3101 07OL3913 07OL4737 07SL3137 08AG(I)5082 08CPB1567 08HCA285 08JA420 08JA14942 08JHC1803 08JOC7498 09AG(I)7480 09AG(I)7600 09AG(I)7616 09CEJ3509 09H(77)855 09JA3472 09JA4904 09JOC2290
S.A. Kozmin, T. Iwama, Y. Huang, V.H. Rawal, J. Am. Chem. Soc. 2002, 124, 4628. J.P. Marino, M.B. Rubio, G. Cao, A. de Dios, J. Am. Chem. Soc. 2002, 124, 13398. S-z. Zhou, S. Bommezijn, J.A. Murphy, Org. Lett. 2002, 4, 443. Y-i. Fukuda, M. Shindo, K. Shishido, Org. Lett. 2003, 5, 749. S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama, Org. Lett. 2003, 5, 1891. S. Sumi, K. Matsumoto, H. Tokuyama, T. Fukuyama, Tetrahedron 2003, 59, 8571. Y. Fukuda, M. Shindo, K. Shishido, Heterocycles 2004, 62, 787. H. Tanino, K. Fukuishi, M. Ushiyama, K. Okada, Tetrahedron 2004, 60, 3273. M.G. Banwell, D.W. Lupton, A.C. Willis, Aust. J. Chem. 2005, 58, 722. R. Iyengar, K. Schildknegt, M. Morton, J. Aube, J. Org. Chem. 2005, 70, 10645. M.G. Banwell, D.W. Lupton, Org. Biomol. Chem. 2005, 3, 213. Z.Q. Yuan, H. Ishikawa, D.L. Boger, Org. Lett. 2005, 7, 741. Y. Choi, H. Ishikawa, J. Velcicky, G.I. Elliot, M.M. Miller, D.L. Boger, Org. Lett. 2005, 7, 4539. H. Ishikawa, G.I. Elliot, J. Velcicky, Y. Choi, D.L. Boger, J. Am. Chem. Soc. 2006, 128, 10596. P. Gao, Y. Liu, L. Zhang, P.-F. Xu, S. Wang, Y. Lu, M. He, H. Zhai, J. Org. Chem. 2006, 71, 9495. Y. Liu, S. Luo, X. Fu, F. Fang, Z. Zhuang, W. Xiong, X. Jia, H. Zhai, Org. Lett. 2006, 8, 115. L.A. Sharp, S.Z. Zard, Org. Lett. 2006, 8, 831. P.D. Rege, Y. Tian, E.J. Corey, Org. Lett. 2006, 8, 3117. J.M. Mejia-Oneto, A. Padwa, Org. Lett. 2006, 8, 3275. K. Suzuki, H. Takayama, Org. Lett. 2006, 8, 4605. J.P. Marino, G. Cao, Tetrahedron Lett. 2006, 47, 7711. X. Hong, J.M. Mejia-Oneto, A. Padwa, Tetrahedron Lett. 2006, 47, 8387. K.C. Nicolaou, U. Majumder, S.P. Roche, D.Y.-K. Chen, Angew Chem. Int. Ed. 2007, 46, 4715. I. Coldham, A.J.M. Burrell, L.E. White, H. Adams, N. Oram, Angew. Chem. Int. Ed. 2007, 46, 6159. H. Ishikawa, D.L. Boger, Heterocycles 2007, 72, 95. J. Pereira, M. Barlier, C. Guillou, Org. Lett. 2007, 9, 3101. R. Beniazza, J. Dunet, F. Robert, K. Schenk, Y. Landais, Org. Lett. 2007, 9, 3913. T. Miyazaki, S. Yokoshima, S. Simizu, H. Osada, H. Tokuyama, T. Fukuyama, Org. Lett. 2007, 9, 4737. K. Matsumoto, H. Tokuyama, T. Fukuyama, Synlett 2007, 20, 3137. P. Selig, T. Bach, Angew. Chem. Int. Ed. 2008, 47, 5082. Y. Yasui, H. Takeda, Y. Takemoto, Chem. Pharm. Bull. 2008, 56, 1567. J.M. Mejia-Oneto, A. Padwa, Helv. Chim. Acta 2008, 91, 285. H. Ishikawa, D.A. Colby, D.L. Boger, J. Am. Chem. Soc. 2008, 130, 420. K.C. Nicolaou, S.M. Dalby, U. Majumder, J. Am. Chem. Soc. 2008, 130, 14942. S. Ando, Y. Okamoto, K. Umezawa, M. Otsukam, J. Heterocycl. Chem. 2008, 45, 1803. T. Ishikawa, K. Kudo, K. Kuroyabu, S. Uchida, T. Kudoh, S. Saito, J. Org. Chem. 2008, 73, 7498. E. Doris, Angew. Chem. Int. Ed. 2009, 48, 7480. H. Ueda, H. Satoh, K. Matsumoto, K. Sugimoto, T. Fukuyama, H. Tokuyama, Angew. Chem. Int. Ed. 2009, 48, 7600. K.C. Nicolaou, S.M. Dalby, S. Li, T. Suzuki, D.Y.-K. Chen, Angew Chem. Int. Ed. 2009, 48, 7616. P. Selig, E. Herdtweck, T. Bach, Chem. Eur. J. 2009, 15, 3509. M. Hayashi, K. Motosawa, A. Satoh, M. Shibuya, K. Ogasawara, Y. Iwabuchi, Heterocycles 2009, 77, 855. D.B.C. Martin, C.D. Vanderwal, J. Am. Chem. Soc. 2009, 131, 3472. H. Ishikawa, D.A. Colby, S. Seto, P. Va, A. Tam, H. Kakei, T.J. Rayl, I. Hwang, D.L. Boger, J. Am. Chem. Soc. 2009, 131, 4904. A.J.M. Burrell, I. Coldham, L. Watson, N. Oram, C.D. Pilgram, N.G. Martin, J. Org. Chem. 2009, 74, 2290.
Recent Advances in the Synthesis of Aspidosperma-Type Alkaloids
09JOC6035 09JOC7533 09TL3675 10AG(I)5767 10CC8436 10JA3009 10JA3685 10JA13533 10JOC7026 10OL2012 10SL944 11AG(I)4884 11EJO1027 11OL1778
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D. Gagnon, C. Spino, J. Org. Chem. 2009, 74, 6035. P. Chen, L. Cao, C. Li, J. Org. Chem. 2009, 74, 7533. H. Nambu, M. Hikime, J. Krishnamurthi, M. Kamiya, N. Shimada, S. Hashimoto, Tetrahedron Lett. 2009, 50, 3675. F. De Simone, J. Gertsch, J. Waser, Angew. Chem. Int. Ed. 2010, 49, 5767. P. Chen, L. Cao, W. Tian, X. Wang, C. Li, Chem. Commun. 2010, 46, 8436. E.L. Campbell, A.M. Zuhl, C.M. Liu, D.L. Boger, J. Am. Chem. Soc. 2010, 132, 3009. D. Kato, Y. Sasaki, D.L. Boger, J. Am. Chem. Soc. 2010, 132, 3685. Y. Sasaki, D. Kato, D.L. Boger, J. Am. Chem. Soc. 2010, 132, 13533. X. Cheng, C.M. Duhaime, S.P. Waters, J. Org. Chem. 2010, 75, 7026. N.T. Tam, E.-J. Jung, C.-G. Cho, Org. Lett. 2010, 12, 2012. D. Sole, M.-L. Bennasar, I. Jimenez, Synlett 2010, 6, 644. Y. Nah-ya, H. Tokuyama, T. Fukuyama, Angew. Chem. Int. Ed. 2011, 50, 4884. W. Tian, L.R. Chennamaneni, T. Suzuki, D.Y.-K. Chen, Eur. J. Org. Chem. 2011, (6), 1027. Y. Hayashi, F. Inagaki, C. Mukai, Org. Lett. 2011, 13, 1778.
CHAPTER
2
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation Dmytro Tymoshenko*, Gyorgy Jeges**, Brian T. Gregg* *AMRI, 30 Corporate Circle, Albany, NY 12203, USA
[email protected];
[email protected] **AMRI Hungary, Zahony u. 7, 1031 Budapest, Hungary
[email protected]
2.1. INTRODUCTION AND SCOPE OF THE REVIEW Palladium-catalyzed reactions are versatile and efficient methods for the synthesis of a large number of heterocycles. Annulations of cyclic and bicyclic alkenes h94AGE2379, 95ACR2, 96CRV365, 99JOM65i, unsaturated cyclopropanes and cyclobutanes, allenes, 1,3- and 1,4-dienes h99JOM111i, as well as internal alkynes h99JOM42, 99JOM111i with appropriately substituted aryl or vinylic halides and sulfonates have been extensively reviewed. Most frequently (Scheme 1), palladiumcatalyzed processes involve (route i) Heck, Stille, Suzuki, or Sonogashira reactions leading to the open-chain precursors followed by (route ii) intramolecular C-heteroatom bond formation. The latter is achieved through transformation of electrophilic functional group E or heteroatom to alkene/alkyne addition. Alternatively (route iii), the C-heteroatom bond could be formed through a palladium-catalyzed Hartwig–Buchwald reaction h07MI564, 02TCC131, 98ACR805, 91JA6499, 97JA8232, 99PAC1417i, giving rise to a variety of heterocyclic systems as well as enabling tandem CC/C-Het palladium-catalyzed annulation sequences (route iv). Several examples of such transformations were included in general palladium-catalyzed amination h98AGE2046, 98ACR805, 99JOM125i and palladium-catalyzed cyclization h04CSY47, 06CRV4644i discussions.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00002-4
#
2011 Elsevier Ltd. All rights reserved.
27
D. Tymoshenko et al.
28
E
N
E
N
[Pd]
[Pd] X
A
E
N
X
i
i C
A
C
ii X
N
C
N
N [Pd]
[Pd]
iii
iv
C
C
X
A/X
X/A
C
A = double/triple bond, SnR3, B(OR)2 X = Hal, TfO
Scheme 1
The current review covers advances in palladium-catalyzed intramolecular heteroarylations (route iii) reported over the past 15 years. Mechanistic details of the transformation are well documented h06CRV4644i; thus this survey involves the synthetic aspects of the N-aryl bond forming cyclizations. The review is organized by the size of the rings formed with further partition into subsections based on number of heteroatoms on the ring or fused ring systems. A separate section deals with tandem sequences and cascades.
2.2. ANNULATION OF FIVE-MEMBERED AZA-RINGS 2.2.1 Indolines and Indoles The pioneering work of Buchwald and coworkers h96T7525i for the synthesis of indolines, oxindoles, and their six- and seven-membered homologs from secondary amine or carbamate precursors served as a touchstone of the intramolecular palladium-catalyzed processes. Usually, these reactions require a suitable ortho-halo-substituted precursor and the proper choice of palladium catalyst, ligand, and base. The original reaction conditions (Scheme 2) result in good yields of cyclized products and include (i) for secondary amines, Pd(PPh)4 in toluene (or DMF) with superior results when K2CO3 or its mixture with t-BuONa was used as a base; (ii) for secondary amides, Pd2(dba)3 as a source of palladium, with P(2-furyl)3 as a ligand with cesium carbonate as a base in toluene; (iii) the “reverse” amides 5 required Pd2(dba)3 as a source of palladium, with more hindered P(o-Tol)3 ligand with potassium carbonate as a base h96T7525i. It was noted that the coordination chemistry involving the oxidative addition complexes of aryl iodides and aryl bromides is substantially different in intermolecular cases; however, for intramolecular cases, no differences were detectable.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
NHBn
29
Pd(PPh)4
n
toluene, X = Br or I K2CO3—62–70% K2CO3/t-BuONa—77–92%
X
n
N Bn
1
2 NHCOR
Pd2(dba)3, P(2-furyl)3
n
Cs2CO3, toluene 100 ⬚C, reflux R = Me, t-Bu 87–99%
Br
n
N O R
4
3 NHBn
Pd2(dba)3, P(o-Tol)3
n
K2CO3, toluene 100 °C, reflux 59–82%
O
Br
n O
N Bn
6
5
Scheme 2
Later developments (Scheme 3) h99OL35, 06SL115i indicated that ligands capable of chelation, such as bis-phosphines or ligands with heteroatoms capable of coordination, are superior in many instances for the palladium-catalyzed cyclization of secondary amides and carbamates.
n O Br
NHBn
Pd(OAc)2, 9 n
base, toluene 100 °C, reflux
N Bn
5 n R1 Br
NHR
O O
N
6
Pd(OAc)2, 10 base, toluene 100 °C, reflux
n N R
R = Ac, Boc, Cbz
7
PPh2 OMe PPh2
14
R1 8
PPh2 O
N Bn
PPh2
PPh2 O
OMe
Me Me 9
Scheme 3 (Continued)
10
11
12a
PPh2
30
D. Tymoshenko et al.
PPh2
PPh2
OMe
12b
PCy2
PPh2 PPh2 i-Pr
12c
i-Pr
i-Pr 13a
13
Scheme 3
Thus, in the case of o-bromo benzylamide 5 (n ¼ 1), the reaction proceeded smoothly in 82% yield when ()-MOP 9 was used as a ligand and K2CO3. Synthesis of indolines 8 (n ¼ 1) requires Cs2CO3 as a base and DPEphos 10 as a ligand h99OL35i. A comparative study of ligands for the formation of oxindole 6 (n ¼ 1, dioxane, Cs2CO3) revealed superior results for phosphine 12a in contrast to ligands 12b and 12c h06SL115i. A similar transformation using X-Phos (13a) and optimized conditions [(Pd(OAc)2, K2CO3, t-BuOH)] allowed synthesis of pharmaceutically valuable intermediate 14 in 90% yield h04TL8535, 07BML3421i. (S)-N-Acetylindoline-2-carboxylate 19, a key intermediate in the synthesis of the ACE inhibitor 20, has been approached in a similar fashion by Buchwald and coworkers h97JA8451, 03JA5139i. Methyl ester 19 was obtained by a palladium-catalyzed intramolecular coupling of the optically active phenylalanine derivative 17a, which was prepared by a Heck coupling reaction of o-bromoiodobenzene 15 with methyl 2-acetamidoacrylate followed by a rhodium-catalyzed asymmetric hydrogenation of the resulting enamide 16 (Scheme 4) h97JA8451i. Alternatively, tert-butyl ester 17b was obtained by the asymmetric alkylation of 18 with commercially available o-bromobenzyl bromide in the presence of a chiral spiro quaternary ammonium phase-transfer catalyst. Subsequent hydrolysis with citric acid and N-acetylation afforded 17b in 86% yield with 99% ee (S) h03JA5139i. In contrast to an intermolecular process, which results in partial or full racemization upon treatment with Pd2(dba)3/P(o-Tol)3, intramolecular palladium-catalyzed CN coupling afforded almost enantiopure 19 (94%, 99% ee). CO2Me I
Pd(OAc)2 TEA, 100 ⬚C
Br 15
Ph2C = N
O
18
Scheme 4
1.
Br
NHAc N
16 [(COD)2Rh]OTf (S,S)-Et-DuPHOS H2, MeOH, rt
Br O
CO2Me
NHAc
Br
chiral cat., toluene 50% aq. KOH 0 ⬚C, 24 h 2. 1 M citric acid/THF 3. AcCl/TEA, CH2Cl2
Br
20
CO2H CO2Et
O Me
Me
CO2R Pd2(dba)3, P(o-Tol)3 Cs2CO3, toluene, reflux NHAc
17a, R = Me 17b, R = t-Bu
N Ac 19
CO2R
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
31
Another example of enantiomerically pure substituted 2-carboxy indolines 22 (n ¼ 0) was reported by Jackson and coworkers h02J(P1)733i. The two-step procedure included a palladium-catalyzed coupling of amino functionalized organozinc reagents with 2-bromoiodobenzene, followed by a palladium-catalyzed intramolecular amination reaction. The yields in the initial coupling were modest (36–52%), while the cyclization gave good to excellent yields of the chiral products with > 99% ee (Scheme 5). CO2R I Br 20
IZn
n
CO2R
NHBoc
n = 0, 1 R = Me, Bn Pd2(dba)3, (o-Tol)3P DMF, rt, 36–52%
n Br 21
NHBoc
Pd2(dba)3, P(o-Tol)3 Cs2CO3, toluene, 100 ⬚C 63–87%
n N H
CO2R
22
Scheme 5
A new and flexible procedure for the synthesis of indolines has been reported h03EJO2888i. The target compounds can be synthesized with high diversity from three building blocks, that is, ortho-bromo- or ortho-chloro-iodobenzenes 23, terminal alkynes, and primary amines. The synthetic strategies include Sonogashira couplings and Cp2TiMe2-catalyzed hydroaminations of alkynes 24 (Scheme 6). The key palladium-catalyzed intramolecular amination of o-halo-substituted phenethylamines 25 and 2-benzyl pyrrolidines 27 results in good to excellent yields of indolines 26. Depending on the nature of the halide (Br or Cl), different catalyst systems are used. The bromo derivatives are treated with t-BuONa and [Pd(PPh3)4], while the chloro derivatives required the presence of t-BuOK, [Pd2(dba)3], and a carbene ligand generated in situ from imidazolium salt 28. Analogous synthesis of chiral N-Boc indolines 26 [R1 ¼ 4-Cl(Br), R2 ¼ (S)-Me, i-Pr, Bn, CH2OTBS, R3 ¼ Boc] has been reported using Pd(OAc)2, DPE-Phos, and Cs2CO3 in toluene at 100 C resulting in 51–97% yields of the products h09TL1920i.
32
D. Tymoshenko et al.
X I
R2
H
R1
R2
X
i
R1
X
R3 NH2
R2 R1
ii, iii
23
HN
R3
25
24 R2 = (CH2)nNH2;
iv or v
ii, iii
X N
iv or v
N R1
Cl 28
R2
R1 HN n-2
R2 + R3 = (CH2)n-2
N R3
26
27
Reagents and conditions: (i) PdCl2(PPh3)2. CuI, PPh3, HN(i-Pr)2, reflux, 78-99%; (ii) Cp2TiMe2, 100 ⬚C, 24 h; (iii) NaBH3CN, ZnCl2, MeOH, 25 ⬚C, 12 h, 48-97%; (iv) X = Cl, Pd2(dba)3, t-BuOK, carbene ligand; (v) X = Br, Pd(PPh3)4, t-BuONa, 64-99%.
Scheme 6
N-Protected-R-aminoacyl-5,7-dinitroindolines 30 are inaccessible through the direct acylation of 5,7-dinitroindoline 31 due to its low reactivity (Scheme 7). Nevertheless, they can be prepared in good yields from phenethyl amides 29 by intramolecular amide N-arylation. Although initial attempts using CuI or Pd2(dba)3/Xantphos failed, reactions succeeded under microwave irradiation using 2-dicyclohexylphosphino-20 -methylbiphenyl (Me-Phos) 32 as a ligand and Pd2(dba)3 as a palladium source. Basic reaction conditions are not compatible with an Fmoc-protecting group, but they tolerate N-Boc, N-Cbz, and serine O-t-Bu protection h09JOC4519i. R1
NH O2N
NH Pg
O
Pd2(dba)3, 32
O2N O
NO2
H N N K2CO3 Pg toluene/MeCN R1 MW, 100 ⬚C
Br NO2
29
30 Cy
P
Cy
X Pg
O
H N
OH R1
Me
O2N
NO2
32 HN
31
Scheme 7
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
33
Intramolecular reaction of intermediate 33 in the presence of Pd2(dba)3, P(o-Tol)3, and t-BuONa in toluene at 80 C cleanly afforded the tricyclic indoline 34 which, when treated with 10 mol% Pd/C in the presence of ammonium formate, gave indole 35 as a product of debenzylation and spontaneous oxidation. The latter serves as an intermediate in the total syntheses of marine alkaloids damirone 36 and makaluvamine 37 (Scheme 8) h96JA1028i.
Me
N
H N
Bn
Pd2(dba)3, P(o-Tol)3 t-BuONa, toluene, 80 ⬚C, 72%
I
MeO
Me
N
MeO
OMe
OMe
33
N Bn
34 Me
Me N
Me
N
N
Pd/C, HCO2NH4, 80% NH
MeO OMe
35
NH
O
NH
HO
O
O
36
37
Scheme 8
Palladium-catalyzed cyclization methodology can be applied effectively to heteroaryl halides. The 9-hydroxy-1H-imidazo(1,2-a)indol-3-one moiety occurs in the potent cholecystokinin antagonist asperlicin 40. The stereochemically controlled method to the hydroxyimidazoindolones from a 3-alkyl indole includes the
34
D. Tymoshenko et al.
palladium-catalyzed amidation reaction [Pd2(dba)3, P(o-Tol)3, K2CO3, toluene, 105 C] and provided 48% of compound 39, containing the crucial imidazoindolone moiety (Scheme 9) h98JA6417, 03JOC545i. CO2Ph 1. Hg(OTFA)2, KI 2. I2 N O
O
CO2Ph
TrocHN
HO
NCbz
NHCbz 3. Pd (dba) , P(o-Tol) 2 3 3 K2CO3, toluene, reflux
40
39
N
O
N O
Me NH
HO
O
N
N O
N H NH
N O
48%
38
N
N
TrocHN
N
Me NH
HO
O NH
O NH
N
N
O 42
41
O
Scheme 9
A similar synthesis of the imidazoindolone motif has been reported by Snider and coworkers as a part of the total synthesis of fumiquinazolines A (41) and B (42), cytotoxic compounds isolated from a strain of Aspergillus fumigatus in the gastrointestinal tract of the fish Pseudolabrus japonicus h00OL4103i. Recently, a report on the synthesis of chaetominine 45, a modified tripeptide alkaloid containing D-tryptophan, L-alanine, and anthranilic acid moieties, came from the same group h07OL4913i. The key step in the synthesis was the palladium-catalyzed cyclization of iodo carbamate 43, which provided tricycle 44 in 64% yield (Scheme 10).
COO2Me Pd2(dba)3, P(o-Tol)3 K2CO3, toluene, reflux
I N O
43
NHCbz
O
COO2Me
TrocHN
HO 9 steps
64%
N
O N N H
NCbz Me
44
Me
O
O
Me
N N
TrocHN
45
Scheme 10
Intramolecular arylations of properly substituted (hetero)aryl amines lead to carbazoles or fused heteroaryl indoles. For example, a palladium-catalyzed cyclization has been reported for the synthesis of staurosporine 48 (Scheme 11).
35
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
This well-known representative of 1H-indolo[2,3-a]pyrrolo[3,4-c]carbazole family of natural alkaloids, isolated from Streptomyces staurosporeu, is the subject of numerous synthetic studies aimed at the challenging distinction of the indole N12 and N13 with high regioselectivity. Regioselective synthesis of N13-protected precursor 47 was reported by Nomak and Snyder h01TL7929i starting from the open-chain ethyl carbamate 46. The relatively low 29% yield can be explained by nonoptimized conditions and 58% recovery of the starting carbamate 46. Me N Br
O
Me N
Pd(OAc)2 t-Bu3P, PhONa
Me N
O
O
29 % N HN H CO2Et
N N H CO2Et
N
N 13
O
12
MeO
46
47
48
NHMe
Scheme 11
Clausenamine-A 51 (Scheme 12) is a natural dimeric carbazole isolated from the stem and root bark of Clausena excavata, which is used as a Chinese traditional medicine for detoxication treatment caused by a poisonous snakebite. Its first synthesis was completed h00T7163i through the intermediate diphenyl 49 which cyclized to carbazole 50 under palladium-mediated conditions. MeO
MeO
Br
H2N
49
Me
OTs
Pd(PPh3)4 Na2CO3, toluene, reflux 97%
MeO
MeO
Me
N H
OTs
50
MeO
MeO
Me
N H
OH
HO
Me
H N
OMe
OMe
51
Scheme 12
Identical conditions have been described for the preparation of a series of carbazole derivatives as neuropeptide Y1 receptor modulators (Scheme 13) h07BML1043i. The central core for the library of amides was based on the ester 53 prepared from substituted methyl 6-amino-20 -bromobiphenyl-3-carboxylate 52.
36
D. Tymoshenko et al.
Br
COOMe
H2N
O
Pd(PPh3)4 Na2CO3, toluene, reflux
COOMe
74%
N H
O
Cl
Cl
53
52
Scheme 13
Iodoquinoline 54 underwent an intramolecular palladium-catalyzed intramolecular amination readily to produce the tetracyclic quinolinoindole ring system 55 in a 65% yield (Scheme 14) h05OL763i. N
N PdCl2(dppf), dppf t-BuOK, toluene/DMF 100 ⬚C, 65%
I
NH
H2N
54
55
Scheme 14
An aza-indole with the fused pyrimidine dione motif 58 has been reported as the product of a two-step sequence. In the first step, chloro compound 56 underwent Stille coupling to produce amine 57, which was further submitted to intramolecular CN bond formation to yield 71% of the tricyclic product 58 (Scheme 15) h07BMC3235i.
O
Me N
Me N
Bu3Sn
Pd2dba3, PPh3
Cl
O
N
Cl
NH2
CuI, LiCl DMF, 55%
56 O Me
N
O N
Me Cl
Pd(OAc)2, Xantphos Cs2CO3, DMF
O
71% NH2 57
Scheme 15
N
Me N
Me N O
N H 58
N
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
37
Suitably substituted imines derived from 2-arylacetaldehydes are convenient precursors of indoles synthesized by intramolecular amination. Thus, palladium-catalyzed cyclization of N,N-dimethylhydrazones of o-chloroarylacetaldehydes 59 resulted in variable yields of N-dimethylaminoindoles 61 (Scheme 16) h00AGE2501i. Sodium tert-butoxide can be used as a base along with cesium or rubidium carbonates. Hindered phosphines, for example, tri-tert-butyl phosphine, give good results, although 2-dimethylaminomethyl-1-di(tert-butyl-phosphanyl)ferrocene was the ligand of choice. The mechanistic details of the reaction remain unknown, but a plausible mechanism involves imine-enamine tautomerization and formation of aryl(enamido) palladium complex 60. In the case of dichloro derivatives (R ¼ Cl), the reaction sequence was extended to a one-pot preparation of N-azole, amino- or aryl-substituted products 62. [Pd(dba)2] ligand, base o-xylene, 120 ⬚C
H R Cl
N
N
H R
Me
Pd
N
L
Me
N
Me
Me
60
59 1. [Pd(dba)2] ligand, base o-xylene, 120 ⬚C
18–74%
2. R = Cl, azole, amine or AB(OH)2 R
A
62
N N Me Me
N N Me Me 61
Scheme 16
Dihydroisoquinoline 63 and its analogues, prepared by the Bischler–Napieralski reaction, were converted into indole-fused derivatives 64 by the action of Pd2(dba)3 with N,N0 -bis(20 ,60 -diisopropylphenyl)dihydroimidazolium tetrafluoroborate (SIPr) as a ligand (Scheme 17) h06S1375i. For undisclosed reasons, this new ring-closure protocol does not work for the analogous closure of six-membered rings (n ¼ 2). This palladium-catalyzed reaction proceeds through the tautomeric enamine form of imines 63, and the process was further extended to the preparation of racemic mangochinine 65.
38
D. Tymoshenko et al.
N
OMe
Br
n = 1, Pd2(dba)3, SIPr
N
OMe
MeO OBn
n MeO OBn
t-BuONa, toluene 89%
OBn
BnO
n = 2, no reaction
63
64
Me I
N
OMe
MeO
OBn
BnO
65
Scheme 17
An alternative route to the enamine species includes a Horner–Emmons reaction of N-aryl a-phosphonylglycines 66, prepared according to the rhodium carbenoid insertion method, with 2-iodobenzaldehydes (R2 ¼ H, 5-NO2, 4-NO2, 5-OMe) using DBU as a base at room temperature to give the corresponding vinyl amines 67 in good to excellent yields. The specific formation of (Z)-isomers from Horner–Emmons reaction is crucial to the success of the next step. Further treatment of these compounds with PdCl2(dppf) and KOAc in DMF at 90 C gave the substituted indoles 68 cleanly. Compounds with electron-withdrawing, neutral, or electron-donating groups reacted equally well, with traces of concomitant de-iodinated products observed (Scheme 18) h00TL1623i. I R2
PO(OEt)2 EtO2C
I
NH
O
R2
R1 DBU, CH2Cl2 73–90%
66
EtO2C
NH
PdCl2(dppf)
R2
CO2Et N R1
KOAc/DMF 90 ⬚C, 83–94%
R1
67
68
Scheme 18
Similar solid-phase synthesis has been reported by Kondo et al. (Scheme 19) h02J (P1)2137, 03JOC6011i. Intermediate resin 69 was prepared by a two-step process involving a Heck reaction followed by sequential intramolecular palladium-catalyzed CN bond coupling and subsequent transesterification/cleavage to afford ester 70. O O CbzNH 69
Scheme 19
X
1. Pd2(dba)3, Cy2NMe t-Bu3P, toluene, 80 ⬚C
CO2Me N H
2. MeONa, MeOH/THF 70
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
39
The palladium-catalyzed intramolecular cyclization methodology discussed above for aryl halides can be successfully extended to vinyl halides. Compound 72, a precursor to b-lactam antibiotics, was synthesized using a palladium-catalyzed CN bond-forming reaction (Scheme 20). In this process, Pd(OAc)2 with DPEphos gave superior results in contrast to other ligands. A significant increase in yields is observed when Pd species are generated in the absence of base. Thus, addition of potassium carbonate after 2 min, as compared to immediate addition, increased the yield from 59% to 74% in the case of bromide (X ¼ Br) and even more dramatically from 20% to 90% for iodide (X ¼ I) h02TL111, 03JOC3064i. TBDMSO
H H
Me
10 mol% Pd(OAc)2 15 mol% DPEphos
NH O
X
CO2Et
H H
TBDMSO
Me
N
K2CO3, toluene, reflux, 36 h
O
CO2Et
72
71
X = Br, 59% X = Br, 74% (add base after 2 min) X = I, 20% X = I, 90% (add base after 2 min)
Scheme 20
Another example is an intramolecular process for bromo-olefins 73, which were subjected to catalytic amidation conditions [Pd(OAc)2 and DPEphos] to give the exo-methylene spiro[4,4]- and spiro[5,4]amides 74a and 74b with 66% and 40% yields, respectively (Scheme 21) h07SL1037i.
O R n
Br CONHPh
O
Pd(OAc)2 DPEphos K2CO3, toluene
N Ph
R n
73
O
74a, n = 1, R = 2-furoyl, 66% 74b, n = 2, R = Ph, 40%
Scheme 21
Suitably substituted vinyl triflates can serve as precursors of ring systems via palladium-catalyzed cyclizations. Thus, construction of the highly strained tetracycles 77, which are represented as a structural motif in (þ)-nodulisporic acids A and B, was achieved through a new modular indole synthesis, with the BuchwaldHartwig cyclization as the last step (Scheme 22) h06OL2167, 07JOC4611i. Removal of the Boc group from intermediates 75 or 76 can be followed by intramolecular Buchwald–Hartwig cyclization between an enol triflate and a secondary amine. Interestingly, initial efforts to achieve the requisite CN bond formation employing Pd2(dba)3/Xantphos and strong bases (e.g., LiHMDS, t-BuONa) in toluene failed, presumably due to incompatibility of strongly basic conditions with the enol triflate moiety. This conversion was achieved employing a milder base, Cs2CO3, in THF.
D. Tymoshenko et al.
40
N Boc
TfO
or
1. TMSI, CH2Cl2, -78 ⬚C
N Boc
TfO
n
2. Pd2(dba)3, Xantphos Cs2CO3, THF reflux, 55–72%
n
76
75
n
N
77
Scheme 22
Several substitution patterns appropriate for further intramolecular CN bond formation can be achieved through Ugi multicomponent reactions. A novel twostep solution phase procedure for the preparation of substituted 3-amino oxindoles 80 has been reported (Scheme 23) h06TL3423i. It includes a Ugi four-component reaction of R1-substituted 2-bromobenzaldehydes, R2-isocyanides, R3-amines, and R4-acids, followed by intramolecular palladium-catalyzed cyclization. The use of catalytic system consisting of Pd2dba3, P(o-Tol)3, and Cs2CO3 (for aliphatic isocyanide-derived intermediates) or K2CO3 (for benzylic derivatives) in refluxing toluene resulted in low yields of highly diverse 3-amino oxindoles 80. O X CN R2 O
R1
H2N R3
X R1
rt, 36–72%
HN
R4
O R1
N
Cs2CO3 or K2CO3, toluene reflux, 4–22%
R1
82
N R2
R1
O R4 O
80
O R3
N R2
O
R3 N
OH
R1
Br
81
R2
79
NH2
R3 N
R4 2. Pd2(dba)3, P(o-Tol)3 O
N
CF3CH2OH
HOOC R4
78
R3
R4
R1 Br
O
83
84
N R2
O
Scheme 23
Application of iodobenzaldehydes (X ¼ I) in combination with microwave irradiation and proper choice of ligand significantly improves the yields of intramolecular N-arylation conditions h06OL4351i. The optimized conditions [Pd(dba)2, Me-Phos, K2CO3, MW, 100 C, PhMe/MeCN 3:1] were applied to the combination of two aldehydes, six amines, five carboxylic acids, and six isonitriles. A range of functional groups such as ester, amine, ether, and heterocyclic nuclei (e.g., pyridine and indole) are tolerated. Even in the case of sterically hindered amides such as tert-butylamide, Ugi intermediates were readily cyclized to give the corresponding oxindoles (R1 ¼ H, R2 ¼ t-Bu, R3 ¼ n-Bu, R4 ¼ Me) in 60% yield. A similar strategy applied to 2-bromoanilines 81 and 2-bromobenzoic acids 83 usually resulted in moderate 25–50% yields of diverse 3,4-dihydroquinoxalin-2-ones 82 and 3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-diones 84, correspondingly h06TL3423i.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
41
2.2.2 Indazoles The first report on intramolecular palladium-catalyzed indazole synthesis included preparation of 1-aryl-1H-indazoles 87 (Scheme 24) h01TL2937i. The reaction involves the corresponding N-aryl-N0 -(o-bromobenzyl)hydrazines 86 as starting materials and a catalytic system of Pd(OAc)2/dppf with t-BuONa (150 mol%) as a base in toluene at 90 C. Under these conditions, cyclization was followed by spontaneous aromatization. Phosphonium bromides 85, which serve as precursors of N, N0 -disubstituted hydrazines 86, when submitted to similar reaction conditions (Pd (OAc)2/dppf, 250 mol% of t-BuONa, dioxane at 90 C) also led to formation of the corresponding 1-aryl-1H-indazoles. The extra equivalent of the base is presumably needed to deprotect the triphenylphosphonium species. Br- Ph3 +P
N
H N R2
NaOH
R1
H N
HN
R
R1 Br
85
Br Pd(OAc)2 dppf, t-BuONa toluene, 41–60%
N
H N R2
R1 Br
88
86 Pd(OAc)2 dppf, t-BuONa toluene, 80–93%
R1
N N
Pd(dba)2 ligand, base, 40–96%
R2
87
Scheme 24
Similarly, palladium-catalyzed cyclization of arylhydrazones of 2-bromoaldehydes 88 (and 2-bromoacetophenones) gave 1-aryl-1H-indazoles h05JOC596i. Cyclization of the arylhydrazones of 2-bromobenzaldehydes can be performed with good to high yields using Pd(dba)2 and chelating phosphines, of which the most effective are rac-BINAP, DPEphos, and dppf, in the presence of Cs2CO3 or K3PO4. Commonly used for intermolecular aminations, electron-rich and bulky ligands such as t-Bu3P and o-PhC6H4P-t-Bu2 are ineffective for cyclization and lead to intractable reaction mixtures. The method developed is applicable for preparation of diverse indazoles bearing electron-donating or electron-withdrawing substituents, including unprotected carboxyl and various indazole hetero analogues. Notably, the purity of the starting hydrazone is a critical parameter, as various impurities inhibit the cyclization. Analogous transformations have been reported for N,N-substituted hydrazines 89 to produce good yields of 2-aryl indazoles 90 (Scheme 25) h00OL519i.
42
D. Tymoshenko et al.
R2 N
NH2 R2
Pd(OAc)2 dppf, t-BuONa
R1
R1
N
toluene, 51–62%
N
Br
89
90
Scheme 25
An efficient method for the preparation of 3-substituted indazoles 92 was developed using the palladium-catalyzed intramolecular amination of 2-bromo(chloro) phenyl hydrazone derivatives 91 (Scheme 26) h04CL1026i. Good functional group compatibility was observed under mild reaction conditions, and various 3-substituted indazoles were obtained in moderate to excellent yields. R1
R1 Pd2(dba)3, P(o-Tol)3 LiHMDS, toluene, reflux
N
N
NHTos
N
X
Tos
91
92
Scheme 26
A new method for the synthesis of tricyclic indolo[1,2-b]indazoles 95 in high yields starts from N-acetamino-2-(2-bromo)arylindolines 93, which are available in three steps starting from 2-(2-bromo)indoles (Scheme 27) h02TL3577i. Intramolecular CN bond formation catalyzed by palladium acetate gave excellent yields of intermediates 94. Their further hydrolysis and basic aluminum oxide catalyzed air oxidation allowed the preparation of fused indazoles 95 in high yields.
Br
Pd(OAc)2 DPEphos
R1
R1
R2 Cs2CO3, toluene, reflux, 18 h, 81–99%
N NH Ac
N N Ac
93 1. NaOH, aq. MeOH 2. Al2O3, CH2Cl2 84–96%
R1 N
R2 N
Scheme 27
95
R2 94
43
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
Synthesis of indazolone derivative 98 has been reported starting from o-iodobenzoic acid 96 through intermediate hydrazide 97 accessible by Schotten-Baumann acylation (Scheme 28) h08JMC2137i. O COOH
1. SOCl2, CH2Cl2 2. n-Bu-NHNH2· C2O4H2, CH2Cl2, NaOH, H2O
I 96
I
O Bu N NH2
Pd(dppf)2Cl2
N Bu
NaOH, C2H5OH
N H
97
98
Scheme 28
2.2.3 Fused Imidazoles, Thiazoles, and Oxazoles A palladium-catalyzed N-arylation that provides a novel synthesis of benzimidazoles from (o-bromophenyl)amidine precursors has been reported h02TL1893i. The catalytic system needed extensive optimization as no reaction was observed using “Buchwald’s conditions” [Pd2(dba)3/P(o-Tol)3 with Cs2CO3, K2CO3 or t-BuONa in m-xylene after 18-h reflux]. The same result was obtained when starting amidine, and Pd(OAc)2 and Na2CO3 were heated under reflux in DMF for 18 h. On the other hand, reaction with Pd2(dba)3/BINAP in toluene for 18 h under reflux was successful. Another successful reaction condition was the use of Pd(PPh3)4 (5–10 mol%) and a mixture of t-BuONa (1.6 equiv.) and K2CO3 (1.6 equiv.) in toluene for 18 h under reflux, which was selected as the optimal protocol. The improved conditions were further developed and optimized (Scheme 29) h03JOC6814i. A range of benzimidazoles was prepared rapidly and in excellent yields using of Pd2(dba)3 and PPh3 in 1:8 molar ratio, NaOH as a base in H2O/DME at 160 C under microwave irradiation in combination with a “catch and release” purification strategy on Amberlyst 15. The route is flexible and allows for the preparation of highly substituted benzimidazoles including regioselective N-substitution.
N H N
N R1 Br 99
R3
R2
1. Pd2(dba)3, PPh3 NaOH, 50% H2O/DME MWI, 160 ⬚C R1 2. Amberlyst, CH2Cl2 3. TEA 50%/CH2Cl2 66–98%
N R3 N R2
100a
N Ph N
100 100b
Bn NH
Ph NH
N Bn
Scheme 29
In a related synthesis of 2-aminobenzimidazoles (R3 ¼ substituted amine) h02TL1893, 03OL133i, the palladium-mediated process was disadvantageous compared to copper(I)-catalyzed cyclization due to purification issues. Notably, when
D. Tymoshenko et al.
44
derivatives of primary amines are used (R2 ¼ Ph; R3 ¼ NHBn), the copper-catalyzed process led exclusively to exo-benzyl product 100a, while Pd catalysis results in the mixture of exo- and endo-products 100a and 100b h03OL133i. A related synthetic strategy has been reported h10BML526i for the synthesis of 1-(3-aryloxyaryl)benzimidazole sulfones as liver X receptor agonists. Similarly, 2-amino- and 2-alkyl-benzothiazoles have been efficiently prepared by palladium-catalyzed cyclization of o-bromophenylthioureas and o-bromophenylthiomides. Pd2(dba)3/o-biphenylP(t-Bu)2 provided the best synthetic results (Scheme 30) h03TL6073i. H N
R1
Br
S
Pd2(dba)3, ligand t-BuONa or Cs2CO3 68–100%
N R1 S 102
101
Scheme 30
N-Substituted o-chloroanilines or 2-chloro-3-aminopyridines 103 can be efficiently converted into benzo(pyrido)imidazolones 105 through intermediate primary ureas 104, which undergo palladium-catalyzed cyclization in a final step. The Pd (OAc)2/dppb catalyst system was effective for the 2-chloropyridine series (X ¼ N). For the less reactive o-chloroanilines (X ¼ CH), the use of more active Xantphos ligand produced good yields of the products (Scheme 31) h06OL3311i. R
X
NH2
1. RCHO, NaBH4 2. CSI
Cl
3. H2O
X
103
N
Cl
H N O
106
O
Cl
NH2
R
X = N, Pd(OAc)2, dppb X = CH, Pd(OAc)2, Xantphos
1
n-Pr
Ph
43%
n-Pr
1H
Pd(OAc)2, Xantphos t-BuONa, THF
O
GW808990 N
O N
3
Me
3
N
N N
N
N X H 105
NaHCO3, THF or i-PrOH 60–99%
104
PhNCO X=N
H N
N
N
O
N
107 OMe
Scheme 31
In the same way, 3-substituted derivative 107 can be obtained starting from the corresponding secondary urea 106 h06SL2083i. This synthetic approach has been recently reported for the synthesis of a potent CRF antagonist GW808990 h06SL2716i.
45
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
3-Anilino-pyrazinones are readily available from dichloro pyrazinones which demonstrate significant electrophilicity under acidic catalysis using camphorsulfonic acid (CSA). They can be easily converted to the tricyclic substituted pyrazino[1,2a]benzimidazol-1(2H)ones by applying a microwave-assisted Buchwald–Hartwigtype cyclization (Scheme 32). The best results were obtained using Pd(PPh3)4 as a catalyst and potassium carbonate as base although reaction time was still considerable (12 h), while using microwave conditions at 150 C for 25 min with 10% Pd(PPh3)4 and anhydrous potassium carbonate in DMF resulted in good yields of the products (Scheme 32) h08T8128i. R2 R2 Cl
R1 N
R2
R1 N
O
Cl
N
N
O
NH2 O Cl
N
R1 N
108
R3
Br
CSA, i-PrOH reflux, 48 h 51–82%
R4
109
Cl
N Br
NH
110
R4
K2CO3, Pd(PPh3)4 R3 DMF, 150 ⬚C (MW) 150 W, 25 min 61–78%
R3
111
R4
Scheme 32
An analogous transformation was reported for 2-(2-bromoanilino)quinolines 112 which resulted in the synthesis of benzimidazo[1,2-a]quinolines 113. The intramolecular Buchwald–Harwtig-type heteroarene N-arylation was applied using optimized reaction conditions. In general, excellent yields (70–93%) of substituted benzimidazo[1,2-a]quinolines 113 were obtained from substrates bearing methyl, isopropyl, or methoxy groups in various positions of either the quinoline ring or the anilino moiety (Scheme 33) h06JOC1280i. R1
R1
R2 R4
Br
N
N H 112
R3
Pd(PPh3)4 DMF/K2CO3 130–140 ⬚C
R2
R4 N
R3
N 113
Scheme 33
2.3. ANNULATION OF SIX-MEMBERED AZA-RINGS 2.3.1 Quinolines and Their Di- and Tetrahydro Derivatives Like indolines and oxindoles (Section 2.2.1, Scheme 2), the six-membered homologs when prepared from secondary amide or secondary carbamate precursors (1 and 3, correspondingly, n ¼ 2) require a proper choice of palladium catalyst, ligand, and base
46
D. Tymoshenko et al.
h99OL35, 06SL115i. As in the case of oxindole 2 (n ¼ 1), reaction using the ()MOP 5 ligand and potassium carbonate resulted in a 94% yield of quinolone 2 (n ¼ 2). Synthesis of tetrahydroquinolines 4 (n ¼ 2) required Cs2CO3 and BINAP ligand 13 h99OL35i. Comparative study of ligands in the formation of quinolone 6 (n ¼ 2, dioxane, Cs2CO3) revealed superior results for phosphines 12a and 12c with lower yields for ligand 12b h06SL115i. Interestingly, chiral N-sulfinyl amine 7 (n ¼ 2, R ¼ SO-t-Bu, R1 ¼ n-Bu, Scheme 3, Section 2.2.1) undergoes spontaneous sulfinyl deprotection under palladium-catalyzed cyclization conditions [Pd2(OAc)3, BINAP, Cs2CO3] resulting in the corresponding unsubstituted tetrahydroquinolines 8 (R ¼ H) h10JOC941i. Synthesis of optically active atropisomeric anilide derivatives through a catalytic asymmetric N-arylation reaction h05JA3676, 06JA12923, 08TL471i can be further extended to the intramolecular variation (Scheme 34). The reaction of anilide 114a (X ¼ Y ¼ CH2, R ¼ H) in the presence of Cs2CO3 in toluene using Pd (OAc)2/(S)-BINAP catalytic system gave the corresponding lactam 115a in 70% ee and 95% yield. Although further attempts to improve enantioselectivity for this product were unsuccessful, the reaction with 2,5-bis-tert-butylanilide 114b (X ¼ Y ¼ CH2, R ¼ t-Bu) led to high enantioselectivity affording atropisomeric lactam 115b of 96% ee and in 95% yield. O Y
X
Y NH t-Bu
I
Pd(OAc)2, (S)-BINAP Cs2CO3, toluene 80 ⬚C
N
X O
t-Bu R
114a-d
115a-d
R
O O O
PPh2 PPh2
114a, 115a; R = H, X = Y = CH2; 95%, 70% ee; 114b, 115b; R = t-Bu, X = Y = CH2; 95%, 96% ee; 114c, 115c; R = t-Bu, X = NBn, Y = CH2; 82%, 94% ee; 114d, 115b; R = t-Bu, X = CH2, Y = NBn; 95%, 96% ee
O 116, (R)-SEGPHOS
Scheme 34
A recent study reported the use of Pd(OAc)2 and (R)-SEGPHOS 116 as conditions which produce the products in a highly enantioselective manner (89–98% ee) h10T288i. Malonamides 117 bearing 2-bromoarylmethyl groups upon treatment with Pd (OAc)2 and various ligands undergo intramolecular double N-arylation giving excellent yields of spiro derivatives 118 (Scheme 35). While treatment with DPEphos gave only a racemic mixture, the use of (S)-BINAP resulted in up to 70% ee of spirobi(3,4-dihydro-2-quinolone) derivatives 118 h09OL1483i.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
47
Br R Br
NH O
NH
Pd(OAc)2, (S)-BINAP K3PO4 97%
O
R
N N O O
R
R 118
117
Scheme 35
Amino-ester 119 can be prepared by enantioselective Mannich reaction and sequential SmI2 reduction and was further transformed into 1,2,3,4-tetrahydroquinoline 120 in 73% yield (Scheme 36) h08JA6676i. NH2 O Me
OMe
1) 5 mol% Pd2(dba)3 20 mol% XPhos Cs2CO3
Br 119
toluene, 90 ⬚C 2) SmI2 73%
O N H Me
OMe
120
Scheme 36
Intramolecular Buchwald–Hartwig aryl amination is a crucial step in the synthesis of (þ)-virantmycin 123, an unusual chlorinated tetrahydroquinoline present in a strain of Streptomyces nitrosporeus (Scheme 37) h04AGE6493i. Aryl aminations with aliphatic amines containing a-quaternary centers are quite rare, and initial attempts using a variety of conditions and ligands gave unsatisfactory results. However, the treatment of formamide 121 with Pd2(dba)3 in the presence of the Keay ligand (BINAPFu) resulted in quantitative cyclization to the precursor 122. The selection of BINAPFu 123 as the Pd ligand of choice was based on model studies of the aryl aminations of other quaternary amines (1-adamantylamine and methyl a,a-dimethylglycinate) with methyl 4-bromo-3-methylbenzoate. Other ligands, such as BINAP, DPPF, PCy3, o-biphenyl-PCy2, o-biphenylPtBu2, DPEphos, MAP, and IMES hydrochloride, failed or produced very low yields of the corresponding arylamines.
48
D. Tymoshenko et al.
Me OMe
Me Pd2(dba)3/BINAPFu HOOC Cs2CO3
Me MeO2C
NHCHO Br
OAc
100%
N CHO
OAc
Me Me
122
121
OMe
Me
O BINAPFu =
Ph2P
HOOC
PPh2
Cl N H
O 124
123
OMe Me Me
Me
Scheme 37
Preparation of the toad poison dehydrobufotenine 127 was one of the first applications of intramolecular palladium-catalyzed arylation in total synthesis (Scheme 38) h96JA1028i. The tryptamine derivative 125 (R1 ¼ Me, R2 ¼ CO2Et, R3 ¼ Bn) when treated with Pd(PPh3)4, K2CO3, and NEt3 gives the tricyclic intermediate 126 in good yield. Unusually, high temperatures are required for this cyclization as only mild potassium carbonate can be used because stronger bases cleave the N-indole carbamate protecting group. Sequential treatment of 126 with BBr3 led to cleavage of both the carbamate and the O-methyl groups and then in situ quaternization by addition of excess MeI and KHCO3 produced 127 as its iodide salt. A recent alternative route h10T4452i included 5-O-silyl and N-tosyl protecting groups, although a lower, 43% yield of intermediate 126 was produced. R3 NH R3
Pd(PPh3)4
I R1O
Me Me N HO
N
R1O N R2 125
K2CO3, TEA toluene, 200 ⬚C
N R2
(i) R1 = Me, R2 = CO2Et, R3 = Bn, 81% (ii) R1 = TBDMS, R2 = Ts, R3 = Me, 43%
I-
126
NH 127
Scheme 38
Extension of palladium-catalyzed CN bond formation to supercritical carbon dioxide media resulted in the synthesis of N-tosyl and N-methylsulfonyl tetrahydroquinolines 129 (Scheme 39) h05OBC3767i. The potential issue with carbamic acid formation is avoided through the use of N-silyl sulfonylamides as the coupling
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
49
precursors to increase the yield of the mesyl derivative (R ¼ Me) from 22% to 55%. The effect of N-silylation on tosyl derivative (R ¼ p-Tol) is less significant.
Br
Pd(OAc)2, P(t-Bu)2(o-biphen), TMS Cs2CO3, scCO2, 1800 psi, N 100 ⬚C, 20–61% SO2R
SO2R N
128
129
Scheme 39
In a similar fashion, intermediate 131, obtained from Baylis–Hillman acetate 130 and p-toluenesulfonamide, underwent cyclization in the presence of palladium acetate and BINAP in toluene at 100 C for 12 h to give dihydroquinoline 132 in 81% yield (Scheme 40) h07SC2677i. OAc COOEt
TosNH2
COOEt
Pd(OAc)2 BINAP
NHTos
K2CO3, toluene 81%
EtOH
Br
Br
130
COOEt N Tos 132
131
Scheme 40
Like 2-arylacetaldehyde derivatives (Scheme 16, Section 2.2.1), substituted imines derived from 3-aryl propionaldehydes are prone to intramolecular palladium-catalyzed N-arylations. Thus, cyclization of N,N-dimethylhydrazones of 2,6-dichlorophenyl propionaldehyde 133 resulted in 5-chloro-1-dimethylamino4H-quinoline 134 in 32% yield (Scheme 41) h00AGE2501i. Cl Cl
H Me N N Me
Cl
[Pd(dba)2] ligand, base o-xylene, 120 ⬚C
N Me
133
N
Me
134
Scheme 41
Tricyclic aldehyde 136, a key intermediate in the synthesis of conformationally restricted pyrrole-based inhibitors of HMG-CoA reductase, was obtained from anilide 135 using a standard C N bond coupling procedure (Scheme 42) h07BML4531i.
50
D. Tymoshenko et al.
O Me
Ph N H
Me
N
O Me
Ph
Me
N
O
N
Pd(OAc)2, Xantphos Cs2CO3, toluene
O
37%
Br F
135
136
F
Scheme 42
2.3.2 Quinazolines The use of 2-(dicyclohexylphosphino)-biphenyl as the ligand of choice with K3PO4 as base and Pd2dba3 as the palladium source leads to the smooth cyclization of aryl benzyl ureas 137 to dihydroquinazolinones 138 (Scheme 43) h04BML357i. The reaction works for either activated aryl chlorides (X ¼ Cl, R1 ¼ NO2) or aryl bromides (X ¼ Br, R1 ¼ H). Good to excellent yields were obtained regardless of the substitution pattern on the N-aryl substituent. O R1
N H
N H
Ar
Pd2(dba)3/ligand K3PO4
R1
NH
R1 = H, NO2 53–93%
X 137
N Ar
O
138
Scheme 43
Another example is the one-pot reaction between secondary o-bromobenzylamines and isocyanates leading to dihydroquinazolinones (Scheme 44) h03S1383i. Thus, addition of isocyanates 140 to the mixture of amine 139, Pd(Ph3P)4, and K2CO3 in anhydrous toluene or DMF and heating for 8–30 h resulted in satisfactory-to-good yields of cyclic products 141.
Br NH-Bn 139
R1 N C O
Pd(PPh3)4 K3PO4
R1 N
toluene, 50–85% 140
O N
Bn
141
R1 = n-Bu, p-MeOC6H4CH2, Ph, p-ClC6H4, p-CNC6H4
Scheme 44
Like anilides 114a and 114b, reaction of 2,5-bis-tert-butyl urea 114c (X ¼ NBn, Y ¼ CH2, Scheme 34, Section 2.3.1) proceeded with excellent enantioselectivity (94% ee) to give the cyclic urea 115c in 82% yield h05JA3676, 06JA12923, 08TL471i.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
51
2.3.3 Quinoxalines, Benzo-oxa(thia)zines, Phenazines, and Related Rings Limited examples exist in the literature for quinoxaline ring synthesis through palladium-catalyzed intermolecular reactions. Like 3-amino-indol-2-ones 80 (Section 2.2.1, Scheme 23) h06TL3423i, quinoxalin-2-ones 82 can be obtained in two steps. The first step includes a Ugi four-component reaction of R1-substituted 2bromoaniline 81, R2-isocyanides, R3-aldehydes, and R4-acids, followed by intramolecular palladium-catalyzed cyclization. An analogous transformation has been reported for linear o-iodo amides 142, prepared in one step by the Ugi four-component reaction, which can be converted into 3,4-dihydroquinoxalin-3-ones 143 or into 2-(2-oxoindolin-1-yl)acetamides 144 dependent on the catalytic conditions. Microwave irradiation was essential for reaction efficiency, while the choice of ligand diverges the reaction pathway. Heating a solution of 142 in dioxane/MeCN in the presence of Pd(dba)2 and Cs2CO3 using X-Phos as a ligand afforded the 3,4-dihydroquinoxalin3-one 143 via an intramolecular N-arylation of the secondary amide. However, using BINAP as ligand under the same conditions, intramolecular R-CH arylation of tertiary amide occurred to give oxindole 144 (Scheme 45) h09JOC3109i.
I
i-Pr t-Bu NH
N C3H7
O 142
O
Pd(dba)2 Cs2CO3, ligand
C2H5
t-Bu N O
O
dioxane/MeCN MWI, 150 ⬚C
N C3H7
i-Pr O
143
N O 144
i-Pr
Ligand 143 144 XPhos 91% 0% BINAP 0% 80%
NH-t-Bu
Scheme 45
As described above for anilides derived from 3-phenylpropanoic acid (Scheme 34, Section 2.3.1), reaction of glycine derivative 114d (X ¼ CH2, Y ¼ NBn) proceeded with excellent enantioselectivity (95% ee) to give piperazinone 115d in 71% yield h05JA3676, 06JA12923, 08TL471i. An efficient synthetic route to aryl- and benzylamino-substituted 4H-1,3-benzothiazines has been developed (Scheme 46) h08SL2433i. 1-(2-Bromobenzyl)(X ¼ Br) and 1-(2-iodobenzyl)-3-phenyl-thiourea (X ¼ I) 145 are readily available by the condensation of the corresponding o-halobenzylamine and phenylisothiocyanate. Applying the palladium-catalyzed protocol to 1-(2-bromobenzyl)-3-phenyl-thiourea using Pd(PPh3)4 in the presence of triethylamine in refluxing dioxane resulted in only 16% of the product 146 (R1 ¼ R2 ¼ H, R3 ¼ Ph) while the iodo derivative afforded a 55% yield. Addition of an extra 10 mol% of triphenylphosphine further increased the yield to 67%. Interestingly, when benzyl urea was used as a starting material (R3 ¼ Bn), a stronger base (DBU) was required to yield the product quantitatively.
D. Tymoshenko et al.
52
R1 R2 S
X
N R
R1 R2
R3 10 mol% Pd(PPh3)4 N 10 mol% Ph3P H Et3N or DBU dioxane, reflux
N S
145
N H
R3
146
Scheme 46
As compared to quinoxalines and benzothiazines, the palladium-catalyzed synthesis of benzoxazines is more common. Thus, the crucial step in the synthesis of 8H-[1,4]oxazino[2,3-f]quinolin-8-ones 149 with androgen receptor modulating activity was the annulation of the morpholino ring according to Scheme 47 (yields are not reported) h07BML5442i. R
NH2
CF3 O Br
Pd2dba3, BINAP t-BuONa, toluene reflux
NH O
N
N
N H
149
148
147
R
CF3 O
NH O
O
R
CF3 O
Scheme 47
Similarly, synthesis of another series of selective androgen receptor modulators, [1,4]oxazino[3,2-g]quinolin-7-ones 151, has been reported. The key step in the 8-step synthetic sequence was palladium-catalyzed amination of intermediate 150 (Scheme 48) h08BML2967i. CF3
CF3
Br O
N H
Pd2dba3, t-BuOK
O R
NH2 H
150
BINAP, toluene 90 ⬚C
O
N H
H N
R
O 151
R = CH2CF3, Bn,CH2CH2SMe
Scheme 48
1,2-Cyclic sulfamidates 152 undergo efficient and regiospecific nucleophilic cleavage with 2-bromophenols 153 (X ¼ O), followed by Pd-mediated amination giving access to substituted and enantiomerically pure 1,4-benzoxazines 155 (X ¼ O). The related anilines (X ¼ NH) and thiophenols (X ¼ S) can be used to produce the corresponding quinoxalines 155 (X ¼ N) and 1,4-benzothiazines (X ¼ S). This chemistry provides a short and efficient entry to (3S)-3-methyl-1,4-benzoxazine 156, a late stage intermediate in the synthesis of antibiotic levofloxacin 157 (Scheme 49) h07OL3283i.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
53
XH Br O R2 N
S
O
Br 153
O
R2 NH
NaH, DMF
X
R1
R1
154
152
Pd(OAc)2, Xantphos, t-BuONa, toluene
X
R1 = Me, Ph, Bn R2 = Me, Bn, Boc 65–88%
N R2
R1
155
O HOOC
F
F
O
R1
N
N
F
HN
156
N
O
R1
Me
157
Scheme 49
The new 2,3,7,8-tetrachlorodibenzo-p-dioxin analogue, phenothiazine 161 (TCPT), has been developed and explored to take advantage of the low-dose effects of dioxins that have potential application as therapeutics. It can be synthesized in three steps with the key ring-closing step performed utilizing a Buchwald–Hartwig amination in the presence of 2-(dicyclohexylphosphino)-biphenyl (DCPB) ligand to provide TCPT in 37% yield (Scheme 50) h07MI890i. Cl Cl
Cl
Cl
SH
158
O2 N
Cl
1. K2CO3, CaCO3 CH2Cl2, 97%
F
Cl
2. Fe/AcOH acetone/H2O, 86%
159
Pd(OAc)2/DCPB t-BuONa, DMF 200 ⬚C, MW, 2 min 37%
Cl S Cl
160
Cl
H N
Cl
Cl
S
Cl
NH2 Cl Cl
161
Scheme 50
Following a report on phenazine synthesis h05OL1549i, a novel methodology for the synthesis of dihydrodipyridopyrazines 164 was developed h09OL5502i. Intermediates 162 (R ¼ Me, Bu), obtained by Smiles rearrangement of nitro-substituted N,N0 -dipyridinylamine precursors, cyclize to 5-alkyl-5,10-dihydrodipyrido [3,2-b:30 ,20 -e]pyrazines 163, which can be further alkylated at position 10 providing moderate yields of 5,10-disubstituted products 164 (Scheme 51). Applying the same reaction conditions to isomeric dipyridinylamine precursor 165 gave [3,2-b:30 ,20 -e] pyrazine 167 as the product of oxidative aromatization of unstable dihydro-derivative 166 h09EJO3753i.
D. Tymoshenko et al.
54
N
Br NH
K2CO3, dioxane
NH
N
H N
N
Pd(OAc)2, Xantphos
N
R
N
R
162
Me N
N
MeI, NaH, DMF 32–33% over 2 steps
N
N
R
163
164
N Cl Pd(OAc) , Xantphos 2 NH
N
K2CO3, dioxane
NH2
165
N
H N N H
N N
N
79% N
N
167
166
Scheme 51
2.3.4 [1,2]-Fusion of Azoles to Six-Membered Rings A special case of bi- or polycyclic ring construction is the fusion of a six-membered ring to pyrrole (or pyrrolidine), indole, or imidazole when N1 and C2 atoms of the latter serve as fusion sites. Thus, pyrrolo[1,2-a]quinoxalines, indolo[1,2-a]quinoxalines, and their aza-analogues of the general formula 169 can be efficiently prepared by palladium-catalyzed intramolecular C N bond formation (Scheme 52) h05S2881i. Pd(OAc)2, BINAP Cs2CO3, toluene 100 ⬚C
2
R
O Z
1
R
N H
R3
N Me
Y X
168
Y = CH, N Z = CH, N R3 = H, Cl, Me
R2
R1
O N
Y
N
Me
Z
66–95% R3
169
Scheme 52
Similar intramolecular arylation of the indole ring requires a hindered t-Bu3P ligand and produced alkaloid arnoamine B 171, a known topoisomerase inhibitor (Scheme 53) h07H(71)1801i.
55
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
Br
NH
Pd(OAc)2, t-Bu3P K2CO3, xylene, 110 ⬚C 81%
N
N
N MeO
OMe 170
171
Scheme 53
Synthesis of the bis(imidazole)-annulated terphenyls 173, planar disc-shaped building blocks for organic semiconductors, can be started from bis-imidazole derivative 172 and involved the intramolecular CN bond formation using palladium acetate, triethylphosphine, and sodium tert-butoxide, affording 72–87% yields of the desired products (Scheme 54) h06JMA4058i. R
R
Cl
N
Pd(OAc)2, PEt3
R N H
H N R Cl
N
t-BuONa, toluene reflux, 48 h, R = p-C6H4-OAlk, 72–87%
N R N N R N
R
172
R
173
Scheme 54
Heterocyclic enamines 174 undergo regioselective C-benzylation and C-benzoylation with o-bromobenzyl bromide and o-halobenzoyl chloride to yield the corresponding C-substituted enamines 175 and 177 as suitable precursors for annulations. Subsequent intramolecular arylation led to the fused 1,4-dihydroquinolines 176 or quinolin-4-ones 178 (Scheme 55) h03ARK146i. The latter do not require the presence of palladium catalyst. The ring size of the cyclic enamine affects the reactivity, and decreased yields of products 176 were found with increasing numbers of atoms n in the ring.
D. Tymoshenko et al.
56
Br
Br Cl
Br
N H
175
NaH 33–57%
Br
Cl
n
pyridine
N H
EtO2C
Pd(dba)2 DPPP, t-BuONa n = 1, 51% n = 2, 36%
O
n
H
n
EtO2C
O
CH2Cl2
EtO2C
N H
85–87% NaH, THF, n = 1–3 40–52%
174
177
O CO2Et
CO2Et N
N
176
178
n
n
Scheme 55
A practical and highly efficient route for the synthesis of pharmaceutically interesting quinoxalinone cores 180 has been reported (Scheme 56) h10OL3574i. The key step involved an intramolecular palladium-catalyzed N-arylation under microwave irradiation. Catalytic system optimization showed that imidazole carbene ligand 181 gives the highest (up to 95%) conversion of starting materials and, in many cases, nearly quantitative yields of the products. The developed methodology tolerates a variety of bromoanilides 179 affording a diverse collection of bicyclic and polycyclic quinoxalinones.
HN R Br
N H 179
BF–4
Pd2(dba)3 ligand, t-BuOK dioxane, MW O
R = H, quant yield
N
N
N
R N H 180
O 181
Scheme 56
2.4. ANNULATION OF MEDIUM SIZE AZA-RINGS The first palladium-catalyzed syntheses of benzazepines were reported by Buchwald and coworkers h96T7525i and later followed by optimization studies h06SL115i. Optimized reaction conditions for indolines and oxindoles (Scheme 3, Section 2.2.1) were smoothly transferred to benzazepine derivatives prepared from secondary amide or secondary carbamate precursors (5 and 7, correspondingly, n ¼ 3). Thus, reaction using ()-MOP 9 ligand and cesium carbonate resulted in 79–88% yields of benzazepines 6 and 8 (R ¼ Boc, Cbz), which are comparable to those of five-membered homologs. Under the same conditions, Xantphos was the ligand of choice for N-acetyl benzazepine 8 (R ¼ Ac). A recent report h09T525i revealed that sterically bulky monophosphines X-Phos 13a and P(t-Bu)3 are particularly effective for the formation of 7-benzolactams using palladium-catalyzed aryl amidation reactions.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
57
A synthetic route to 1-benzyl-tetrahydro-1-benzazepines 184 with alkyl and aryl substituents at C2 of the azepine ring has been reported (Scheme 57) h03TL3675i. Palladium catalysis can be utilized in two of the three steps (i.e., Heck condensation and CN bond formation) constructing the seven-membered rings effectively from 2-bromoiodobenzene 182. The reactive intermediate 185 undergoes competitive b-hydride elimination, and imine 187 was the main product in the attempted CN bond formation in the case of a bulky substrate (R ¼ t-Bu). Use of bulky phosphine ligands under milder reaction conditions to suppress the b-hydride elimination pathway was not effective and resulted only in the recovery of starting material.
R 1. I
OH Pd(OAc)2, DMF R = H; Bu4NCl, NaHCO3 R = Me, Ph, t-Bu, LiCl, DIEA 56–89%
Br
R HN
Bn
Pd(dba)2/PPh3 t-BuONa/K2CO3 R = H, Me, Ph N Bn 184
60–83%
2. BnNH2, Ti(i-OPr)4 NaBH4, 60–80%
Br 183
182
X
Pd(dba)2/PPh3 t-BuONa/K2CO3 R = t-Bu N H
187
Ph reductive elimination
H Pd N
186
Ph β-H-elimination
R
H Ph L Pd N
185
Scheme 57
Like 3-amino-indol-2-ones 80 and quinoxalin-2-ones 82 (Scheme 23, Section 2.2.1) h06TL3423i, benzodiazepine-2,5-diones 84 can be obtained in two steps. The first step includes a four-component Ugi reaction of R1-substituted 2-bromobenzoic acid, R2-isocyanides, R3-amines, and R4-aldehydes, followed by intramolecular palladium-catalyzed cyclization. A convenient procedure for the preparation of tetrahydro-1,4-benzodiazepin-3(3H)-ones 188 from chiral a-substituted N-n-butyl-N-(o-iodobenzyl)glycinamides 187 has been developed. Seven-membered ring formation occurs through an intramolecular N-arylation catalyzed by palladium and bis(phosphine) ligands. The use of chelating bis-phosphines allows minimization or entire suppression of C2 racemization, which occurs when a mono-phosphine ligand is used (Scheme 58) h01SL803i. Recently, analogous synthetic methodology has been reported for the synthesis of benzodiazepine type agents for suppression of vitamin D receptor (VDR)-mediated transcription h10BML1712i.
58
D. Tymoshenko et al.
I
Bu N
NH2
O
O
R1 BINAP or DPPE t-BuOK or Cs2CO3
N Bu
187
N
Cl
R N
R1
H N
Pd2(dba)3
188
HN
O
Pd(OAc)2
N
N O
BINAP t-BuOK or Cs2CO3
N R
189
190
Scheme 58
A similar transformation was reported for the synthesis of pyrido[2,3-e] pyrrolo [1,2-a][1,4]diazepin-10-ones 190 h10TL4053i. Notably, N-unsubstituted proline amide 189 (R ¼ H) failed to cyclize due to the predominant Z-rotamer conformation unfavorable for cyclization. An improved synthesis of oxazepine and thiazepine ring systems 192 (Scheme 59) h03JOC644i includes a palladium-catalyzed intramolecular amination. General conditions include Pd2(dba)3, t-Bu3P, and t-BuONa alone (X ¼ O) or with K2CO3 (X ¼ S) in toluene at 95 C. Interestingly, attempted cyclization of o-aminobenzyl ether 191 did not give the expected cyclization product. Substitutions on the phenyl ring gave the expected electronic trends: electron-deficient and neutral substitutions on the bromo-substituted ring facilitated transformations, while yields from electron-rich substrates were slightly lower.
X
Pd0 O NH2
191
no reaction Br
N H
192
Pd2(dba)3, t-Bu3P t-BuONa/K2CO3 toluene, 95 ⬚C X = S, 65% X = O, 82%
X NH2
Br
193
Scheme 59
Palladium-catalyzed intramolecular aryl amination on sugar derivatives has been accomplished by using bulky biaryl phosphine ligands. An application of this methodology on a variety of D-glucose-derived substrates 194 led to the synthesis of highly functionalized cis-fused tricyclic oxazocines 195 (Scheme 60) h06JOC3291i. Preparative approach to the analogous tricyclic diazocines has been reported recently h10EJO1754i.
59
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
R1 X HN
R2
R1
Pd(OAc)2, BINAP
O
R3
R2
O O
K2CO3-t-BuOK, toluene 90 ⬚C, 48 h, 68–77%
N
O O
R3
O
O
O
195
194
Scheme 60
Pyridobenzodiazepinones 198 (and dibenzo[b,e][1,4]diazepinones, not shown in the scheme) have been approached by intramolecular Buchwald–Hartwig reactions between an (hetero)aryl halide and the aromatic amino group intermediate 197 (Scheme 61) h05T61i. NO2
NO2 Cl
N
Cl
1. pyridine
O
2. MeI, NaH DMF
H2N
O
Me
N
N
196
H N
1. Fe/AcOH
Cl
2. Pd(OAc)2 BINAP t-BuOK toluene
O
N
N Me 198
197
Scheme 61
The final step in a synthesis of the 9-membered triaza o-cyclophane ring system was a palladium-catalyzed Buchwald–Hartwig N-arylation affording N,N0 -dimethyltribenzo-1,4,7-triazacyclononatriene 201 in 50% yield (Scheme 62) h10JOC7887i.
O 2N H2N
1. NH2
I
Me N
N Cl
2. Me2SO4, 86% N
3. CuCl, KBH4, 100%
Me Me
Pd(dba)2 BINAP t-BuOK toluene
Me N N Me
50% N H
Cl 199
200
201
Scheme 62
The amino group of 3-amino-4-cyano-5-aryl pyrazoles 202 is reactive enough to participate in intramolecular palladium-catalyzed reactions leading to benzo[d]pyrazolo[1,5-a][1,3]diazepine 203a (n ¼ 1) and benzo[d]pyrazolo[1,5-a][1,3]diazocine 203b (n ¼ 2) ring systems, respectively, lymphocyte-specific kinase (Lck) inhibitors (Scheme 63) h10BML112i.
60
D. Tymoshenko et al.
Ar
NC
N n Br
50%
Ar
NC
Pd2(dba)3 BINAP Cs2CO3 dioxane
N
H2N
HN
N N
R1 n R2
R2 R1
203a, n = 1 203b, n = 2
202
Scheme 63
2.5. MACROCYCLES Palladium-catalyzed macrocyclizations are rare but they provide novel approaches to large ring systems. Thus the synthesis of benzoaza crown ethers 205 with 12- to 18-membered rings has been reported by Fort et al. (Scheme 64) h07MI322i. The key to successful cyclization is the use of N,N0 -bis(20 ,60 -diisopropylphenyl)dihydroimidazolium tetrafluoroborate (SIPr) ligand. The chelation study using different metal tert-butoxides revealed that the 12-membered product 205 (n ¼ 1) can be formed efficiently in the presence of t-BuOLi and t-BuONa (77% and 75% yields, respectively) with a lower, 43% yield using t-BuOK. In the case of the 15-membered crown ether (n ¼ 2), comparable 55% and 45% yields were found using t-BuONa or t-BuOK. The use of t-BuOLi furnished only 25% of the product. An 18-membered ring (n ¼ 3) was produced in 35% yield under optimized conditions using t-BuONa.
O
O
O n
Cl 204
NH2
Pd(OAc)2, SIPr, t-BuOM 1,4-dioxane, 100 ⬚C n = 1−3, M = Li, Na, K 25–77%
NH
O
O
O n
205
Scheme 64
Macrocyclic compounds 208 were designed as BACE-1 inhibitors, promising therapeutics for the treatment of Alzheimer’s disease h07BML5831i. They were synthesized from 2-chloropyridine derivatives 206. Reductive amination was followed by palladium-catalyzed macrocyclization and deprotection resulting in good yields of the target compounds 208 (Scheme 65).
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
Me
N
Ms
Me
N
R
61
Ms
N
N
RCHO, NaBH(OAc)3
NH2Cl O
NH Cl
60–80%
O
O
NHBoc
O NHBoc
Me
Me
206
207
1. Pd[P(t-Bu3)3]2 K3PO4, DMA 65–82% 2. TFA, CH2Cl2 99%
Me
N
Ms
N R
N O
O NH2 Me
208
Scheme 65
The synthesis of conformationally constrained cyclic peptides 210 with biarylamine linkers using palladium-catalyzed intramolecular Buchwald–Hartwig C N coupling has been described h06JOC8954i. A wide variety of di-, tri-, and tetrapeptides with 16- to 22-membered rings were prepared in good yields with no racemization (Scheme 66).
R3 HN
R2
H N
R3
NH O
O
O
R1 O
H 2N Br
R 209
( )n
Pd(OAc)2 rac-BINAP t-BuOK, CH3CN, 100 ⬚C, 15 h
HN
R2
H N
NH O
O
O
R1 O
H N
( )n
R = H, CH3, R1 = CH2Ph R2 = CH3, CH(CH3)2 R3 = CH3, CH(CH3)2, CH2CH(CH3)2 n = 1–2
R 210, 32–50%
Scheme 66
Several macrocyclizations have been reported for symmetrical di-bromoaryls and diamines. Although formally an intermolecular process, it apparently involves a late stage intramolecular cyclization. Thus, palladium-catalyzed amination of 3,5-dibromoand 3,5-dichloropyridines 211 with a variety of linear polyamines 212 led to the formation of pyridine-containing macrocycles 213 in low to moderate yields (Scheme 67) h05HCA1983i. Open-chain mono- and bis(5-halopyridin-3-yl)-substituted polyamines 214 and 216 and 3,5-bis(polyamino)-substituted pyridines 215 were used as intermediates for the preparation of macrocycles with larger cavities.
D. Tymoshenko et al.
62
X
X
NH2 HN X
H2N X
X
HN
Br
N
NH2
N
213, 5–42%
212 NH2
Pd(dba)2, BINAP t-BuONa, dioxane
N
NH
214, 10–36% Br
H2N
X
X
211
Br
X = NH; CH2NHCH2; NH(CH2)2NH; NH(CH2)3NH; CH2NH(CH2)2NHCH2; CH2NH(CH2)3NHCH2; NH[(CH2)2NH]2; NH[(CH2)2NH]3; O(CH2)2O
HN
N
HN
NH N
X
N H
N
216, 3–33%
215, 6–14%
Scheme 67
A fragment-coupling approach for the synthesis of azacalix[m]arene[n]pyridines has been developed by Wang et al. h04AGE838i. It includes (Scheme 68) the condensation of m-phenylenediamine with 2,6-dibromopyridine in the presence of an excess of t-BuOK to give N,N0 -bis(6-bromopyrid-2-yl)-m-phenylenediamine 217 in excellent yield. Further treatment with methyl iodide followed by palladium-catalyzed double aryl amination with N,N0 -dimethyl-m-phenylenediamine in refluxing toluene gave macrocyclic azacalix[2]arene[2]pyridine 219a (n ¼ 1) and azacalix[4] arene[4]pyridine 219b (n ¼ 3) in 26% and 22% yields, respectively. The larger ring compound 219b was obtained as a single product in 26% yield when the reaction was performed at a lower temperature.
t-BuOK, THF NH2 Br
H2N
N
Br
rt, 97%
Br
N
N H
N H
N
Br
217 MeI, t-BuOK, THF, 90%
Me
Me N
N Me
N Me
N H
Me
N Me n
219a, n = 1, 26% 219b, n = 3, 22%
Scheme 68
N H
Pd(dba)2/dppp t-BuONa
Br
N
N Me
N Me 218
N
Br
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
63
In the pursuit of ligands with multidentate coordination sites and significant flexibility for preparation of oligonuclear metal complexes, Yamaoto et al. h05SL263i reported the synthesis of N-(p-Tol)azacalix[n](2,6)pyridines 221 (Scheme 69). Synthetic routes included palladium-catalyzed (or Cu-catalyzed) aryl amination reactions, and macrocycles with various numbers (1–5) of an N-(p-Tol)aminopyridine recurring unit were isolated.
R = p-tolyl Pd2dba3, Xantphos Br
N
N H
R
R
N
N
N
N
t-BuONa, toluene 80 ⬚C, 5 d
R n = 1, 38% n = 2, 31% n = 3, 6% n = 4, 7% n = 5, 2%
n
N N R
221
220
Scheme 69
2.6. TANDEM SEQUENCES, CASCADES, AND MISCELLANEOUS CYCLIZATIONS Palladium-catalyzed CN bond formation can be a part of various synthetic sequences including tandem reactions and cascades resulting in molecular entities of varying complexity. Thus, dipyrido[1,2-a:30 ,20 -d]imidazole 224 (Scheme 70) and its benzo- and aza-analogues (not shown) can be prepared by a novel tandem process using intermolecular Buchwald–Hartwig amination followed by intramolecular ring formation with excellent 82–98% isolated yields h04CC2466i. I Cl
N
N
Pd(OAc)2 BINAP or Xantphos N
NH2
N
Cs2CO3, toluene, reflux
223
222
N
224
Scheme 70
A new palladium-catalyzed one-pot methodology for the synthesis of N-arylated heterocycles has been developed (Scheme 71) h04S2527i. The process involves a sequential intra- and intermolecular amination, and it includes the use of an in situ generated Pd catalyst supported with N,N0 -bis(2,6-diisopropylphenyl)dihydroimidazol-2-ylidene (SIPr) ligand and t-BuONa. It allows, in one pot, the synthesis of a wide range of N-arylated nitrogen five-, six-, and seven-membered heterocycles 227.
X
NH2 n
Pd(OAc)2, SIPr.HCl t-BuONa dioxane
X
Cl 225
Scheme 71
226
N H
X
ArCl n 227
N Ar
n
X = CH2, O n = 1–3, 41–99%
D. Tymoshenko et al.
64
A variety of 2,3,4,9-tetrahydro-1H-carbazoles has been accessed through a three-step synthetic sequence (Scheme 72) h05AGE403i. The first step involved palladium-catalyzed a-arylation of cyclohexanone followed by formation of triflate 229. The latter produced tetrahydrocarbazoles 230 through an inter-/intramolecular double amination cascade with the best yields reported for Xantphos and DPEphos as ligands. The method was extended to a variety of cyclic and acyclic 1,2-disubstituted indoles. Br PhNTf2, NaH THF, 0 ⬚C
I O
Pd2(dba)3, Xantphos Cs2CO3, toluene 228 78%
Br
O
RNH2
87%
Br
OTf
229
Pd2(dba)3 ligand, Cs2CO3 46–86%
N R 230
Scheme 72
In a similar fashion, 2-(2-haloalkenyl)aryl halides 231 can undergo two sequential palladium-catalyzed amination reactions, the first intermolecular, the second intramolecular, providing efficient routes to a range of N-functionalized indoles 232 (Scheme 73) h06ASC851, 07CC4764i. The sequence tolerates a wide variety of substituents, although a careful choice of ligands and halogen leaving groups is required. Thus, the use of 20 -dimethylamino-2-dicyclohexylphosphine (233a) as a ligand is superior for dichlorides 231 (X ¼ Y ¼ Cl), while dimethoxy ligand S-Phos (233b) was more efficient in the case of dibromo substrates (X ¼ Y ¼ Br) h06ASC851i. Use of sterically hindered amines (tert-butyl amine, 1-adamantyl amine, 2,6-di-isopropyl aniline) required P(t-Bu)3 ligand as its HBF4 salt h07CC4764i. An interesting variation is a synthetic sequence starting from 2-(2-bromovinyl)-1,3-dichlorobenzene with the addition of one equivalent of secondary amine (morpholine) which resulted in the one-pot preparation of functionalized indole 234 in 55% yield h06ASC851i. R2 R1 X
NH2 R3
R2
R1
Pd2(dba)3 ligand t-BuONa 46–86%
Y
231
N R3 232
O Cl
N
N PCy2 NMe2
PCy2 OMe
MeO
Cl
Br
234 OMe
233a
233b
Scheme 73
The complex polycyclic structure of ()-murrayazoline 238 has been constructed by a combination of the intramolecular Friedel–Crafts-type Michael addition and palladium-catalyzed CO coupling reactions of the key intermediate
65
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
237 (Scheme 74, h08OL1999i). This N-substituted carbazole was synthesized by a one-pot double N-arylation of sterically hindered amine 236 with a dibromobiphenyl derivative 235. The use of Pd2(dba)3 as a palladium source, XPhos 13a ligand, and t-BuONa gave acceptable results when the sterically hindered amine 236 was used, providing a 59% yield. The use of other ligands resulted in lower yields of the carbazole 237.
Me
NH2
O
Me
O
Me Me
Me OMOM
OMOM 236
O N
Pd2(dba)3, ligand, t-BuONa, toluene 16–59%
Br Br 235
Me Me
O
N Me Me
O 237
Me 238
Scheme 74
The palladium-catalyzed inter-/intramolecular sequence discussed above h05AGE403, 06ASC851, 07CC4764i can be further extended to an intermolecular aminocarbonylation/intramolecular amidation cascade for an efficient transformation of various 2-(2-haloalkenyl)aryl halides 239 into the corresponding 2-quinolones 241 in 33–80% yields (Scheme 75). Delaying the introduction of the CO allows another sequence, which starts with amination on a vinyl moiety and is followed by carbonylation, to produce isoquinolone 242 in 68% yield h09OL583i.
1. o-Toluidine, Pd2(dba)3 Xantphos, t-BuONa R1 2. CO
Me N 242
R2
3
CO X
R1 = R2 = H X = Br
O
R2
R NH2, 240
R1
X
239
Pd2(dba)3, ligand Cs2CO3, toluene, 100 ⬚C
241
N R3
O
Scheme 75
A cascade process with two C N arylation steps was used for amines 243 and was achieved using P(t-Bu)3 ligand in Pd-mediated cross-coupling reaction conditions (Pd (dba)2, t-BuONa, refluxing toluene). Although the resulting polycyclic amino-ether 244 (X ¼ O) was produced in 34% yield, application of similar conditions to a thioether starting material (X ¼ S) gave the product in less than 3% yield, but this was improved by switching to copper catalysis (Scheme 76) h04CL1174, 05AGE4056i.
Br
NH2 X
Br X
Pd(dba)2, P(t-Bu)3 t-BuONa, toluene X = O, 34% X = S, 3%
243
Scheme 76
N X 244
X
D. Tymoshenko et al.
66
Another synthetic sequence involving a final CN intramolecular coupling was established as a new route to antiepileptic drug oxcarbazepine 249 (Scheme 77) h05OL4787i. The sequential key steps were palladium-catalyzed intermolecular C-arylation of ketone enolates and intramolecular N-arylation reactions. Interestingly, Xantphos, a ligand commonly employed in N-arylation reactions but rarely used in C-arylation of enolates, is the best ligand for the preparation of C-arylated product 247. This protocol can be readily extended h07T690i to benzazepinones with annulated thiophene rings 250 complementing the traditional methods of benzothienoazepinone synthesis h08AHC1i. The proposed reaction pathway did not afford pyridine annulated target 251 for undisclosed reasons under a variety of reaction conditions. Pd(OAc)2, Xantphos Cs2CO3, toluene 100 ⬚C
O Br
Me NHTs
86%
Br
O 1. H2SO4 2. Pd(OAc)2, BINAP Br K3PO4, toluene, 100 ⬚C
NHTs
245
91%
247 246
O
O
O
O S
steps N
N H 249
248
N
R
O
O NH2
N
N O
NH2
250
NH2 251
Scheme 77
The similarity of the reaction conditions for palladium-catalyzed CN and CC bond couplings encouraged extensive studies of precursors demonstrating such dual reactivity. Thus, a novel two-step procedure was devised for the preparation of 1-methyl-4-(hetero)aryl oxindoles 254 in moderate to high yields (Scheme 78) h06TL4361i. The key steps comprise an intramolecular palladiumcatalyzed amidation reaction followed by an in situ intermolecular Suzuki cross-coupling reaction in a one-pot reaction. In the absence of boronic acid, bis-oxindole 253 was the sole product as the result of CN intramolecular arylation followed by dimerization via oxindole a-arylation and palladium-catalyzed debromination.
O Br
Ar O
ArB(OH)2 N H
Br 252
Scheme 78
Me N
Me
O
Pd(OAc)2, Xantphos K2CO3, t-BuOH, 85 ⴗC 18–90% 253
N Me
N Me
O 254
67
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
A one-pot procedure involving a tandem cyclization–coupling process for the preparation of 2-functionalized indoles starting from readily accessible 1,1dibromo-1-alkenyl aniline derivatives 255 (X ¼ NAc) has been developed by Bisseret and coworkers (Scheme 79) h04TL907i. This method involves Suzuki or Stille coupling with the higher reactivity of the trans C Br bond relative to the cis CBr bond toward oxidative Pd insertion followed by intramolecular palladium-catalyzed CN bond formation. This process is complementary to the most efficient palladium- or copper-catalyzed processes for the preparation of similar heteroaryls involving alkynes instead of dibromoalkenes. A similar reaction starting from the corresponding phenol derivatives led to benzo[b]furans 257 (X ¼ O). XH
XH
Br
Ar-SnMe3 or ArB(OH)2 X = O, Pd(OAc)2, dppf X = NAc, Pd2(dba)3, dppf TEA, toluene 100 °C
Br
255
X
Br
Ar 70–91%
Ar
257
256
Scheme 79
Another report revealed that amino group protection is not required for a Suzuki cyclization cascade when SPhos is used as a ligand in the presence of potassium phosphate giving rise to N-unsubstituted indoles in 73–86% yields h05OL3549i. In addition, the corresponding gem-dichlorides can be used instead of bromides 255 when a higher (5%) loading of the catalyst is used. Later work h08JOC538i disclosed that the CN bond formation could be the first coupling step followed by a Suzuki process, although no reaction was observed in the absence of boronic acid. This methodology was further applied as a general method for the preparation of diverse indoles. Thus, an efficient synthesis of KDR kinase inhibitor 258 (Figure 1), N/Suzuki coupling as the key step, using similar palladium-catalyzed tandem C was reported h07JOC1341i providing 86% yield of the intermediate for the key palladium-catalyzed cascade step. S Ph
Ph N Ms
N
N
N H
N
S
Boc
NH
Boc
O
258, 86%
259a, 73%
259b, 76%
ON+ Ph N Cbz
260a, 75%
Figure 1
N
Ph N
N
Ph N
Boc
Boc
260b, 87%
260c, 87%
Ph N
N Bn
260d, 90%
D. Tymoshenko et al.
68
A palladium-catalyzed reaction of gem-dichloro olefins and a boronic acid via a tandem intramolecular CN and intermolecular Suzuki coupling process gave two isomers of thienopyrroles 259a and 259b and all four isomers of azaindoles 260a–d in good to excellent yields h07JOC5152i. Lautens and coworkers reported a catalyzed indole synthesis involving not only a N/Heck combination h06OL4203i. CN/Suzuki h08JOC538i but also a C Thus, the tandem reaction including a Buchwald–Hartwig/Heck sequence (Scheme 79) h06OL4203i did not require expensive phosphine ligands and involved tetramethylammonium chloride, producing moderate to good yields of alkenes 262. An intramolecular version used substrates 263 where the alkene moiety is tethered to the nitrogen of the ortho-gem-dibromovinylaniline and provided tricyclic systems 264. Various palladium sources and ligands were screened, and Pd2dba3 with nBu4NCl in the presence of NEt3/K3PO4 in toluene at 120 C gave the desired tricyclic adduct in good yield (76%) as a mixture of two easily separable isomers 264a and 264b, formed in 3:1 ratio (Scheme 80). Br R2
Br
261
NH R1
CO2t-Bu Pd(OAc)2, Me4NCl TEA/K3PO4, toluene reflux 39–69%
R2
262
N R1
CO2t-Bu
Br Br NH
263
CO2t-Bu
CO2t-Bu
CO2t-Bu
CO2t-Bu
Pd2(dba)3, n-Bu4NCl TEA/K3PO4, toluene reflux 76%
N
N
264a
264b
Scheme 80
Another variation of the Heck/Buchwald–Hartwig cascade was reported for the preparation of 4-aryl-2-quinolones 267 (Scheme 81). They were prepared from readily available o-bromocinnamamide 265 and aryl iodides using phosphine-free palladium(II) acetate as the catalyst and a molten tetra(n-butyl)-ammonium acetate/ tetra(n-butyl)ammonium bromide mixture as the reaction medium. The reaction proceeds through a pseudo-domino process involving two mechanistically independent, sequential catalytic cycles: a Heck reaction followed by an intramolecular Buchwald–Hartwig CN bond formation h07ASC297i. Ar Br
O NH2 Br
265
Scheme 81
Ar Pd(OAc)2
ArI Pd(OAc)2
H2N
266
O
n-Bu4NOAc (2.5 equiv.), n-Bu4NBr (4 equiv.), 120 ⬚C 48 h, 33–73%
N H
267
O
69
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
Recent developments of the Heck/CN arylation sequence include synthesis of diverse 3-methylindoles 271 (Scheme 82) h10OL668i. Although each of the steps, that is, a Heck reaction, carbamate/aryl chloride coupling, and isomerization, is run separately, the elaborated route is highly efficient and general, enabling the regiocontrolled synthesis of substituted indoles starting from readily available chloro-triflates.
OTf
NHBoc
NHBoc
R
R Pd(OAc)2, dppf, AcONa, MeCN
Cl
Pd(OAc)2, XPhos, K2CO3, DMF
Cl
269
268
Me R
CSA, CH2Cl2
R N Boc
N
54–80% over 3 steps
Boc
271
270
Scheme 82
A four-step approach to alkyl- and aryl-substituted dihydro benzoxazines can be accomplished by a palladium-catalyzed domino CC/CN bond coupling using a norbornene template (Scheme 83). The route begins with oxidative insertion of palladium(0) into the aryl iodide 272 followed by carbopalladation with norbornene leading to 273. This is followed by intramolecular CH functionalization, oxidative addition of 1-bromoalkane (or arene), and reductive elimination to form palladium species 274. Next, retro-carbopalladation of norbornene, which occurs as a result of the steric constraints imposed by the two ortho substituents, leads to the formation of 275, which undergoes an aromatic amination resulting in benzomorpholine 276. Extension of this method gave phenoxazine 277 and dihydrodibenzoxazepine 278 h10JOC3495i. H N
O
PMP
I
Pd(OAc)2, P(2-furyl)3, norbornene, Cs2CO3, MeCN
PdL2I
PMP
H N
PdL2Br O RBr R
272
273
O BrL2Pd
H N
275
274 O
O
O
PMP PMP
R
Scheme 83
H N
O
N
HN
HN
R
Ar
Ar
276
277
278
PMP
70
D. Tymoshenko et al.
A catalytic domino process that generates significant molecular complexity was established by Zhu et al. (Scheme 84) h03AGE4774, 04JA14475i. This novel process was applied to the construction of azaphenanthrenes fused with an 8-, 9-, 10-, 11-, and 13-membered lactam motif 280. I
O
O
I Pd(dppf)Cl2
N H
N H
n
O
KOAc, DMSO 80–120 ⬚C 18–57%
N HN
O n
279
O N N
280
O N N
Me
O
O
R
281
282
Scheme 84
It is suggested that a domino process starts with an intramolecular Buchwald–Hartwig amination, followed by CH activation, and aryl-aryl bond formation to produce polyheterocycles 280 from linear diamides 279 h04JA14475i. In contrast to other intramolecular amide N-arylations, this process is much less sensitive to the ligands used. Both bidendate phosphines, such as dppf and BINAP, and the monodentate ligand PPh3 were suitable, while t-Bu3P seemed to be less efficient. Potassium acetate was more effective than cesium carbonate as base, while DMSO was a better solvent than DMF and toluene. The optimal conditions involved PdCl2(dppf) as the catalyst, KOAc as the base in DMSO at 120 C. The scope of the process was further extended to the polycyclic systems 281 and 282, derived from acyclic amino acids (51–98%) and L-proline (97% yield), correspondingly. A regiocontrolled palladium-catalyzed domino sequence involving an intramolecular N-arylation followed by intermolecular Heck reaction provided rapid access to functionalized benzodiazepine-2,5-diones 284 (Scheme 85). The reaction of 283 in the presence of dihydrofuran afforded the expected benzodiazepinedione in 54% yield (Scheme 85). Notably, a two-step procedure involving a copper-catalyzed benzodiazepinedione synthesis, followed by a Heck reaction, resulted only in a 25% yield of the product h08OL857i.
Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
71
O I
O
H N
N O
I
Pd(OAc)2, KOAc, dihydrofuran, 120 ⬚C
O
N
54% N
283
O
284
Scheme 85
2.7. CONCLUSIONS The current review includes numerous very useful cyclizations or annulations that involve palladium-catalyzed CN bond formation. This chemistry generally involves initial oxidative addition of an organic halide or triflate to the palladium(0) complex, which readily undergoes intramolecular nucleophilic attack by a neighboring nitrogen nucleophile to form the ring or to produce reactive organopalladium intermediates useful in the subsequent transformations. Another type of development covered by this survey is the formation of organopalladium intermediates as a result of CC bond couplings, usually Suzuki or Heck processes, which are prone to intramolecular CN bond formation. The reactions proceed under relatively mild conditions and tolerate a wide variety of functional groups enabling the construction of a wide range of heterocycles. One can expect numerous future examples of heterocyclic systems synthesized based on this methodology. We hope this review to be a background for such advances in heterocyclic, medicinal, and natural products chemistry.
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01SL803 01TL2937 01TL7929 02J(P1)733 02J(P1)2137 02TCC131 02TL111 02TL1893 02TL3577 03AGE4774 03ARK146 03EJO2888 03JA5139 03JOC545 03JOC644 03JOC3064 03JOC6011 03JOC6814 03OL133 03S1383 03TL3675 03TL6073 04AGE838 04AGE6493 04BML357 04CC2466 04CL1026 04CL1174 04CSY47 04JA14475 04S2527 04TL907 04TL8535 05AGE403 05AGE4056 05HCA1983 05JA3676 05JOC596 05OBC3767 05OL763 05OL1549 05OL3549 05OL4787 05S2881 05SL263 05T61 06ASC851
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Synthesis of Heterocycles by Palladium-Catalyzed Intramolecular Heteroarylation
06CRV4644 06JA12923 06JMA4058 06JOC1280 06JOC3291 06JOC8954 06OL2167 06OL3311 06OL4203 06OL4351 06S1375 06SL115 06SL2083 06SL2716 06TL3423 06TL4361 07ASC297 07BML1043
07BMC3235 07BML3421 07BML4531
07BML5442
07BML5831
07CC4764 07H(71)1801 07JOC1341 07JOC4611 07JOC5152 07MI322 07MI564 07MI890 07OL3283 07OL4913 07SC2677
73
R.C. Larock, G. Zeni, Chem. Rev. 2006, 106, 4644. O. Kitagawa, M. Yoshikawa, H. Tanabe, T. Morita, M. Takahashi, Y. Dobashi, T. Taguchi, J. Am. Chem. Soc. 2006, 128, 12923. W. Pisula, F. Dierschke, K. Muellen, J. Mater. Sci. 2006, 16, 4058. C. Venkatesh, G.S.M. Sundaram, H. Ila, H. Junjappa, J. Org. Chem. 2006, 71, 1280. A. Neogi, T.P. Majhi, R. Mukhopadhyay, P. Chattopadhyay, J. Org. Chem. 2006, 71, 3291. V. Balraju, J. Iqbal, J. Org. Chem. 2006, 71, 8954. A.B. Smith, III., L. Kuerti, A.H. Davulcu, Org. Lett. 2006, 8, 2167. M. McLaughlin, M. Palucki, I.W. Davies, Org. Lett. 2006, 8, 3311. A. Fayol, Y.-Q. Fang, M. Lautens, Org. Lett. 2006, 8, 4203. F. Bonnaterre, M. Bois-Choussy, J. Zhu, Org. Lett. 2006, 8, 4351. Z. Vincze, A.B. Biro, M. Csekei, G. Timari, A. Kotschy, Synthesis 2006, 1375. Y. Kitamura, A. Hashimoto, S. Yoshikawa, J. Odaira, T. Furuta, T. Kan, K. Tanaka, Synlett 2006, 115. J.P. Scott, Synlett 2006, 2083. M.E. Popkin, R.K. Bellingham, J.F. Hayes, Synlett 2006, 2716. C. Kalinski, M. Umkehrer, G. Ross, J. Kolb, C. Burdack, W. Hiller, Tetrahedron Lett. 2006, 47, 3423. A. van den Hoogenband, J.H.M. Lange, W.I. Iwema-Bakker, J.A.J. den Hartog, J. van Schaik, R.W. Feenstra, J.W. Terpstra, Tetrahedron Lett. 2006, 47, 4361. G. Battistuzzi, R. Bernini, S. Cacchi, I. De Salve, G. Fabrizi, Adv. Synth. Catal. 2007, 349, 297. C.P. Leslie, R. Di Fabio, F. Bonetti, M. Borriello, S. Braggio, G. Dal Forno, D. Donati, A. Falchi, D. Ghirlanda, R. Giovannini, F. Pavone, A. Pecunioso, G. Pentassuglia, D.A. Pizzi, G. Rumboldt, L. Stasi, Bioorg. Med. Chem. Lett. 2007, 17, 1043. K. Ohshita, H. Ishiyama, K. Oyanagi, H. Nakata, J. Kobayashi, Bioorg. Med. Chem. 2007, 15, 3235. K. Flyren, L.O. Bergquist, V.M. Castro, C. Fotsch, L. Johansson, D.J. St. Jean, L. Sutin, M. Williams, Bioorg. Med. Chem. Lett. 2007, 17, 3421. J.A. Pfefferkorn, C. Choi, Y. Song, B.K. Trivedi, S.D. Larsen, V. Askew, L. Dillon, J.C. Hanselman, Z. Lin, G. Lu, A. Robertson, C. Sekerke, B. Auerbach, A. Pavlovsky, M.S. Harris, G. Bainbridge, N. Caspers, Bioorg. Med. Chem. Lett. 2007, 17, 4531. R.I. Higuchi, A.W. Thompson, J.-H. Chen, T.R. Caferro, M.L. Cummings, C.P. Deckhut, M.E. Adams, C.M. Tegley, J.P. Edwards, F.J. Lopez, E.A. Kallel, D.S. Karanewsky, W.T. Schrader, K.B. Marschke, L. Zhi, Bioorg. Med. Chem. Lett. 2007, 17, 5442. K.P. Moore, H. Zhu, H.A. Rajapakse, G.B. McGaughey, D. Colussi, E.A. Price, S. Sankaranarayanan, A.J. Simon, N.T. Pudvah, J.H. Hochman, T. Allison, S.K. Munshi, S.L. Graham, J.P. Vacca, P.G. Nantermet, Bioorg. Med. Chem. Lett. 2007, 17, 5831. A.J. Fletcher, M.N. Bax, M.C. Willis, Chem. Commun. 2007, 4764. S. Nakahara, A. Kubo, Y. Mikami, H. Mitani, Heterocycles 2007, 71, 1801. Y.-Q. Fang, R. Karisch, M. Lautens, J. Org. Chem. 2007, 72, 1341. A.B. Smith, III, L. Kuerti, A.H. Davulcu, Y.S. Cho, K. Ohmoto, J. Org. Chem. 2007, 72, 4611. Y.-Q. Fang, J. Yuen, M. Lautens, J. Org. Chem. 2007, 72, 5152. R. Omar-Amrani, R. Schneider, Y. Fort, Lett. Org. Chem. 2007, 4, 322. J.M. Janey, In Name Reactions for Functional Group Transformations (Eds.: J.J. Li, E.J. Corey), Wiley, Hoboken. pp. 564–609, 2007. K.W. Fried, C.M. Schneider, K.-W. Schramm, A. Datta, N. Chahbane, C. Corsten, D.R. Powell, D. Lenoir, A. Kettrup, P. Terranova, G.I. Georg, K.K. Rozman, ChemMedChem 2007, 2, 890. J.F. Bower, P. Szeto, T. Gallagher, Org. Lett. 2007, 9, 3283. B.B. Snider, X. Wu, Org. Lett. 2007, 9, 4913. Y.S. Park, M.Y. Cho, Y.B. Kwon, B.W. Yoo, C.M. Yoon, Synth. Commun. 2007, 37, 2677.
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H. Habib-Zahmani, J. Viala, S. Hacini, J. Rodriguez, Synlett 2007, 1037. M. Carril, R. SanMartin, E. Dominguez, I. Tellitu, Tetrahedron 2007, 63, 690. D.O. Tymoshenko, in Advances in Heterocyclic Chemistry (Ed.: A.R. Katritzky), Academic Press, 2008, 96, 1. Y.O. Long, R.I. Higuchi, T.R. Caferro, T.L.S. Lau, M. Wu, M.L. Cummings, E.A. Martinborough, K.B. Marschke, W.Y. Chang, F.J. Lopez, D.S. Karanewsky, L. Zhi, Bioorg. Med. Chem. Lett. 2008, 18, 2967. G.T. Notte, J.L. Leighton, J. Am. Chem. Soc. 2008, 130, 6676. A. Cappelli, C. Nannicini, A. Gallelli, G. Giuliani, S. Valenti, G.P. Mohr, M. Anzini, L. Mennuni, F. Ferrari, G. Caselli, A. Giordani, W. Peris, F. Makovec, G. Giorgi, S. Vomero, J. Med. Chem. 2008, 51, 2137. Y.-Q. Fang, M. Lautens, J. Org. Chem. 2008, 73, 538. A. Salcedo, L. Neuville, C. Rondot, P. Retailleau, J. Zhu, Org. Lett. 2008, 10, 857. A. Ueno, T. Kitawaki, N. Chida, Org. Lett. 2008, 10, 1999. D. Orain, A.-C. Blumstein, E. Tasdelen, S. Haessig, Synlett 2008, 2433. J. Alen, K. Robeyns, W.M. De Borggraeve, L. Van Meervelt, F. Compernolle, Tetrahedron 2008, 64, 8128. O. Kitagawa, D. Kurihara, H. Tanabe, T. Shibuya, T. Taguchi, Tetrahedron Lett. 2008, 49, 471. O.-I. Patriciu, A.-L. Finaru, S. Massip, J.-M. Leger, C. Jarry, G. Guillaumet, Eur. J. Org. Chem. 2009, 3753. W. Erb, L. Neuville, J. Zhu, J. Org. Chem. 2009, 74, 3109. J.-L. Debieux, C.G. Bochet, J. Org. Chem. 2009, 74, 4519. A.C. Tadd, A. Matsuno, M.R. Fielding, M.C. Willis, Org. Lett. 2009, 11, 583. K. Takenaka, N. Itoh, H. Sasai, Org. Lett. 2009, 11, 1483. O.-I. Patriciu, A.-L. Finaru, S. Massip, J.-M. Leger, C. Jarry, G. Guillaumet, Org. Lett. 2009, 11, 5502. E.L. Cropper, A.-P. Yuen, A. Ford, A.J.P. White, K.K. Hii, Tetrahedron 2009, 65, 525. D.J. Michaelis, T.A. Dineen, Tetrahedron Lett. 2009, 50, 1920. T. Takayama, H. Umemiya, H. Amada, T. Yabuuchi, T. Koami, F. Shiozawa, Y. Oka, A. Takaoka, A. Yamaguchi, M. Endo, S. Masakazu, Bioorg. Med. Chem. Lett. 2010, 20, 112. J.M. Travins, R.C. Bernotas, D.H. Kaufman, E. Quinet, P. Nambi, I. Feingold, C. Huselton, A. Wilhelmsson, A. Goos-Nilsson, J. Wrobel, Bioorg. Med. Chem. Lett. 2010, 20, 526. Y. Mita, K. Dodo, T. Noguchi-Yachide, H. Miyachi, M. Makishima, Y. Hashimoto, M. Ishikawa, Bioorg. Med. Chem. Lett. 2010, 20, 1712. N. Das Adhikary, P. Chattopadhyay, Eur. J. Org. Chem. 2010, 1754. B.-L. Chen, B. Wang, G.-Q. Lin, J. Org. Chem. 2010, 75, 941. P. Thansandote, E. Chong, K.-O. Feldmann, M.J. Lautens, J. Org. Chem. 2010, 75, 3495. A.M. Panagopoulos, M. Zeller, D.P. Becker, J. Org. Chem. 2010, 75, 7887. C.A. Baxter, E. Cleator, M. Alam, A.J. Davies, A. Goodyear, M. O’Hagan, Org. Lett. 2010, 12, 668. X. Luo, E. Chenard, P. Martens, Y.-X. Cheng, M.J. Tomaszewski, Org. Lett. 2010, 12, 3574. M. Takahashi, H. Tanabe, T. Nakamura, D. Kuribara, T. Yamazaki, O. Kitagawa, Tetrahedron 2010, 66, 288. E.J.L. Stoffman, D.L.J. Clive, Tetrahedron 2010, 66, 4452. L. Legeren, D. Dominguez, Tetrahedron Lett. 2010, 51, 4053.
CHAPTER
3
Three-Membered Ring Systems Stephen C. Bergmeier*, David J. Lapinsky** *Department of Chemistry and Biochemistry, Ohio University, Athens, OH, USA
[email protected] **Division of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA
[email protected]
3.1. INTRODUCTION This review covers the chemical literature on epoxides and aziridines for the year 2010. As in previous years, this review is not a comprehensive listing of all uses and syntheses of epoxides and aziridines, but rather it covers a selection of synthetically useful and interesting reactions.
3.2. EPOXIDES 3.2.1 Preparation of Epoxides The direct conversion of an alkene into the corresponding epoxide remains one of the most straightforward methods for synthesizing epoxides. Several methods designed to address shortcomings of epoxidation reactions of specific classes of olefins have been reported this past year. A series of Ti-salan and Ti-salalen complexes were reported as improved catalysts for the epoxidation of olefins with H2O2 h10TA374i. These complexes are somewhat easier to prepare than previously reported salen complexes. Methyltrioxorhenium (MTO) is a widely used oxidant for the expoxidation of alkenes. A recent report indicated that inclusion of an additive (1-methylimidazole or 3-methylpyrazole) provided improved yields of acid-sensitive epoxides h10OBC2377i. For example, treatment of an acid-sensitive chromene under these conditions provided the epoxide in excellent yield. As an example of the acid sensitivity of this alkene, epoxidation with mCPBA provided only 46% yield of the epoxide, while 33% yield of a rearrangement product was also formed. O
2 mol% MTO, H2O2 O
2 mol%
O
NH N
99%
An improved procedure using in situ generated ClO2 as an epoxidizing reagent was reported h10TL6481i. This method uses sodium chlorite (NaClO2) as the source of ClO2 and formaldehyde as a promoter to provide improved reproducibility and shorter reaction times. A variety of alkenes were epoxidized using this protocol.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00003-6
#
2011 Elsevier Ltd. All rights reserved.
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S.C. Bergmeier and D.J. Lapinsky
Dioxiranes are well-known epoxidizing agents. The use of asymmetric dioxiranes has proven to be a valuable method for the enantioselective synthesis of epoxides. A unique ketone derived from 8-azabicyclo[3.2.1]octane provided useful levels of enantioselectivity h10T6309i. A two-step process that uses NBS, DMSO, and DBU was reported as a useful epoxidation method h10TL6830i. This reaction proceeds through an intermediate b-bromodimethylalkoxysulfonium ion that cyclizes to yield the epoxide ring. This method provided the expected epoxides in generally good yields with good chemoselectivity. Electron-poor olefins were not epoxidized, while the more electron-rich olefin was selectively epoxidized. Of particular note, the facial selectivity was opposite to that observed with other epoxidizing agents such as mCPBA. O
1) 150 mol% NBS/DMSO 2) 200 mol% DBU
R
R
R = Ph, 77% R = n-C6H13, 70% O
O
1) 150 mol% NBS/DMSO 2) 200 mol% DBU
H
H
58%
O
74%
O
O
O
1) 150 mol% NBS/DMSO 2) 200 mol% DBU
H
H
The use of Fe-based catalysts for epoxidation of alkenes is well known, however, most of these catalysts tend to contain rather complex ligands. A recent report using formamidine ligands showed that these simple ligands can readily catalyze epoxidation reactions h10MI1771i. Primarily substituted styrenes were epoxidized with this catalytic system in excellent yields. Aliphatic alkenes (e.g., cyclooctene and 1-octene) provided the expected epoxides in significantly lower yields. 2.5 mol% FeCl3•6H2O, 30% H2O2 R
2.5 mol% pyridine-2,6-dicarboxylic acid
O R
R = Ph, 87% R = n-C6H13, 9%
Me
6 mol% Me
N
N
Given their synthetic utility, the development of new methods for the asymmetric epoxidation of allylic alcohols continues to attract attention. A recent report indicated that niobium can be an effective metal catalyst for the asymmetric epoxidation of allylic alcohols h10JA5886i. The reaction of Nb(Oi-Pr)4 with ligand 1 and H2O2 produces an epoxidizing agent that provides moderate yields of the hydroxy epoxides. Moderate levels of enantioselectivity were obtained using this ligand.
77
Three-Membered Ring Systems
O
4 mol% Nb(Oi-Pr)4, 5 mol% 1 OH
R
aq. H2O2
NH HN
OH
R
OH HO Ph Ph
R = n-C3H7, 57% yield, 91% ee R = Ph, 61% yield, 74% ee
1
While the development of methods for asymmetric epoxidation of allylic alcohols is fairly well established, similar methods for asymmetric epoxidation of homoallylic alcohols are not as established. A recent report showed that combination of a hafnium catalyst with ligand 2 provided a good method for epoxidizing 1,1-substituted homoallylic alcohols in an asymmetric fashion h10JA7878i. The 1,1-disubstituted alkene appears to be crucial for successful asymmetric induction, as simple homoallylic alcohols (R ¼ H) provided significantly reduced enantioenrichment. Ph R
O
10 mol% Hf(Ot-Bu)4, 10 mol% 2 n
OH
20 mol% DMPU, cumene hydroperoxide
R
O n
R = H, n = 1, 37% yield, 63% ee R = Me, n = 1, 81% yield, 97% ee R = Ph, n = 1, 69% yield, 98% ee R = Ph, n = 2, 75% yield, 99% ee
Ph N
OH
N
OH OH Ph
O
2
Ph
The expoxidation of a-branched a,b-unsaturated aldehydes has been a popular reaction this past year. Several interesting methods were reported that show promise for asymmetric epoxidation. The use of a quinidine/binol complex 3 and H2O2 provided excellent enantiomeric ratios along with good yields h10JA10227i. Only this single example of an a-branched a,b-unsaturated aldehyde was reported for this method. A similar method using chiral diamine 4 and cumene hydroperoxide provided the epoxide in excellent yield, albeit with lower enantiomeric purity h10EJO6840i. This reaction showed a significant salt effect, with a mixture of triflic acid and 2 M NaCl providing optimal enantioselectivity. A combination of prolinol derivative 5 and H2O2 provided the corresponding epoxide in moderate yield and good enantiomeric purity h10OL5434i. A wide range of a-branched a,b-unsaturated aldehydes were effectively epoxidized in similar yields and enantiomeric excess using this reagent system.
78
S.C. Bergmeier and D.J. Lapinsky
O Ph
O H
Ph
H
O
78% yield, 99:1 er, (R)
10 mol% 3, aq. H2O2
10 mol% 4, PhMe2COOH, 2M NaCl, 10 mol% TfOH 90% yield, 79% ee, (S) 65% yield, 86% ee, (S)
20 mol% 5, H2O2 R
+NH3 +
2
N H
Ph O O P O O−
N
Ph NH2
3
Ph N H
4
R
MeO
Ph n-Pr N n-Pr
OSiPh2Me 5
R = 2,4,6-i-Pr3C6H2
Methods for epoxidizing a,b-unsaturated ketones continue to attract attention. Two methods for the asymmetric epoxidation of a,b-unsaturated ketones were reported using chiral ligands. The presence of a unique amino acid in peptide 6, plus ureaH2O2 as the oxidant, provided an enantioenriched epoxide in excellent yield and enantiopurity h10OL3564i. The glucose-based crown ether 7 provided similar levels of enantioselectivity with a slightly lower overall yield h10TA919i. The dioxirane derived from trichloroacetone provided an excellent yield of the racemic epoxide h10TA2223i. The very interesting dihydroperoxydioxolane 8 provided the racemic epoxide in excellent yield h10SL2755i. O Ph
O
conditions
N H
99% yield, 98% ee (2R,3S)
7 mol% 7, t-BuOOH, 20% NaOH
82% yield, 94% ee (2R,3S)
1,1,1-trichloroacetone, Oxone, NaHCO3
90%
100 mol% 8, aq. KOH
96% OMe
N H
O 6
3
O O
O O N (CH2)3OH
OMe O
O O
O
O
H N
Ph
5 mol% 6, urea•H2O2, DBU
OMe
H
O
Ph
Ph
HOO 8
O
O Ph
OOH
7
The addition of a nucleophilic carbon bearing a leaving group to an aldehyde is a common one or two-step epoxidation method. Such methods include the Darzens reaction as well as sulfur ylides. Several approaches to the Darzens reaction were reported including a chiral Se-base h10TL5778i and a zirconium catalyst h10MI1123i. A useful Darzens reaction for the synthesis of fluoroepoxides was reported in the past year h10OL844i. As shown below, reaction of the dibromofluoro ester with
79
Three-Membered Ring Systems
Et2Zn and N,N-dimethyl ethanolamine, followed by addition of a ketone, provided isomeric fluoro ketones in generally good yields. While the majority of these fluoroepoxides are unstable, when R2 ¼ i-Pr, the epoxide is moderately stable and a number of side chain reactions can be carried out, including Grignard addition to the ester, amidation, hydrolysis, and reduction. Et2Zn
O R1
Me2N
OH
R1 O
O
R2 F Br
R2
O
R1
F O
EtO
EtO
OEt
R2 O
F
Br R1 = Ph, R2 = Me, 83% yield, 47:53 R1 = Ph, R2 = i-Pr, 98% yield, 9:91
An interesting variant of this method was recently reported. Treatment of benzyl bromide with silver oxide in DMSO provided stilbene oxide in moderate yield h10TL6649i. While the mechanism of this process has not been established, it seems likely that the observed product comes from a hydrolysis/oxidation followed by an addition reaction. O Br R
R = H, 48% R = 2-Cl, 48% R = 4-CO2CH3, 58%
100 mol% Ag2O DMSO R
R
The use of sulfur ylides for the direct synthesis of epoxides from aldehydes is a useful reaction that has seen a considerable amount of activity in the past year. Three notable examples are shown below. The synthesis of unsubstituted epoxides (R ¼ H) has proven to be challenging using this approach. A recent study showed that careful selection of the base and counterion provides excellent yields of terminal epoxides h10OL608i. The authors showed that methyl triflate as the alkyl source and P2 phosphazene base 9 provided essentially quantitative yields. The same reaction system also provided excellent yields of ketone-derived epoxides h10MI2089i. The choices of base used for the synthesis of epoxides via sulfur ylides has been relatively small to date. A recent publication showed that guanidine bases are quite effective h10SL769i. Standard reaction conditions using bicyclic guanidine TBD provided trans-stilbene oxide in excellent yield with a trans:cis ratio of 92:8. A variety of additional aldehydes and benzylic sulfonium salts were used providing similar yields and trans:cis ratios. The use of a chiral sulfonium salt has lead to the enantioselective synthesis of stilbene oxides h10JA1820i. Isothiocineole was converted into a sulfonium ylide and coupled to aldehydes, providing the corresponding epoxide in good yield and excellent enantioselectivity. A variety of aromatic aldehydes were studied producing similar yields and enantioselectivities. Allyl halides were also converted to chiral sulfonium ylides yielding the corresponding unsaturated epoxides in similar yields and enantioselectivities.
80
S.C. Bergmeier and D.J. Lapinsky
O
+ Ph–CHO + R1-SR2 •X− + base
R
Ph
R1 = CH3, SR2 = tetrahydrothiophene, X = OTf, base = 9
R = H, 95%
R1 = Bn, SR2 = tetrahydrothiophene, X = Br, base = TBD
R = Ph, 88% yield, t:c 92:8
1 = Bn,
R
R = Ph, 77% yield, t:c 95:5, 99:1 er
SR2 = isothiocineole. X = OTf, base = KOH
t-Bu
N NMe2 Me2N P N P NMe2 NMe2 NMe2
N N TBD
9
N H
S + isothiocineole
Other examples of sulfur ylides for the synthesis of epoxides have been reported. For example, the reaction of allylic sulfonium ylides with a,b-unsaturated ketones provided ring-fused epoxides in good yields h10JOC3454i. As a variant to the sulfur ylide approach, an ammonium ylide prepared from brucine proved to be an effective reagent for synthesizing epoxides h10SL2330i. One last method for the synthesis of epoxides is the conversion of one epoxide into another. Several methods exist for doing this, including modification of epoxide side chains while leaving the epoxide ring intact. One interesting example is the reaction of allyl potassium trifluoroborate with a keto epoxide h10OL5490i. Addition to the ketone provides generally good levels of diastereoselectivity. O
HO BF3K O
O In, CH2Cl2/H2O
83%, 95:5
An additional method for the interconversion of epoxides is the generation of oxiranyl lithium derivatives. The reaction of an oxiranyl anion was used for the synthesis of epoxy alcohols h10T1581i. The coupling reaction of an oxiranyl anion was used in an iterative fashion for the synthesis of gambierol h10MI7586i.
3.2.2 Reactions of Epoxides The primary type of epoxide reaction is nucleophilic ring opening. As shown in the table below, the use of metallocene catalysts to effect ring opening with amines has been reported h10BMCL6820i. Zr, as well as Ti and V catalysts, were examined with no significant differences. An intriguing aspect of this catalytic system was the reversal of normal regiochemistry of ring opening when t-BuNH2 was used to open the epoxide. Aniline adds to the internal carbon of styrene oxide with a selectivity of 93:7, while t-BuNH2 adds primarily to the terminal carbon with a selectivity of 80:20. A complex of BINOL, MeLi, and n-Bu2Mg with cyclohexene oxide led to excellent yields of ring-opened product using both aryl and aliphatic amines
81
Three-Membered Ring Systems
h10EJO6722i. The enantioselectivity of the ring opening was variable with aliphatic amines providing the best levels of enantioselection. N-formyl proline as a catalyst led to excellent yields of the ring-opened product, albeit in a racemic form h10SL707i. Reaction of stilbene oxide with aniline in the presence of bipyridine ligand 10 and zinc dodecyl sulfate provided the expected product h10T1111i. A biaryl urea 11 was shown to be a good catalyst for ring opening h10T3042i. This catalyst provided excellent yields of the ring-opened product with poor levels of regiocontrol, as only an 85:15 mixture of the product of addition at the internal carbon versus the terminal carbon was obtained. OH
O R1
+
Conditions
3
R -NH2
R
H N
1
R2
R3
2
R
92% yield, 93:7 internal:terminal 89% yield, 20:80 internal:terminal
R1 = H, R2 = Ph, R3 = Ph, 5 mol% Cp2ZrCl2 R1 = H, R2 = Ph, R3 = t-Bu, 5 mol% Cp2ZrCl2 R1,R2 = (CH2)4, R3 = Ph, 1 mol% (R)-BINOL, 1 mol% MeLi, 1.3 mol% n-Bu2Mg R1, R2 = (CH2)4, R3 = i-Pr, 1 mol% (R)-BINOL, 1 mol% MeLi, 1.3 mol% n-Bu2Mg
87% yield, 73% ee
R1,R2 = (CH2)4, R3 = Ph, 10 mol% N-formyl proline
99%
1
2
90% yield, 94% ee
3
97% yield, 92% ee
R = Ph, R = Ph, R = Ph, 6 mol% 10, 5 mol% Zn(DS)2 1
2
96% yield, 85:15 internal:terminal
3
R = H, R = Ph, R = Ph, 5 mol% 11
CF3
CF3
CO2H N CHO
N
S
N t-Bu
t-Bu HO
OH
N-formyl proline
F3C
N H
10
N H
CF3
11
The reaction of amino acid-derived epoxides with amino acids has proven to be a useful approach for the synthesis of peptidomimetics h10OL1652i. An initial ring opening of an epoxy amino acid by the amine of an a-amino acid is followed by an intramolecular lactamization. A key aspect of this reaction was the use of trifluoroethanol (TFE) as the reaction solvent. Carrying out the reaction in acetonitrile provided only 10% yield. This reaction sequence provided a unique peptidomimetic building block shown below.
FmocHN O
HO TFE, cat. BzOH
+ H2N OMe
O
O
O
OMe R
80 °C
N
FmocHN O
OMe R = H, 46% R = Me, 65% R = i-Pr, 85% R R = Bn, 82%
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S.C. Bergmeier and D.J. Lapinsky
An interesting intramolecular ring opening followed by a rearrangement provided aryl azaisoflavones h10SL1635i. A typical acid-catalyzed 6-endo cyclization was followed by a rearrangement to yield the azaisoflavone ring system. The authors postulated the intermediacy of a phenonium ion leading to the observed product. A variety of aryl substitutions were tolerated with uniformly excellent yields. O
O O R
O OH
300 mol% TfOH rt, CH2Cl2 N H
NH2
R
N H
R R = Ph, 90% R = 4-Me-C6H4, 94% R = 2-Cl-C6H4, 85% R = 3-NO2-C6H4, 78%
The popular dipolar cycloaddition of azides with alkynes to form 1,2,3-triazoles has given an impetus to examine additional reactions of azides with epoxides. Several catalytic systems including Zr(DS)4 h10HCA405i and Er(OTf)3 h10TL5150i have been reported. A one-pot method involving an initial ring opening of an epoxide with sodium azide followed by copper-catalyzed dipolar cycloaddition has been reported h10HCA435i. Amides are rarely used as nucleophiles in the ring-opening reactions of epoxides, thus two recent examples are noteworthy. The reaction of a terminal epoxide with N-Boc p-toluenesulfonamide proceeds via an initial addition of the amide to the epoxide, followed by N to O transfer of the Boc group. The resulting sulfonamide then adds to a second molecule of the epoxide to provide the observed monoprotected diol h10OPRD705i. A subsequent reaction yielded a morpholine derivative. Another interesting example utilized a sulfonamide as a nucleophile to open an epoxide h10OL1216i. After the initial ring opening, an SNAr reaction leads to the observed sultam. OPh
O
+
0.75 eq. Ts
Boc NH
200 mol% K2CO3 10 mol% BnEt3NCI dioxane, 90 °C 75%
F
O O n-Bu S N + H F
O
OBn
Cs2CO3, BnEt3NCI MW 110 °C 73%
OH
Ts N PhO
OPh
OBoc
F O O n-Bu S N O
OBn
Application of a polystyrene supported diazaphosphorine base (PS-BEMP) has been shown to be useful in the ring opening of epoxides with phenols h10MI2489i. As expected, when R is an alkyl group, the ring opening proceeded almost exclusively at the terminal end of the epoxide. Even aryl epoxides showed rather poor selectivity by providing a 2:1 mixture of regioisomers. In keeping with a popular theme this past year of reacting ambiphilic nucleophiles with epoxides and aziridines to form new bicyclic ring systems, the reaction of an epoxide with 2-iodophenol provided the product benzodioxane in good yield h10JOC8533i.
83
Three-Membered Ring Systems
The reaction also works well with aziridines to provide the corresponding benzoxazines.
O
OH
5 mol% PS-BEMP R
PhOH
R
OPh OPh
N Et2N P N N PS
OH
R
R = CH2OPh, 99% yield, 100:0 R = Ph, 94% yield, 32:64 R = n-C6H13, 98% yield, 92:8 OH + I
O
PS-BEMP
Cs2CO3, DMF, 4 mol% Cu/AI2O3, 100 °C
Ph
81%
O
Ph
O
The reaction of epoxides with CO2, CS2, and isocyanates continues to be a highly active research area. A recent review highlighted recent progress in this area h10AG(I)9822i. Two recent papers used an Al-salen complex to catalyze the reaction of CS2 with epoxides to form 1,3-oxathiolane-2-thiones h10JOC6201, 10SL623i. A Zn-salen catalyst was used for the reaction of epoxides with CO2 at 10 bar to form the corresponding carbonates h10CC4580i. A novel bifunctional phenolate catalyst was used to convert a series of epoxides to the corresponding carbonates in excellent yield h10OL5728i. + NMe3 3 mol% O O R
−
O
1 MPa CO2, 120 °C
O R
O
R = n-Bu, 99% R = Me, 99% R = Ph, 98% R = CH2Cl, 85%
Organolithium and Grignard reagents are commonly used to open epoxide rings. Grignard reagents were shown to regioselectively open the epoxide of g,d-epoxya,b-unsaturated esters and amides upon catalysis by FeCl3 h10OL1012i. The ring opening of b-silyl epoxides with organolithium reagents induced a Brook rearrangement to form a carbanion that can subsequently be alkylated h10OL1260i. Several examples of epoxides being opened by enolates were reported this past year. An interesting example is the reaction of a Zn-enolate with a vinyl epoxide to provide allylic alcohols in good yields h10OL576i. A similar reaction between a thio ester in an ionic liquid provided an a-thio g-lactone h10SL1797i. Two noteworthy examples are shown below. A vinyl epoxide was treated with a Pd-catalyst to form a p-allyl palladium intermediate. Reaction with a Zn-enolate derived from an a-amino acid provided the allyl alcohol-substituted a-amino acid h10SL137i. This reaction provides primarily the E-olefin. A tandem Blaise reaction/epoxide opening was used to prepare a-(aminomethylene)-g-lactones h10TL6893i. A range of aliphatic nitriles and epoxides participate in this reaction providing a-(aminomethylene)-g-lactones in yields ranging from 38% to 72%.
84
S.C. Bergmeier and D.J. Lapinsky
Ot-Bu O
+
O N Zn TFA
1.5 mol% [Pd(ally)Cl]2, PPh3 98%
O HO
Ot-Bu NHTFA
Br R
CN
Zn, BrCH2CO2Et
HN
Zn
NH2 O OEt
R
n-BuLi O Ph
O
R O Ph R = Ph, 55% R = Et, 68%
The reaction between an epoxide and a sulfur ylide, or Horner–Wadsworth–Emmons reagent, is a useful technique for converting epoxides to other ring systems. Treatment of a terminal epoxide with a phenyl sulfone-substituted Horner–Wadsworth–Emmons reagent provided the corresponding sulfone-substituted cyclopropanes in excellent yields h10JOC4652i. A substituted Horner–Wadsworth–Emmons reagent provided the substituted cyclopropane in excellent yields as well h10CC5867i. O R1
+
ESG
P(O)(OEt)2
Conditions
ESG
R1
R2
R2 R1 = Ph, R2 = H, ESG = SO2Ph, NaH, DME, 140 °C, 86% R1 = c-C6H13, R2 = H, ESG = SO2Ph, NaH, DME, 140 °C, 85% R1 = Ph, R2 = Me, ESG = CO2Et, n-BuLi, DME, 130 °C, 95% R1 = Ph, R2 = Bn, ESG = CO2Et, n-BuLi, DME, 130 °C, 98%
The reactions of p-nucleophiles with epoxides continue to attract significant attention. A recent review summarized inter- and intramolecular reactions between p-nucleophiles and epoxides (and aziridines) h10T7337i. A study of the reaction of an epoxide with a polyene was communicated this past year h10OL3548i. The presence of an ether oxygen in the chain strongly influenced the stereochemistry of the product. An interesting example using hexafluoroisopropanol as a solvent and reaction catalyst was reported h10CC2653i. This intramolecular reaction between the epoxide and the tethered electron-rich arene was catalyzed by this solvent to provide the cyclized product in excellent yield. OH O
MeO
O
Ph
F3C
CF3
MeO
O
99% OMe
OH OMe Ph
A common reaction of epoxides is the acid-catalyzed Meinwald rearrangement leading to aldehydes, usually with migration of an alkyl/aryl group on the epoxide. Several examples of this reaction were reported in the past year featuring catalysis by Fe2O (O2CCF3)6(H2O)3 h10T2373i, Cu(OTf)2 h10T8377i, and BF3OEt2 h10TL955i.
Three-Membered Ring Systems
85
A particularly interesting example is the reaction between an epoxide and an allylic alcohol to provide a pyran ring h10TL6511i. An initial Meinwald rearrangement converted the epoxide into its corresponding aldehyde, which then participates in a Prins cyclization. A key feature of this reaction was the use of recyclable celluloseSO3H as the acid catalyst. A second example of this general reaction was also reported h10JOC2081i. OH O
OH
+
Ph
cellulose-SO3H 78%
Ph
O
Reductive elimination of epoxides to provide allylic alcohols is a useful transformation. A common method utilizes Cp2TiCl h10EJO856i. A recent report provides an operationally very simple method to carry out this reaction h10SL595i. Treatment of a cyclohexanone-derived epoxide with p-TSA and DMPU provided the allylic alcohol in good yield. A large number of epoxides were examined under these reaction conditions. HO
O 50 mol% p-TSA, 200 mol% DMPU rt, 2 h, 62%
An interesting reaction of unsaturated epoxides was reported to provide cisdisubstituted tetrahydrofurans upon treatment with Cu(hfacac)2 h10AG(I)1648i. A positional isomer provided the same product with a slightly poorer yield and diastereoselectivity. OBn
5 mol% Cu(hfacac)2
O OBn
O OBn
toluene, 150 °C 94% yield 20:1 cis:trans 5 mol% Cu(hfacac)2
O
toluene, 150 °C 88% yield 13:1 cis:trans
O
OBn
3.3. AZIRIDINES 3.3.1 Preparation of Aziridines There are a host of strategies toward synthesizing aziridines, including asymmetric approaches whose developments were recently reviewed h10T1509i. The catalytic aziridination of alkenes with transition metal species in combination with suitable oxidants and coordinating ligands continues to attract significant
86
S.C. Bergmeier and D.J. Lapinsky
attention. With respect to copper catalysis, asymmetric aziridination of dihydronaphthalenes using Jacobsen’s diimine catalyst was reported as the key step in the enantioselective synthesis of substituted 2-aminotetralins h10T9790i. Likewise, copper-catalyzed enantioselective aziridination of styrenes with N-tosyloxycarbamates h10PAC1827i and the utilization of chiral nitrenes generated from sulfonimidamides h10TA1447i were reported. Additionally, methylene aziridines were synthesized via intramolecular trapping of rhodium-bound nitrenoids with tethered allenes h10CC2835i. As shown below, [Tp*,BrAg] was found to be an excellent catalyst for the synthesis of vinyl aziridines from dienes bearing a terminal hydroxy group h10AG(I)7092i. This catalyst displayed high regioselectivity and stereospecificity with respect to aziridination of a wide variety of dienes, including a precursor of (þ)-sphingosine. R1 2
R
HO
[Tp*,BrAg] PhINTs 99% conversion >98:<2 trans:cis
1
R1
R 2
R
HO
R2
+ HO TsN
TsN
Br Regioselectivity
Diene
Br
H N N B N N N N Br Tp*,Br
1
2
R =R =H 1 2 R = H, R = Et 1 2 R = R = Me 1 2 R = R = Ph R1 = H, R2 = C13H27
88:12 85:15 86:14 93:7 86:14
Aziridination of alkenes in the absence of conventional metal catalysts such as Rh (II) and Cu(II) is particularly attractive from a green chemistry perspective. In this regard, a stereodivergent protocol for synthesizing a range of aziridines from cyclic allylic amine derivatives using Atkinson’s C(2)-trifluoromethyl-substituted 3-acetoxyaminoquinazolinone reagent was reported h10T6806i. Likewise as exemplified below, alkenyl sulfonyliminoiodanes were shown to undergo intramolecular aziridination under thermal conditions h10OL364i. The scope of this nonmetal process can be related to the conformational flexibility of the alkenyl sulfonyliminoiodane, where rigid molecular systems were converted in near quantitative fashion. R1 R2
(PhIO)n DCM, H+ 4 A MS SO2NH2 40 °C
R1 R2 N SO2
R1 = R2 = H, 70% conversion, 60% yield R1 = Me, R2 = H, 90% conversion, 78% yield R1 = R2 = Me, 100% conversion, 92% yield
The aza-MIRC (Michael-Initiated Ring Closure) reaction represents an intriguing approach to aziridines in one synthetic step from a,b-unsaturated systems. An efficient one-pot system was reported for the synthesis of cyano aziridines using a,b-unsaturated nitriles and N,N-dichloro-p-toluenesulfonamide (4-TsNCl2) as a nitrogen source h10MI392i. Additionally, an assortment of aziridines were prepared
Three-Membered Ring Systems
87
via aza-MIRC starting from vinyl selenones and variously functionalized primary amines h10T6851i, while trans-N-unsubstituted vinyl aziridines were accessed by organocatalytic amine-promoted regioselective nucleophilic aziridination of a,b,g,d-unsaturated carbonyl compounds h10JOC3499i. Highlighted below is the first example of a highly enantioselective organocatalytic aziridination of a-substituted a,b-unsaturated aldehydes h10MI3201i. This reaction is catalyzed by simple chiral amines giving rise to highly functional terminal aziridines containing an a-tertiary amine stereocenter. O R1
+
TsO
H N
O R2
NaOAc R1 20 mol% Ph Ph N H OTMS
R1 = Bn, R2 = Cbz, 88% yield, 97:3 er R1 = Bn, R2 = Boc, 89% yield, 98:2 er NR2 R1 = allyl, R2 = Boc, 73% yield, 96:4 er R1 = n-butyl, R2 = Boc, 81% yield, 98:2 er
Several examples of aziridines prepared via a 1,2-amino leaving group motif, either generated in situ or as part of the starting material, were reported h10T715, 10JOC219, 10TA909, 10T9401, 10S3423, 10JOC4769i. This aziridination strategy traditionally features an amine lone pair or an amide anion facilitating an intramolecular SN2 reaction. Two particularly interesting examples of this type of reaction are the transformation of 1-alkyl-4-aryl-3-chloroazetidin-2-ones into 2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction using LiAlH4 h10OBC607i and a three step, one-pot protocol for the general enantioselective synthesis of terminal N-alkyl aziridines via organocatalysis h10OL3276i. This latter procedure shown below features enantioselective a-chlorination of an aldehyde, reductive amination with a primary amine, followed by chloride displacement to generate a chiral aziridine where, in most cases, > 90% ee is achieved. 10 mol%
NH2 Ph
NH Ph
Cl
NCS
Cl
N
Boc NaB(OAc)3H
KOH N
three steps, one pot 49% yield 95% ee
O BocN
In addition to alkenes, imines are tremendously popular aziridine precursors via an aza-Darzens or Darzens-like approach. A new method for preparing 2-fluoroaziridine-2-carboxylates by a chemo- and diastereoselective Reformatsky-type aza-Darzens reaction was reported h10TL4246i. An additional example of the Darzens approach includes utilization of N-protected imines and a sulfur ylide derived from Eliel’s oxathiane h10MI11744i. Likewise, cis-vinylaziridines were generated in a one-pot highly diastereoselective manner by sulfur-ylide-mediated aziridination and palladium(0)-catalyzed isomerization h10OL504i.
88
S.C. Bergmeier and D.J. Lapinsky
− Br + Me2S
+
1) t-BuOK, THF, 0 °C 2) 10 mol% Pd(PPh3)4
O O S N O
O O S O N
>99/1 cis/trans for all examples
Ph R
R
R = Ph, 86% R = CO2Me, 65% R = TMS, 64%
Ph
Additional aziridine synthesis reports employing imines include the reaction of (R)-N-sulfinylaldimines with 2-(p-tolyl sulfonyl)benzyl iodine in the presence of sodium hexamethyl disilazide h10MI9874i. This reaction took place with almost complete stereoselectivity to afford optically pure N-sulfinyl trans-2,3-disubstituted aziridines. In a similar light, chiral 1,2,2-trisubstituted aziridines were isolated in high overall yield (51–85%) and with excellent enantiomeric excess (> 98% ee) upon reacting chiral a-chloro N-tert-butanesulfinyl ketimines with Grignard reagents h10OBC3251i. The stereoselectivity of the Grignard addition was rationalized via the coordinating ability of the a-chloro atom, where the opposite stereochemical outcome was observed for nonfunctionalized N-sulfinyl ketimines. t-Bu O
S
O
RMgCl
N
Ph
t-Bu S
R = Et, 67% yield, crude dr 89:11 R = Me, 61% yield, crude dr 98:2, R = allyl, 85% yield, crude dr 94:6
N
Cl
Ph
R
>98% ee
Chiral and achiral aziridination of imines with carbenes generated from diazo compounds continues to attract significant attention. The Shioiri acylation of trimethylsilyldiazomethane with aliphatic chlorides was coupled to catalytic asymmetric aziridination of aldimines via a chiral polyborate Bronsted acid catalyst derived from the vaulted biaryl ligands VANOL and VAPOL h10OL4908i. Likewise, a number of other reports featured utilization of the chiral polyborate-VANOL/VAPOL catalyst system with imines h10JA13100, 10JA13104, 10JOC5643i. K-10 montmorillonite was found to be an efficient catalyst for the aziridination of Schiff bases with ethyl diazoacetate, affording aziridines with high diastereoselectivity and excellent yields in short times h10SL745i. Additionally, trisubstituted aziridines were synthesized in a stereoselective manner via N-a-diazoacyl camphorsultam h10OL1668i. A particularly interesting reaction shown below is the aziridination and unpredicted homologation of N-sulfonylimines via a very simple, rapid, and mild procedure using diazomethane without any catalyst h10OBC2968i. This reaction represents the first time that in situ homologation of imines has been reported.
R1
R2
CH2N 2 R1
N
NR2
NR2
+ R1
R1 = 4-CI-C6H4, R2 = Ts
78%
0%
R1
R2 = Ts
74%
0%
R2 = Ns
0%
78%
0%
77%
1
= 4-NO2-C6H4,
R = 4-MeO-C6H4,
R1 = furanyI, R2 = Ts
89
Three-Membered Ring Systems
A rather unique approach toward synthesizing aziridines features utilization of rearrangement reactions. A facile synthesis of highly functionalized aziridine derivatives by phosphite-mediated annulation was reported h10T304i. Additionally, a highly diastereoselective Baldwin rearrangement of isoxazolines into cis-acylaziridines was disclosed h10JOC6050i. In a similar manner shown below, the first formal acylaziridination of imidazolones was developed through [3 þ 2] cycloaddition of terminal alkynes with imidazalone N-oxide h10OL2718i.
BnN
N +
O
O
R EtOH 80˚C
R = Ph, 92% BnN
BnN
N O R
O
O
N
O R = 4-Br-C6H4, 89%
H
R
R = n-Bu, 62% R = TMS, 61%
Finally, N-benzoyl aziridines were synthesized by an efficient oxidative cyclization of amidoalkylation adducts of activated methylene compounds via a combination of iodosobenzene and a catalytic amount of n-Bu4NI under neutral conditions h10TL453i. With respect to bioorganic chemistry, several racemic trans-3-arylaziridine-2-carboxamides were prepared and then resolved by Rhodococcus rhodochrous IFO 15564-catalyzed hydrolysis h10JOC6614i. This report also disclosed similar bacterial resolution of racemic 1-arylaziridine-2-carboxamides and -carbonitriles.
3.3.2 Reactions of Aziridines The reactions of aziridines (like epoxides) are largely dominated by nucleophilic ring-opening reactions. Recent developments have been reviewed with respect to regioselective ring opening of aziridines h10T2549i. The desymmetrization of meso-aziridines with a variety of nucleophiles continues to attract significant attention. One example is the enantioselective desymmetrization of meso-N-(heteroarenesulfonyl)aziridines with TMSN3 catalyzed by chiral Lewis acids Mg(NTf2)2 and 12 h10TL3820i. To demonstrate the utility of this reaction, the azido product from aziridine ring opening was subsequently transformed into the selective k-opioid agonist (1S,2S)-()-U-50,488. CI 1) 10 moI% Mg(NTf2)2 20 mol% 12 O = S = O 2) TMSN 3 N
N
CI N3
NH O = S= O
steps O
O N NMe 63% yield 99% ee after recrystallization
O N
N Ph
12
Ph
N (-)-U-50,488
A number of interesting reactions involving oxygen-based nucleophiles, including a convenient method for preparing b-tosylamino nitrates via aziridine ring opening with tetranitromethane h10TL2254i and ring opening of a resin-bound chiral
90
S.C. Bergmeier and D.J. Lapinsky
aziridine with phenol nucleophiles h10JOC4983i, were reported. A formal synthesis of ()-swainsonine was disclosed featuring regioselective ring opening of an aziridine derived from 1-(R)-a-methylbenzylaziridine-2-carboxylic acid ()-menthol ester with acetic acid h10TL3284i. Upon studying the reductive activation of mitomycin C in aqueous bicarbonate buffer, a novel oxazolidinone derivative was characterized, which resulted from cyclization of bicarbonate with the aziridine ring of aziridinomitosene h10BMCL31i. A number of aziridine reaction reports were published featuring halogenated phenols as nucleophiles. Subsequent Cu(II) h10JOC8533i or Pd-catalyzed h10T8108i intramolecular CN bond formation between the nitrogen that originated from the aziridine ring, and the halogen containing aromatic carbon, led to the formation of a number of interesting aromatic-fused N-containing heterocycles. Exemplified below is a domino process for the synthesis of 1,4-benzo- and pyrido-oxazepinones via one-pot sequential ring-opening/carboxamidation of various N-tosylaziridines with a range of 2-halophenols/pyridinol under phase-transfer catalysis h10OL192i. A similar report utilized 2-iodothiophenols to generate a range of 1,4-benzothiazepin-5-ones h10OL5567i. The oxygen within carbonyls can also be used to facilitate aziridine ring-opening. An unactivated aziridine was regioselectively converted to an oxazolidinone in high yield using carbon dioxide and ammonium iodide as a catalyst h10TL4552i. Likewise, naturally occurring a-amino acids successfully catalyzed aziridine cycloaddition with carbon dioxide X NTs
+ HO X = Br or I
R
1.5 moI% PdCI2(pph3)2 1.5 moI% PPh3 10 moI% TEBA K2CO3, CO (200 psi) 80 ˚C, 24 h
Ts N
O
O
R
R = H, 71% R = t-Bu, 55% R = CI, 69% R = Ph, 94%
to generate 5-aryl-2-oxazolidinones without the need of additives h10TL928i. Additionally, a catalyst- and organic solvent-free version of this reaction was reported in which chemoselectivity was controlled by tuning CO2 pressure h10SL2159i. With respect to sulfur-based nucleophiles, aziridinemethanol sulfonate esters were shown to react with [BnEt3N]2MoS4 via an unprecedented thia-aza-Paynetype rearrangement, giving rise to thiirane derivatives as major products and cyclic disulfides as minor products h10JOC5533i. Late-stage modification via thiolmediated aziridine ring opening was also reported in the synchronized synthesis of peptide-based macrocycles by digital microfluidics h10AG(I)8625i. Methylthiocarbonylaziridine was described as a new tool to site-specifically install acetyl-Lys mimics into peptides and proteins by alkylation of Cys residues h10JA9986i. As exemplified below, chemoselective peptidomimetic ligation was achieved using thioacid peptides and N-H aziridine-terminated amino acids/peptides h10JA10986i. This method enables incorporation of a peptidomimetic linkage at the site of ligation without epimerization, and further, the reaction is not affected by competing thiol nucleophiles known to react with aziridines.
91
Three-Membered Ring Systems
O BocHN
H N
HN SH
O
O NHPh
+
BocHN
EtOH rt
N H
BnO
SH H N
O NHPh
BnO 89%
Nitrogen-based nucleophiles continue to remain popular in ring-opening reactions of aziridines. Mixtures of anti-1,2-[3-N-(substituted-amino)glycals] and anti1,4-addition products were obtained when primary and secondary aliphatic amines were reacted with glycal-derived N-mesyl-aziridines h10T689i. When this reaction was performed with epoxides, regio- and stereoselectivity were observed due to an isomerization process. In contrast, the results involving aziridines were explained by the absence of effective substrate-amine coordination. The stereospecificity of ring opening of aziridinium ions with MeNH2 as a route to chiral diamines was investigated h10TA1563i. As shown below, when the aziridinium ion contained a phenyl or para-methoxyphenyl substituent, stereospecific ring opening occurred. However, switching to a para-N,N-dimethylamino group gave a racemic diamine product. Carbanion nucleophiles continue to be examined in ring-opening reactions of aziridines. Several reports featured utilization of organocuprate reagents h10T8982, 10MI12474i. Thioether and sulfone-stabilized carbanions possessing a variety of functional groups were NHMe N
Et3N MsCI OH
R
+ N
aq. MeNH2 Et3N
R
N
R
R = H, 90% yield, 98:2er R = OMe, 58% yield, 97:3 er R = NMe2, 50% yield, 50:50 er O Ts N Ph
+ EtO2C
CO2Et
NaH, Cu(OTf)2
EtO2C
NTs
R Ph
R
R = Et, 92% R = n-Pr, 62% R = vinyl, 58% R = allyl, 73%
reacted with vinyl- and hydroxymethyl-substituted aziridines in a highly regioselective and stereospecific manner h10T6376i. g-Amino acids were accessed in one step upon reacting aziridines with carboxylic acid dianions h10MI9135i. As shown below, functionalized chiral g-lactams were synthesized by a Lewis acid-catalyzed domino ring-opening cyclization of activated aziridines with enolates h10JOC6173i. These g-lactams can be desulfonated and decarboxylated to provide pyrrolidinone-3carboxylate and N-tosylpyrrolidinone derivatives. With respect to p-nucleophiles, a review highlighting both inter- and intramolecular reactions with epoxides and aziridines has been reported h10T7337i. Solid-state
92
S.C. Bergmeier and D.J. Lapinsky
silica gel-catalyzed opening of an aziridine was reported as a key step in the synthesis of C-1 derivatives of 7-deoxypancratistatin h10JOC3069i. Likewise, silver(I)-diene complexes were reported as versatile catalysts for the C-arylation of N-tosylaziridines h10JOC4402i. A particularly interesting variant of carbon-based nucleophiles is the carbonyl umpolung reaction of enals with terminal aziridines catalyzed by N-heterocyclic carbenes h10TL1657i. This regioselective reaction exemplified below generates b0 -amino-a,b-unsaturated ketones, which can be converted to 2,6-disubstituted piperidine-4-ones via intramolecular aza-Michael addition h10S2957i. Ts N
O + Ph
H
25 mol% DBU 25 mol% R
O
NHTs R
Ph
+ Bn − Cl N
R = Ph, 91% R = 4-MeO-C6H4, 81% R = 4-NO2-C6H4, 92%
N Bn
Halides have attracted noteworthy attention as nucleophiles for opening aziridine rings. A highly regioselective BF3OEt2-mediated SN2-type ring opening of N-sulfonylaziridines with tetraalkylammonium halides was described h10JOC137i. Stereospecific and regioselective chlorination of an in situ generated aziridinium ion was used to prepare (3R,4S)-1-benzyl-4-phenylpyrrolidine-3-carboxylic acid, a key chiral building block for synthesizing biologically active compounds h10OPRD127i. To gain insight on the prominent factors dictating regioselectivity, computational analysis was performed on the hydride- and halide-induced ring openings of 1-benzyl-1-(a-(R)-methylbenzyl)-2(S)-(phenoxymethyl)aziridinium bromide h10JOC885i. Likewise, an experimental study and theoretical rationalization were put forth to explain the opposite regiospecificity observed when 2-(cyanomethyl)aziridines were treated with HBr and BnBr (shown below) h10JOC4530i. Both frontier molecular orbital analysis of LUMOs and nucleophilic Fukui functions showed a clear preference for bromide ion attacking the substituted aziridine carbon in the BnBr case versus the unsubstituted aziridine carbon in the HBr case. R2 R2 R1 R1
120 mol% HBr
Br N Br
R1
HOAc
N
NH
CN Br
NC
66–87%
R1 = H, Me, Cl, OMe
CN
51–87%
In addition to the nucleophiles previously noted, hydrides have been utilized to open aziridine rings. A new synthetic protocol for LiAlH4-promoted reduction of nonactivated aziridines under microwave conditions was described h10OBC4266i.
93
Three-Membered Ring Systems
In a related transformation shown below, active manganese (Mn*) promoted the regioselective transformation of aromatic N-4-methoxyphenylaziridine 2-carboxamides into 2-amino amides h10JOC2407i. O
O R
NEt2
N
R NH
Mn• THF reflux
MeO
NEt2 R = Ph, 75% R = 4-Cl-C6H4, 81% R = 3-F-C6H4, 72% R = 3-CH2 = CHC6H4, 67%
OMe
Additional studies have been pursued employing aziridines as masked 1,3-dipoles or three-atom components in both intra- and intermolecular annulation reactions. The torquoselectivity of aziridines lacking a plane of symmetry was investigated as an essential component to calculating the overall relative reaction rate and prediction of stereochemistry for 2,3-trans compounds in 1,3-dipolar cycloadditions h10JOC2510i. During ring-opening reactions of unactivated trans-3-(3,4-methylenedioxyphenyl) aziridine-2-carboxylate with nitrile reagents, formation of an azomethine ylide by C2C3 bond cleavage was observed when trimethylsilylcyanide was treated under thermal conditions h10T3836i. Likewise shown below, site-, regio-, and stereoselective synthesis of 4-methylenepyrrolidines was achieved by [3 þ 2] cycloaddition of allenoates with azomethine ylides generated from aziridines h10T8815i. Bn
Bn N
BnO2C Ph
Ph
+
• R
O
toluene MW
Ph
150 °C 15 min
BnO2C
N
O R = Me, 59% Ph R = t-Bu, 46% R = Ph, 43%
R
A number of reports were disclosed with respect to gold-catalyzed ring expansion of alkynyl aziridines to pyrroles h10JOM159, 10JOC510, 10EJO1644i. Substituted 1,2-diamines were synthesized in a regio- and stereoselective manner via ring opening of ethynyl-trisubstituted aziridines with amines h10OL4244i. As exemplified below, linked nitrogen heterocycles were constructed via palladium (0)-catalyzed intramolecular domino cyclization of 2-alkynylaziridines bearing a 2-aminoethyl group upon ring expansion with isocyanates h10JOC3396i. Interestingly, bis-adducts were selectively obtained when excess isocyanate was employed at lower reaction temperature.
PhN TsN NPh O 99%
O
TsHN
O NTs
5 mol% Pd(PPh3)4
5 mol% Pd(PPh3)4
500 mol% PhCNO THF, −40 °C 25 min
110 mol% PhCNO THF, rt 1 min
NTs
NTs
PhN
NTs 82%
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Much like propargyl aziridines, vinyl aziridines are popular precursors of various nitrogen heterocycles. Unprecedented bicyclic aziridines were prepared by rhodium (II)-catalyzed allene aziridination of buta-2,3-dienyl carbamates and found to undergo SNV-mode ring opening with organometallic reagents h10OBC3060i. Palladiumcatalyzed carbonylation of vinyl aziridines gave rise to trans- or cis-b-lactams preferentially, and d-lactams when the reaction parameters were properly adjusted h10CC267i. Functionalized vinyl aziridines were readily synthesized from water-stable aldehydes and subjected to relay cascade transformations to produce a variety of stereochemically rich heterobicycles h10OL240i. Nitrogen heterocycles, for example, 1H-pyrroles and 1H-indoles (shown below), served as competent nucleophiles in palladium-catalyzed dynamic kinetic asymmetric alkylation of vinyl aziridines h10JA15800i. The power of this reaction was demonstrated via application during the synthesis of several natural products and medicinal chemistry lead compounds. H N
OMe
+
6 mol% (R,R)-L2 NR
O
O R = PMB, 72% yield, 93% ee R = Bn, 97% yield, 96% ee
O
O
NR
N
2 mol% Pd2(dba)3•CHCl3 DCE, rt
NH HN PPh2Ph2P (R,R)-L2
Metalated aziridines were featured in a number of reports, including a review on generation, reactivity, and synthetic use of aziridinyl anions h10CRV5128i. The scope and limitations of organolithium-mediated conversion of methoxy aziridines to substituted allylic sulfonamides were fully mapped h10TL588i. With respect to cross-coupling reagents, aziridinyldifluoroborates were found to be efficient coupling partners in Suzuki–Miyaura reactions h10MI2683i, while an aziridinylzinc chloride intermediate was coupled to a variety of alkenyl and aryl halides with retention of aziridine stereochemistry h10OL5085i. Shown below is the synthesis of a key aziridinolactam prepared from a lithiated aziridine that arose via tin–lithium exchange h10OL4030i. This lactam ultimately provided access to several aziridinomitosane ketones. O O HN
OEt
SnBu3
200 mol% n-BuLi
O LiN
NTr
OEt
O Li
EtO
OEt
HN NTr
NTr
65%
Several reports were published featuring the nitrogen atom of N-H aziridines behaving as a nucleophile. One such report is an efficient and general synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes via copper-catalyzed cascade reaction of N-H aziridines with ethyl diazoacetate h10TL4763i. Another example highlighted below
Three-Membered Ring Systems
95
features amphoteric aziridine aldehydes as important building blocks for synthesizing cyclic peptides from a-amino acids or linear peptides h10JA2889, 10MI1813i. These cyclizations proceeded without epimerization and provided aziridine-based products featuring sites for highly specific, late-stage structural modification. O
O
O O
NH Pro-Leu
t-BuNC TFE rt, 4 h
O
O
O
N
SH
t-BuHN
N
NH
Et3N
S H N
O
O
O t-BuHN
63%
N
NH O
59%
With respect to aziridines functioning as catalysts, aziridine-functionalized tridentate sulfinyl ligands aided in highly enantioselective addition of phenylethylzinc to aldehydes h10TA2687i. Likewise, similar aziridine catalysts facilitated highly enantioselective conjugate addition of diethylzinc to enones h10TA1890i. Finally, an aziridine was utilized in the synthesis of (þ)-lycoricidine h10OL2544i. As shown below, Dess–Martin periodinane (DMP) and silica gel facilitated oxidative ring opening of an aziridine to provide an a,b-unsaturated ketone (allyl amine) as a key intermediate. OH
O O
I
O N
O O O
H
O
DMP, CH2Cl2 0 °C to rt then silica gel
I O O
O HN
H
O 82%
Reactions involving oxaziridines as three-membered ring heterocycles continue to be investigated. Prominent examples include the synthesis of dihydrobenzisoxazoles by [3 þ 2] cycloaddition of arynes h10JOC7381i, terminal copper(II)-catalyzed olefin oxyamination h10TL5223i, and sulfide oxidation for the asymmetric synthesis of proton pump inhibitors h10OPRD1264i. Unusual 1,3-dipolar carbonyl imines were produced in the presence of a bulky scandium(III) catalyst via rearrangement of N-sulfonyl oxaziridines h10AG(I)930i, whereas aminal products (shown below) were generated via highly regioselective copper(II)-catalyzed oxyamination of Nacyl indoles with oxaziridines h10AG(I)9153i. When a chiral acyl group was placed on the indole nitrogen, the resulting aminals could be transformed into the core fragment of some pyrroloindoline alkaloids with high enantiomeric excess.
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NHR2
O N
Bs
R1
R2HN R1
CuCl2 n-Bu4NCl
N Ac
Bs N
R1 = H, R2 = Ac, 81% O
N H Ac
R1 = OMe, R2 = Ac, 89% R1 = H, R2 = Moc, 82%
Azirines are structurally interesting compounds representing unsaturated derivatives of N-H aziridines. Analogs of the antifungal marine natural product (E)-dysidazirine were prepared and evaluated for activity against a panel of clinically relevant yeasts h10BMCL2029i. Photolysis of aziadamantanes in the presence of fumaronitrile unexpectedly resulted in carbene addition to a nitrile, giving rise to conjugated 2Hazirines as the major product h10OL2366i. 2,3-Disubstituted indoles were synthesized by Fe(II)-catalyzed amination of aromatic CH bonds upon ring opening of 2H-azirines h10OL3736i. Finally, as shown below, an interesting domino reaction was reported featuring norbornene-mediated palladium-catalyzed reaction of 2Hazirines with aryl iodides h10OL3312i. Slow addition of the 2H-azirine was required to generate indole-based products, whereas excess norbornene gave rise to dihydroimidazole heterocycles. 10 mol% Pd(OAc)2 25 mol% P(m-Cl-C6H4)3 300 mol% Cs2CO3
I N +
200 mol% Norbornene CH3CN (0.05 M) reflux, 16 h, slow addition of 2H-azirine
Ph 10 mol% Pd(OAc)2 45 mol% P(m-Cl-C6H4)3 300 mol% Cs2CO3 800 mol% Norbornene CH3CN (0.2 M) 90 °C, 16 h,
Ph HN
95% Ph N N
Ph
86%
REFERENCES 10AG(I)930 10AG(I)1648 10AG(I)7092 10AG(I)8625 10AG(I)9153 10AG(I)9822 10BMCL31
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Three-Membered Ring Systems
10OL3276 10OL3312 10OL3548 10OL3564 10OL3736 10OL4030 10OL4244 10OL4908 10OL5085 10OL5434 10OL5490 10OL5567 10OL5728 10OPRD127 10OPRD705 10OPRD1264 10PAC1827 10S2957 10S3423 10SL137 10SL595 10SL623 10SL707 10SL745 10SL769 10SL1635 10SL1797 10SL2159 10SL2330 10SL2755 10T304 10T689 10T715 10T1111 10T1509 10T1581 10T2373 10T2549 10T3042 10T3836 10T6309 10T6376 10T6806 10T6851 10T7337 10T8108 10T8377 10T8815
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S.C. Bergmeier and D.J. Lapinsky
10T8982 10T9401 10T9790 10TA374 10TA909 10TA919 10TA1447 10TA1563 10TA1890 10TA2223 10TA2687 10TL453 10TL588 10TL928 10TL955 10TL1657 10TL2254 10TL3284 10TL3820 10TL4246 10TL4552 10TL4763 10TL5150 10TL5223 10TL5778 10TL6481 10TL6511 10TL6649 10TL6830 10TL6893
E. Aaseng, O.R. Gautan, Tetrahedron 2010, 66, 8982. S. Fioravanti, S. Gasbarri, L. Pellacani, F. Ramadori, P.A. Tardella, Tetrahedron 2010, 66, 9401. J.E. Aaseng, S. Melnes, G. Reian, O.R. Gautun, Tetrahedron 2010, 66, 9790. D. Xiong, M. Wu, S. Wang, F. Li, C. Xia, W. Sun, Tetrahedron Asymmetry 2010, 21, 374. A. Cruz, I.I. Padilla-Martinez, E.V. Garcia-Baez, Tetrahedron Asymmetry 2010, 21, 909. A. Mako, Z. Rapi, G. Keglevich, A. Szollosy, L. Drahos, L. Hegedus, P. Bako, Tetrahedron Asymmetry 2010, 21, 919. F. Robert-Peillard, P.H. Di Chenna, C. Liang, C. Lescot, F. Collet, R.H. Dodd, P. Dauban, Tetrahedron Asymmetry 2010, 21, 1447. S.J. Oxenford, S.P. Moore, G. Carbone, G. Barker, P. O’Brien, M.R. Shipton, J. Gilday, K.R. Campos, Tetrahedron Asymmetry 2010, 21, 1563. M. Rachwalski, S. Lesniak, P. Kielbasinski, Tetrahedron Asymmetry 2010, 21, 1890. S. Hajra, M. Bhowmick, Tetrahedron Asymmetry 2010, 21, 2223. M. Rachwalski, S. Lesniak, P. Kielbasinski, Tetrahedron Asymmetry 2010, 21, 2687. R. Fan, H. Wang, Y. Ye, J. Gan, Tetrahedron Lett. 2010, 51, 453. S.C. Coote, P. O’Brien, Tetrahedron Lett. 2010, 51, 588. H. Jiang, J. Ye, C. Qi, L. Huang, Tetrahedron Lett. 2010, 51, 928. K. Kokubo, K. Harada, E. Mochizuki, T. Oshima, Tetrahedron Lett. 2010, 51, 955. L.S. Yadav, V.K. Rai, S. Singh, P. Singh, Tetrahedron Lett. 2010, 51, 1657. Y.A. Volkova, E.B. Averina, T.S. Kuznetsova, N.S. Zefirov, Tetrahedron Lett. 2010, 51, 2254. H.G. Choi, J.H. Kwon, J.C. Kim, W.K. Lee, H. Eum, H. Ha, Tetrahedron Lett. 2010, 51, 3284. S. Nakamura, M. Hayashi, Y. Kamada, R. Sasaki, Y. Hiramatsu, N. Shibata, T. Toru, Tetrahedron Lett. 2010, 51, 3820. A. Tarui, N. Kawashima, K. Sato, M. Omote, A. Ando, Tetrahedron Lett. 2010, 51, 4246. C. Phung, A.R. Pinhas, Tetrahedron Lett. 2010, 51, 4552. Y. Zhu, S. Wang, S. Wen, P. Lu, Y. Wang, Tetrahedron Lett. 2010, 51, 4763. A. Procopio, P. Costanzo, R. Dalpozzo, L. Maiuolo, M. Nardi, M. Oliverio, Tetrahedron Lett. 2010, 51, 5150. S.M. DePorter, A.C. Jacobsen, K.M. Partridge, K.S. Williamson, T.P. Yoon, Tetrahedron Lett. 2010, 51, 5223. S.-I. Watanabe, R. Hasebe, J. Ouchi, H. Nagasawa, T. Kataoka, Tetrahedron Lett. 2010, 51, 5778. A. Jangam, D.E. Richardson, Tetrahedron Lett. 2010, 51, 6481. B.C. Subba Reddy, A. Venkateswarlu, G.G.K.S. Narayana Kumar, A. Vinu, Tetrahedron Lett. 2010, 51, 6511. F.M. Wong, Y.M. Chan, D.X. Chen, W. Wu, Tetrahedron Lett. 2010, 51, 6649. G. Majetich, J. Shimkus, Y. Li, Tetrahedron Lett. 2010, 51, 6830. Y.O. Ko, Y.S. Chun, Y. Kim, S.J. Kim, H. Shin, S.G. Lee, Tetrahedron Lett. 2010, 51, 6893.
CHAPTER
4
Four-Membered Ring Systems Benito Alcaide*, Pedro Almendros** *Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quı´mica Orga´nica I, Unidad Asociada al CSIC, Facultad de Quı´mica, Universidad Complutense de Madrid, 28040 Madrid, Spain
[email protected] **Instituto de Quı´mica Orga´nica General (IQOG), Consejo Superior de Investigaciones Cientı´ficas, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
[email protected]
4.1. INTRODUCTION Four-membered heterocycles, where a noncarbon atom is part of the ring, have probably been, during the past year, one of the most studied groups of compounds within many fields of science, including organic chemistry, inorganic chemistry, medicinal chemistry, and material science. Oxygen- and nitrogen-containing heterocycles dominate the field in terms of the number of publications. In general, the chemistry of sulfur, silicon, and phosphorus heterocycles is much less developed than the analogous oxygen and nitrogen chemistry. The aim of this chapter is not to present a full coverage of all the aspects of the vast research area of four-membered heterocyclic chemistry reported in the literature of 2010. The main goal of this contribution is to highlight some of the topics which we believe are the most significant.
4.2. AZETIDINES, AZETINES, AND RELATED SYSTEMS An overview on the synthesis and properties of four-membered ring nitrogen heterocycles has appeared h10MI685i. The synthesis of mugineic acids 1, azetidine2-carboxylic acid derivatives, and their transport activities have been reviewed h10CRE140i. A review on strategies for heterocyclic synthesis, including azetidines, via cascade reactions based on ketenimines, has been published h10SL165i. An efficient and versatile method for the preparation of labeled mugineic acid derivatives, which form water-soluble FeIII complexes similar to that of natural mugineic acid, has been established h10AGE9956i. The pendant sulfoxide group of an (E)-2-protected amino-3,4-unsaturated sulfoxide was used as an intramolecular nucleophile to functionalize an alkene regio- and stereoselectively to furnish a bromohydrin, which was employed as the key intermediate in the preparation of the azetidine subunit during the synthesis of penaresidin A, 2 h10JOC748i. A synthesis of nicotianamine, a natural product found in plants, has been achieved by using a new strategy based on N-alkylation h10EJO6609i. A new series of azetidine derivatives 3 have been designed and synthesized, and some of these were shown to bind with high affinity to a4b2-nicotinic acetylcholine receptor-selective partial agonists h10JMC6973i. The stereocontrolled synthesis of enantiopure polyhydroxylated azetidines via 1,2-oxazines has been Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00004-8
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2011 Elsevier Ltd. All rights reserved.
101
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B. Alcaide and P. Almendros
accomplished h10SL42i. A direct method for the transformation of a-amino acids into 2-acetoxyazetidines has been described h10SL659i. A rapid approach to chiral 2,3,4trisubstituted N-tosylazetidines, possessing multiple contiguous stereogenic centers, has been achieved through an asymmetric tandem conjugate addition/Mannich reaction h10AGE2728i. The rarely studied N-thiopivaloyl group played a crucial role in mediating efficient a-lithiation and incorporation of diverse electrophiles onto an azetidine ring, providing the first example of an enantioselective electrophilic substitution on a four-membered ring h10AGE2900i. The product obtained in the Br nsted acid-catalyzed reaction of dialkyl but-2-ynoates with anilines and an excess of formaldehyde, a 2,3-dioxopyrrolidine-3-carboxylate was generated via cleavage of the CN bond in an azetidine intermediate followed by intramolecular lactamization h10T3651i. CO2H HO2C
HO
HO
() N
HO
N
R2
R1
H
2
1
R3
N
O
7
OH
N H
N
N
OH
CO2H
3
An improved synthesis of the fatty acid amide hydrolase inhibitor VER-156084, 4, relied on a novel, environmentally benign etherification to form an unusual, highly hindered azabenzhydryl ether h10TL5191i. A stereoselective synthesis of functionalized azetidines 5 from a [2 þ 2]-cycloaddition of 2-aminomalonates with chalcones via a grind-promoted, solvent-free Michael addition and a PhIO/Bu4NI-mediated oxidative cyclization has been developed h10OL2802i. The catalytic asymmetric synthesis of a-alkylazetidine-2-carboxylic acid tert-butyl esters has been accomplished by asymmetric phase-transfer C-alkylation of a-alkyl-amino acid derivatives and subsequent intramolecular N-alkylation h10T4900i. The formal asymmetric trans-aminohydroxylation of a,b-unsaturated aldehydes in an organocatalytic multibond forming one-pot reaction cascade, providing a general entry to 3-substituted-2-(methoxy)azetidin-3-ols, has been developed h10JA9188i. Azetidines or pyrrolidines can be obtained regioselectively by selenocyclization of homoallylic amines, according to the double bond substitution h10TL4437i. The iodine-mediated cyclization of homoallyl amines at room temperature delivers cis-2,4-azetidines 6 through a 4-exo-trig cyclization h10OL5044i. Azetidinic 1,2-diamines, easily accessible from 2-cyano azetidines, have been screened as organocatalysts for the enantioselective addition of 1,3-dicarbonyl compounds onto b-nitro styrenes h10TA2385i. N
Cl
NHCOR1 N
4
R3 i
+
N
R3
CO2R2 CO2R2 N
O
O Cl
CO2R2
R2O2C O
R4OC R4
COR1
5 (46–75%)
I N R2
R1
6
Reagents: (i) (a) PhNEt3Cl, K2CO3, neat, grind; (b) PhIO, TBAI, toluene, 25 C.
Four-Membered Ring Systems
103
Azetidines 7 are novel spirotetracyclic zwitterionic dual H1/5-HT2A receptor antagonists for the treatment of sleep disorders h10JMC7778i. A short and efficient synthesis of two hitherto unreported conidine iminosugars 8, one of which is a selective inhibitor of a-mannosidase, and their conformational study by 1H NMR, DFT calculations, and molecular docking has been described h10OBC3307i. The generation and use of cyclopropylazetoindoline 9, which represents a novel class of fused heterocycle, couples with hetero and carbon nucleophiles to give quaternary-substituted pyrroloindolines h10JA8282i. When six- to eight-membered spirocyclic 1-aminoindanes were treated with K2CO3 in methanol, eight- to ten-membered medium-sized lactams were obtained through a trans-acylation process involving tricyclic azetidine intermediates h10AGE1611i. CO2H N
N
OH N
OH HO
i
N Boc
Boc
N H Boc
β-H = 8a α-H = 8b
X
CO2Me
CO2Me
Br
N H Boc
9 (90%)
7 X = CH2, O
Reagents: (i) KOt-Bu, THF, 2 h. The straightforward access and structural analysis of previously unreported substituted azaspiro[3.3]heptanes 10, which generally show higher aqueous solubility than their cyclohexane analogues, has been reported h10OL1944i. The framework of related spirocycles 11 can be mounted onto scaffolds of drug-like structures, such as fluoroquinolones, to afford active compounds with similar or even improved metabolic stability h10AGE3524i. A practical synthesis, exploiting classical malonate alkylation chemistry for the construction of the cyclobutane ring, of the Boc-protected aminospiroazetidine 12 allows selective chemical modification of the amino functions h10JOC5941i. A recombinant Escherichia coli expressing P450pyr monooxygenase of Sphingomonas sp. HXN-200 has been developed as a useful biocatalyst for the regio- and stereoselective hydroxylation of N-tert-butoxycarbonylazetidine h10ASC3380i. R1 N
R1 N
HO
Br
HO
Br
X
X
i−vii
Boc N
NH2
12 (18%) 10 X = O, SO2, NR2
11 X = O, SO2, NR2
Reagents: (i) (a) PhCHO, PTSA; (b) NaH, diisopropyl malonate. (ii) H2, Pd/C. (iii) (a) MsCl, Et3N; (b) TsNH2, K2CO3. (iv) (a) NaOH; (b) HCl. (v) (a) py, D; (b) Na/Hg, MeOH. (vi) (a) Boc2O, NaOH; (b) DPPA, PhCH2OH. (vii) H2, Pd/C.
104
B. Alcaide and P. Almendros
Rhodium-catalyzed CH bond activation and b-carbon elimination were combined in a net intramolecular hydroacylation of alkylideneazetidines 13 to afford 1,2,4,5-tetrahydroazocin-3(8H)-ones 14 in good yields h10AGE620i. A highly regioselective BF3OEt2-mediated SN2-type ring opening of N-sulfonylazetidines with tetraalkylammonium halides in CH2Cl2 solution affords 1,2- and 1,3-haloamines in excellent yields h10JOC137i. The enolates from amino-acetone derivatives are readily prepared using the reduction of azetidin3-ones with titanium tetraiodide; subsequent CC bond formation with aldehyde or imine proceeds in poor to good yields h10CAJ473i. A convenient N-heterocyclic carbene-catalyzed synthesis of b-thiolactams 15 in favor of the cis isomer via [2 þ 2] cycloaddition of aryl isothiocyanates and nitroolefins has been reported h10SL1784i. A DABCO-catalyzed reaction of 2,3-allenoates, bearing a chiral auxiliary on the ester moiety, with N-arylidenebenzenesulfonamide provided optically active 2-azetines h10EJO3249i. The sequential one-pot reaction of methoxy-stabilized carbenes with acetylides and imines provides stable, metal–carbene-containing 2-azetines 16, which after treatment with an alkyne afforded substituted fused 1,3-oxazines h10AGE1306i. A possible mechanism of ring contraction in arylnitrenes via fused azetines has been identified h10JOC1600i. The final steps in the formal conversion of [meso-tetra-phenylporphyrinato]Ni(II) into the corresponding pyrrole ring-contracted chlorin analogue [2-methylazeteochlorinato]Ni(II) have been described h10TL4505i. The formal [2 þ 2] cycloaddition reaction of various ketenes and nitroso compounds to give the corresponding 1,2-oxazetidin-3-ones 17 in moderate to good yields with high enantioselectivities has been catalyzed by both a copper salt h10ASC945i and a chiral N-heterocyclic carbene h10OBC5007i. A rapidly formed intermediate 18 with absorption at 1645 cm 1, which decayed with an observed rate of 1.99 106 s 1, was detected during the time-resolved IR investigation of a photochemically generated chloromethylhydroxamic carbene h10OL4616i. Highly strained, four-membered 1,2-diazetidine rings are produced in good yields (50–98%) in nucleophilic ring closure reactions under Mitsunobu conditions when “soft” leaving groups such as iodide are used h10TL382i. An intermediate 1,3-diazetidine-2-thione has been postulated in the intermolecular alkyl/aryl exchange of 2-iminothiazoles with isothiocyanates h10T5707i. The reaction of triazolinediones with tri-O-acetyl-D-glucal provided the corresponding fused diazetidines as single stereoisomers possessing the mannosamine configuration at C2 h10S2292i. A possible mechanism for the formation of 3,4-dihydroquinazolines from a sequential Ugi four-component condensation (4CC)/aza-Wittig/carbodiimide-mediated cyclization presumably involves the formation of diazeto[2,1-b] quinazoline intermediates through intramolecular cycloaddition between the N, N-disubstituted amides and the carbodiimide moieties h10EJO1088i. O N Ts CHO
R R
13
R i
R2 N
Ts
R
14 (70–85%)
R1
R2
R3
(OC)5M
Ar
S
15
R1
Bu
16
O N O
N O
Ar1
N
N
Ar2
O
R
Cl
17
Reagents: (i) 10 mol% [Rh(nbd)2]BF4, 10 mol% BINAP, acetone, 56 C.
18
105
Four-Membered Ring Systems
4.3. MONOCYCLIC 2-AZETIDINONES (b-LACTAMS) The various pharmacological activities of the 2-azetidinone nucleus have been reviewed h10EJM5541i. A monograph on novel anticancer b-lactams has been published h10THC349i. A compendium on the stereoselective synthesis of a-fluorinated amino acid derivatives, including fluoro-b-lactams, has been reported h10ASC2733i. The synthetic contributions to obtain saframycin analogues, including a b-lactam approach, have been updated h10CEJ9722i. An overview presenting the utility of the venerable Passerini and Ugi reactions, including the preparation of b-lactams, has appeared h10SL23i. The most important aspects in recent years of the syntheses of functionalized cyclic b-amino acids, including b-lactams, have been reviewed h10SL1302i. Recent approaches toward solid-phase synthesis of b-lactams have been compiled h10THC261i. 4-Oxo-b-lactams 19, previously reported as acylating agents of porcine pancreatic elastase, have been found to be selective and potent inhibitors of human leukocyte elastase (HLE); a structure–activity relationship analysis showed that inhibitory activity is very sensitive to the nature of C3 substituents h10JMC241i. The synthesis and study of the structure–activity relationships of a series of rigid analogues of combretastatin A-4 which contain the 1,4-diaryl-2-azetidinone (b-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products have been described h10EJM5752, 10JMC8569i. Based on (Z)-5-(4-fluorophenyl)pent-4-enoic acid as a starting compound, a convenient and efficient total synthesis of ezetimibe 20, an intestinal cholesterol absorption inhibitor and useful anticholesteremic agent, has been achieved h10SL3433i. The utilization of chiral ketenes from carbohydrates for the asymmetric synthesis of anticancer b-lactams via Staudinger reactions has been carried out h10EJM846i. It has been shown that by carefully controlling the reaction parameters (temperature, [Pd], [CO]), b-substituted a,b-unsaturated aziridines undergo Pd-catalyzed carbonylation reactions to give trans-b-lactams 21 h10CC267i. A novel class of b-lactam derivatives of 1-aminophosphonates was synthesized by Staudinger [2 þ 2] cycloaddition reactions of ketenes with imines derived from 1-aminophosphonates h10S3504i. Mild and efficient oxidative N-dearylation of N-alkoxyphenyl-b-lactams with cobalt(III) fluoride proceeds in good yields to afford the corresponding N-unsubstituted b-lactams h10TL5791i. A Pd (II)/bis-sulfoxide catalyst was used for intra- and intermolecular allylic CH amination reactions to rapidly diversify structures containing a sensitive b-lactam core similar to that found in the monobactam antibiotic aztreonam h10T4816i. A series of novel aryl-substituted b-lactams condensed with 1,3-benzothiazines, isoquinolines, or 1,4-benzothiazepine have been obtained by means of the Staudinger reaction and isomerized in the presence of sodium methoxide to the thermodynamically more stable form h10JST54i. R2
OH
OH
R3
H H
R1
R2
N R1
19
R2
R1
i
O
O
F
N
N Ts
O
20
N O
Ts
21 (59−77%) F
Reagents: (i) 10 mol% Pd2(dba)3CHCl3, PPh3, CO (1 bar), toluene, RT.
106
B. Alcaide and P. Almendros
Monamphilectine A, 22, a new diterpenoid b-lactam alkaloid showing potent antimalarial activity, was isolated in milligram quantities following bioassay-directed extraction of a Puerto Rican marine sponge Hymeniacidon sp. A one-step semisynthesis of monamphilectine A was based on a multicomponent Ugi reaction that also established its absolute stereostructure h10OL5290i. Cycloadducts from the catalytic enantioselective 1,3-dipolar cycloadditions of nitrones with propiolylpyrazole using chiral p-cation catalysts could be stereoselectively converted to anti-2,3-difunctionalized b-lactams 23 via reductive cleavage of the NO bond using SmI2 and subsequent cyclization without any loss of enantiomeric excess h10JA15550i. Evidence of a concerted pathway for the reaction of chlorosulfonyl isocyanate with monofluoroalkenes to afford 4-fluorob-lactams has been presented h10JOC7913i. a-Alkylidene-b-lactams 24 have been successfully prepared using hydrolysis–intramolecular cyclization of (E)-a-alkylideneb-amino esters, which were obtained through thermal Overman rearrangement h10OL3234i. An electrogenerated N-heterocyclic carbene behaves as an organocatalyst in the Staudinger reaction in an ionic liquid, yielding predominantly trans b-lactams h10CC4121i. The synthesis of a range of imidazolinium salts derived from acyclic 1,2-diamines, and an evaluation of the reactivity and asymmetric induction of the corresponding NHCs as catalysts for the asymmetric synthesis of b-lactams, has been reported h10TA582, 10TA601i. It has been observed that acyclic N-Ca-branched, N-bis(trimethylsilyl)methyl diazoamides undergo preferential Rh(II)-carbenoid CH insertion to give g-lactams, while the corresponding b-lactams, arising from insertion at the N-CaH unit, were obtained as a minor product h10OL5386i. Me O Me Me N O
22
N H
H
Bn N
H H
N
Me C
O
O
R1
R
O N N
R2
R
i N O
N Bn
23 (54−57%; >99/de)
O
Boc
24
Reagents: (i) SmI2, THF, 0 C. N-[4-(2-oxoazetidin-1-yl)-but-1-enyl]acetamides 25 have been prepared in a two-step approach starting from N-(2-propenyl)-b-lactams, involving initial rhodium-catalyzed hydroformylation followed by subjection of the obtained aldehydes to Staudinger reaction conditions after initial imination h10NJC1079i. A b-amino ester, obtained by the reaction of the chiral titanium enolate of menthyl ester prepared using the TiCl4/Et3N reagent system with a prochiral imine, was converted into the corresponding b-lactam using ethylmagnesium bromide h10TA385i. Treatment of 4-alkenylepoxy-N-(1-cyano-1-dimethylethyl)-2-azetidinones with Cp2TiCl produced unsaturated 2-azetidinone-tethered nitriles and aldehydes h10SL1227i. The stereomodulating effect of remote groups on the NADH-mimetic reduction of alkyl aroylformates with 1,4-dihydronicotinamide-b-lactam amides has been studied h10T3187i. A versatile method for the synthesis of cis-b-lactams 26 using methoxymethylene-N,N-dimethyliminium salt as an acid activator in Staudinger reactions has been reported h10T5017i.
107
Four-Membered Ring Systems
The synthesis and structure determination of 2-(oxo-4-phenylazetidin-3-yl)-3-ferrocenylpropanoates have been reported h10JST8i. A synthetic route for the preparation of (Z)- and (E)-3-allylidene-b-lactams via thermal b-elimination of trans-3-allyl-3-sulfinyl-b-lactams has been described h10TL1719i. The chemoand diastereoselective synthesis of syn-a-bromo-a-fluoro-b-lactams has been achieved using the diethylzinc-mediated Reformatsky-type reaction of ethyl dibromofluoroacetate with imines h10TL2000i. b-Lactams have been synthesized in two steps from b-hydroxy oximes, providing a new strategy for the synthesis of this kind of compound h10JOC1961i. The synthesis of novel pyrroloisoquinoline and indolizinoindole derivatives with a b-lactam unit has been achieved by sequential intermolecular 1,3-dipolar cycloaddition and Pictet-Spengler cyclization h10T969i. A study has provided evidence that sequence-random copolymers containing a b-lactam ring can mimic the in vitro surface-active behavior of lung surfactant proteins in a mixed lipid film h10JA7957i. An efficient synthesis of novel bis-b-lactams via Staudinger reaction of imines with the bis-ketene derived from adipic acid has been reported h10MI1581i. An approach to highly rigid macrocyclic bisazetidinones, obtained as a mixture of cis-syn-cis and cis-anti-cis isomers, with interesting structural features has been achieved via sequential Staudinger ketene–imine cycloaddition of o-allyloxyphenoxyketene and bis-arylidenediamines followed by ring-closing metathesis (RCM) h10JOC4508i. The cyclodimerization of 1,3-bis-o-alkenoyl-3(S)-amino-2azetidinones catalyzed by the second generation Grubbs’ carbene has allowed the synthesis of bis-azetidinone macrocycles, which acted as potent inhibitors of R39 D,D-carboxypeptidase, a bacterial model enzyme for penicillin-binding proteins h10T9519i. Cu-Catalyzed alkyne–azide cycloaddition produces macrocyclic bis-b-lactams h10CEJ1592i. New b-lactams containing a bis(indolyl)-framework have been synthesized h10NJC2861i. R1 H
R1
R2O R3 N O
25
N
O N R4
OR5
+ Me R2
i N Me
R2
R3
OMe MeSO4
N O
R1
26 (82−94%)
Reagents: (i) R3CH2COOH, Et3N, CH2Cl2. Examples of a Cope rearrangement in which the C3 C4 bond of the b-lactam nucleus is the central bond of the 1,5-hexadiene system, thus providing an easy and efficient entry to novel, and in some cases optically pure, functionalized azocinones 27 have been described h10ARK74i. Aminocyclobutanes, as well as eight-membered enamide rings, have been made from N-vinyl b-lactams through a one-pot domino process h10CEJ4100i. a-Chloroaldehydes have proved to be useful starting materials for the stereoselective Staudinger synthesis of (3S,4S)-4-[(1S)-1-chloroalkyl]azetidin2-ones, which have been used as chiral building blocks for the preparation of a number of azetidines and pyrrolidines h10JOC5934i. Using common 2-azetidinone-tethered
108
B. Alcaide and P. Almendros
allenols as starting substrates, structurally different compounds, namely, tetramic acids (from N-bromosuccinimide) or spirocyclic seleno b-lactams (from N-phenylselenophthalimide), have been readily synthesized h10ASC621i. Molecular iodine (10 mol%) efficiently catalyzes the ring expansion of 4-oxoazetidine-2-carbaldehydes in the presence of tert-butyldimethylsilyl cyanide or allylic and propargylic trimethylsilanes to afford protected 5-functionalized-3,4-dihydroxypyrrolidin-2-ones 28 with good yields and high diastereoselectivity, through a C3C4 bond cleavage of the blactam nucleus h10ASC1688i. The synthesis of macrocycle 29, a precursor of lankacidins, using Stille reactions of 4-(2-iodo-alkenyl)azetidinones and related compounds for ring closure has been reported h10T6613i. 4,1-Benzothiazepines have been obtained via the b-lactam ring opening of azeto[1,2-a][3,1]benzothiazin-1-ones with sodium ethoxide in ethanol h10T3207i. The synthesis of 1,4-benzothiazepines from 1,3-benzothiazines via the ring transformation of b-lactam-condensed 1,3-benzothiazine derivatives has been reported h10S2943i. A hybrid library of the marine natural products dictyostatin and discodermolide, incorporating the taxol or taxotere sidechains, have been synthesized using the b-lactam synthon method h10CC261i. The use of b-lactams for the synthesis of functionalized b-amino esters and their transformation into trisubstituted octahydroisoquinolone derivatives has been described h10TL4272i. An unusual b-lactam ring opening occurred during aqueous TFAmediated release of b-lactam peptide hybrids from solid support, leading to the formation of a pseudopeptide that expresses a high HLA-A2-binding affinity and stimulates melan-A-specific T cells h10OBC5345i. A synthetic approach has been developed to access a structurally novel class of b-amino-functionalized a-exo-methylene-g-butyrolactones using chiral b-lactam synthons h10S3282i. A new enzymatic and b-lactambased strategy for the preparation of (2R,3S)-3-phenylisoserine, a key intermediate for the taxol side-chain, has been developed h10TA637, 10EJO3074i. The synthesis of enantioenriched mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers has been accomplished starting from a racemic bicyclic b-lactam h10TA957i. A route has been presented for the preparation of regio- and stereoisomers of novel azepane b-amino esters, starting from bicyclic b-lactam isomers h10TL82i. Stereoisomers of 1,2,3-triazole-functionalized, conformationally restricted b-amino esters with a cyclopentane skeleton have been synthesized from the bicyclic b-lactam 6-azabicyclo[3.2.0]hept-3-en-7-one h10T3599i. A novel route to functionalized pyrroloxazines utilizing the b-lactam synthon methodology has been developed h10TL2312i. A bridged bicyclic pyrrolidinedione has been obtained under basic conditions by rearrangement of the b-lactam ring h10ARK228i. trans- and cis-1Alkyl-4-aryl-3-chloroazetidin-2-ones have been transformed into trans- and cis-2-aryl-3-(hydroxymethyl)aziridines via reductive ring contraction h10OBC607i. R2
R2 R1 R1
R3O R2
i N
O
R3
O
N R3
27 (60–100%)
O N
O
R1
ii R3 ≠ Ar
R3O R2 O
Boc AcO HN
OY N R1
Nu
TBSO
28 (39–89%) SEMO
CO2Me OH
29
Reagents: (i) toluene, D. (ii) Me3SiNu (3 equiv.), 10 mol% I2, MeCN, RT.
Four-Membered Ring Systems
109
4.4. FUSED AND SPIROCYCLIC b-LACTAMS A review article on how connecting Nature’s small molecules, including b-lactam antibiotics, to the genes that encode them has sparked a renaissance in natural product research h10JA2469i. A monograph discusses novel aspects of the preparation of spirocyclic and fused unusual b-lactams h10THC1i. The direct, catalytic synthesis of carbapenams 30 via Kinugasa cycloaddition/rearrangement cascade process catalyzed by Cu(I) ion has been reported h10JOC7580i. The relationship between the molecular structure and chiroptical properties of carbapenams through the use of electronic circular dichroism spectroscopy has been examined h10JOC7219i. It has been demonstrated that the Ferrier–Petasis rearrangement at the C4 carbon atom of azetidin-2-ones can be performed in good yield, and this reaction offers an attractive entry to carbapenem and carbacephem antibiotics h10JOC6990i. The viability of fluorescently labeled genetically modified b-lactamases under physiological situations has been explored with the newly designed and synthesized cephalosporin-based fluorescent probe 31 h10CC7403i. The design, synthesis, and crystal structures of 6-alkylidene-20 -substituted penicillanic acid sulfones as potent inhibitors of Acinetobacter baumannii OXA-24 carbapenemase have been reported h10JA13320i. 6-Aminopenicillanic acid sodium-gossypolone has less toxicity than gossypol in vivo and significantly increased chemotherapeutic sensitivity against colon cancer in combination with the traditional chemotherapeutic agent 5-fluorouracil h10JMC5502i. A fluorescent probe based on quinine bearing two quaternary ammonium groups and a long hydrophobic chain has shown highly selective recognition of carbenicillin (a typical b-lactam antibiotic) in 100% aqueous solution h10CC2435i. A highly proficient class A b-lactamase from the bacterium Oceanobacillus iheyensis, the habitat of which is the sediment at a depth of 1050 m in the Pacific Ocean, has evolved to be an extremely halotolerant blactamase capable of hydrolyzing common b-lactam antibiotics in the presence of NaCl at saturating concentration h10JA816i. It has been reported that nonheme iron oxygenases generate natural structural diversity in carbapenem antibiotics h10JA12i. A fluorescence assay, comprising two components (a) solid beads coated with a fluorophore-conjugated b-lactam antibiotic and (b) amyloid fibrils (acting as fluorescence enhancer and visual tool), for detecting bacterial b-lactamases has been designed h10CEJ13367i. QM/MM studies of the hydrolysis of a b-lactam antibiotic molecule (biapenem) catalyzed by a monozinc b-lactamase have revealed the complete reaction mechanism and shown that an experimentally determined enzyme–intermediate complex is a stable intermediate or product in a minor pathway h10JA17986i. OtBu R
i
+
R
N O
H H
O
OtBu
N O
N H HO2C
H N
S N
O
S
O O
CO2H
30 (35–80%) O
O
O
OH
31
O NO2 H N
O2N
Reagents: (i) 5 mol% CuI, Et3N, MeCN, RT.
O
NH
110
B. Alcaide and P. Almendros
The chemoenzymatic syntheses of functionalized five-, six-, and sevenmembered N-heterocycles and their use for preparing bicyclic b-lactam derivatives employing carboxymethylproline synthases and a carbapenem synthetase have been described h10CC1415i. Although the deprotection of the cephalosporin 30 -acetoxy group is difficult using chemical methods, the enzymatic deacetylation has been successfully carried out on gram scale, when the cephalosporin is protected as either the benzhydryl or tert-butyl esters and on the corresponding sulfoxide and sulfone of the tert-butyl ester h10JOC1289i. A concise synthesis of 14C-labeled meropenem prepared from 14C dimethylamine hydrochloride has been described h10TL197i. The stereoselective synthesis of compound 32, a fluorine-containing analogue of the anti-bacterial sanfetrinem, has been accomplished h10T4144i. Photolysis of a-diazo-N-methoxy-Nmethyl (Weinreb) b-ketoamides derived from enantiomerically pure a-amino acids has afforded the corresponding b-lactams via an intramolecular Wolff rearrangement h10JA11379i. The regioselective gold/acid cocatalyzed direct bis-oxycyclization of alkynyldioxolanes has allowed the efficient synthesis of optically pure tricyclic bridged b-lactam acetal systems 33 h10ASC1277i. Selenium-containing bicyclic b-lactams 34 have been obtained through stereoselective insertion of (but-3-enyl)seleno and propargylseleno moieties at the C4 positions of azetidinones with subsequent ring-closing enyne metathesis h10EJO2742i. It has been reported that the acyliminium cations derived from 4-vinyloxy- or 4-acyloxy-azetidin-2-ones in the presence of Lewis acids can alkylate nucleophilic arenes bound to the b-lactam nitrogen atom through methyloxy or methylthio tethers to afford the corresponding 3-oxa- or 3-thia-4,5-benzocephams h10T8974i. The synthesis of novel tricyclic b-lactams has been accomplished by intramolecular nitrilimine cycloadditions onto b-lactams bearing an alkenyl dipolarophile h10TA2603, 10TA2607i. HO
R2
R2 H H
F3C
O N O
O O
OMe CO2Na
32
H H N
O
R1
i
O
O O H
TBSO
H H
Se
Me N
N O
O R1
33 (55–59%)
34
R
Reagents: (i) 2.5 mol% [AuClPPh3], 2.5 mol% AgOTf, 10 mol% PTSA, 100 mol% H2O, CH2Cl2, sealed tube, 80 C. The Lewis acid-catalyzed intramolecular substitution reactions of 4-vinyloxy- or 4-acyloxy-azetidin-2-ones with nitrogen-bound allyl-, propargyl-, and vinyl-silanes leading to carbacephams or carbacephems have been reported h10T3904i. Some bicyclic C-fused chlorinated tetrahydrofuro[3,2-c]azetidin-2-ones 35 have been prepared by a route involving Staudinger reaction of allylic imidates with dichloroketene followed by highly diastereoselective CuCl/PMDETA-catalyzed 5-exo-trig chlorine atom transfer radical cyclization h10JOC7408i. It has been reported that while the Ag(I)-catalyzed oxycyclization of b-lactam trishomopropargylic alcohol
111
Four-Membered Ring Systems
36 gave the 6-exo-dig cyclization product 37, Pt(II)-catalysis afforded the isomeric bicycle 38 and Au(III) yielded the oxycyclization/hydroxylation adduct 39 with concomitant MOM cleavage h10EJO4912i. The dichloro-b-lactam ring, obtained via Staudinger reaction of 4-aryl-2H-1,3-benzothiazines, has been proved to be a useful protecting strategy for the synthesis of 4-aryl-2H-1,3-benzothiazine 1,1-dioxides h10TL3205i. Biotransformations of nitriles and amides has provided an approach to enantioenriched b-lactams, which are useful intermediates in the synthesis of heterocycles fused to the b-lactam nucleus h10OBC4736i. A study has demonstrated that the borylstannane [N(Me)CH2CH2(Me)N]BSnMe3 is a superior reagent capable of effecting bisfunctionalization–cyclization in several 1,n-diynes (including 1,4-dipropargyl-b-lactams) for which the more well known silylstannanes fail h10JA13078i. The synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones, a novel class of 3,4-fused bicyclic b-lactams, and their transformation into methyl cis-3-aminotetrahydrofuran-2-carboxylates have been described h10EJO352i. A strategy for the highly diastereoselective synthesis of furo[3,2-b]-b-lactams via a Ag(I)-mediated intramolecular 1,3-dipolar cycloaddition of acyclic precursors, oxo-N-propargylamides, has been developed h10CC1269i. A series of novel phosphono-substituted benzo-fused tricyclic b-lactams were prepared by a route which makes use as key reactions of the Staudinger reaction and a radical ring closure h10EJO1333i. An enantioselective access to a spirocyclic oxindole-b-lactam has been developed using a nickel catalyst h10JA1257i. The Staudinger reaction between ketenes generated from natural O,N-protected trans-4-hydroxy-L-prolines and the N-benzyl-N-benzylideneamine has allowed the synthesis of several enantiomerically pure pyrrolidinederived spiro-b-lactams with a relative cis configuration, some of which were also susceptible to subsequent transformations, thus leading to greater chemical diversity h10JOC2010i. R3 R4 Cl
Cl
O R2
Cl
i
R3
R2
O
H N
N R1
OMOM
O H
O Cl
N O
R4
O
R1
Bn
38 (60%)
35 (55–84%)
HO Me
iii OMOM
O H
H H
H
ii HO
Bn
O
N O
OMOM O iv
N
37 (69%)
36
OH H
H N
Bn
O
Bn
39 (81%)
Reagents: (i) 60 mol% CuCl/PMDETA, DCE, reflux. (ii) AgOAc, Et3N, acetone, RT. (iii) 1 mol% [PtCl2(CH2¼¼CH2)]2, 2 mol% TDMPP, CH2Cl2, RT. (iv) 5 mol% AuCl3, 10 mol% PTSA, CH2Cl2, RT.
112
B. Alcaide and P. Almendros
4.5. OXETANES, DIOXETANES, DIOXETANONES, AND 2-OXETANONES (b-LACTONES) A review aiming to summarize the advantages of oxetanes in drug discovery as well as to outline chemical transformations involving oxetanes has appeared h10AGE9052i. Recent research on salinosporamides, g-lactam-b-lactone marine natural products isolated from Salinispora tropica, has been summarized h10AGE9346i. An overview on the highly alternating ring-opening polymerization of a mixture of two different enantiomerically pure 4-substituted b-propiolactones of opposite absolute configuration has been published h10AGE2662i. The use of a two-phase terpene synthesis strategy and how known oxidative transformations could benefit an eventual biomimetic synthesis of TaxolÒ have been reviewed h10SL1733i. The structures and the absolute configuration of two highly oxygenated new diterpenes, trigochinins A and B (40 and 41), isolated from Trigonostemon chinensis, have been determined by X-ray crystallography and CD analysis h10OL1168i. The dynamic kinetic resolution of racemic a-chloro b-ketoesters through ruthenium-mediated asymmetric hydrogenation has allowed an efficient preparation of the anti phenylisoserine side-chain of TaxotereÒ 42, which has been used for the hemisynthesis of the cancer therapeutic agent itself h10TA1436i. A silver-catalyzed late-stage fluorination reaction of complex small molecules, including polypeptides, polyketides, taxanes, and alkaloids has been presented h10JA12150i. Paclitaxel loaded liposomal cerasomes, successfully fabricated using molecularly designed proamphiphilic organoalkoxysilane by a self-assembly and sol–gel process, have exhibited controlled release behavior and remarkably high stability, thus demonstrating that they can be a new promising drug delivery system h10CC5265i. The fermentation of 10-deacetylbaccatine III with Curvularia lunata has afforded 4-deacylwallifoliol 43 and wallifoliol 44, the only natural taxoid with the unusual 5/6/6/6/4 ring system h10JNP1049i. The synthesis of paclitaxel (PTX)-Phe-Phe-Arg-chloromethyl ketone (FFR) followed by coupling with factor VIIa (fVIIa) formed PTX–FFR–mk-fVIIa, which was evaluated in vitro against paclitaxel-resistant cells h10JMC3127i. A series of potential taxoid substrates were prepared in radiolabeled form to probe in vitro for the oxirane formation step and subsequent ring expansion step to the oxetane (ring D) presumably involved in the biosynthesis of the anticancer agent Taxol h10TL2017i. Because an oxetane ring can trigger profound changes in aqueous solubility, lipophilicity, metabolic stability, and conformational preference when replacing commonly employed functionalities such as gem-dimethyl or carbonyl groups, it has been reported that grafting the small oxetane unit onto a molecular scaffold may have significant impacts on key physico- and biochemical properties h10JMC3227i. OAc
H OH
RO O O
O H OAc OAc
O
HO
O t Bu
NH
O
Ph
O OH
40 R = H 41 R = Ac
O OH
OH
OH
O OH O H OAc PhOCO
42
HO
O O
H
O H OBz OR
43 R = H 44 R = Ac
Four-Membered Ring Systems
113
The reaction of a perbenzylated 3,3-difluorinated hexono-1,5-lactone with MeOH/p-TsOH or with ammonia followed by a treatment with ion-exchange resin forms the exocyclic oxetane-derived vinyl ethers h10T1313i. An approach to access structurally diverse 3-aminooxetanes through the reactivity of oxetan-3-sulfinylaziridine 45 has been described h10OL1116i. Surprising secondary photochemical reactions leading to oxetane derivatives have been observed on conventional photolysis of diazotetrahydrofuranones h10TL2713i. A density functional theory (DFT) study of 1,4-biradical intermediates involved in stereoselective Paterno`–Bu¨chi reactions has been published h10EJO3831i. Consecutive ring-expansion reactions of oxiranes to oxetanes 46 and tetrahydrofurans with dimethylsulfoxonium methylide have been studied experimentally and modeled computationally at the DFT and second-order M ller–Plesset levels of theory utilizing a polarizable continuum model to account for solvent effects h10JOC6229i. Solvent and temperature effects on diastereodifferentiating Paterno`–Bu¨chi reaction of chiral alkyl cyanobenzoates with diphenylethene upon direct versus charge-transfer excitation have been studied h10JOC5461i. Aromatic alkynes, p-toluenesulfonyl azide, and aromatic 2-oxobut-3-ynoates undergo a copper(I)-catalyzed multicomponent reaction to provide functionalized 2-iminooxetanes 47, which can be converted selectively into five-membered nitrogen-containing heterocycles h10AGE9210i. An unanticipated cleavage of 2-azido-2-(hydroxymethyl)oxetanes with RuO4 has been reported h10JOC7565i. The reaction of butyric acid and benzyne produces an o-hydroxyaryl ketone via a fused oxetane intermediate h10OL3117i. Domino reactions afford readily polyfunctionalized oxetanes starting from alkynyl esters tethered to 2-methyl-1,3-cycloalkanediones h10T7012i. Strained polycyclic oxetanes generated photochemically from the Diels–Alder adducts of cyclic dienes and enones undergo deep skeletal rearrangements under protolytic ring-opening conditions offering expeditious access to chlorohydrins and other products of unique skeletal topology h10OL3398i. The exposure of a novel dipentaenone with a high degree of conjugation to Streptomyces coelicolor cytochrome P450 leads to an unexpected intramolecular cyclization to a Paterno`–Bu¨chi-like product, without oxidation/ reduction h10JA15173i. Polycyclic oxetanes have been obtained by the photoinduced Paterno`–Bu¨chi [2 þ 2] reactions of the 1,2-dicarbonyl compounds phenanthrenequinone and 1-acetylisatin with oxazoles h10JOC7757i. Sequential transformation of arynes into ortho-disubstituted arenes by one-pot procedure using formamides and dialkylzincs proceeded via the trapping of bicyclic oxetane intermediates h10OL1956i. An efficient access to pyrroles via gold-catalyzed cycloisomerization of alkynylaziridines involves 7-oxa-2-azabicyclo[3.2.0]hept-3-ene intermediates h10JOC510i. The silver-catalyzed carbonyl olefination employing electron-rich siloxyalkynes proceeds through intermediate siloxyoxetenes h10ASC839i. The synthesis of thermally stable acylamino-substituted bicyclic dioxetanes 48 and their base-induced chemiluminescent decomposition have been described h10JOC5920i. Sulfanyl-, sulfinyl-, and sulfonyl-substituted bicyclic dioxetanes have been synthesized and their base-induced chemiluminescence studied h10JOC879i. Thermodynamic aspects of thermal decomposition and charge-transfer-induced chemiluminescent decomposition for bicyclic dioxetanes bearing a
114
B. Alcaide and P. Almendros
4-(benzothiazol-2-yl)-3-hydroxyphenyl moiety have been reported h10JOC3678i. Experimental evidence for the occurrence of intramolecular electron transfer in catalyzed 1,2-dioxetane decomposition has been encountered h10JOC6574i. O N S
R1
O
i
R2
O
R1
i O
R1 R1
O
R2
R3
O O t -Bu
O
R2 46 (80–91%) (56–91%)
45
H CO2R2
TsN HO ROC
47
N
48
Reagents: (i) Dimethylsulfoxonium methylide, DMSO, RT. The synthesis and structure–activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors have been reported h10JMC5770i. An asymmetric total synthesis of the aggregation pheromone of Acalymma vittatum, vittatalactone 49, was carried out to determine its absolute configuration and to further examine the pheromone response in field studies h10JOC4424i. The concise formal synthesis of ()-salinosporamide A (marizomib) 50 using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy has been realized h10JOC3882i. A concise, enantioselective synthesis of the Phase I anticancer agent ()-salinosporamide A stems from a key bis-cyclization of a b-keto tertiary amide h10CC4803i. A nine-step total synthesis of ()-tetrahydrolipstatin (THL) 51 incorporates a phosphate tether approach h10OL1556i. The total synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of THL, provided the necessary functionality for target identification via bio-orthogonal “click chemistry” h10JA656i. A small natural product-based library of lipstatin analogues was synthesized using click chemistry and tested for cellular activity and protein specificity h10CC8335i. An intramolecular cyclopropanation reaction can serve as a direct methodology for the synthesis of the 3-(trans-2-aminocyclopropyl) alanine and 3-(trans-2-nitrocyclopropyl) alanine moieties found in the core of belactosin A and hormaomycin, respectively h10OL672i. A synthetic strategy toward an analogue of the spiro-b-lactone-g-lactam ring found in a class of potent antibiotics, the oxazolomycins and lajollamycin, has been described h10S3301i. A synthesis of the b-lactone esterase inhibitors ()-ebelactones A and B features the use of a Hoppe homoaldol reaction and a Cu(I)-mediated 1,2-metallate rearrangement of a metallated enol carbamate as key fragment linkage reactions h10T6462i. O Me
Me
Me
Me
Cl
NH
Me
H
Me O O
H N
O
O
O
OH
O
49
O
O
50 51
O
Four-Membered Ring Systems
115
A chiral phosphine-catalyzed homodimerization of ketoketenes that provides access to a variety of highly substituted ketoketene dimer b-lactones 52 has been developed h10JOC7901i. The mechanism of the PBu3-catalyzed homodimerization of ketoketenes has been investigated by way of NMR studies and intermediate trapping experiments h10TL6690i. The dimerization of indanedioneketene to spiro-oxetanone has been studied theoretically h10JOC5499i. Double diastereoselective, nucleophile-catalyzed aldol lactonizations leading to b-lactone-fused carbocycles and extensions to b-lactone-fused tetrahydrofurans have been reported h10OL3764i. Chiral N-heterocyclic carbenes derived from L-pyroglutamic acid have been found to be efficient catalysts for the formal [2 þ 2] cycloaddition reaction of disubstituted ketenes and isatins to give the corresponding spirocyclic oxindoleb-lactones 53 in good yields with good diastereoselectivities and excellent enantioselectivities h10ASC1892i. The development of the trans-selective catalytic asymmetric [2 þ 2] cyclocondensation of acyl halides with aliphatic aldehydes furnishing 3,4-disubstituted b-lactones within the context of asymmetric dual activation catalysis has been described h10CEJ9132i. Chiral phosphine-catalyzed formal [2 þ 2] cycloaddition of aldehydes and ketoketenes provides access to a variety of highly substituted b-lactones h10OL1664i. Functionalized b-lactones have been prepared starting from propargyl alcohols by means of an efficient rhodium-catalyzed silylcarbocyclization reaction h10T265i. Substituted a-pyrones 54 have been directly synthesized in good to excellent yields by a gold(I)-catalyzed rearrangement of b-alkynylpropiolactones h10OL5362i. Diketene has been identified as a new substrate for the Biginelli reaction and a diverse set of 5-carboxamide-substituted 3,4-dihydropyrimidine-2(1H)ones were synthesized without using any activation in high yields at room temperature h10T4040i. Four stereoisomers of nodulisporacid A have been synthesized efficiently from diketene by a three-component and one-pot construction of the whole framework h10TL2765i. The one-pot iodinecatalyzed domino reaction of diketene, amine, aromatic aldehyde, and naphthalenamine for the synthesis of benzoquinolinamides has been described h10OBC4803i. The highly enantioselective synthesis of (þ)- and ()-fluvastatin and their analogues has been facilitated by the reaction of an aldehyde with diketene in the presence of Ti(Oi-Pr)4 and a chiral Schiff base ligand h10JOC7514i. A novel, one-pot, solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-one and 1,4-dihydropyridine derivatives via a four-component cyclocondensation reaction of diketene, alcohol, and aldehyde with urea or ammonium acetate has been presented h10S4057i. The use of heterogenized quinidine derivatives in the asymmetric organocatalytic dimerization of ketenes afforded high enantioselectivity values (90–97% ee) in the course of 20 reaction cycles h10ASC1434i. Direct and selective acylation of holo-acyl-carrier proteins using readily accessible b-lactones as electrophilic partners for the phosphopantetheine-thiol has been demonstrated h10OL2330i. A simple access to isotactic polymers involves polymerization of racemic b-butyrolactone using supported catalysts h10CC1032i. The use of compatible epoxide carbonylation and lactone polymerization catalysts allowed for a one-pot reaction that eliminated the need to isolate and purify the toxic b-butyrolactone intermediate h10JA11412i. A concise enantioselective multistep, including b-lactone ring opening, synthetic procedure
116
B. Alcaide and P. Almendros
leads to ()- and (þ)-trans-whisky lactones h10EJO687i. The catalytic asymmetric synthesis of the complex polypropionates erythronolide B and apoptolidin C aglycone was achieved using b-lactones as key intermediates h10AGE2593, 10AGE8679i. Both enantioselective, organocatalyzed, intramolecular aldol lactonizations with keto acids leading to bi- and tricyclic b-lactones as well as topologymorphing transformations have been demonstrated h10AGE9479i. A new approach that takes advantage of N-heterocyclic carbene/Lewis acid cooperative catalysis provided access to cis-1,3,4-trisubstituted cyclopentenes from enals and chalcone derivatives via ring opening of fused b-lactone intermediates h10JA5345i. A general strategy for the catalytic asymmetric syntheses of the bakkenolides which involved, as key steps, an N-heterocyclic carbene catalyzed desymmetrization of a 1,3-diketone and a decarboxylation of the resulting tricyclic b-lactone has been reported h10OL2830i. A Reformatsky/Claisen cascade condensation of silyl glyoxylates with b-lactones afforded highly substituted ketone products bearing an a-quaternary center h10JA17393i. R2 R2
O i
• R1
O
R
R1
1
Ar O
O
R2
O
R1
R2
O
R
R
ii O
N
52 (45–99%) up to 96% ee
R2
2
O
O
O
1
R1
54 (29–81%)
53
Reagents: (i) 10 mol% Josiphos, CH2Cl2, 25 C. (ii) R3PAuOTf, CH2Cl2, RT.
4.6. THIETANES AND RELATED SYSTEMS The synthesis of isonucleosides 55 containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton used the cleavage of an epoxide group with a thiol followed by Mitsunobu reaction h10JOC4161i. The photoinduced electron-transfer cycloreversion of thietane radical cations 56 led to formation of thiobenzophenone and the corresponding alkenes, eventually followed by secondary [4 þ 2] cycloaddition h10OL1884i. The synthesis and biological evaluation of C5-spirothietane-containing C-glycosides have been discussed h10TL1880i. A novel use of the dinuclear palladium(I) catalyst 57 in aqueous medium is for the double arylation of phosphonoalkynes as well as diarylalkynes h10ASC3069i.
HO
R2
O S
B
55 (B = adenine, thymine)
Ph Ph
PPh3 O
R1 S
56
O O
S
Pd
P
P
Pd
S
PPh3
O
57
Four-Membered Ring Systems
117
Hot base treatment of (Z)-2-benzylidene-2H-thieto[3,2-b]quinolines 59, obtained from the reaction of 2-aminobenzaldehydes and (Z)-2-benzylidenethietan-3-one 58, causes a novel rearrangement to 2-phenylthieno[3,2-b]quinolines h10TL6687i. NH2
O
58
Ph
N
ii
S
+ S
N
i
R
CHO
R
S R
59 (35–75%)
(70–94%)
Reagents: (i) 10% KOH in EtOH, RT. (ii) 10% KOH in EtOH, reflux.
4.7. SILICON AND PHOSPHORUS HETEROCYCLES: MISCELLANEOUS A review on reagents for protecting oxygen functionalities, including organosiletanes as surrogate hydroxyl groups, has appeared h10SL841i. An overview including fourmembered silaheterocycles on the inspiration of new chemistry by interstellar molecules has been published h10CC6016i. Metal-catalyzed silylene transfer conditions have been utilized in a rearrangement reaction with allylic sulfides to afford silacyclobutanes 60, not the expected silacyclopropanes h10JOC5729i. The nickel-catalyzed ring expansion of benzosilacyclobutenes with ethyl cyclopropylideneacetate proceeded smoothly to give benzosilacycloheptenes in good yields h10TL6028i. Monomeric silylsilylene 61 has been synthesized by treating [{PhC(Nt-Bu)2}SiHCl2] with potassium graphite through an intermediate silicon(II) hydride that underwent a hydrosilylation with the amidinate of another silicon(II) hydride h10CEJ10250i. Homogeneous catalytic reactions involving P-heterocycles, including fourmembered phosphetanes and phosphetenes as ligands, have been reviewed h10CRV4257i. Cleavage and reorganization of the ZrC/Si C bonds of zirconacyclobutene–silacyclobutene fused compound led to a variety of novel heterocyclic compounds h10JA14042i. The first, room temperature stable, 1,4-disilabenzene was prepared from the reaction between LSi–SiL (L ¼ PhC(Nt-Bu)2) and diphenyl alkyne h10CC5873i. The reaction of a stable heterocyclic three-coordinate silylene L2SiCl [L2 ¼ PhC(Nt-Bu)2] with aromatic compounds containing CF and CH bonds has been reported h10JA10164i. The reaction between the N-donor base-stabilized monochloro silylene PhC(Nt-Bu)2SiCl and benzophenone afforded a silaoxirane with an NSi N four-membered ring h10AGE3952i. 7,8-Disilabicyclo [4.2.0]oct-7-ene 62 was obtained from the reaction of a bulky, diaryl-substituted disilyne, BbtSiSi Bbt (Bbt ¼ 2,6-bis[bis(trimethylsilyl)methyl]-4-[tris(trimethylsilyl) methyl]phenyl) with 4 equiv. of cyclohexene, as orange–red crystals in 65% yield h10JA2546i. A novel amidinate-stabilized singlet delocalized biradicaloid [LSi (m2-C2Ph2)2SiL] (L ¼ PhC(Nt-Bu)2) was synthesized by the reaction of [{PhC(NtBu)2}Si]2 with diphenylacetylene h10CEJ12956i. A silylene was treated with biphenyl alkyne to afford a disilacyclobutene system, which is a rare example of two five-coordinate silicon centers arranged adjacent to each other in a four-membered ring h10JA1123i. The first isolable oxygen-bridged bis-silylene has been synthesized
118
B. Alcaide and P. Almendros
by facile dehydrochloration of the corresponding disiloxane [LSiH(Cl)OSiH (Cl)L] precursor [L ¼ PhC(Nt-Bu)2] with LiN(SiMe3)2 h10JA15890i. The Ru¼¼P double bond in the five-coordinate terminal phosphido complex [Ru(Z5-indenyl) (PR2)(PPh3)] undergoes regioselective [2 þ 2] cycloaddition with simple and activated alkynes to give metallaphosphacyclobutene complexes 63 h10CC4592i. The Ru¼¼PR2 p-bond in a terminal phosphido complex undergoes regio- and stereoselective [2 þ 2] cycloaddition reactions with alkenes to yield metallaphosphacyclobutanes, which are analogous to olefin metathesis intermediates h10AGE3367i. A general route for the functionalization of P4 mediated by four-membered phosphorus–nitrogen–metal heterocycles yielding novel phosphorus-rich clusters has been introduced h10CC6921i. Homoleptic sandwich anions that contain diphosphacyclobutadiene ligands result from the reaction of anthracene metalates [Fe(Z4C14H10)2] and [Co(Z4-C14H10)2] with phosphaalkynes h10CEJ14322i. t -Bu
t -Bu
R2
SPh
t -Bu2Si
60
N
Si
Ph R1
N
Cl Si
N t -Bu
N t -Bu
61
H
Bbt Si
Ph
Ru
Si Bbt
Ph3P H
62
PR2
R1
63
Using a geminal dianion as precursor, a nucleophilic four-membered scandium carbene complex 64 was synthesized by salt metathesis on ScCl3(THF)3 in 52% isolated yield h10JA13108i. Trisubstituted allenynes were conveniently synthesized under mild reaction conditions through phosphane-mediated deoxygenation of 2,4-pentadiyn-1-ol derivatives involving a phosphaoxetane intermediate h10EJO4450i. The use of easily prepared oxygen, moisture, and thermally stable 1,3,2,4-diazadiphosphetidine compounds as reusable ligands for Heck coupling reactions has been reported h10T2415i. Diphosphines and cyclic polyphosphines react with the Lewis acid B(C6F5)3 and either H2 or an alkyne, under thermolysis conditions, to provide new synthetic routes to functionalized four-membered phosphino–phosphonium salts h10CEJ988i. The room temperature reactions of the stannocene Cp*2SnCl2 with primary phosphines result in the formation of diphosphanes and cyclo-tetraphosphanes h10CC5000i. Reaction of 2,4-bis(phenyl)-1,3-diselenadiphosphetane 2,4-diselenide [{PhP(Se)(m-Se)}2] 65, Woollins’ reagent, with aromatic diols in refluxing toluene, afforded a series of novel five- to ten-membered phosphorus-selenium heterocycles h10EJO2607i. 2,5-Diarylselenophenes have been prepared by direct reaction of Woollins’ reagent 65 with 1,4-diarylbutane-1,4-diones h10OBC1655i. A 2-rhodaoxetane underwent efficient transmetalation with a variety of functionalized aryl- and alkenyl boronic acids h10AGE9219i. The ditelluronic acid 67 is the first heavy congener of sulfonic and selenonic acids and was obtained by the O2 oxidation of the tellurinate 66 in the presence of [18]crown-6 h10AGE8030i. Stoichiometric and catalytic reactions of group 3 (Sc, Y) amides or alkaline earth (Mg and Ca) alkyls and amides with Me2NHBH3 resulted in
Four-Membered Ring Systems
119
formation of aminodiborane 68 h10CC7587, 10CEJ8508i. Precatalysts Cp2TiCl2/ 2n-BuLi and Cp2Ti(PMe3)2, which are believed to act as precursors to [Cp2Ti], have been found to promote the transformation of Me2NHBH3 to [Me2NBH2]2 68 in a homogeneous catalytic process h10JA3831i. According to the 11B NMR spectra, ammonia borane (H3NBH3) was converted into B-(cyclodiborazanyl)aminoborohydride under metal-free transfer hydrogenation conditions h10AGE2058i. A catalyst-free reaction between ammonia borane and tetrahydrofuran borane produced aminodiborane via the formation of a dihydrogen bond and subsequent elimination of molecular hydrogen h10JA10658i. Novel Ru(0) nanoclusters have been reported as highly active and reusable heterogeneous nanocatalysts in the dehydrogenation of dimethylamine–borane affording aminodiborane h10CC2938i. A transient intermediate Z2-ureato-N,O four-membered titanacycle has been proposed during the synthesis of carbodiimides using a titanium imido complex h10T9182i. The synthesis and reactivity of new boron amidinates are isolated as four-membered heterocycles; however, they are reactive h10JA13559i. Transition-metal-base-stabilized metalloborylenes have been prepared by a direct synthetic approach h10CEJ10635i. A combined experimental and DFT study of the [2 þ 2] cycloaddition reactions of diamide-amine supported titanium hydrazides with alkynes leading to azatitanacyclobutenes has been presented h10JA10484i. The interaction of FeCl3 in THF with 3 equiv. of n-BuLi at 78 C led in 80% yield to an iron–carbene of the type n-BuFe¼¼CHn-Pr, which was trapped by cycloadditions with alkynes affording ferracyclobutenes h10EJO2971i. Ph Py Cl
S
Se
Sc Py
S
OH
Se
P Ph Ph P Ph Ph
P Ph
P Se Se
65
64
R
Te O O Te R
i–iii
OH OH R Te O OH HO O Te R
OH
66
HO
OH
Me2N H2B
BH2 NMe2
68
67
Reagents: (i) 4NaH. (ii) O2, 18-crown-6. (iii) H2O.
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10JA9188 10JA10164 10JA10484 10JA10658 10JA11379 10JA11412 10JA12150 10JA13078 10JA13108 10JA13320 10JA13559 10JA14042 10JA15173 10JA15550 10JA15890 10JA17393 10JA17986 10JMC241 10JMC3127 10JMC3227 10JMC5502 10JMC6973 10JMC7778
10JMC8569 10JNP1049 10JOC137 10JOC510 10JOC748 10JOC879 10JOC1289 10JOC1600 10JOC1961 10JOC2010 10JOC3678 10JOC3882 10JOC4161
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Four-Membered Ring Systems
10JOC4424 10JOC4508 10JOC5461 10JOC5499 10JOC5729 10JMC5770 10JOC5920 10JOC5934 10JOC5941 10JOC6229 10JOC6574 10JOC6990 10JOC7219 10JOC7408 10JOC7514 10JOC7565 10JOC7580 10JOC7757 10JOC7901 10JOC7913 10JST8 10JST54 10MI685 10MI1581 10NJC1079 10NJC2861 10OBC607 10OBC1655 10OBC3307 10OBC4736 10OBC4803 10OBC5007 10OBC5345 10OL672
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10OL1116 10OL1168 10OL1556 10OL1664 10OL1884 10OL1944 10OL1956 10OL2330 10OL2802 10OL2830 10OL3117 10OL3234 10OL3398 10OL3764 10OL4616 10OL5044 10OL5290 10OL5362 10OL5386 10S2292 10S2943 10S3282 10S3301 10S3504 10S4057 10SL23 10SL42 10SL165 10SL659 10SL841 10SL1227 10SL1302 10SL1733 10SL1784 10SL3433 10T265 10T969 10T1313 10T2415 10T3187 10T3207 10T3599 10T3651 10T3904 10T4040 10T4144 10T4816 10T4900 10T5017
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Four-Membered Ring Systems
10T5707 10T6462 10T6613 10T7012 10T8974 10T9182 10T9519 10TA385 10TA582 10TA601 10TA637 10TA957 10TA1436 10TA2385 10TA2603 10TA2607 10THC1 10THC261 10THC349 10TL82 10TL197 10TL382 10TL1719 10TL1880 10TL2000 10TL2017 10TL2312 10TL2713 10TL2765 10TL3205 10TL4272 10TL4437 10TL4505 10TL5191 10TL5791 10TL6028 10TL6687 10TL6690
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CHAPTER
5.1
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives Edward R. Biehl Southern Methodist University, Dallas, TX 75275, USA
[email protected]
5.1.1. INTRODUCTION A tremendous amount of synthetic effort has been expended in preparing a wide variety of thiophenes and benzo[b]thiophenes with important drug activities or for use as valuable precursors in drug synthesis. Additionally, the proper design and synthesis of thiophenes for polymeric, electronic, superconducting, and nonlinear optical materials continued unabated this year. Due to space limitations, we will focus mainly on the synthetic aspects of thiophene and Se/Te chemistry. Reports with a common flavor have been grouped together whenever possible.
5.1.2. REVIEWS, ACCOUNTS, AND BOOKS ON THIOPHENE, SELENOPHENE, AND TELLUROPHENE CHEMISTRY The chemistry of thiophenes has appeared in several review articles. Those involving synthesis include the synthesis of a wide variety of thiophenes using phosphorus decasulfide (P4S10) h10CRV3419i; the synthesis of heterocycles using selenoamides, selenoureas, selenazadines, and isoselenocyanates in the synthesis of selenium-containing heterocycles h10H(81)2027i; recent trends in the chemistry of aminobenzo [b]thiophenes h10JSC205; 10MI1i; synthesis of thionucleosides, h10CRV3337i; combinatorial syntheses of sulfur-containing heterocycles including thiophene using CS2 h10JCO393i; recent advances in the application of the Heck reaction in synthesis of heterocyclic compounds h10H(81)1979i; synthesis of heterocycles mediated by benzotriazoles h10CRV1564i; a summary of major design and synthetic methods for tuning thiophene-containing small molecule and polymer properties h10MA1533i. Fagnou et al. wrote the featured article in the Journal of Organic Chemistry h10JOC1047i on moderate reactivity and direct selectivity in palladium-catalyzed heteroaromatic direct arylation using a chloprid activating/blocking group. Reviews involving the thiophenes in materials include the key role thiophenes and selenophenes carrying phosphorus functional groups play in construction of unique n-conjugated systems hB10MI1001i; the use of azine- and azole-functionalized oligo- and polythiophene semiconductors for organic thin-film transistors h10MA1533i; the use of transition-metal complexes based on thiophene–thiolene ligands on ligand synthesis and complex preparation of molecular structure and solid state properties of Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00005-X
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various compounds h10CCR1479i; recent progress in the study of electroconducting nanomaterials based on the supramolecular self-assembly of oligo(thiophene) h10CSR2420i and a complication of X-ray structures of a variety of thiophenes is available h10AX(E)(o)271i.
5.1.3. SYNTHESIS OF THIOPHENES 5.1.3.1 Thiophene Rings Electrophilic cyclization of alkynes possessing tethered heteroatom nucleophiles and various catalytic reagents has found extensive use in synthesis of heterocycles including benzothiophenes and selenophenes. For example, metal carbonyl-promoted reactions of ferrocenylacetylenes in presence of sulfur using UV light have been developed for the synthesis of 2,5-diferrocenylthiophenes 1 h10JOM2532i. hexane, S8-powder M(CO)6 hn, −10 °C, 20 min
Fe
S Fe
Fe
M = Mo, W 1
Iodocyclization and subsequent palladium-catalyzed coupling has emerged as an important method for the synthesis of diverse methyl sulfone-containing benzo[b] thiophene library h10JCO278i and polyheterocyclic compounds h10JOC1652i. Similarly, fused 4-iodoselenophene[2,3-b]thiophenes were obtained by electrophilic cyclization of 2-sulfur-containing 3-alkylthiophenes h10EJO705i. Diarylalkynes 2 possessing an ortho-thiomethyl group underwent electrophilic cyclization in the presence of PTSA (p-toluenesulfonic acid) to give a variety of heterocycles including thiophenes 3 h10T3775i. R
R
PTSA, 1 equiv. S
EtOH, MW
SMe 2
3
R = OMe, -CH = CH-CH = CH
In addition, regioselectively functionalized benzo[b]thiophenes 5 were prepared from bromoamide 4 by combined ortho-lithiation, Sonagashira coupling, and halocyclization strategies h10JOC7433i. Br
OCONEt2 4
1. LDA 2. Me2S2
Br SMe OCONEt2
R PdCI2, XPhos CsCO3
E SMe OCONEt2
R S E = I, Br, CI
5
129
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
An interesting HPHT (N-methylpyrrolidine-2-one)-promoted bromocyclization of ortho-arylalkynes 6 and ortho substituted conjugated aryldiynes 8 was described for the preparation of 2-substituted 3-bromobenzothiophenes 7 and 3,30 -dibromo-2,20 bibenzo[b]thiophenes 9, respectively h10EJO4492i. Further functionalization by palladium-catalyzed coupling reactions at the C Br bond gave benzothiophenes of biological interest. Ar
Br
MPHT 1,2 equiv.
Br
Br
MPHT Ar
4.2 equiv.
S SMe 6
SeMe SeMe 8
7
S 9
Several sulfur-assisted synthesis of thiophenes from appropriate alkynes were carried out this year. For example, a sulfur-assisted propargyl-allenyl isomerization of diyne 10 and subsequent intramolecular cyclization gave tricyclic thiophene derivatives 11 h10TL6240i. Ar Ar S
DBU S 11
10
An intriguing synthesis of EDOT 13 and EDOS 14 was reported in which a common diyne 12 was treated with zirconocene dichloride followed by disulfur dichloride and selenium dichloride (prepared in situ), respectively h10JOC4868i. S2CI2 o
o
Cp2ZrCI2
o
o
TBAF 13 o
n-BuLi
o
SiMe3
Me3Si 12
Se2CI2
Se 14
Another EDOT synthesis was reported from the reaction of commercially available (Z)-but-2-ene-1,4-diol or but-2-yne-1,4-diol using epoxidation, etherification, and thiophene formation h10H(82)449i. A sulfur-assisted five-cascade sequential reaction starting from dieneyne sulfide 15 provided a convenient and efficient synthesis of allylthiophen-2-yl derivatives of acetates, propionates, and ketones 16 h10OL356i. The key step here is the in situ formation of allenyl allyl sulfides.
130
E.R. Biehl
1. Propargyl–Allenyl Isomerization 2. Thio-Claisen rerarrangement 3. Thione enolization 4. Michael addition 5. 1,5-H migration/aromatization
R2 R4
EWG
DBU
S R3
O
O
15 EWG =
EWG S R3 R2
O Ar
OEt
R4
16 Alkyl
In addition, 1,3-dihydrobenzo[c]thiophenes 18 were prepared by a sulfur-assisted propargyl–allenyl isomerization of 17 followed by a [4 þ 2] cycloaddition promoted by Ga(OTf)3 h10JOC2706i. R
R Ga(OTf)3
EWG
EWG S
S Et3N–toluene 17
18
An interesting synthesis of bis(benzo[b]thiophenyl)methane’s 20 by gold-catalyzed double carbothiolation of diyne 19 was reported this year h10H(82)689i. R2
R2 cat. AuCI S
S
toluene, 25 °C R1
19
S
S R1
R1
R1 20
Several syntheses of thiophenes using Gewald type reactions were reported this year. For example, general protocols were established for the synthesis of an array of 2-aminothiophene-3-carboxamides (40 compounds) from cyanoacetamides, aldehydes, or ketones, and sulfur via a 3-component Gewald-3CR variation was described h10JCO111i. Synthesis of 3-bromobenzo[b]-5-aminothiophene carboxylic acids (esters) 23 was also prepared by a modified Gewald reaction of 21 and 22 and was used as starting materials for the preparation of new macrocyclic peptidomimetics h10EJO6319i.
M3SiO
+ CO2Me 21
CO2R2
CO2R2
R1
CN 22
+ S8
MeO2C R1
R1 = H, Bn, R2 = t-Bu, Me, Bn
S 23
NH2
131
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
Treatment of a-substituted 2-bromo-b-methoxystyrenes 24 with n-BuLi in the presence of elemental sulfur followed by concentrated HI gave 3-substituted benzo [b]thiophenes 25 h10H(80)1703i. R3
1. n-BuLi, Et2O, S; H3O+
OMe
R1
R3 R1
2. conc, HI, MeCN, rt R2
Br
S
R2 R1,
24
R2 = H,
OMe;
R3 = Me,
Ar
25
An interesting synthesis of 2-trifluoromethylbenzothiophenes 27 involved a copper-catalyzed thiolation annulation of 1,4-dihalides 26 with Na2S h10JOC7037i. CF3
Na2S, CuI
X 26
CF3
DMF, 80 °C
CI
S
X = I, Br, CI
27
Other convenient methods were developed for a wide variety of substituted thiophenes and benzo[b]thiophenes including copper-catalyzed tandem 5-alkenylation of potassium sulfide with 1,4-diiodo-1,3-dienes 28 to yield tetrasubstituted thiophenes 29 h10OL3930i and a facile two-step synthesis of 3-nitro-2-substituted thiophenes 32 from 1,4-diol 30 and nitroalkene 31 h10JOC2534i. R1 R2
I Cul (10 mol%) I
R3
R3
R2
HO
S
R
R1 R4
S
S
OH
NO2
NO2
+R
two steps
S
R4 28
30
29
32
31
In addition, a one-pot synthesis of phenylbenzo[b]thiophenes 35 by a CS cross-coupling reaction of nitro- and formyl-substituted aryl halides 33 with benzyl thiols 34 was carried out. h10OL2434i. Y
Y
KOH PEG-600
+ X 33
HS
R
S R
34 X = F, CI. I
Y = NO2, CHO
35
The high biological activities of thieno[2,3-b]pyridines attracted much synthetic attention this year. Thus, a microwave sulfur-assisted synthesis of various 2-amino derivatives of benzothiophenes 37 was carried out by subjecting 1-(2-chloropyrin3-yl)ethanone 36 to microwave heating for 10–20 min in the presence of elemental sulfur, sodium acetate, and DMF h10H(80)1291i. Also, 3-aminothieno[3,2-b]pyridine-2-carboxylates 40 were prepared from 3-fluoro- or 4-nitropicolinonitriles 38
132
E.R. Biehl
and methyl thiogylcolate 39 h10TL281i. Suzuki–Miyaura (CC) or Buchwald–Hartwig (CN) coupling readily functionalized these compounds. Novel thienopyridine derivatives were also synthesized by the cyclization of 6-aryl-2-thioxo-1,2-dihydropyridine-3-carbonitrile, which were prepared by a two-step reaction starting with an appropriate acetophenone h10BMCL6282i. O
N
R1 S,AcONa
+ HN
X
R2 DMF, MW
36 X = F, CI
N S
R1
N
CN +
R2
CO2Me
SH
F 38
37
NH2
N
CO2Me
S
39
40
Several substituted benzothiophenes were prepared in which one of the steps involved a sulfur-assisted reaction h10JMC1819i. Route 1 involved the reaction of a multisubstituted benzaldehyde with ethyl thiogylcolate to give the ethyl benzo[b] thiophene-2-carboxylates, Route 2 consisted of treatment of a 2-nitrobenzaldehyde with ethyl sulfide to give the 2-ethyl sulfide thiophenecarbaldehyde which was treated with ClCH2COCH3 to give the 2-acetylthiophene.
5.1.3.2 Construction of Fused and Bridged Thiophene Rings Electrophilic cyclization of 3-alkylthiophenes was also successively used to synthesize fused thiophene rings. For example, fused 4-iodoselenophene[2,3-b]thiophenes 42 were readily prepared from 41. Additionally, these fused derivatives were elaborated into more complex molecules by palladium or copper-catalyzed crossed-coupling with thiols, boronic acids, and organozinc reagents to give the respective fused rings 43, 44, and 45 shown below h10EJO705i. CI SH S
CI
Cul
Ph S
43
R
E, DMe S
Se-n-Bu
41
B(OH)2
I
Se
Br S
Ph Se
Pd(PPh3)
42
S
Ph Se
44
ZnCl
PdCl2)PPh3
Ph S
Se
45
A three-step synthesis of asymmetrically functionalized 4H-cyclopental [2,1-b:3,4-b0 ]dithiophenes 49 from 2-thienylmagnesium bromide 46 via dithiophene 47 and hydroxy derivative 48 was developed h10JOC7202i.
133
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
S S
S
s
2
1
MgBr
46
OH
47
Br
S
S
S
S
R2
R1
R1
48
R2
49
A convenient method of one-pot synthesis of [1]benzothieno[3,2-b]benzophenes (BTBT) 51 from readily available o-dihalostilbenes 50 using sodium sulfide nonahydrate or sodium hydrosulfide hydrate and sulfur was reported h10TL5277i. X S
NaSH(H2O) + S NMP
X
S BTBT
X = CI, Br
50
51
A series of dipropargylic disulfides 52, whose preparations proved challenging, underwent facile tandem rearrangements and cyclization reactions under mild conditions to give novel thieno-thiophenes 53 and 3-thienylmethylene disulfides 54 h10T1925i. A possible mechanism for these reactions has been proposed in which the key step involves a double [2,3]-sigmatropic rearrangement to the elusive diallenyl disulfides via a thiosulfoxide intermediate. O S S R1
Δ S
S
S
R1
R1
O
+
S
R1
52
53
S
54
R1 R1
S
The activation of a section, or of all carbons of the bromine atom in thiophene 55 by bromine in lithium–halogen exchange reactions followed by treatment with W(CO)6 or Cr(CO)4, gave adducts 56 which were then converted to novel thiophenes 57 decorated with a Fisher carbene ligand h10DT5777i. Ammonolysis of 57 gave the amino thiophene 58. S
1. n-BuLi
1. LDA 2. Et3OBF4
S
2. M
(M)(C))
Br 55
S
O 56
M = W(C)4, Cr = Cr(CO)4
NH3 M
M = Cr
S M
OEt
NH2
57
58
A palladium-catalyzed cyclocoupling of 2-bromo heterobiaryls 59 with isocyanates 60 gave a wide variety of fluorenone imines 61. The isocyanates functioned as catalyst for CH bond functionalization at the 20 -position of the 2-biaryls. The reaction was
134
E.R. Biehl
applicable to a variety of heterocyclics including bithiophenes 62 which allowed the construction of a wide range of ring systems such as 63 h10JOC4835i. S + Br
S
S
Pd(OAc)2, PPh3 CsOPiv
R N
+
NAr
NAr
C
C
S
60
59
S
Pd(OAc)2, PPh3 CsOPiv
R N
S
62
61
60
63
The construction of fused thiophene ring systems 67 by the intramolecular CH arylation of 66 by palladium catalysts was discovered. Intermediates 66 were prepared by the reaction of 3-substituted thiophenes 64 with o-halo phenols 65 h10H(80)103i. In addition, 4,6-dimethylthieno[3,4-c]thiophene-1(3H)-thione 69 OH X′
X +
H
S
O
Pd Cat. S
64
O
X′
base H
65
S
66
67
was formed unexpectedly when 2,5-dimethylthiophene-3,4-dicarboxaldehyde 68 was treated with excess Lawesson’s reagent h10H(81)2229i. S
S
O H
H
O
Lawesson’s reagent
S
68
S 69
Another microwave-assisted reaction involving three-component coupling-addition-SNAr (CASNAR) sequences was reported h10OBC90i. Thus, treatment of 2,5dichlorothiophene-3-carbonyl chloride 70 with the appropriate alkyne with 2% PdCl2(PPh3)2/4% CuI is followed by the addition of Na2S and microwave heating to give 2-chloro-4H-thieno-2,3[b]thiopyran-4-ones 71. The reaction probably involves initial coupling to give alkyne 72 which undergoes Michael addition in the presence of Na2S (H2O)9 to give vinyl sulfide 73 which undergoes intramolecular cyclization to 71. CI
S CI
CI
R′ 70
CI
1, PdCI2(PPH3)2
+
R1
S
S 2. Na2S (H2O)9/MW
71 O
O
SNAr coupling S
CI
CI
S R′
Michael addition
CI
R′
CI
Na2S (H2O)9 O O 73 72
S−
135
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
Similar treatment of the 2-carbonyl chloride with the appropriate alkyne gave 7Hbenzo-[b]thieno[3,2-b]thiopyran-7-ones. This novel protocol opens new synthesis of related annulated heterocycles for studies in medicinal and material sciences. A versatile synthesis of [3,4-b]diheteropentalenes, that is, thieno[3,4-b]thiophene, alkyl derivatives thereof, and seleno[3,4-b]thiophene, were prepared from readily available thiophene-2carboxylic acid. Accordingly, the acid 74 was converted to the 5-bromo-2,3-dicarboxylic acid 75 by successive treatment with n-BuLi/CO2, n-BuLi, and RBr. Intermediate 76 was treated LiAlH4 and then PBr3 to give 76 which was allowed to react with Na2S in DMF followed by oxidation (DDQ, DCM) gave 77 h10TL2089i. See Section 5.1.5 for discussion on the application of these three fused ring systems in material sciences. CO2H CO2H
S
74
1. n-BuLi CO2
Br
2. n-BuLi -78 3. RBr
S
CO2H
1. LiAH4 2. PBr3
1. Na2S 2. DDQ
Br Br
75
S Br
S
Br
S 76
77
5.1.4. ELABORATION OF THIOPHENES AND BENZOTHIOPHENES Cross-coupling reactions continued this year to be used extensively in the elaboration of thiophene rings. In addition, the use of direct arylation reactions in synthesizing biaryls is increasing in importance, as they avoid the need of stoichiometric organometallics and other experimental problems, for example, functional group compatibility. See Ref. h10JOC1047i for pertinent references. A palladium-catalyzed (Pd(OAc)2/dppb) C2 or C5 direct arylation of 3-formylthiophene derivatives with aryl bromides was carried out. When this reaction was performed with 3-formylthiophene 78, the 2-arylated thiophene 79 was the major product (76–86% regioselectivity). However, when the 3-diethyl-acetyl derivative 81 was used, 5-arylated thiophenes 80 were obtained. This procedure was tolerant to a wide variety groups on the aryl bromide such as formal, benzyl, nitro, or acetyl, propionyl h10EJO611i. O
O H + ArBr dppd = [1,4-bis(diphenylphosphanyl)butane]
78
H +
Ar
79 76–80%
Et
O
S 80
O
O
1. Pd(OAc)2/dppb
O + ArBr
S
Ar
S
S Et
O H
Pd(OAc)2/dppb
H
2. Pd/base
81
functional groups of Ar = formy, nitro, nitrile, benzoyl, propionyl
Ar
S 79
H +
Ar
S 80 64–88%
136
E.R. Biehl
Extending the scope of trifluoroborates in coupling reactions, Molander et al. have successfully carried out nickel-catalyzed cross-coupling of potassium aryl- and heteroaryltrifluoroborates with unactivated alkyl halides h10OL5783i. Nearly quantitative amounts of organoboron compounds could be employed to cross-couple many challenging heteroaryl nucleophiles. Several functional groups were tolerated on both reactants and chemoselective reactivities of C(sp3)Br bonds in the presence of C(sp2)Br. An interesting HPHT (N-methylpyrrolidine-2-one)-promoted bromocyclization of ortho-arylalkynes was described for the preparation of 2-substituted 3-bromobenzothiophenes h10EJO4492i. Further functionalization by palladium-catalyzed coupling reactions at the CBr bond gave benzothiophenes of biological interest. Thus, Larock et al. h10JCO278i, using solution-phase parallel synthesis, generated a diverse sulfone-containing 72-membered benzo[b]thiophene library. The synthetic procedure involved preparing methyl sulfone-containing 3-iodobenzo[b]-thiophenes by electrocyclic cyclization of electron-rich alkynes using iodine (this was discussed in Section 5.1.3.1) which were further elaborated by palladium-catalyzed Suzuki–Miyaura, Sonogashira, and Heck chemistry. Other unique noble metal catalysis included a Au/ Ag-cocatalyzed rearrangement of thiophene-3-carbaldehyde oxime 82 to thiophene3-carboxamide 83 in 99% yield under solvent and acid-free conditions h10JOC1197i. The latter is a rare example of cooperative catalysis involving well-defined gold species. O S
S
I(IPRAuCI, AgBF4)
OH N
NH2
100 °C, 20H
82
83 99%
Several facile methods for direct Pd(OAc)2-catalyzed oxidative cross-coupling of thiophenes was reported. These include the reaction of thiophene-2-carbaldehyde 84 with electron-deficient pentafluorobenzene 85 to give 2-perfluorophenyl derivative 86 h10JA12850i; the reaction of benzothiophene 87 with aryl bromides and chlorides 86 gave 2-arylbenzothiazine 89, respectively h10JOC6998i; and the reaction of free NH2F
F (CI)Br H
F F
H H
S O
F
F
F 85
O S
cat. PdOAc2
84
88
H
F
S F
F 86
PdCI2(PPH3) Lio-tBu
87
S 89
substituted thiophenes 90 and 92 to afford the respective 2- and 4-aryl amines 91 and 93 h10OL4320i. H3C
H3C
NH2 OMe
S
ArBr a.
O 90
Ar
H 3C
NH2
91
S O
a, PDCI(C3H5)(dppb), KOAc, DMAc
NH2
ArBr
OME
S
H 3C
NH2 a. 92
S
R 93
137
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
A facile method for synthesizing 3-aminobenzothiophene 95 via the reaction of lithium amides with zinc reagent 94 (prepared by the reaction of 2-bromobenzothiopehene with Zn) and lithium amides was reported this year h10S2313i. LiNRR!
Zn
NRR!
S 94
S 95
2
Until this year, direct alkynylation of thiophenes remained elusive owing to their low reactivity. However, using cooperative activation of TIPS-EBX with gold and Bronsted acids leads to directed alkynylation h10AG(I)7304i. As shown below, treatment of thiophene 96 with alkyne 97 gave 2-(98) or 3-alkynyl (99) derivatives. O
i-Pr3Si
O Sii-Pr3 97 R1
R S
R1
TIPS-EBX
or
R
5 mol%, AuCI, TFA 23 °C
S
SiiPr3
96
98
R R1
S 99
The introduction of perfluoro alkyl groups into the thiophene ring in the usual ways is difficult due to the high electronegativity of the fluorine atom. However, a direct synthesis involving a cothermolysis (200 C) between bis-trifluoromethyl peroxide and 2-substituted thiophenes was developed which made it possible to prepare new 2-substituted-5-(trifluoromethoxy)thiophenes 101 h10TL5242i. It is believed that the reaction involves scavenge of CF3O radicals by cothermolysis with thiophene to give intermediate thiophene radical 100. 2CF3O-
CF3OOCF3
CF3OF
+ CF3O
S R
–H• F3CO
R
S 101
H S F3CO H
R
100
Directed ortho-borylation of phenol derivatives catalyzed by a silica-supported iridium complex was shown to give borylated aryl O-carbamates and to show their utility in synthesis, one of the carbamates 102 was coupled with 2-bromothiophene by a Suzuki–Miyaura reaction and the resulting coupled product 103 was reduced by LiAH4 to give 2-(2-thienyl)phenols 104 h10OL3978i.
138
E.R. Biehl
NEt2
O Pd(PPH3)4 (5 mol%)
NEt2
O
Br
+
O Bpin
S
Na2CO3 (1 equiv.)
O
LiAH
OH
S
DME, 90 °C
102
S
103
104
In addition, a concise synthesis of formyl- and cyano-ester-substituted bithiophenes and furanothiophenes was developed in which the key step involves Stille coupling of substituted bromo 5-ring sulfur-containing heterocycles h10JHC167i. Using the eco-friendly carbonate solvents, palladium-catalyzed direct arylation of thiophene occurred to give adducts in good yields h10GC2053i. Direct transition-metal catalyzed alkylation of X-H is not common. However, this year, a new iron-catalyzed heterocycle deprotonative alkylation was developed in which both primary and secondary alkyl halides can be coupled with several heterocycles including thiophenes h10OL4277i. A typical example involving the conversion of substituted thiophenes 105 to substituted 2-cyclohexylthiophenes 106 is shown below. NHMe R
NHMe S 105
R
FeCI3 c-hexylbromide TMPMgCI/LiCI
Cy
S 106
A unique one-pot, high-yield desulfurative-fluorination-bromination reaction was developed that provides ready access to 2,5-dibromo-3-(1,1-difluoroalkyl)thiophenes was reported h10OL4428i. A single dithiolane reactant can be used to prepare 2,5-dibromo-3-(1,1-difluoroalkyl)thiophenes 107 and 2,5-dibromo-3-(1,1-difluoroalkyl)thiophenes with longer alkyl chains 108. F
Br
S
F R
NOBF4/PPHF R = C6H13, C8H17
S 108
Br
S R S
F
F R
DBH /PPHF R = CF6H13, CH3, H
Br
S
Br
107
In addition, the use of a half-sandwich iron N-heterocyclic carbene complex, which obviated the use of noble metal catalysts h10CAJ1657i, catalyzed CH bond activation which allowed thiophenes to be borylated. Ring opening of dithieno[2,3b:30 ,20 -d]thiophene by the action of n-BuLi was reported to give substituted bithiophenyl aldehydes which have the potential to serve as valuable pharmaceutical intermediates h10T2168i
139
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
S
S HOF/MeCN
O O S S S
109
110
B(OH)2
+e +
O2
115
O2 Me
S 111
H2O2
cat. Me
Me
O S 117
S 116
S 112 O
Me
SiO2-Tio2
S 113
S O
cat. = [(C16H37)]N(CH3)]5[IMo5O24]
O 114
using the HOFCH3CN complex in high yield and under very mild conditions h10JOC4623i Second, 2,8-dimethylbenzothiophene was oxidized to the corresponding sulfone 112 using a Anderson-type catalyst [(C18H37)2N (CH3)2]5(ImO)6O24] h10GC1954i. Third, nonhydrolytic SiO2–TiO2 mesoporous xerogels were found to be efficient catalysts for the mild oxidation of DBT (dibenzothiophene) 113 to the sulfoxide 114 with hydrogen peroxide h10CT270i. Finally, benzo[b]thiophene-2-boronic acid 115 was oxidized by an electrochemical cathodic hydroxylation under an oxygen atmosphere to give benzo[b]thiophen-2(3H)-one 117 in a low yield (27%). The major product, however, was benzo[b]thiophene 116 which was obtained in a 47% yield h10CC1284i. The mechanism of this reaction is being studied. Other examples of oxidation of thiophenes include the following. The mild oxidation of thiophene was also reported to occur over modified alumina catalyst under mild conditions h10EF3443i. An exciting piece of work involving in situ thiophene oxidation was reported for the synthesis of oxoisoindolones. The first step involved preparing thiophenecontaining the tri-keto derivative by the Ugi reaction is shown below. As shown, 2-thiophene-2-carbaldehyde was successively treated with a primary amine and then with a ketovinyl acid. This resulting acid subsequently underwent an oxidation-triggered IMDA/aromatization cascade to the appropriate 3-oxoisoindolones 118. The thiophene ring in the oxoindolone, which normally lacks diene behavior, is oxidized to a thiophene sulfoxide, which now exhibits diene properties, and thus undergoes a [4 þ 2] Diels–Alder intramolecular cyclization with concomitant loss of SO2 to give desired 3-oxoisoindolone h10JOM2532i. R O
O O
1. RNH2
N R
S
S
R
2.
O O
CO2H
118
NHR
140
E.R. Biehl
A novel synthesis of calix[4]thiophenes were also achieved by the addition of thienyllithium to various ketones followed by dehydration to give 1-(2-thienyl) cycloalkenes and (2-thienyl)alkenes which were converted to the calyx[4]thiophenes alkenes by treatment with 10 mol% NIS h10CC5009i. In addition, the low-temperature Evans–Tishchenko coupling of functionalized thiophene with b-hydroxy ketones 119 in the presence of Sm(II) catalyst to give interestingly modified thiophenes 120 h10JOC7475i. The authors believe that this heteroaryl variant of the Evans–Tishchenko reaction will find use in the synthesis of hybrid natural analogues and unrivalled potential of natural product frameworks as drug leads. O O
S
OH
OH
Sml2/PhCHO
O R
S R
119
120
Bis-(thienyl-2-yl)methane was found to be regioselectively lithiated at the interring methylene carbon using dimsyl anion. Quenching with appropriate electrophiles furnishes meso derivatives exclusively h10T3682i. To meet the soaring demand for clean fuels, hydro-desulfurization is an important industrial process for removing sulfur from thiophenes which is very abundant in fossil fuels. Previous methods have had their particular problems. However, three new catalysts, NiWO4 nanoparticles h10CC7430i, [Rh(dippe)(m-H)], and [Rh2(dippe)2(m-Cl)(m-H)] h10OM4923i, have come on the scene and were found to greatly activate CS bond cleavage. Cu(I) thiophene (CuTC) has been shown to be a good catalyst for the efficient synthesis of 1-sulfonyl-1,2,3-triazoles by the reaction of in situ generation of copper(1) acetylides and sulfonyl azides. The titled compound is formed in good yields using CuTC catalyst using both nonbasic anhydrous and aqueous conditions h10OL4952i. Three novel methanofullerenes having ethylthienyl or pentyl group were synthesized. All three were found to exhibit conversion efficiencies of over 2.2% that are superior to PCBM devices h10T7136i. In addition, a one-pot synthesis of tricyclic heteroaromatic cores, that is, 2,30 dibromo-1,1-bisthiophenes 123 from 2-bromothiophene by an interesting base-catalyzed halogen dance reaction involving 2-bromothiophene 121. The resulting 3-bromo-2-lithiothiophene 122 underwent CuCl2-oxidative coupling with the in situ formed a-lithio-b-bromothiophene 122 to give 123. Treatment of the 2,30 dibromo derivatives with anilines gave heterocyclic tricyclic cores, namely, dithieno-[2,3-b:30 , 20 -d]pyrroles h10OL2136i.
S
121
Br
3. LDA
Br
Br
1. LDA 2. TMSCI
CuCI2 TMS
S
122
Li
S TMS
S
123 Br
TMS
141
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
5.1.5. SYNTHESIS OF THIOPHENES FOR USE IN MATERIAL SCIENCE Interest in thiophene-based oligomers and polymers continued unabated during the year since they constitute active materials in transistors and photovoltaics. A review on azine and azole-functionalized oligo and polythiophene semiconductors has been reported h10MA1533i. Several terthienyl b-substituted with (thienyl)cyanovinylene groups 127 were prepared by Stille coupling of 2,5-dibromo derivative 124 with 125 followed by treatment of the resulting terthienyl 126 with TosMIC. Their electronic properties were analyzed by UV–vis spectroscopy and cyclic voltammetry h10TL4117i. OHC S C6H13 C6H13 Br
SnBu3
C6H13 Br
S
C6H13
S
125
S
S
S
S
Pd(Ph3)4
OHC
C6H13
C6H13
TosMIC t-BuOK
S
126
CHO 127
CN
124
NC
The effect of substitution on packing and conjugation was studied by synthesizing a series of tetrathiophenes with systematically varied alkyl thiophene substituents h10TL2956i. Several copolymers of 3-substituted thiophenes were electrochemically polymerized to give new copolymers that were characterized by electrochemical analysis and shown to be suitable for applications in electrochromic displays h10SM22i. Optical and electrochemical studies of 1,3-disubstituted benzo[c]thiophenes in which heterocycles such as thiophenes and benzo[b]thiophenes/1-hexylindole/benzo[b]furans were incorporated were carried out and found to be suitable candidates for application as hole-transporting materials in double-layer OLEDs h10JOC6096i. Poly(3-dodedyl-2,5-thienylenevinylene)s were obtained in nearly quantitative yields by the polymerization of 3-dodecyl-5-formylthiophene-2ylmethyl-phosphonic acid diethyl ester by Stille coupling and Horner–Emmons reactions h10JCS(PC)663i. The diester was prepared from 2-bromo-3-dodecyl by a series of well-established reactions h10JCS(PC)480i.
O
O
O
OH (CH2)n HOBT/ DCC Br
S 128
Br
Leu-OMe
N (CH2)nH Br
S
Br 129
O O
O
NH
(CH2)n
ThSnBu3
N (CH2)nH S
S
S 131
MeOH
S
Pd(PPH3)4
S
S 130
OH O
OH O
O
O
N (CH2)n H S
O
S S 132
n
HCI
142
E.R. Biehl
Polythiophenes bearing a specific chiral center, for example, L-leucine 132 were prepared by the electrochemical oxidation of a series of L-leucine functionalized oligothiophenes 131. The L-leucine-oligothiophenes 131 were prepared by multistep synthesis (shown below) in which the 2,6-dibromothiophenes 128 are condensed with Leu-OMe to give the amide 129. Stille cross-coupling of 129 with thiophene followed by hydrolysis of the crossed-coupled product 130 gave L-leucine-oligothiophenes 131. The electroactive polymers exhibit excellent adhesive properties on varies electrode surfaces h10JOC6096i. A wide variety of [3,4-b]diheteropentalenes such as thieno[3,4-b]thiophene 135 from thiophene-2,3-dicarboxylic acid 133 were prepared since these fused heterocycles are of great interest as semiconductors as well as applications including OLEDs and organic photovoltaic cells h10TL2089i.
CO2H S
CO2H
CO2H n-BuLi-78°C
n-BuLi CO2H
S
CO2
S R
R
RBr
1. LiAH 2. PBr3 3. Na2S 4. DDQ, DCM
133
S
S
CO2H 134
135
New phosphorescent diethenobismoles 137 were prepared by the reaction of dilithiobithiophene 138 with aryldihalobismuthanes h10OM3239i. Several of these bismuthanes showed stable phosphorescence even in the solid state in air and at room temperature. The large heavy-atom effect of bismuth seems applicable to the development of novel organic phosphorescence materials. R1
R
Br
Ar
1. 2 n-BuLi 2. ArBiX2
S
R1
S
R Br
R1
Bi
R1
S
S
R
R 137
136
Several naphtho[1,2-b:5,6-b0 ]dithiophene 140 were prepared from a key intermediate, 1,5-dichloro-2,6-bis-(trifluoromethanesulfonyloxy)naphthalene 139, prepared from 2,6-dihydroxyphenol 138 in three steps, which were subjected to usual Sonogashira coupling and subsequent electrophilic ring closure reactions h10JOC1228i. R
OH
1. SO2CI2 2. Tf2O
OTf NaBH4/Se
Pd(PPh3)2CI2 TfO
HO
X
NaS or
R
R
141
142 R
X 143 X = S, Se
R
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
143
Novel liquid crystalline benzothieno[3,2-b]benzothiophene (BTBT)-based soluble semiconducting molecules were synthesized via a Horner–Emmons coupling reaction using 5-alkylthiophene-2-carbaldehyde and BTBT-diethylphosphonate h10OE1584i. Their improved solution processability and high-field effect makes them promising candidates for future flexible electronic devices. The syntheses of several fluorenyl benzo[c]thiophene analogs were carried out. A typical example is given below. Photophysical and electrochemical studies indicate these analogs to suitable candidates for application as hole-transporting materials in double-layer OLEDs h10T5660i
S
S S
S
1. FeCI3/DCM 2. NH2NH2
R2 R1
Ar
S
R2
R2
R1
R1 141
142
An iterative extension of thiophene ring leading to head-to-tail-type oligothiophenes via a stepwise CH arylation and halogen exchange sequence (via 143 þ 144 leading to 145) was reported and is shown below h10H(82)505i.
S
+ S 143
I
n-hexyl
n-hexyl
n-hexyl
S
n-hexyl
Br 144
S 145
head to tail oligiothiophene copolymer
l
A tailored hybrid BODIPY-oligothiophene donor for molecular bulk heterojunction solar cells with improved performances was synthesized. Preliminary results on solar cells reveal a large increase of current density and a conversion factor which rank among the highest reported for molecular BHJ. Copolymers of biphenyl and thiophene were prepared by potentiostatic electropolymerization of biphenyl and thiophene h10JAPS1494i. These copolymers are candidates for electronic applications. In addition, a facile and rapid synthesis of unsubstituted polythiophenes were carried out and were found to high electrical conductivity using binary organic solvents h10POP4069i. Thiophene-containing naphthalene diimide n-type copolymers were prepared and characterized. Polymer crystallinity and general macromolecular order were shown to improve by increasing the number of thiophene units in the backbone h10MM6348i. The synthesis of a series of nucleobase functionalized thiophene monomers has been accomplished by the synthesis of 2-bromo-1-thiophene-3-yl-ethanone 147, prepared from 2-bromo-1-thiophen-3-yl-ethanone 146 with the corresponding DNA base anion. The use of thiophenes substituted with an acetyl bromide functionality shows promise for nucleobase functionalization of several thiophene
144
E.R. Biehl
monomers 148 which can be chemically/electrochemically oxidized to form corresponding polymers 149 which may serve as DNA biosensors h10TL5483i. O
O
DNA
CUBr2/THF
S 146
O
Br
S 147
DNA
DNA
O
[ox] S 148
S 149
n
A new linear 6-thiophene-fused system of hexathienoacene was prepared and its OTFT was evaluated h10CAJ1550i. A series of 5,10-porphodimethene-type thiophene-containing calixphyrins were prepared and were found to complex well with Znþ 2. The resulting complex was found to induce fluorescence indicating they may be promising turn-on fluorescent probes for Znþ 2 testing h10PS1098i. Fully conjugated p-expanded macrocyclic oligothiophenes with 24p to 180p electron systems were reported h10PAC831i. Space limitations prevent the graphical presentation of these oligothiophenes. Suffice to say that these systems were prepared using a modified McMurray coupling reaction in the key step. Interestingly, the 24p, 60p, and 72p systems were shown by X-ray analysis to be planar with fairly large cavities. Moreover, the 90p, 108p, and 120p systems self-aggregate to form red nanofibers whereas the 150p and 180p systems formed red nanoparticles. Finally, thiophenes have been incorporated into efficient organic dyes for possible use in solar cells h10OL4164, 10OL16, 10OL5454i. Soluble poly(arylene)thiophenes containing amide bridge bonds and free nitrile groups have been prepared through polycondensation of arylene-bis-(2-aminothiophene-3-carbonitrile)s with arylene-dicarboxylic acid dichlorides. Stille cross-coupling procedures provided ready access to a variety of C3-symmetric oligoarylobenzenes containing thienyl and/or furyl groups h10TL2396i.
5.1.6. THIOPHENE DERIVATIVES IN MEDICINAL CHEMISTRY Interest in thiophenes in medicine continues unabated this year especially in the synthesis and biological studies of several new thiophene-based drugs. An exciting synthesis of isotopically labeled of two similar SGLT inhibitors AVE2268 and AVE8887 synthesized by different routes h10T1472i. The radioactive labeled [14C]-AVE2268 was prepared in five steps including a Friedel–Crafts acylation as the key step for the 14C-label insertion. This route was not successful with [14C]-AVE8887, however, an alternative metallation/Weinreb amide synthesis was developed. A scalable, chromatography-free, seven-step, multikilogram synthesis of a prostaglandin EP4 receptor antagonist was developed h10JOC4078i. A wide variety of novel Staphylococcus aureus Sortase inhibitors were prepared by several synthetic methods. The synthesis method for the preparation of one of the inhibitors 151 from 3-(thiophen-2-yl)properly acid 150 is given here as a typical example h10EJM3752i
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
145
O S COOH 150
1. EDAC, DMAP
N
S
COOH
ClCH2CH2Cl 2. NaOH N H
O 151
The solution behavior and the spectroscopic properties of novel Schiff bases derived from norephedrine (1S,2R)-R1(CH¼NCH-(Me)CH(OH)Ph with R1 ¼ferrocenyl-(Fc) 5- or 3-methylthieny, respectively, were published. The synthesis involved condensing the 5-methyl or 3-methylthiophenecarbaldehyde with norephedrine. NMR studies showed the existence of tautomeric equilibrium between these imine forms and 2-substituted-4-methyl-5-phenyloxazolidines h10JOC3294i. Thiophenes have been incorporated into various nitrogen-containing heterocycles to improve medicinal properties of biologically active compounds. Due to space limitation, these conjugates will be listed without further comment: novel thiophene derivatives such as ethyl cycloheptathiophene-3-carboxylates, (5-HT2A receptor antagonists) h10EJM1805i; use of thiophenecarbaldehydes in a seven-step synthesis of methyl-substituted 3-(2-pyridyl)-2-(2-thienyl)thiazolidin-4-ones (antibacterial, anticancer, antileukemic, anti-HIV activities) h10JCR296i; novel benzothiophenes (H1-antihistamines in treatment of insomnia) h10BMCL2316i; 1-aminoindeno[1,2-c] thiophenes and a series of [(2-aminoindeno[2,1-b]thiophene-3-yl)(phenyl)-methanones (orthosteric antagonist) h10JMC6550i; fused thiophene and thienopyrimidine derivatives (H5N1activity) h10EJM5251i; thiophene-fused thieno[2,3-d]pyrimidin-4) 3H)-ones h10EJM1805i; Meldrum’s acid route to prodigiosin analogs h10S1707i; 5glycosido-thieno[2,3-d]-pyrimidines (anti-inflammatory/analgesic) h10EJM1485i; 2,5-dichloro thienyl substituted thiazoles (antimicrobial properties h10EJM3490i; thiazole and pyrazole derivatives (antimicrobial activity) h10EJM1338i; microwave-assisted regioselective synthesis of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines (antitubercular activity) h10EJM682i; novel benzothiophene H1-antihistamines (treatment of insomnia) h10BMCL2316i; 2-thiophenecarboxamides possessing heteroaryl-linked 5-(1H-benzimidazol-1-yl) groups potent inhibition of polo-like kinase 1 (PLK1) h10BMCL4587i; benzothiophene containing Rho kinase inhibitors (efficacy in animal model of glaucoma) h10BMCL3361i. Three routes were used to prepare several substituted benzothiophenes. Due to space considerations, the two routes that involve a sulfur-assisted reaction are given here h10JMC1819i. Route 1 involved the reaction of a multisubstituted benzaldehyde 152 with ethyl thiogylcolate to give the ethyl benzo[b]thiophene-2-carboxylates 153, Route 2 consisted of treatment of a 2-nitrobenzaldehyde with ethyl sulfide to give the 2-ethyl sulfide thiophenecarbaldehyde that was treated with ClCH2COCH3 to give the 2-acetylthiophene.
146
R4
E.R. Biehl
R3
R3
O
R4
CHO a
R5
OEt
R1 R6 152
R5
CHO
O
O
R6
O b, c
O
NO2
S 155
154
153
O
b. HSCH2CH3 K2CO3, DMF; c. ClCH2COCH3
a. HSCH2COOC2H5, K2CO3, DMF
Novel thienopyridine derivatives were also synthesized by the cyclization of 6aryl-2-thioxo-1,2-dihydropyridine-3-carbonitrile prepared by a two-step reaction from appropriate acetophenone h10BMCL6282i. New substituted thiophene-3-carboxamides and many substituted 4-methyl-5phenylthiophene-carboxylic acids were prepared. Of these, ethyl 2-amino-4methyl-5-phenylthiophene-3-carboxylate, 159 whose synthesis is shown below, was found to have the highest activity with an IC50 ¼ 0.75 mM at the GluR6 receptor h10EJM69i. O
O
O
Me
Ph
Me
Et
+
O
OEt S, NH(Et2) Ph
Ph
N 156
O Me
158
157
NH2
S
N
159
The use of substituted thiophenes as starting materials for potentially biologically active compounds was shown in a recent study where novel S. aureus Sortase inhibitors were prepared. Examples are shown below h10EJM3752i. There is much compelling evidence that PTP1B is associated with many human diseases (e.g., type II diabetes, obesity, breast cancer, etc.). Consequently, much attention has been given to develop PTP1B inhibitors. To this end, an excellent paper appeared this year in which novel thiophene derivatives were synthesized and their selectivity and cellular activity were evaluated. Several thiophene derivatives were synthesized by Gewald type reactions h10BMC1773i. Many of the synthesized thiophenes were found to exhibit moderate inhibitory activities with IC50 values less than 10 mM. The synthesis of 163, which demonstrated remarkable high selectivity against other PTPs, involved treating ketone 160 with elemental sulfur, cyano ester 161, and morpholine to give intermediate 162 that was converted to 164 by treatment with anhydrides 163. O O Me
S, CNCH2COOR 161 morpholine MW
Me
O
O O O RCOCR 163
H 2N S
R
O
HN R
S 162
164
160 R = Cl
O
R1
R1 = COOH
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
147
This year, bioactive thiophenes were isolated from natural products. For example, 2-(penta-1,3-diynyl)-5-(3,4-dihydroxybut-1-ynyl)thiophene was isolated from Echinops grijsii Hance and was found to have potent NAD(P)H quinone oxidoreductase1 inducing activity and could activate Keap1-Nrf2 pathway effectively in murine hepatoma 1c1c7 cells h10MO5273i. Characterization of bioactive thiophenes from a dichloromethane extract of E. grijsii Hance showed then to be powerful Michael addition acceptors, which regulate many signal pathways in cells h10ABA1975i. The distribution and accumulation of thiophenes in plants and Calli of different Tagetes species were evaluated this year h10JEB322i. 3-Chloro-5,6-dihydroxy-7-nitro-2,3-dihydrobenzo[b]thiophene-2-carboxylic acid is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor bioavailability, most likely due to low lipophilicity throughout most of the gastrointestinal tract. These lipophilic esters were prepared in an attempt to optimize presystemic drug absorption. Esterification of the acid and/or hydroxy groups of thiophene moiety was easily carried out. However, only modest success was obtained concerning bioavailability problems. h10BMCL2614i. 4,7-Dichlorobenzothien-2-ylsulfonylaminomethyl boronic acid (DSABA) was discovered to be the first boronic acid based beta-lactamase inhibitor with Class A, C, and D activity h10BMCL2622i. Conformational modeling was successfully applied to the design of bioisosteres used to replace conformationally rigid amide bonds in some thiophene carboxylate inhibitors of HCV NSSB polymerase inhibitors. Numerous groups and numerous modeling experiments carried out replaced the biosteric amide bond. The data suggest that the new series interacts at the ThumbII domain of NSSB. Inhibition binding at the ThumbII site was confirmed by solving a crystal structure of 4-methylcyclohexyl group attached to the 3-position of thiophene-2 carboxylate complexed with NSSB h10BMCL4614i. Previous research on histamine H3 antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. This year, the central core was replaced by 3,5-disubstituted benzothiophenes and various substituted indoles. Biological studies revealed that these substituted heterocycles were satisfactory replacements showing good to excellent hH3 activities h10BMCL6226i.
5.1.7. SELENOPHENES AND TELLUROPHENES Although not as actively studied as thiophenes, the uses of selenophenes continued to increase in intensity, especially in the material science area, which will be addressed shortly. A few syntheses involving electrophilic cyclization were reported and are shown below. 2,3-Dihydroselenophene and selenophene derivatives were prepared by electrophilic cyclization/oxidation of homopropargyl selenides h10OL1952i.
148
E.R. Biehl
Se
1.E+
R SeBu
R
2. DDQ
165
166
E
A series of 3-alkynyldihydroselenophene 168 were prepared by palladium-catalyzed Sonogashira cross-coupling of 3-iododihydroselenophenes 167 and were subsequently underwent either selective intramolecular cyclization when treated with iodine to 3-iodoselenopheno[2,3-b]selenophene 169 or were oxidized with DDQ to give aromatic selenophenes h10EJO5601i (see Section 5.1.3.2 for discussion of preparation of selenopheno[2,3-b]thiophenes). R 1. DDQ 2. I2
I PdCl2(PPh3)2 Se
I Se
R
+ SeMe
Cul Se
167
Se
SeMe 168
R = alkyl, aryl, alcohol, ether
R
169
o-Ethynylbenzyl phenyl selenides 170 regioselectively reacted with trifluoromethanesulfonic acid to afforthe (Z)-1-methylidene-2-phenyl-1,3-dihydro-1Hbenzo[c]selenophenium salts 171 as the major products during the 5-exo-dig mode cyclization together with minor amounts of E isomers. The structure of the major (Z)-selenophenium salt was established by the single crystal X-ray crystallographic analysis using a tert-butyl derivative h10TL5395i. R2
TfOH or BF4H
+ Se-R1
Se R1 170
171
The reaction of selenium dibromide with divinyl sulfone 172 gave novel fivemembered selenium heterocycles 173 which could be converted to 174 by treatment with pyridine or silica gel h10TL5258i. O
O Br SeBr2
S
S
+
O
O 172
Se 173
Br
pyridine or silica gel
O
O Br
S Se 174
An efficient procedure for the preparation of 3-bromo-2-phenylbenzo[b]selenophene from selenium dibromide and diphenylacetylene was presented h10RJOC1421i. A copper-catalyzed synthetic method for Ebselen and related SN heterocycles 176 from the reaction of 2-haloamide 175 with Se and CuI was reported h10OL5394i. This is the first report of a catalytic process of selenation and SeN bond formation.
149
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
O R
O
R Cul
NHR X 175
N Se
Se powder
R
176
X = Cl. Br, l
Novel 2,5-diarylselenophenes 180 were prepared either by the selenation of 1,4-diarylbutane-1,4-diones 177 with Woollins reagent 178 to give dithioketone 179 which underwent cyclization to 180 or simply by heating 177 in toluene in the presence of Woollins reagent. Some of these compounds demonstrated significant redox, fluorescence, and thin conducting film properties, indicating that the 2,5-diarylthiophene may be of interest for material applications h10OBC1655i. S R 8
7 ,1
R
R
+
Se
Se p
R Ph
177
–C
S
W
O
Cy cliz
R
179
Se 178
O
Ph
toluene
p Se
S 2
ati
on
R
R
Se
heat 180
WR (Woollins Reagent)
Cyclopenta[c]selenophenes 182 were prepared by the reaction of 1,7-bis(trimethylsilyl)-4,4-bis(methoxymethyl)-1,6-heptadiyne 181 with bis(cyclopenta-dienyl)-zirconium-1,4 dichloride and n-butyllithium followed by treatment with in situ prepared selenium dichloride and then electrochemically polymerized a new polyselenophenes 183 h10CC1168i. O
O
2.SeCl2
O
O
O
O
1.Cp2ZrCl2/n-BuLi
ECP
3.Hcl work up
n
Se
n
Se
SiMe3
SiMe3
183
182
181
Poly(3-hexylselenophene-block-3-hexylthiophenes 184 have been prepared by selenophene–thiophene copolymerization (182 and 183). These are important new classes of copolymer, in that they have broad optical absorption properties and the ability to undergo phase separation in the solid state h10JA8546i. R R R Br
Se
1) n-BuMgCl 2) Ni(dppp)Cl2 Br R = C6H13
ClMg
R Br
Se 184
n
S 185 Ni(dppp)Br
Br Br
B
Se n 186
S m R
150
E.R. Biehl
New paramagnetic selenophenes were synthesized this year h10S1702i. The chain alignment and OTFT characteristics of polythiophene. The resulting polymer (PTZT2T) was found to be 18 times more mobile and its on/off ratio was 52 times higher than that of the unmodified polythiophene (PQT2T) h10SM2273i. The addition of alkynes to zwitterionic m-vinyliminium diiron complexes gave new selenophenes, thiophenes, and vinyl chalcogenides functionalized bridging ligands h10OM1797i. Three different types of products can be formed; however, the possibilities can be controlled by suitable reaction conditions, and interestingly, each transformation is selective and, in most cases, a single product is formed. Selenophenes have been incorporated into many heterocyclic system intermediates in medicinal chemistry research and appear to greatly enhance the biological activity of the conjugate. Owing to page limitations, only a few can be mentioned here: 1-benzyl-3-(5-hydroxymethyl-2-furyl)seleno[3,2-c]pyrazole derivatives (excellent anticancer activity) h10EJM1395i; (Z)-3-(selenophen-2-yl-methylene)indolin2-ones h10BMCL5065i (potent against CHK1 inhibitors); and selenium-containing sulfa drugs (antibacterial activity) h10RJBCi. Tellurophenes were much less studied than selenophenes, however, there were some notable examples. For example, novel 21,23-ditelluraporphyrins and the first 26,28-ditellurasapphyrin and 30,33-ditellurarubyrin were prepared h10OM3431i. The reaction involved first preparing 2,5-di(1-hydroxy-1-arylmethyl)tellurophenes 188 by the addition of the corresponding diynediols 187 to Li2Te prepared by the reduction of Te powder with 2 equiv. of LiBHEt3. Ar HO
pyridine
Ar
Ar
CuCl
Te/LiEt3BH
Ar
Ar Te
HO
HO
OH 187
OH
188
The dihydroxytellurophenes 188 were then treated with pyrrole and BF3-etherate followed by oxidation with p-chloranil (not shown here) to give the desired compounds. The preparation of benzo[b]tellurophene, 3-benzotellurophenes, and 1-H-isotellurochromene 190 involving a tin-tellurium exchange with 189 was published h10H (82)441i. H
H TeCl4
Sn 189
R
Sn–Te exchange
Te
R
190
A neat synthesis of 1,10 -di(benzo[c]tellurophenylidene) and 6,12-dihydro-5,11ditellurachrysene was reported by first preparing 1,6-bis[2-(bromomethyl)phenyl] hexa-1,5-diyne from the corresponding o-benzylalcohol. Treatment of the diyne with NHTe in DMF and heating overnight resulted in a 5-exo, 5-exo double closure to the trans product and a 6-endo–endo chrysene product h10T5149i.
Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
151
REFERENCES 10AG(I)7304 10ABA1975 10AX(E)(o)271 B-10MI1001 10BMC1773 10BMCL2316
10BMCL2614 10BMCL2622 10BMCL3361
10BMCL4587 10BMCL4614 10BMCL5065 10BMCL6226
10BMCL6282 10CAJ1550 10CAJ1657 10CC1168 10CC1284 10CC5009 10CC7430 10CCR1479 10CRV1564 10CRV3337 10CRV3419 10CSR2420 10CT270 10DT5777 10EF3443 10EJM69 10EJM682 10EJM1338
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Five-Membered Ring Systems: Thiophenes and Se/Te Derivatives
10JOC2706 10JOC3294 10JOC4078 10JOC4623 10JOC4835 10JOC4868 10JOC6096 10JOC6998 10JOC7037 10JOC7202 10JOC7433 10JOC7475 10JOM2532 10JSC205 10MA1533 10MM6348 10MO5273 10OBC90 10OBC1655 10OE1584 10OL16 10OL356 10OL1952 10OL2136 10OL2434 10OL3930 10OL3978 10OL4164 10OL4277 10OL4320 10OL4428 10OL4952 10OL5394 10OL5454 10OL5783 10OM1797 10OM3239 10OM3431 10OM4923 10PAC831 10POP4069
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CHAPTER
5.2
Five-Membered Ring Systems: Pyrroles and Benzo Analogs Jonathon S. Russel*, Erin T. Pelkey**, Jessica G. Greger** *St. Norbert College, De Pere, WI 54115, USA
[email protected] **Hobart and William Smith Colleges, Geneva, NY 14456, USA
[email protected]
5.2.1. INTRODUCTION The synthesis and chemistry of pyrroles, indoles, and other fused ring systems reported during 2010 are reviewed in this monograph. Indoles and pyrroles continue to draw a lot of attention from the scientific community due to their prevalence in natural products and their wide range of biological and materials science applications. Indoles (by J. S. R.) and pyrroles (by E. T. P. and J. G. G.) are treated in separate sections. Coverage of indole and pyrrole natural product total synthesis is directly incorporated into advances in ring synthesis or ring substitution. Review articles and monographs from 2010 will be mentioned in the relevant sections.
5.2.2. SYNTHESIS OF PYRROLES As has been past practice for the past several years, de novo pyrrole syntheses have been organized systematically into intramolecular and intermolecular approaches as well as by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below). Multicomponent reactions leading to pyrroles and pyrrole syntheses accomplished by transformation of other heterocycles appear at the end of this section. Thompson and coworkers wrote two reviews focused on the synthesis of chiral pyrroles h10CC1797i and the synthesis of pyrrole natural products h10NPR1801i. type a N R
5.2.2.1 intramolecular
c d
b e
N R
a
type ad 5.2.2.2 intermolecular
N R
5.2.2.1 Intramolecular Approaches to Pyrroles 5.2.2.1.1 Intramolecular Type a Increasingly ubiquitous are type “a” approaches to pyrroles that involve base or metal-mediated 5-endo cyclizations of unsaturated amine systems. The synthetic power of these approaches has been further demonstrated in the synthesis of a variety Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00006-1
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2011 Elsevier Ltd. All rights reserved.
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of complex, fused pyrroles including pyrrolocoumarin 1 h10S4207i, thieno[2,3-b] pyrrole 2 h10T1800i, pyrrolo[3,2-d]pyrimidine 3 h10T1800i, and pyrrolo[2,3-d]thiazole 4 h10S3152i. The So¨derberg group prepared several fused pyrroles (including 2 and 3) by reductive 5-endo cyclizations of the corresponding o-nitroalkynylheteroaromatics.
N O
S
Ph
N H
O
S
N N H
Ph
N H
MeO method B
method A
1
Ph
N
N H
method C
2
F method D
4
3
method A = PdCl2, FeCl3 method B = Pd(OAc2)–PPh3 (from nitrothiophene derivative) method C = Pd(dba)2–1,10-phenanthroline (from nitropyrimidine derivative) method D = t-BuOK, N-methylpyrrolidinone
Gevorgyan and coworkers reported a tandem type “a” cyclization/arylation sequence in the synthesis of N-fused pyrrole derivatives h10OL3242i. For example, treatment of pyridine 5 with aryl iodide 6 and a palladium catalyst led to the formation of N-fused pyrrole 7 in 88% yield. CO2Me
OPiv
CO2Me +
n-Bu
N
5
PdCl2(PPh3)2 PPh3, TBAI, K2CO3, DMF 88%
I
PivO Na
n-Bu
7
6
Malacria and coworkers have investigated an interesting gold-catalyzed cycloisomerization approach to N-aminopyrroles from allenyl-substituted hydrazones h10OL4396i. Microwave irradiation of allene 8 in the presence of a gold catalyst gave highly substituted pyrrole 9 in 71% yield. The overall transformation includes a selective 1,2-alkyl migration. Saito and colleagues explored a related gold-catalyzed type “a” cyclization to pyrroles h10OL372i. Treatment of N-propargyl enaminones with a carbene–gold complex led to an allene intermediate (via Claisen rearrangement) which then cyclized to give highly functionalized pyrroles. Ph PPh3AuNTf2, DCE, μW 71%
N NHTs
8
Na NHTs
9
Ph
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
157
5.2.2.1.2 Intramolecular Type c Type “c” cyclization reactions of enaminones are an attractive de novo approach to differentially substituted pyrroles. Gauvreau and colleagues prepared nonsymmetrical pyrrole-2,5-dicarboxylates (e.g., 11) from enaminones (e.g., 10); the latter were accessible via rhodium-catalyzed insertion reactions of enamines with diazoketones h10SL3086i. In the event, treatment of enaminone 10 with zinc led to a cyclization–reduction–deprotection sequence that produced 11 in 60% yield. Ph Ph
O
c
SPh Zn, i-PrOH, H2O
EtO2C
N
EtO2C
60%
CO2Me
CO2Me
N H
Troc
10
11
The Snyder group investigated a biomimetic approach to the myrmicarin family pyrrole-fused alkaloids including higher-order members (dimers, trimers) h10AG(I) 9693i. They prepared enantiomerically pure dienaminone 12 which readily underwent a “type c” cyclization to give myrmicarin 215B (13) upon dissolution in argon-purged methanol. Lhommet and coworkers investigated a related approach to this class of natural products h10H(81)2523i from enantiomerically pure diketone 14. Treatment of 14 with lithium hydroxide produced tricyclic pyrrole 15 via an intramolecular aldol condensation. This constituted a formal total synthesis of 13. O O
O O
c
c
MeOH, rt N
12
LiOH N
N
N
13
15
14
myrmicarin 215B
5.2.2.2 Intermolecular Approaches to Pyrroles 5.2.2.2.1 Intermolecular Type ab Type “ab” cyclizations reminiscent of the Thorpe–Ziegler reaction have been utilized by the groups of Takayama h10BMCL108i and Awadallah h10EJMC482i in the preparation of potentially biologically active aminocyanopyrroles. For example, treatment of malononitrile derivative 16 with a-chloroacetanilide 17 in the presence of K2CO3 produced fused pyrrole 18 h10EJMC482i. NC + NH
16
NH2
NC
CN
H N
Cl O
17
K2CO3, acetone 55%
H N
b
Na
NO2
O
18
NO2
158
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5.2.2.2.2 Intermolecular Type ac Several variants of the Trofimov reaction, the type “ac” cyclocondensation of oximes and alkynes under basic conditions, have been reported during the past year. Trofimov and coworkers reported a three-component reaction between 2-tetralone, hydroxylamine, and acetylene, which produced 4,5-dihydrobenz[e]indole h10TL1690i. Camp h10JOC6271i and Trofimov h10TL6189i investigated the use of alkynes containing electron-withdrawing groups. For example, treatment of ethyl propiolate (19) with benzaldoxime (20) and a nucleophilic catalyst (DABCO) under microwave irradiation produced pyrrole ester 21 h10JOC6271i. Anderson and colleagues reported a similar synthesis of pyrroles via a [3,3]-sigmatropic rearrangement of O-vinyl oximes h10OL2290i. EtO2C CO2Et
H
+
HO
c
DABCO, toluene, mW
19
a
58%
N
20
N H
21
Part and coworkers prepared N-alkoxypyrroles (e.g., 24) via a [3 þ 2] cycloaddition between a-diazo oxime ethers (e.g., 22) and enamines (e.g., 23) h10AG(I) 7963i. MeO2C
N2 N
CO2Et OMe
+
Me
O
N Me
22
1. Cu(hfacac)2, CH2Cl2 2. 1N HCl, THF
Me
MeO2C
c
CO2Et
N a Me OMe
75% O
23
24
The Glorius group reported an interesting rhodium-catalyzed cyclization approach to pyrroles from enamines and unactivated alkynes h10JA9585i. Treatment of diphenylacetylene (25) with enamide 26 in the presence of a rhodium–silver catalyst system produced pyrrole 27 in 72% yield. The proposed mechanism of the reaction involves a C H activation of the enamine component. Ph
CN +
Ph
25
AcHN
Me
[Cp*RhCl2]2, AgSbF6 Cu(OAc)2, DCE, Δ 72%
Ph Ph
c aN
CN Me
Ac
26
27
The Narsaiah group investigated a variety of catalysts (e.g., silver(I) oxide) for the preparation of 4-hydroxypyrroles via type “ac” cyclocondensation reactions between alkynes and amino acids h10SC3152i. The Donohue group used a cross-metathesis reaction to produce aminoenones (e.g., 29) which readily cyclized into pyrroles under acidic conditions h10OL4094i. They investigated both a stepwise process and one-pot process. The one-pot sequence represents a type “ac” cyclization approach to pyrroles. In the
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
159
event, treatment of allylic amine 28 and methyl vinyl ketone with Grubbs–Hoveyda second-generation catalyst (G-H-II), followed by exposure to p-TsOH, produced pyrrole 30. O Ph
Ph
O
G-H-II, CH2Cl2
then p-TsOH
c
Ph
NHCBz
N a Me CBz
NHCBz
28
30
29
5.2.2.2.3 Intermolecular Type ad Deb and Seidel further investigated a type “ad” cyclocondensation reaction leading to fused pyrroles between 1,3-diketones and secondary amines h10TL2945i. After much experimentation, the optimal conditions for obtaining fused pyrrole 31 from 1,3-diphenylketone and pyrrolidine involved using 0.5 equiv. of p-TsOH (0.5 equiv.) and xylenes as the solvent. Ph Ph
Ph O
+
p-TsOH, xylenes, mW, 280 ⬚C
NH
d
Na
O
Ph
31
5.2.2.2.4 Intermolecular Type ae Type “ae” cyclocondensation name reactions involving primary amines and 1,4dicarbonyl compounds (Paal–Knorr) remains the most commonly utilized approach for de novo pyrrole synthesis. Recent applications of the Paal–Knorr pyrrole synthesis include the synthesis of b-trifluoromethylpyrroles h10AG(I)2340i, tetraarylpyrrole fluorophores h10JOC4004i, atorvastatin lactone h10T9738i, 1,30 -bipyrroles h10JCC541i, 1-acylaminopyrroles h10JHC707i, pyrrole-fused azepines h10OBC3316i. The Paal–Knorr reaction has also been investigated with a variety of different acid resin catalysts h10JHC446, 10JHC486, 10TL2109i. Yasmin and Ray reported an interesting pyrrole cyclocondensation (Paal–Knorr variant) for the preparation of fused pyrroles h10SL924i. They prepared doubly activated diene 33 from bromovinyl aldehyde 32 via a Heck reaction with methyl acrylate. Treatment of 33 with benzylamine then gave fused pyrrole 34 in 93% yield. CO2Me PdCl2, Bu4NBr Na2CO3, H2O Br
O H
32
93%
BnNH2, CH2Cl2 93%
O H
33
CO2Me
eNa
Bn
34
CO2Me
160
J.S. Russel et al.
A variety of metal-mediated type “ae” cyclization strategies involving primary amines and unsaturated 4-carbon substrates have been reported in the synthesis of 2,5-disubstituted pyrroles. After much experimentation, Zheng and Hua found that CuCl catalyzed the double hydroamination of 1,4-diphenylbutadiyne 35 with m-chloroaniline giving 2,5-diphenylpyrrole 36 in 95% yield. Skrydstrup and coworkers performed similar double hydroamination reactions with a Au(I) catalyst h10TL4512i. The Demir group used Au(I)/Zn(II) catalyst system to prepare 2-aminopyrroles via the hydroamination/cyclization of 4-yne nitriles h10CC8032i. Xi and colleagues investigated double cross-coupling reactions between 1,4-diiodo-1,3dienes and anilines in the synthesis of substituted pyrroles h10EJOC5426i. NH2 Ph
Ph
CuCl, 100 ⬚C
+
Ph
eNa
Ph
96% Cl Cl
35
36
5.2.2.2.5 Intermolecular Type bc Kawase and coworkers reported a novel approach to trifluoromethyl-substituted pyrroles using a Wittig-type transformation between 1,3-oxazolium-5-olates (Mu¨nchnones) and phosphorus ylides h10OL4776i. For example, generating “PPh3¼¼CH2” in the presence of mesoionic 1,3-oxazolium-5-olate 37 followed by treatment with AcOH led to the formation of b-trifluoromethylpyrrole 38 in 90% yield. O O Ph
N Me
CF3 O
37
1. Ph3PCH3Br n-BuLi, THF 2. AcOH 90%
b
CF3
c
Ph
N Me 38
Konakahara and coworkers reported a novel “type bc” approach to 3-aminopyrroles using a Yb-catalyzed annulation reaction between trimethylsilylcyanide and 2-azadienes h10EJOC4237i.
5.2.2.2.6 Intermolecular Type bd Pyrrole name reactions that fall into the category of type “bd” cyclizations leading to pyrroles include Hinsberg (iminodiacetates), Barton–Zard (activated isocyanides þ nitroalkenes), Montforts (activated isocyanides þ vinyl sulfones), van Leusen (TosMic þ electron-deficient alkenes) and Huisgen (1,3-dipoles þ alkynes). The van Leusen pyrrole synthesis has been employed to prepare pyrrole building blocks in studies aimed at developing intramolecular CH activation reactions h10OBC4374i and synthetic bacteriochlorins h10JOC1016i. The Carretero group explored the 1,3dipolar cycloaddition between the azomethine ylides derived from a-imine esters and
161
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
bis-sulfonyl dipolarophiles h10CEJ9864i. Elimination of the two sulfone groups gave 3,4-unsubstituted pyrroles. Melo and colleagues studied the reactivity of aziridines with allenes in the synthesis of pyrroles via a dipolar cycloaddition h10T8815i.
5.2.2.2.7 Intermolecular Type abd In a variation of the Huisgen reaction, Arndsten and coworkers reported the generation and reactions of 1,3-phospha-mu¨nchnones (or their synthetic equivalents) with electron-deficient alkynes in the synthesis of substituted pyrroles h10JOC4261, 10OL4916i. For example, treatment of imine 39 with acid chloride 40, DBU, and a phosphite (Arbuzov reaction) generated a 1,3-dipole intermediate (possibly 41), which underwent a cycloaddition with methyl propiolate to give pyrrole 42 in 88% yield. DBU, CHCl3 H
NBn Cl
O
O
CO2Me
P Ph R3P O
O
CO2Me
+ p-Tol Me
OMe
39
40
b
d
p-Tol
Bn
Na Bn
41
42
PMP
N
88% yield
PMP
5.2.2.2.8 Intermolecular Type ace A relatively large number of three-component type “ace” cyclization approaches to pyrroles were reported during the previous year. Jia and coworkers reported a silvermediated homodimerization of enamines derived from aldehydes and primary amines approach to 3,4-diarylpyrroles h10OL4066i. For example, treatment of 2 equiv. of aldehyde 43 and amine 44 with silver acetate led to 3,4-diarylpyrrole 45 in 59% yield. Synthesis of 45 represents a formal total synthesis of the biologically active marine natural product, purpurone (46). MeO OMe
OMe
OMe +
43
AgOAc NaOAc THF
HO
OH
HO
OH
OMe c e
Na
O
five steps
O N
59%
H O
OMe
MeO
HO NH2
OH HO
OH
44 OMe
45
OH
purpurone (46)
Additional three-component type “ace” approaches to pyrroles include the following sets of three components: alkynoates ( 2) þ primary amines h10OL312i or hydroxylamine h10SC3699i, 1,3-diketones þ propargyl alcohols þ tert-butyl carbamate h10JHC233i, propargyl acetate þ silyl enol ether þ aniline h10SL2345, 10OBC3064i, 1,2-diketone þ dimethyl acetylenedicarboxylate þ ammonium acetate h10SC3472i, and a-bromoketones þ primary amines þ dialkyl acetylenedicarboxylates h10S1625i.
J.S. Russel et al.
162
5.2.2.2.9 Other Multicomponent Reactions Menendez has written an extensive review article detailing the synthesis of pyrroles using multicomponent reactions h10CSR4402i. This highly recommended review article makes use of color to illustrate how the three and four components in each reaction come together in pyrrole formation. Jana and colleagues reported an interesting Fe(III)-catalyzed four-component approach to pyrroles h10JOC1674i. The four components that were brought together include primary amines, aldehydes, 1,3-diketones (and b-ketoesters), and nitroalkanes.
5.2.2.3 Transformations of Other Heterocycles to Pyrroles This section discusses the synthesis of pyrroles from other heterocycles. The Boger ring contraction of pyridazines to pyrroles remains one of the more reliable synthetic approaches to pyrroles. The Boger group applied their methodology to the total synthesis of lycogarubrin C (49) h10OL1132i. Treatment of pyridazine 47 with zinc and acetic acid led to the formation of 48 in 68%. The latter was converted into 49 in 89% yield by exposure to lithium hydroxide. Gribble and Fu investigated a similar approach to 49 via a ring contraction of a pyridazine h10TL537i. Dubreil and coworkers utilized a pyridazine ring contraction in the synthesis of donor–acceptor tripyridyl-dipyrroles h10CEJ11876i. CO2Me CO2Me N N
CO2Me CO2Me N N Zn, HOAc
MeO2C
N N 47
CO2Me
H N
H N LiOH
68%
89% MeO2C
N H
CO2Me
48
MeO2C
N H
CO2Me
lycogarubrin C (49)
A variety of other approaches to pyrroles from heterocycles have been reported. Melo and coworkers investigated the synthesis of 4-isoxazolines and their rearrangements to pyrroles h10T6078i. Ray and Barman reported the synthesis of bisformylated pyrroles via a Vilsmeier–Haack reaction of 5-oxopyrrolidine-2-carboxylic acids h10TL297i. In two separate reports, aziridines have been converted into pyrroles using gold catalysts h10EJOC1644, 10JOC510i.
5.2.3. REACTIONS OF PYRROLES 5.2.3.1 Substitutions at Pyrrole Nitrogen Substitutions at the pyrrole nitrogen are commonly used in the total synthesis of pyrrole natural products. Kanakis and Sarli investigated N-arylation of pyrroles 50 to marinopyrroles 52 using microwave irradiation. The copper catalyst afforded a clean transformation; however, the reaction was highly dependent on the solvent and base h10OL4872i.
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
163
O O
Br +
N H
O
N Ts
O
50
N
Cu(OAc)2, DBU DMF, 200 ⬚C
O
O
43%
O
N H
O
52
51
Reeves and coworkers used a tandem N-arylation/N-imination to synthesize fused pyrroles (e.g., 55). They combined 2-formylpyrrole (53) and 2-iodoaniline (54), which gave unsubstituted pyrrolo[1,2-a]quinoxaline 55 in 83% yield h10JOC992i.
I N H
H
+ NH2
O
53
10 mol% CuI 20 mol% sparteine K3PO4, NMP, 130 °C
N N
83%
54
55
Chen explored a similar tandem N-Michael/imination to form fused pyrroles, specifically pyrrolo[1,2-a]pyrazine, from vinyl azides in the presence of base h10OL3863i. In the enantiospecific total synthesis of pyrrole-imidazole natural product cyclooroidin, Mukherjee and colleagues described an intramolecular N-alkylation of pyrroles h10OL4940i. They employed an intramolecular nucleophilic substitution reaction to form the key N1C9 bond.
5.2.3.2 Substitutions at Pyrrole Carbon 5.2.3.2.1 Electrophilic Imaoka and colleagues produced a method for the synthesis of quaternary chiral aminals by employing an enamide-type Overman rearrangement. En route to developing a synthetic approach for the enantioselective preparation of (þ)-phakellstatins and (þ)-dibromophakellstatins, they were able to selectively introduce bromines at the C-4 and C-5 positions using 2 equiv. of NBS to give (þ)-dibromophakellstatin in 90% yield h10CAJ1810i. Tutino conducted a study on the acid catalyzed halogen dance (ACHD) reaction, also known as halogen scrambling. They found that, when a halogen at C-2 or C-3 of a pyrrole was treated with PPA/P2O5 at 105 C, the substrate cyclized and the bromine atom is shifted to C-3 or C-2, respectively h10JHC112i. Murat-Onana and coworkers developed a new way of accessing a wide variety of 2,20 -dipyrromethanes and tripyrromethanes. Their strategy involved the treatment of N-hydroxylamines with hydrogen chloride in the presence of substituted pyrroles. By monitoring reaction time and concentrations of starting materials, the ratio of dipyrromethane to tripyrromethane products could be controlled h10OBC2204i.
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Faugeras and colleagues suggested a synthesis of meso-substituted dipyrromethanes via a molecular iodine catalyst. Using nitrobenzaldehyde as the electrophile and molecular iodine as a Lewis-acid catalyst, a variety of aromatic dipyrromethanes were afforded in good yields h10TL4630i. Tsuchimoto investigated an indium-catalyzed reductive b-alkylation utilizing Nsubstituted pyrroles 56 and ketones. First, pyrrole 56 and cyclohexanol were subjected to an indium catalyst at 85 C to afford a dipyrrolylalkane intermediate. Once the ketone was completely consumed, cyanomethylsilane was added to give 57 h10CEJ8975i.
O 1. In(NTf2)3, 1,4-dioxane 2. Me3SiCN
+
CN
73%
N
N
Me
Me
56
57
In the total synthesis of tolmetin, Reddy and colleagues used a Lewis acid-free electrophilic substitution of N-methylpyrrole and oxalyl chloride followed by a Wolff–Kishner reduction in potassium hydroxide h10OPRD362i. Taylor used a similar approach in showing that 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) was an effective nucleophilic catalyst for the regioselective Friedel–Crafts C-acylation of pyrroles and indoles. They screened a variety of organocatalysts and found that DBN gave the highest yields in the shortest amount of time. Pyrrole 56 was treated with benzoyl chloride in DBN and toluene to give substituted pyrrole 58 in excellent yield h10OL5740i. O
15 mol% DBN, PhMe, Δ
+ N Me
56
Cl
Ph
95%
N Me
Ph O
58
Although Friedel–Crafts acylations have proven effective, they have drawbacks including multiple side reactions such as the formation of a reactive acid chloride which poses significant threats to the environment. Thus, Sharma and colleagues took the route of treating pyrroles with aldehydes to form functionalized pyrroles. They reported a novel one-pot Zr-mediated benzoylation of pyrroles in good yield h10TL2039i. Additions to nitroalkenes can also be facilitated by microwave irradiation. Kusurkar and Alkobati used a microwave technique to carry out the Michael addition of pyrroles to b-nitrovinyl compounds. These reactions selectively afforded monosubstituted pyrroles h10SC320i. De Rosa and Soriente focused on the combination of microwave irradiation and “superheated water” in solvent-free addition reactions. They found that under microwave irradiation, the catalyst-free conjugate addition of b-nitrostyrene to 1-methyl pyrrole in water at 150 C gave the desired Michael adduct h10T2981i.
165
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
Microwave-assisted methods are limited in that all require catalysts to achieve high product yields. Habib and colleagues employed a similar method of catalyst-free conjugate addition of pyrroles and indoles to nitroalkenes under solvent-free conditions h10T7050i. This was a more cost effective and environmentally friendly method to generate substituted pyrroles.
5.2.3.2.2 Electrophilic, Stereoselective Electrophilic substitution of pyrroles has shown to be stereoselective. Singh and Singh reported the enantioselective Friedel–Crafts alkylation of pyrroles catalyzed by PYBOX-DIPH-Zn(II) complexes. Pyrrole was treated with benzylidene-2-acetylpyridine N-oxide 59 and Lewis acid in chloroform giving substituted pyrrole 60. Optimized reaction conditions revealed Zn(OTf)2 to be the best Lewis acid, affording the highest yield and greatest enantioselectivity. Singh also extended the generality of the reaction to substituted pyrroles and various b-substituted 2-enoylpyridine N-oxides h10OL83i. O N
O + N H
PYBOX-DIPH-Zn(OTf)2 CHCl3, –60 °C, 9 h 95%
Ph
N H
59
Ph
N O
O
60
Highly enantioselective Friedel–Crafts alkylation of indoles and pyrroles has been shown by Wang and coworkers. By using chalcone derivatives and a chiral catalyst, N,N0 -dioxide-Sc(OTf)3, a wide range of asymmetric substrates have been prepared in excellent yields and high enantioselectivities h10CEJ1664i. Huang and colleagues also explored an enantioselective Friedel–Crafts reaction by treating pyrroles with b-trifluoromethylated acrylates and optically active trifluorinated heliotridane to afford chiral trifluoromethylated compounds h10OL1136i. Asymmetric Friedel–Crafts alkylation of pyrroles and indoles has been reviewed by Terrasson, de Figueiredo, and Campagne h10EJOC2635i.
5.2.3.2.3 Radical Villarreal and Martinez devised a synthesis of pyrroloazepinone 63 in which radical substitution played a key synthetic role. In this synthesis, a b-substituted pyrrole 61 underwent C-2 alkylation via xanthate-based oxidative radical substitution followed by a reduction of the introduced nitrile, protection of the resulting amine, ring closure, and deprotection to give the desired pyrroloazepinone 63 h10S3346i. O CO2Et
CO2Et [CNCH2SC(S)OEt], DLP
N Bn
61
44%
NH
CN
N Bn
62
N H
63
166
J.S. Russel et al.
5.2.3.2.4 Organometallic Suzuki–Miyaura cross-couplings of pyrrole boronic acids have been extensively studied and employed in the synthesis of many compounds. Some examples of compounds synthesized using this methodology include tambjamines (e.g., 64) h10BMCL5207i, marineosins (e.g., 65) h10OL1048i, lamellarins (e.g., 66) h10H (80)841i, prodigiosenes (e.g., 67) h10SL2561i, and dictyodendrins (e.g., 68) h10TL533i. MeO
MeO
OH
HN
N H
OMe
O
N H2N
HO
O
N
O
MeO
N H
H
N
H
tambjamine A
64
lamellarin A 66
marineosin A
65 O
O
MeO
OSO3Na
HO
MeO NH
N H
OMe N
O
OH
N
HN prodigiosene
67
OH
HO OH
dictyodendrin B
68
Beaumard and colleagues reported an unsymmetrical Suzuki–Miyaura cross-coupling of pyrroles with indolyl boronic acids. The resulting substrate was coupled with a variety of aryl- or heteroaryl boronic acids thus providing the corresponding nonsymmetrical 2,5-disubstituted pyrroles in good yields h10S4033i. Similarly, Arroyave and Reynolds report a decarboxylative cross-coupling reaction involving 3,4-dioxypyrrole. They optimized reaction conditions, finding acetylacetonate to be the best palladium ligand h10OL1328i. Studies have been conducted on halogen–metal exchange. Nakao and colleagues were interested in novel pyrrole derivatives with a tetrahydropyridine group at the b-position. These types of compounds showed promise as anti-inflammatory agents. To introduce the N- and a-substituted tetrahydropyridinyl group to the b-position of the pyrrole ring, a halogen–metal exchange was employed. A TIPS-protected pyrrole with bromine substituted at the C-4 position was treated with n-BuLi followed by piperidin-4-one derivatives to give 2,3-diaryl-4-piperidinylpyrroles h10BMCL2435i. Nakao continued this study of halogen–metal exchange in the synthesis of R-132811, a promising antirheumatic drug. In this synthesis, the same
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
167
halogen–metal exchange was utilized with bromine at the C-4 position of the pyrrole and lithium from n-BuLi. Subsequently, the resulting substrate was treated with bicyclic aminoketone derivatives to afford 2,3,4-trisubstituted pyrroles with a bicyclic THPy derivative at the C-4 position h10BMCL4774i. The directed lithiation of pyrroles has been a reliable method of producing 2substituted pyrroles. Fukuda and coworkers reported on the directed lithiation of N-benzenesulfonyl-3-bromopyrrole by using LDA in THF to generate a C-2 lithio species. This substrate could then be treated with reactive electrophiles to give corresponding 2-functionalized pyrroles. However, when the same substrate was subjected to less reactive electrophiles, substitution at the C-5 position was observed. This could be explained by the dynamic equilibrium between compounds where Li had added at the C-2 or the C-5 positions h10OL2734i.
5.2.3.2.5 CH Activation
CH activation has received a lot of attention by synthetic chemists in recent years as it serves as an alternative to classical cross-coupling reactions. Jafarpour and colleagues reported a phosphane-free palladium-catalyzed C-2 arylation of unactivated NH-pyrroles. By treating pyrroles with various substituted iodoarenes (e.g., 69) in the presence of Pd(OH)2/C and triethanolamine (TEA), 2-arylpyrroles 70 were obtained in good yield with high regioselectivity h10JOC3109i. I Me +
Pd(OH)2/C TEA, 100 ⬚C, 24 h 80%
N H
Me N H
NO2
NO2
69
70
In the total synthesis of rhazinal, an antitumor alkaloid, Le Floc’h and coworkers employed CH bond activation. They functionalized a pyrrole in a palladium (II) catalyzed reaction to form the biaryl system of rhazinal h10ARK(i)247i. Shibahara and colleagues explored bis-arylation reactions of heteroarenes. One reported example was the double CH arylation of N-methylpyrrole to 2,5-disubstituted pyrrole, a rarely observed reaction. By treating N-methylpyrrole with aryl iodides, cesium carbonate, and a palladium catalyst in DMA, the desired 2,5-disubstituted pyrrole was afforded in high yield h10CC2471i. Shibahara used a palladium catalyst that is often employed to promote direct CH bond arylation with a wide variety of heteroarenes. Gao and Yi investigated a ruthenium-catalyzed intermolecular coupling reaction of pyrroles and terminal alkynes. These types of coupling reactions and transition-metal-catalyzed CH bond activation methods have been explored; however, routes to cis- and gem-selective vinylation continue to be a problem, as the trans-selective vinyl product is often favored. Gao and Yi treated N-alkyl- and N-arylpyrroles with aryl-substituted terminal alkynes and a cationic ruthenium catalyst. Each case resulted in the synthesis of an a-gem-vinylpyrrole in significant yields h10JOC3144i.
168
J.S. Russel et al.
Schiffner and coworkers focused their attention on Fujiwara–Moritani annulations of N-substituted pyrroles. The ring closures involved an alkene tethered to the pyrrole nitrogen atom 71 and were performed using a palladium–nicotine catalyst. It was found that five-membered rings (e.g., 72) were formed in good yield and in enantiomeric excess, while six-membered rings gave no desired product. This may be due to different mechanisms, one through CH bond activation and the other through alkene activation h10EJOC174i. Pd(OAc)2, NicOx Ligand tert-amyl alcohol/AcOH, 80 ⬚C N
71
44%
Me
Me
N
72
O Ligand =
Me
MeO O
N N
iPr
Reyes-Gutierrez and colleagues reported an intramolecular radical-oxidative cyclization of polysubstituted pyrroles to afford isoquinolines using van Leusen’s polysubstituted pyrrole construction. The polysubstituted pyrrole, obtained in three steps, was treated with tributyltin hydride and toluene in DLP in a radical cyclization to give the desired 5,6-dihydropyrroloisoquinoline, a phosphodiesterase inhibitor, in 90% yield h10OBC4374i. A rhodium carbenoid approach for the 2-substitution of pyrroles was reported by Lian and Davies. Sterically hindered, highly substituted pyrroles were treated with 4-substituted (Z)-pent-2-enoates in the presence of a rhodium catalyst. It was found that the (Z)-vinylcarbenoids are more likely than (E)-vinylcarbenoids to react at the vinylogous position of the carbenoid rather than at the center. Thus, the regiospecific functionalization of pyrroles may easily be achieved h10OL924i.
5.2.3.2.6 Ring Annulation Samarium diiodide induced 5-exo-trig to 8-exo-trig reductive cyclizations of N-alkylated pyrrole derivatives were reported by Beemelmanns and colleagues. They found that ring annulation was successful by using SmI2 in the presence of a proton source to afford the cyclized product h10EJOC2716i. Marcus and Sarpong employed an oxidative CC bond-forming methodology to obtain a ring annulation product. By treating N-substituted pyrrole 73 with 2.5 equiv. of Dess–Martin periodinane in water and methylene chloride, the desired tetracycle 74 was formed. This tetracycle serves as the core to tetrapetalones, a class of alkaloids that have shown significant soybean lipoxygenase inhibitory activity h10OL4560i.
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
HO
O Dess–Martin periodinane H2O, CH2Cl2, 50 °C, 16 h
N
Me H Me
169
82–91%
N
Me H Me
OMe
OMe TBSO
TBSO
74
73
A synthesis of biologically active pyrroloazepinones was reported by Gruit and colleagues. Through an intramolecular cyclization, specifically a 7-endo-dig process, of alkyne-substituted 1H-pyrrole-2-carboxylic acid amides, the desired fused pyrroloazepinones were formed. Gruit and colleagues attempted the reaction with a variety of catalysts finding that platinum and gold catalysts gave the highest yields and the greatest activity. They also tried altering reaction conditions and found that the ratio of products was strongly dependant on solvent, temperature, and catalyst h10T3341i.
5.2.3.3 Functionalization of Pyrrole Side-Chain Substituents Polyfunctional pyrroles are a structural moiety contained in many naturally occurring compounds as well as synthetic pharmaceuticals and agrochemicals. However, pyrroles containing multiple functional groups are relatively difficult to prepare and thus selective reactions of pyrroles are desirable. McNulty and colleagues attempted a Wittig reaction of pyrrole-2-carboxaldehydes 53 and ylides to afford heterostilbenes 76 in good yields. In a one-pot synthesis, a microwave vial was charged with benzyl alcohol 75 and a phosphonium salt. After heating, the flask was charged with potassium carbonate, water, and pyrrole2-carboxaldehyde 53. The synthesis was accelerated by microwave irradiation at 75 C for 30 min to afford the desired heterostilbene 76 h10CEJ6756i.
H
N H
53
OH
+
1. Et3P–HBr, 100 ⬚C, 8 h 2. H2O2, NaOH 98%
O
75
N H
76
Marth and coworkers investigated the regioselective Wittig reaction to form polyfunctional pyrroles. By treating pyrrole-2,4-dicarboxaldehyde with different ylides in varying amounts, either one or both aldehydes are replaced on the pyrrole ring by functional groups. It was found that the 2-formyl group was more reactive than the 4-formyl group since when trace amounts (1.05 equiv.) of the ylide were added, only the monosubstituted product formed in high yields. Conversely, when 1.75 equiv. were added, 2,4-dialkenyl adducts resulted. These regioselective reactions are useful in the synthesis of a wide range of substituted pyrroles h10T6113i. The total synthesis of marinopyrrole A, a class of potential antibiotic and anticancer agents, was reported by Cheng and colleagues. One crucial step in this synthesis
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involved the functionalization of pyrroles. Pyrrole-2-carboxaldehydes were treated with Grignard reagents, specifically 2-methoxyphenylmagnesium bromide, in THF or toluene to give a substituted diol. This diol was then converted to marinopyrrole A in four steps h10JCC541i. In a similar fashion, Ivanov and colleagues reported treating 1-vinylpyrrole-2carboxaldehydes 77 with L-lysine 78 in a condensation reaction with trifluoroacetic acid in ethanol to afford imine-substituted pyrroles 79. These imine-substituted pyrroles are unnatural amino acids, which represent flexible building blocks for drug design. This methodology was found to be chemo-, regio-, and stereospecific, as all amino acids were formed exclusively as (E) isomers. These unnatural amino acids tend to be potential optical molecular switches due to E/Z isomerism under UV irradiation around the imine bond h10EJOC4554i. H +
N O
MeO
77
O
H3N H2N
O
78
CF3COOH EtOH
O O
N
89%
N NH3
MeO
79
Iwamoto and coworkers explored functionalization of pyrrole side-chains at the C-4 position of the pyrrole. They performed a regioselective oxidation of t-butyl 1H-pyrrole-2-carboxylates with DDQ in methanol and methylene chloride to afford 4-acylpyrroles. These reactions were attempted with various pyrrole substituents at C-2, C-3, and C-4. The synthesis is unique in that the starting pyrrole is more accessible than pyrroles containing aldehyde and/or nitro side-chains employed as starting materials in many other reported syntheses h10CL176i.
5.2.4. SYNTHESIS OF INDOLES The science of indole alkaloid chemistry continues to be driven by imaginative strategies for establishing discrete bonding arrangements. And while highly efficient protocols for indole ring synthesis and functionalization continue to be unveiled, this survey also highlights the untamed elements of experimental control and limitations of mechanistic understanding that help define the next generation of synthetic inquiry. As an opening example, a synthesis of ()-phalarine has been reported by Danishefsky and coworkers that involved, as an intermediate step, construction of the bridged pentacycle 83; the reaction proceeded through an intramolecular Pictet–Spengler cyclization of the iminium ion 80 to afford 83 as a single diastereomer h10JA8506i. Two mechanistic rationales have been proposed for the cyclization step involving electrophilic trapping at either indole C3 or C2 to generate the charged intermediate 81 or 82, respectively. The authors note that the uncertainty surrounding the regiochemistry of the initial cyclization step precludes a definitive assessment of the mode in which the native asymmetry of 80 has influenced the facial selectivity of the transformation to 83.
171
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
CO2Me N Bn CO2Me N Bn
81
80
N Ts HO
N Ts HO
OMe
N Bn
OR
OMe
CO2Me O Bn N
CO2Me
82
N Ts
OH
N Ts
OMe
83 (91%, one diastereomer) OMe
The following sections of this chapter will highlight recent activity in the general areas of indole ring construction and methodology for elaboration of the indole core. Following a listing of recent reviews, the remaining indole syntheses will be categorized utilizing a systematic approach. Intramolecular approaches and intermolecular approaches are classified by the number and location of the new bonds that describe the indole forming step (two examples shown below). In addition, oxindoles, carbazoles, carbolines, and azaindoles will be treated separately. Intramolecular Approaches c d
Intermolecular Approaches c
type a b
e N a H
d eNa H
c
type ac b
d
b eN a H
General reviews have been published on the broad topics of indole marine natural products h10CR4489i as well as the biology of indole alkaloids h10JHC491i. A targeted review on 3-alkenyl-oxindole natural products, pharmaceuticals, and synthesis has also appeared h10EJOC4527i. Review articles on synthetic methodology have included the asymmetric synthesis of oxindoles bearing a C3 quaternary center h10ASC1381i, the synthesis of indolines h10EJOC3975i, the synthesis of bis- and tris-indolylmethanes h10CR2250i, and organocatalytic methodology for asymmetric functionalization of indole h10CSR4449i. A topical review of indole ring synthesis via direct CH functionalization has also appeared with a focus on carbene chemistry, direct sp2 to sp2 coupling, and transition metal-catalyzed CH amination reactions h10ARK(i)390i.
5.2.4.1 Intramolecular Approaches 5.2.4.1.1 Intramolecular Type a Transition metal-catalyzed intramolecular 5-endo-dig type cyclization of o-alkynyl anilines remains a preeminent strategy for “type a” de novo indole ring synthesis. While palladium-catalyzed ring closures have received the most attention h10CC8770, 10OL3279, 10ASC3355, 10CEJ12746, 10T2378, 10OL3336i, gold-catalyzed indolizations have also been reported h10TL1493, 10AG(I)942, 10ASC971i. In a variation on this theme, Chan and coworkers have reported a gold-catalyzed 5-exo-dig cyclization of anilines bearing a propargyl alcohol at the ortho position h10AG(I)4619i. The Zhou group has implemented a metal-free cyclization of o-alkynyl anilines, for example, 84; a mechanism has been proposed involving cyclization of aniline
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nitrogen onto an intermediate allene 85 h10ASC2127i. The indole adduct, bearing a 2-(phenylsulfenylmethyl) subunit, was obtained in 84% yield. An interesting photochemical ring closure has been observed by Zhang and coworkers who prepared a series of complex heterocyclic scaffolds, for example, indolo [3,2-c]quinoline-6-one 87 h10CC3973i. In one experiment, photolysis of the azide 86 in the presence of Cu-catalyst set forth an intramolecular cyclization with subsequent ring expansion of the oxindole nucleus to afford 87 in 82% yield. O
O SPh
NH
DBU N nBu H
84
NH
SPh
N3
N nBu H
85
a (82%)
86
87
N H
a) CuI (100 mol%), hn.
Kulkarni and coworkers have prepared furo[2,3-b]indoles via ozonolysis of functionalized nitrobenzenes, for example, 90, followed by reductive cyclization to close the Ia bond h10TL4494i. The requisite ortho-substituted nitrobenzene 90 was prepared by a sequence of Wittig olefination of 88 followed by Claisen rearrangement of allyl vinyl ether 89. O
CHO
CHO a NO2
NO2
88
NO2
90
89
O
b (79%)
91
N H
a) O3, DCM, Me2S, 0 ⬚C, 20 min; b) Na2S, NaHCO3, MeOH, reflux 12 h.
An intriguing example of “type a” ring closure has been reported by Levesque and Fournier who generated a wide range of substituted indoles from 2-aminobenzaldehyde precursors. In one variation, the cyclization chemistry was set up by treatment of 2-aminobenzaldehyde with ethyl diazoacetate under basic conditions to afford addition adduct 92; the intermediate 92 collapsed via a [1,2]-aryl shift to reveal, after condensation, the indole scaffold 93 h10JOC7033i. The Wu group has prepared substituted carbazoles from enediyne precursors, for example, 94 h10OL5652i. While the transformations proceeded in one step with Cu(II)/Pd(II) cocatalysts, the authors have demonstrated that the indolization step (Ia ring closure) was promoted by Cu(II) while the annulation step to afford the carbazole 95 proceeded under Pd-catalysis. Pd-promoted F3B H
-
O CO2Et
N2 NHR
92
CO2Et
93
94
Cl
H
R2
(74%) N H
iBu
R3
R1
N Me Me
(95%)
N Me H 95 CuX2-promoted
173
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
Intramolecular cyclizations (“type a”) to generate indoles have also been achieved using o-dibromovinyl aniline h10JA11416, 10TL6342i and o-dibromovinyl isocyanide precursors h10OL3034i.
5.2.4.1.2 Intramolecular Type b The Chatani group has implemented a “type b” cyclization strategy to prepare 2-silyl or 2-borylindoles, for example, 97, from 2-alkenylphenyl isocyanides h10JOC4841i. The 2-boryl adducts were further manipulated using a Suzuki–Miyaura coupling protocol to prepare a number of 2- aryl, vinyl, and alkynyl indoles. Isocyanides have also been employed by Fukuyama and coworkers for indole ring synthesis en route to tryprostatins A and B h10AG(I)9262i. As illustrated, radical cyclization of 98 (promoted by nBu3SnH and V-70 radical initiator) afforded 2-stannylindole 99 that underwent, in the same pot, Stille coupling with prenyl acetate to reveal the desired 2-prenylindole 100 in 80% yield. NBoc O
CO2Me
CO2Me
a N C
(80%) N C MeO
B(Pin)2
(98%)
96
97
N H
MeO
a) cat. CuOAc, PPh3, B2(pin)2, MeOH.
Boc N
two steps, one-pot
O R N H 99: R = SnnBu3 100: R =
98
5.2.4.1.3 Intramolecular Type c Willis and coworkers have closed the indole “c” bond using a Pd-mediated arylation of vinyl bromides tethered to aniline nitrogen, for example, 101–103 h10AG(I) 7958i. The use of ligand 102 and DMF as the solvent proved to be important for achieving optimal yield. Additional approaches to indolization via intramolecular fusion of the “c” bond have relied on transition-metal catalyzed oxidative coupling of aniline derived enamines h10SL2899, 10CC2823i. An iodine-promoted ring closure for the preparation of 3H-indoles (indolenines) from aryl enamines has also been disclosed h10JOC4636i. OMe
Br
OMe a
101
N H
N H
(81%) Cy2P
iPr
a
103 N
iPr
102 iPr
a) Pd(OAc)2, 102, Cs2CO3, DMF, 90 ⬚C
OMe
104
(71%) N H
OAc OMe
105
a) Pd(dba)2, CsCO3, toluene, 150 ⬚C, 24 h.
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J.S. Russel et al.
5.2.4.1.4 Intramolecular Type e Two independent reports have appeared that involved indole ring synthesis via Pdpromoted intramolecular aromatic CH amination h10JA3676, 10T5692i. In one account, Tan and Hartwig observed Pd-catalyzed cyclization of oxime acetates, for example, 104, to prepare indoles bearing a range of functionality h10JA3676i. In an alternate approach, Fe(II)-catalyzed ring opening of 2H-azirines was used by the Zheng group to set up CH aromatic amination for the synthesis of several 2,3disubstituted indoles h10OL3736i.
5.2.4.2 Intermolecular Approaches The myriad of routes available for the preparation of functionalized benzenes, including anilines, phenylhydrazines, diazonium salts, and phenols, makes these monocyclic species attractive platforms for de novo construction of substituted indole scaffolds via intermolecular annulation strategies.
5.2.4.2.1 Intermolecular Type ab In one account, Waldmann, Kumar, and coworkers have described a silver ion-catalyzed cascade sequence for indolo[2,1-a]isoquinoline ring synthesis under microwave conditions. As illustrated for 106, a one-pot sequence of intermolecular imine formation, Ag-promoted imine addition onto the tethered alkyne, and intramolecular trapping of the incipient iminium ion with the o-pendant anion afforded, after loss of CO2, a new tetracycle in up to 95% yield h10CC4622i. A similar strategy involving the use of various electron-withdrawing groups (EWG) to generate anions ortho to arylimine electrophiles has been employed by the Kraus group for the synthesis of a series of substituted indoles, for example, 108 h10S1386i; the authors have suggested a mechanism for the conversion of 107–108 involving a base-mediated electrocyclic ring closure followed by a 1,5-hydrogen shift. Butin and coworkers have set up a similar indolization sequence that involved nucleophilic ring closure on an aniline derived imine by an ortho-pendant furyl group h10EJOC920i. CO2tBu CO2tBu
EWG R
106 Ph
Ag+
NHBoc
Ar
N N
CO2Et
Ph
N H
Ar
107 imine condensation
108 (68%) Ar = 3-indolyl
EWG = SO2Ph, CN, PPh3Br, CO2Me. EWG = SMe (with R = SMe)
N
109
Ac Rh(III) cat. oxidative annulation
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
175
5.2.4.2.2 Intermolecular Type ac The Stuart group has prepared a collection of indoles and pyrroles using a Rh(III)promoted direct CH activation protocol to fuse unsymmetrical internal alkynes to acetanilides or enamides, respectively h10JA18326i. In one example, indole 109 was prepared in 71% yield via oxidative coupling of N-acetylaniline and the complementary alkyne; indole 109 was further manipulated to form the seven-membered lactam of paullone. Additional examples of type “ac” ring synthesis have included a heterogeneous Pd-catalyzed coupling of N-tosyl o-iodoanilines with alkynes (Larock type indole synthesis) by the Sajiki group for the synthesis of 2- and 2,3-substituted indoles h10OBC3338i, as well as a Pd-catalyzed route to 2-indolylphosphines that involved the treatment of o-iodoanilines 110 with 1-alkynylphosphine sulfides 111. In the latter case, the C2-diphenylphosphine moiety of the indole adducts was revealed upon reductive removal of sulfur with (TMS)3SiH/AIBN h10OL1476i. X I
I + N H
110
R2
PPh2 S
111
O
I
I
O
+ NH
HN
H2N
112
HO O
O
O reductive cleavage following annulation
X
X
R1
R3
113
R
115
114 4-haloindoles
The Sanz group has employed a Smiles rearrangement to access 2,3-dihaloanilide 114 from 2,3-dihalophenols h10OBC3860i. Under Sonogashira conditions, a onepot or stepwise indolization of 114 with terminal alkynes 115 afforded 2-substituted 4-haloindoles, for example, 4-bromo-2-phenylindole (83%). A Sonogashira coupling has also been employed by the Fukayama group for the fusion of o-iodoaniline with a terminal alkyne en route to ()-mersicarpine h10JA1236i. A copper-catalyzed strategy for “type ac” indole ring synthesis has been reported by Qiao and coworkers that involved treatment of aniline derived o-bromo trifluoroacetamides with a-cyanoacetates; the methodology provided access to 2-amino indole-3-carboxylates h10ASC1033i. New methodologies for “type ac” bond construction continue to evolve from the classic Fischer indole synthesis. In one account, Knochel and coworkers have set up Fischer indolization via the coupling of organozinc reagents 117 with aryldiazonium salts 116 h10AG(I)9513i. The scope of the methodology was demonstrated through the synthesis of a series of highly functionalized indoles, for example, 118 (90%). In an alternate study, Garg and coworkers have prepared hexahydropyrroloindoles using an interrupted Fischer indolization strategy h10T4687i. For example, hexahydropyrroloindole 120 was synthesized in 88% yield upon treatment of phenylhydrazine with hemiaminal 119. Two independent reports have appeared that describe Fischer cyclization chemistry set up by the coupling of aryl hydrazines with terminal alkyne partners h10OBC1149, 10EJOC6831i.
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J.S. Russel et al.
116
modified Fischer
R1
R3
ZnX 3 117 R
N2 R2
R1
-
BF4
R1 = CO2Me R2 = NO2 R3 = OMe
R2
Fischer (interrupted)
PhNHNH2 +
N H
HO
Me
AcOH
Me
100 ⬚C
N
N
N
119 Ts
120 R1
118 (90%)
H
Ts
iminium ion trapping
5.2.4.2.3 Intermolecular Type ce A few variations of “type ce” ring fusion have appeared that employed the following coupling partners: o-chloro aryltriflates with allylamines h10OL668i, o-silyl aryltriflates with 2-azidoacrylates h10OL4608i, and o-chloro arylsulfonates with imines h10CEJ11707i.
5.2.4.2.4 Intermolecular Type ae In the Konakahara group’s synthesis of ellipticine 125, a Suzuki–Miyaura coupling of aryl iodide 122 and aryl boronic acid 121 was used to access the ditriflate 124; Pd-catalyzed double N-arylation of the ditriflate 124 with O-t-butyl carbamate proceeded in 62% yield and established the requisite carbazole core of the natural alkaloid h10TL2335i. Suzuki− Miyaura B(OH)2
121
steps
(69%)
I OH
N
CHO
CHO
OR
OH
OR
122
123: R = H 124: R = OTf
double N-arylation
N H
125 ellipticine
Two additional reports have appeared that detail palladium-catalyzed double amination sequences that involved the coupling of primary amines with o-vinylhalo arylhalides; the methods provided access to an array of 2-trifluoromethylindoles h10S1521i or 4-, 5-, 6-, and 7-chloroindoles h10T6632i.
5.2.5. REACTIONS OF INDOLES 5.2.5.1 Pericyclic Transformations The application of pericyclic transformations continues to provide rapid and controlled entry into indole polycyclics. A variety of pentacyclic ring systems have been constructed by the Boger group through implementation of an intramolecular [4 þ 2]/[3 þ 2] cycloaddition cascade strategy h10JA3009, 10JA3685, 10JA13533i. For example, in their approach to ()-vindoline, Boger and coworkers employed
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
177
an inverse electron demand Diels–Alder cyclization to construct the dipole progenitor 126. Loss of N2 from 126 set forth a 1,3-dipolar cycloaddition of 127 to afford 128 in diastereoselective fashion h10JA3685i. An intriguing five- to six-membered ring expansion was used in a downstream transformation to forge the requisite pentacyclic skeleton of vindoline. O O
OMOM -N2
N
MeO
126
N O N N Me MeO2C
Et MeO OBn Diels–Alder
five- to six-membered ring expansion
OMOM
N + [3 + 2] O Et – N OBn Me CO2Me 127 MeO
OMOM
O N
Et OBn
O
128
N Me
CO2Me
A pair of reports have appeared that detail asymmetric organocatalytic Diels–Alder transformations of 2- or 3-vinylindoles. In one account, chiral diaryl prolinols, for example, 130, were employed by Zhao and coworkers to facilitate the synthesis of the tetrahydrocarbazoles h10CEJ5853i. In one variation, 129 was prepared from 2-vinylindole in 77% yield and 96% ee h10CEJ5853i. The Diels–Alder route to 131 (75–90%, 98% ee) and related tetracycles has been investigated by Gioia, Bernardi, and Ricci h10S161i. The authors employed a series of thiourea and quinine based H-bonding organocatalysts, for example, 132, to promote the cycloaddition of maleimide dienophiles onto 3-vinylindole dienes; similar reactions with 2-vinylindoles provided low yields of cycloadducts. Diels–Alder CHO Ph
Diels–Alder H
Ph
129
N Me
O N
R1
Ph N H
OMe CF3
NPh
Ph OR2
130 R1 = OBn, R2 = H
N HH O O 131 F C 3
S N
N H
N H
CF3
132
In a final example of Diels–Alder type cycloadditions, the Buszek group has reported on the regiochemical outcomes of furan cycloaddition chemistry across 4,5- 5,6- and 6,7-indolynes h10OL96i. Sigmatropic rearrangement chemistry has also received attention as a means for elaboration of the indole core. In one example, the Westwood group has described an enantioselective Claisen rearrangement on an indolo[2,3-b]quinoline scaffold 133 that afforded an all-carbon quaternary center at the indole/quinoline ring juncture h10OBC442i. The Claisen adduct 134 houses key structural features found in the communensin family of natural products. In an unrelated investigation, Morales-Rı´os and coworkers have studied the formation of 2-indolylcyanomalonate 136 from a-cyano ketene O,O-acetal 135; a mechanism has been proposed involving a sequence of [1,3]sigmatropic shifts that proceeded via an indole 2,3-cyclopropyl intermediate h10JOC1898i.
J.S. Russel et al.
178
CN
H Br
O
Br
OMe
O O
N 135 N
N Bn
N
N Bn
CN
CO2Me N
CO2Me
MeO2C
134 (93:7 er)
133
136 (quantitatative)
5.2.5.2 Substitution at C3/C2 5.2.5.2.1 C3 Substitution The literature continues to be flooded with new examples of methodologies for the selective introduction of functionality at indole C3. Within this collection of works, much emphasis has been placed on the development of asymmetric variations of Friedel–Crafts alkylation chemistry. Toward that end, a variety of phosphoric acids have been employed as organic catalysts for the asymmetric addition of indoles to electrophiles including aryl imines h10JOC8677i, nitroalkenes h10OBC5448i, a,b-unsaturated trifluoromethylketones h10TL4658i, a,b-unsaturated acyl phosphonates h10CC4112i, and trifluoropyruvate h10CAJ470i. Other organocatalytic systems for promoting asymmetric additions at indole C3 have included a tartaric acid derivative for additions to a-imino esters h10TA1203i, a bipyrrolidine catalyst for additions to a,b-unsaturated aldehydes h10OBC4011i, and a squaramide catalyst for additions to aryl imines h10CC3004i. A broad range of chiral organic ligand/Lewis-acid systems have also been explored for promoting asymmetric Friedel–Crafts chemistry h10JA11418, 10AG(I)4476, 10ASC1113, 10CEJ1638, 10TL2326i. In an account by the You group, chiral phosphoric acid/Ir-mediated intramolecular allylic alkylation of indoles provided adducts with two new stereocenters upon spirocyclization to indolenines, for example, 137 h10JA11418i. In another example, Feng and coworkers have observed a reversal in enantioselectivity for the Friedel–Crafts alkylation of indole with b,g-unsaturated a-ketoesters depending on the choice of Lewis-acid metal complex. While use of AgAsF6 in conjunction with the chiral N,N0 -dioxide ligand 139 afforded the (S)-enantiomer of indole 138 (82%, 85% ee), implementation of the same organic ligand 139 with Sm(OTf)3 complex afforded the enantiomeric indole (R)-138 (96%, 98% ee) h10OL180i. Related investigations of indole/Friedel–Crafts chemistry involving N,N0 -dioxide ligand types have been reported by the same group h10CEJ1664, 10ASC3174i.
FriedelCrafts
Ph O
*
N O
N Bn allylic alkylation
137 (95%, 99:1 d.r., 96% ee)
N H
OMe
O N H
O
N O
O H N
R
R
138(S) with M = AgAsF6 and 139.
139 R = CHPh2
138(R) with M = Sm(OTf)3 and 139.
179
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
An organocatalytic four-component cascade sequence has been orchestrated by the Enders group who prepared 3-(cyclohexylmethyl)indoles, for example, 140. As illustrated, treatment of indole with 2 equiv. of acrolein, b-nitrostyrene, and (S)diphenyl-prolinol TMS-ether 141 afforded the adduct 140 (R1 ¼ H, R2 ¼ Ph) in modest yield (55%) and respectable stereoselectivity (d.r. 95:5, 94% ee); yields up to 82% and 99% ee were observed with R2 ¼ piperonyl h10CC2447, 10AG(I)846i. Michael
R2
NO2
Friedel−Crafts
Michael
indole
R1 FeCl3
Ph H N H
O H
N H
Aldol
140
Ph OTMS
142 α-pinene 143
141
N H
In a final example of Lewis-acid catalyzed alkylation, the Yadav group has observed an interesting FeCl3-promoted addition of various indoles to a- or bpinene h10TL244i. As illustrated for the synthesis of indole 143, the transformation proceeded with cleavage of the pinene bridgehead to afford the monoterpene alkaloid with a preference (85:15) for trans-substitution about the terpene ring. Nucleophilic additions to indole C3 have also been reported. As an extension of an investigation of the synthesis of C3-quaternary substituted pyrroloindolines from C3-bromide precursors, for example, 144, Rainier and coworkers have prepared and isolated the cyclopropylazetoindoline 146 (89–95%), a putative intermediate in the base-promoted substitution chemistry of 144 h10JA8282i. Subsequent treatment of 146 with various nucleophiles afforded the corresponding C3-substituted pyrroloindolines. In one example, dimeric indole 145 was prepared in 70% yield. Related reports on C3N10 dimeric indole construction have been disclosed h10OL2154, 10JA7119, 10CC2501, 10OBC5179, 10OBC5294i. An alternate example of nucleophilic addition to indole C3 has been reported by Gribble and coworkers who observed addition of diorganocuprates to indoles bearing a C2 phenylsulfonyl EWG h10ARK(iv)66i. nuc R CO2Me N H Boc
N
N
t-BuOK Boc
144: (R = Br) 145: (R = N-indolyl)
indole t-BuOK
N H Boc
Ph
TBSO CO2Me
O steps
Br
Ph
TBSO
O
Br
Boc
146
N oxidative coupling
O2N
147
N Me
N H
148
Various approaches to C3 substitution involving oxidative couplings have been disclosed. Reports have included the direct coupling of indoles to iodobenzene h10ASC2929i, anilines h10ASC3230, 10CEJ5723i, anisoles h10TL2004i, and cyanide ion h10OL1052, 10TL3334i. In their synthesis of ()-communesin F, the Ma group set the C3-spirocyclic center of indoline 147 via an intramolecular iodinepromoted oxidative coupling between indole C3 and a pendant enolate anion
180
J.S. Russel et al.
h10JA13226i. Reduction of the nitro group followed by intramolecular cyclization onto the imine completed the C2C3 annulation sequence. The modest diastereoselection imparted during the oxidative coupling step became apparent with the isolation of 148 in 50% yield in comparison to 16% for the minor diastereomer of 148.
5.2.5.2.2 C2 C3 Annulation
The previous example represents one of many synthetic entries into indole C2C3 heteroannulated systems. Within this class of alkaloids, the distinctive hexahydropyrrolo[2,3-b]indole (pyrroloindoline) scaffold has received considerable attention. The Piersanti group has prepared the hexahydropyrroloindole framework 149 (R1 ¼ H; R2, R3 ¼ Me) via a cascade conjugate addition/cyclization strategy h10OL3844i. In the event, 3-methylindole was treated with an a,b-unsaturated amino ester coupling partner in the presence of ZrCl4. An enantioselective approach to an analogous ring system has been reported by Reisman and coworkers. Accordingly, the pyrroloindoline 149 (R1 ¼ Me; R2 ¼ CF3; R3 ¼ OBn) was constructed via fusion of 1,3dimethylindole and the requisite a,b-unsaturated amino ester in the presence of an (R)-BINOL/SnCl4 catalyst system (4:1 d.r., 94/91% ee) h10JA14418i. A unique enantioselective entry into the pyrroloindoline framework has been devised by Yoon and coworkers who prepared 152 from N-prolytryptamine 150 h10AG(I)9153i. In the event, treatment of 150 with Davis’ oxaziridine in the presence of Cu(II) catalyst afforded oxyamination product 151; subsequent base catalyzed cyclization provided the 3-aminopyrroloindoline 152 in good yield (78%). Boc-protection of the proline chiral auxiliary, low temperature ( 30 C), and the use of chloroform as the solvent proved essential for achieving optimal enantioselectivity (91% ee). conjugate addition
MocHN OR3
Me
O
149
N H R1
N O
R2 iminium ion trapping
Bs N
NHMoc N a
150 O
151 BocN O N
a) CuCl2, Bu4NCl, Ph
H
N R*
O
NHBs Ph b
Bs
N H H
NMoc
152
(78%, 91% ee)
; b) NaOMe, MeCN.
Liam and Davies have prepared 2,3-annulated indolines (e.g., 155 and 156) via an enantioselective [3 þ 2] cycloaddition of Rh-stabilized vinylcarbenoids across indole C2C3 h10JA440i. Notably, the enantioselective transformations provided exo adduct 155 from 1,2-dimethylindole and the endo adduct 156 from 1,3dimethylindole; as illustrated, the regiochemistry of annulation was also influenced by the substitution pattern (1,2- vs. 1,3-substitution) on indole. In an alternate investigation, functionalized tetrahydrocarbazole scaffolds were prepared by Xiao and coworkers in enantioselective fasion; the chemistry involved a sequence of Michael additions between 2-propenylindoles and nitroalkenes in the presence of a chiral bis-sulfonamide H-bonding catalyst h10OL1140i.
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
CO2Me
R3
MeO2C
181
Ph
H N2 R2
Ph
N R1
153: R1, R2 = Me; R3 = H 1
3
exo 155 (68%, 97% ee from 153)
2
154: R , R = Me; R = H
or N H Me
N Me
Rh2(S-DOSP)4 toluene, –45 ⬚C
CO2Me
endo 156 (74%, 99% ee from 154)
A few other C2 C3 annulation strategies have included a Nazarov photocyclization to establish the indole-fused cyclopentyl moiety of the indole diterpene 16epi-terpendole E 157 h10OL2096i, as well as a Cp2FePF6-promoted oxidative radical cyclization to set the C2 linkage of bridged tetracycle (þ)-subincanadine F 158 h10CC8436i. H N
OH N H
N H
H H
O
Nazarov 4π-electrocyclization 157 16-epi-terpendole E
OH
H
Pd-catalyzed double C–H activation Ph
O
radical cyclization 158 (+)-subincanadine F
N SEM
MeO2C
159
5.2.5.2.3 C2 Substitution As with indole C3 substitution, methods for direct oxidative coupling (CH activation) at indole C2 have been the subject of intense investigation. In one account, DeBoef and colleagues have described a dual CH activation sequence involving the oxidative coupling of various benzenes to indole C2. For example, SEM-protected indole 159 was prepared in 97% yield (9:1 mixture C2:C3 isomers) from the Pd-promoted coupling of the corresponding indole with benzene. A concerted metallation-deprotonation (CMD) mechanism has been proposed for the transformation h10JA14676i. A number of other oxidative couplings have been disclosed for installation of aryl h10CEJ1124i, indolyl h10JOC170i, vinyl h10CEJ9676i, alkynyl h10CC4184i, or amide substituents h10ASC632i at the C2 position. Methods for C2-functionalization have also included the Pd-catalyzed benzylation of indole C2-boronic acids h10TL2281i, a copper-catalyzed malonyl carbenoid insertion h10OL4956i, a ruthenium-catalyzed carbenoid insertion of a-arylesters h10OL604i, and nucleophilic addition of heteroaryllithium reagents to 3-nitroindoles h10H(80)831i. In the Kerr group’s synthesis of (þ)-isatisine A, the indole C2 quaternary center of the penultimate acetonide 162 was established through a sequence of m-CPBA oxidation of 160 followed by indole addition to the N,O-ketal of 161 h10AG(I) 1133, 10JOC6830i. While 162 was formed as a mixture of diastereomers, the reversible reaction became enriched in the desired diastereomer 162 over a period of 42 h at rt.
182
J.S. Russel et al.
H N O
N Ts
O O
O
O
OTBS m-CPBA rt
MeO2C O O
160
N
N Ts
161
O
indole CSA rt, 42 h
MeO2C O O
O
OH
O O
162 (50%, >98% ee)
5.2.5.3 Substitution at Nitrogen A variety of methods have been explored for the introduction of chiral centers alpha to indole nitrogen. The Trost group has employed vinyl aziridine electrophiles in conjunction with chiral diphenylphosphino ligands to direct Pd-catalyzed asymmetric N-alkylations on indoles or pyrroles. In one example, N-substituted indole 163 was prepared in 91% yield and 93% ee with Pd/164 complex h10JA15800i. Intramolecular aza-Michael additions at indole nitrogen have been carried out in asymmetric fashion using either chiral phosphoric acids h10AG(I)8666i or Cinchona-derived phase transfer catalyst systems h10CEJ12462i. As illustrated, NC2 annulated indole 165 was prepared in good yield and enantioselectivity via chiral phosphoric acid promoted N-alkylation h10AG(I)8666i. CO2Me O
O
aziridine ring opening
PPh2 Ph P 2 PMB
N
N
NH HN
N
H
164 163 (91%, 93% ee)
aza Michael Ph
O
165 (95%, 92% ee)
In the realm of NC2 annulation, a Rh-catalyzed oxidative coupling of 2-arylindoles with alkynes has been used to establish indolo[2,1-a]isoquinoline ring systems via an NH, CH activation sequence h10OL2068i. A visible light/Ru (II) photoredox system has been investigated for the N C2 radical annulation of indoles h10OL368i. In other works, the Kitagawa group has developed an enantioselective synthesis of atropisomeric indoles bearing an NC chiral axis h10CEJ6752i. The key transformation proceeded through a “type a” Pd-promoted cyclization of N, N-diarylaniline onto an o-pendant alkyne (a 5-exo-aminocyclization) directed by a chiral bis-phosphine. In a study on N-deprotection, an interesting N- to C3-tosyl migration has been observed by Koutentis and coworkers who prepared 3-aminotosyl 2-cyanoindoles from the corresponding N-tosyl 2-cyanoindoles h10T3016i.
183
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
5.2.5.4 Functionalization of the Benzene Ring A wide range of tactics have been implemented for selective functionalization of the indole benzenoid positions. In an account by the Hartwig group, direct substitution at indole C7 has been observed following an iridium-catalyzed, N-silyl directed borylation h10JA4068i. The 7-borylindole adducts, for example, 167, were prepared in modest to good yield (44–66%) and were further manipulated to C7 aryl-, allyl-, or halo-functionalized indoles. CO2Me
Ph a,b
O
N SiEt2
166
N H
N
O
167 Bpin (66% from indole)
O
N(Boc)2 N Boc
Br
Asymmetric Michael addition/ bromination
168
a) [Ir(cod)Cl]2, dtbpy, B2Pin, HBpin. b) 3 M NaOAc.
Halogens on the benzenoid positions remain versatile handles for installation of carbon–carbon bonds. Jia and coworkers have staged an asymmetric Michael addition/bromination sequence to set the C6 carbon linkage of 168 h10OL956i. Accordingly, a C6 iodide of indole fragment 168 was metallated (i-PrMgCl and then CuBrMe2S) and treated with the corresponding a,b-unsaturated oxazolidinone coupling partner to afford 168 in 65% yield as a single diastereomer. In an alternate example, the Martin group has stitched together the requisite C3C4 annulated core of N-methylwelwitindolinone C isothiocyanate through implementation of an enolate arylation strategy that involved the coupling of a C4-bromide with a C3-tethered b-ketoester h10OL2492i. In the event, the tricyclic intermediate 169 was prepared via Pd-catalyzed coupling in 71% yield. The same group has employed a reductive Heck cyclization of a C4-bromide and C3-tethered alkyne to access a tricyclic scaffold en route to (þ)-isolysergol h10OL2610i. TBDPSO HO MeO2C
HN O
enolate arylation
N Me
169
N Me
170
N Me
N Me 91% (12.5:1)
171
73% (3:1)
172
The regiochemistry of nucleophilic additions to 4,5-, 5,6-, and 6,7-indolynes has been investigated by Garg, Houk, and coworkers h10JA1267, 10JA17933i. While 4,5- or 5,6- indolynes displayed a preference for substitution at the 5-position, 6-substituted indoles were obtained from the corresponding 6,7-indolynes. As illustrated, nucleophilic addition of aniline to 4,5- or 5,6- indolyne (170 or 172, respectively) afforded 5-substituted indole 171 as the major adduct h10JA17933i.
J.S. Russel et al.
184
5.2.5.5 Elaboration of Indole Side-Chains New strategies for precision bond installation continue to provide access to the compelling molecular architectures that decorate the indole core. In one example, the Overman group has orchestrated an aza-Cope/Mannich rearrangement to set the [4.2.1] bridging scaffold of ()-actinophyllic acid h10JA4894i. As designed, [3,3]sigmatropic rearrangement of reactive intermediate 173 (prepared from the corresponding secondary amine and monomeric formaldehyde) set up an intramolecular Mannich reaction of 174 to reestablish a bridgehead a to indole C3 (93% yield). In their total synthesis of ()-aurantioclavine, the Ellman group established the requisite side-chain chirality center via Rh-catalyzed addition of MIDA boronate 176 to the N-sulfinyl imine 175 h10OL2004i. The desired adduct was formed in 81% yield (97:3 d.r.) and further manipulated to form 177 in > 99% ee. An alternate route to 177 has been reported by Jia and coworkers h10JOC7626i
HO
HO
[3,3]
N
OH
173
O
N H
174
H N
OTs
N
CO2H
N H
H
S N
steps
CO2H OH
175
N Ts
MeN B O O
O O
176 (MIDA)
N H 177 (−)-aurantioclavine
The Martin group has reported a streamlined route toward the C–D ring system of indole tetracycle 178, an advanced intermediate in the synthesis of the Aspidosperma alkaloid ()-pseudotabersonine h10OL3622i. As illustrated, a double ringclosing metathesis reaction using Hoveyda–Grubbs II catalyst afforded a mixture of cis and trans fused isomers. Removal of the TBS protecting group and reduction of the C-ring double bond allowed for separation of the cis/trans mixture (26% cis, 44% trans). A parallel set of protocols for stitching together the pentacyclic framework of 181 has been developed by Cook and coworkers; the bridged motif is characteristic of alkaloid intermediates of the ajmaline biosynthetic pathway h10JOC3339i. While the enolate-driven Pd-crossed coupling of 179 provided 181 in up to 83% yield, the authors noted the relative ease of the workup protocol following the Cumediated transformation that afforded 181 from 180 in 75% yield. RCM TBSO N H
C N SO2Ph
H
H
D
O
H N R
RCM
178 (7:10 cis/trans)
179: R = H 180: R = Me
a or b
N H
I
O
181
N R
N
Pd or Cu coupling
a) 5.0 mol% Pd2(DBA)3, 7.0 mol% DPEPhos, 1.5 equiv. tBuONa (83%). b) 50 mol% CuI, 50 mol% 1,2-cis-cyclohexanediol, 2 equiv. Cs2CO3 (75%).
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
185
5.2.6. OXINDOLES AND SPIROOXINDOLES The development of methodology for the synthesis of oxindoles and spirocyclic variants remains an area of intense investigation. In a report by White and coworkers, an intriguing route to spirocyclic oxindole frameworks has been devised via an intramolecular photochemical [2 þ 2] cycloaddition of a,b-unsaturated malonate esters onto the indole C2C3 p-system; following photocyclization, the spirocyclic ring systems were revealed through a spontaneous retro-Mannich reaction h10JOC3569i. As illustrated, indole 182 was converted to spiroindolenine 184 in 60% yield through the cyclobutane intermediate 183; the adduct 184 was further manipulated to generate ()-horsfiline. An alternate synthesis of (þ)-horsfiline has been reported by the Douglas group who made use of an asymmetric cyanoamidation to set the C3 quaternary center h10OL952i. NH NH MeO
CO2Et
hn CO2Et [2 + 2]
N Boc
N CO2Et
MeO N H Boc
182
CO2E2
183
MeO
CO2Et
retroMannich (60%)
N Boc
CO2Et
184
Numerous reports have appeared that detail methodology for the asymmetric installation of C3 quaternary centers. In one example, Trost and Czabaniuk have employed an asymmetric benzylation strategy for the synthesis of all-carbon quaternary centers at oxindole C3 h10JA15534i. As illustrated for 185, the dimeric indole was prepared in excellent yield and enantioselectivity via a Pd-catalyzed benzylation using a chiral bis-phosphine ligand. The nitrogen-containing stereocenter of 186 was set by Matsunaga, Shibasaki, and colleagues through implementation of a Schiffbase/nickel-promoted asymmetric amination h10JA1255i. While a bimetallic nickel catalyst afforded 186, the enantiomer, (S)-186, was prepared in 99% yield and 94% ee using a monometallic Schiff-base complex. The Zho group has accessed oxindoles with C3-oxygen containing chiral centers, for example, 187 by means of an asymmetric Morita–Baylis–Hillman addition of acrolein to isatins h10JA15176i. CO2Me N
asymmetric benzylation
R
CHO
R N N H
HO
O O N H
185 (98%, 96% ee)
N Boc
186: R = CO2tBu (99%, 97% ee)
O asymmetric amination
N Me
Morita− Baylis−Hillman
187 (96%, 98% ee)
Other works on the construction of all-carbon h10ASC416, 10OL1912, 10CEJ2852, 10CEJ296, 10CEJ14290, 10TL5662i, nitrogen-containing h10EJOC2845, 10OL5696i, and oxygen-containing h10AG(I)9460, 10AG(I)744, 10ASC1621, 10ASC833i oxindole C3 quaternary centers have been disclosed.
186
J.S. Russel et al.
5.2.7. CARBAZOLES The intriguing biomedicinal properties of the carbazole alkaloids continue to stimulate efforts in fundamental methodology development and natural product total synthesis. An electrocyclic route to carbazole 190 has been described by Choshi, Hibino, and coworkers h10TL3593i. In the event, the key 2-allenylindole intermediate 189 was generated via treatment of the corresponding 2-propargyl ether 188 with TBAF; electrocylization afforded the desired carbazole in modest yield (40%). OMOM OEt
OMOM OEt
OMOM OEt a
Me
OMOM
N H
N H
188
iPrO
iPrO
(40%)
OMOM
N H iPrO
189
OMOM
190
A synthesis of ellipticine 125 has been reported by the Chern group h10JHC454i. Late stage installation of the D-ring was achieved in good yield (76%) by means of a microwave-assisted cyclization; the N-tosyl functionality on the side chain of 191 proved to be important for optimization of the cyclization chemistry. Jana and Mal have devised an efficient route to prenylcarbazoles for application to the synthesis of a series of alkaloids including clausamine C-D, clausevatine D, and clausine F h10CC4411i. As illustrated for the formation of 193 from 192, a para-Claisen rearrangement was employed to establish the requisite prenyl functionality at carbazole C4. NTs
CO2Me
OEt
CO2Me
OEt N H
191
N N H
192
a (76%)
N H
CO2Me
O
CO2Me a b
125 ellipticine a) 6M HCl, dioxne, MW, 140 ⬚C.
OCH3 N H 193 (two steps, 48%)
a) DEA, reflux, 10 min. b) K2CO3, MeI.
5.2.8. CARBOLINE ANALOGS AND AZAINDOLES A variety of strategies for indole ring annulation have been applied for the synthesis of b-carbolines and structural analogs. For example, Wu, Cao, and colleagues have orchestrated an enantioselective, three-component synthesis of indoloquinolizidines h10CC2733i. As illustrated, organocatalytic fusion of b-keto ester 195,
Five-Membered Ring Systems: Pyrroles and Benzo Analogs
187
a,b-unsaturated aldehyde 196, and tryptamine 194 afforded the tetracyclic scaffold 198 with excellent enantioselectivity.
N H
Me
NH2 O O
N H
CO2iPr
195
imine condensation
OTMS Ph Ph
Me N
197 cat. benzoic acid
N H
194 196
Pictet− Spengler
CO2iPr
H Michael addition
198 (95%, 96% ee)
In other works on carboline scaffolds, a study on the nucleophilic substitution at the THb-carboline 4 position (a vinylogous Michael addition alpha to indole C3) has appeared h10OL1240i. Pfeffer, Stewart, and coworkers have reported a two-step protocol for THb-carboline synthesis that involved Heck coupling of butyl acrylate to tryptamine C2-bromide, followed by Michael addition of the C3-pendant amine onto the a,b-unsaturated carbonyl of the C2 acrylate h10JOC1787i. Aromatization of THb-carbolines has been achieved by Panarese and Waters who used 2-iodoxybenzoic acid (IBX) to access b-carbolines; the methodology was extended to a synthesis of eudistomin U h10OL4086i. An asymmetric synthesis of tangutorine has been reported by Hamada and coworkers h10OL872i. The three chiral centers of the pentacyclic b-carboline alkaloid were established through an early stage asymmetric amination of the tryptamine side-chain using a DIAPHOX/Pd catalyst system. Synthetic routes toward a-carbolines h10EJOC6665i and d-carbolines h10TL6022i have also been described. In an additional example of carboline synthesis and functionalization, Padwa and coworkers have prepared lavendamycin analogs, for example, 199, through implementation of a Stille coupling protocol to link the carboline and quinoline heterocycles h10JOC424i. The requisite b-carboline scaffold was prepared using a gold-catalyzed cycloisomerization of a C2-tethered N-propargyl moiety. gold-catalyzed cycloisomerization O B
Stille
Me
R N
199 (63%)
Cl
201
N
NH2
N H
200
N
OEt
O
a (98%)
OEt
N
NH2
202
b
N
(93%)
203
N H
NO2 MeO
a) Pd(OAc)2, SPhos, K3PO4, MeCN/H2O; b) AcOH, reflux.
O2N
A collection of reports have appeared that describe methodology for the synthesis of azaindole scaffolds. The Hoelder group has developed a general method for the synthesis of a large array of 4-, 5-, 6-, and 7-azaindoles as well as diazaindoles
188
J.S. Russel et al.
h10JOC11i. In one example, 4-azaindole 203 was prepared in two steps from amino pyridine 200; modified Suzuki–Miyaura coupling of 200 with commercially available borolane 201 afforded ortho-ethoxyvinlyaminopyridine 202 (98%) that cyclized upon treatment with acidic acid to afford azaindole 203 in 93% yield. A Stille coupling strategy has been employed by the Mukai group for the synthesis of C2-functionalized 5-, 6-, and 7-azaindoles h10H(80)133i. Syntheses of 5h10OL3168i or 7-azaindoles h10JOC5316, 10OL4438i have also been described.
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Five-Membered Ring Systems: Pyrroles and Benzo Analogs
10BMCL108 10BMCL2435 10BMCL4774 10BMCL5207 10CAJ470 10CAJ1810 10CC1797 10CC2447 10CC2471 10CC2501 10CC2733 10CC2823 10CC3004 10CC3973 10CC4112 10CC4184 10CC4411 10CC4622 10CC8032 10CC8436 10CC8770 10CEJ296 10CEJ1124 10CEJ1638 10CEJ1664 10CEJ2852 10CEJ5723 10CEJ5853 10CEJ6752 10CEJ6756 10CEJ8975 10CEJ9676 10CEJ9864 10CEJ11707 10CEJ11876
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189
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CHAPTER
5.3
Five-Membered Ring Systems: Furans and Benzofurans Kap-Sun Yeung*, Xiao-Shui Peng**, Jie Wu{, Xue-Long Hou{ *Bristol-Myers Squibb Research and Development, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492, USA
[email protected] **Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
[email protected] { Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
[email protected] { Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China
[email protected]
5.3.1. INTRODUCTION This chapter aims to review papers that were published in 2010 on reactions and syntheses of furans, tetrahydrofurans, and their derivatives. Reviews published in 2010 covered recent syntheses of furans and 2,5-dihydrofurans h10CEJ5836i and synthesis of tetrahydrofurans h10CJOC515, 10EJO3533, 10OBC2900i. Many new naturally occurring molecules containing tetrahydrofuran and dihydrofuran rings were identified in 2010. References on compounds whose biological activities were not mentioned are: h10HCA870, 10HCA1101, 10JNP123, 10T1716i. Articles on those naturally occurring compounds containing tetrahydrofuran or dihydrofuran skeletons whose biological activities were assessed are: h10HCA746, 10HCA920, 10JNP83, 10JNP127, 10JNP221, 10JNP563, 10JNP806, 10JNP998, 10JNP1337, 10OL1016, 10OBC1876, 10OBC2352, 10P1787, 10T2306, 10T2855i. References on those furan-containing compounds whose biological activities were not mentioned are: h10HCA698, 10TL754, 10JNP835, 10JNP962, 10JNP1344, 10JNP1456, 10OL252i. Naturally occurring compounds containing furan skeletons whose biological activities were assessed were mentioned in the following papers: h10AGE4471, 10HCA169, 10JNP51, 10JNP263, 10JNP644, 10JNP905, 10JNP541, 10JNP1151, 10JNP1188, 10JNP1327, 10P1395, 10P1174, 10T641, 10TL751i. References of those benzo[b]furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: h10JNP897, 10P1708i. References on those naturally occurring compounds containing benzo[b]furan or dihydrobenzo[b]furan skeletons whose biological activities were assessed are:
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00007-3
#
2011 Elsevier Ltd. All rights reserved.
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h10CEJ6338, 10HCA272, 10JNP598, 10JNP818, 10JNP1002, 10JNP1398, 10OL2390, 10P1756i.
10JNP854,
10JNP995,
5.3.2. REACTIONS 5.3.2.1 Furans A number of novel applications of furans for the construction of oxa-bridged sevenmembered rings were reported in 2010. Transannular [4 þ 3] cycloaddition between a furan moiety and an oxyallyl cation generated from an a-chloroketone was realized for the first time, as depicted below h10SL2797i. The reaction appeared diastereoselective with only one diastereomer isolated, and the stereochemistry of the methine protons depended on the length of the carbon chain. An intermolecular version of this type of cycloaddition was employed to construct the oxa-bridged seven-membered ring of cortistatin A h10OL5135i. Gold-catalyzed transannular [4 þ 3] cycloadditions of furan initiated by a 3,3-rearrangement of propargyl acetate to acetoxyallene were also demonstrated h10CEJ639i. Cl
O
H
Et3N (3 equiv.)
H
O
Et2O/CF3CH2OH (1 : 1) –78 °C to rt then 55 °C, overnight 80%
O
O
An interesting intermolecular [4 þ 3] cycloaddition between a furan and an alkoxy silyloxyallyl cation, generated from a silyloxyallyl acetal, was used to construct the oxa-bridged seven-membered ring of urechitol A h10AGE5527i. The cycloadduct shown below was obtained as the sole regio- and stereoisomer. Density functional calculations of the [4 þ 3] cycloaddition between furan and a chiral (a-methyl)benzyloxy silyloxyallyl cation indicated that the reaction proceeds in a stepwise manner h10OL444i. The stereoselectivity was controlled by an edge-toface interaction between furan C2-H and the phenyl group, in addition to the minimization of steric interaction between the allyl and the methyl groups. The [4 þ 3] cycloaddition between furans and zwitterionic oxazolidinone-substituted oxyallyls was shown by density functional calculations to be a concerted but asynchronous process h10OL5506i. 2- and 3-substituted furans provided cycloadducts with synand anti-regioselectivity, respectively. OSiEt3
OH
+ O
OBn OBn
TiCl4 NaHCO3 EtNO2 –78 °C 46%
OBn
HO O
O
Five-Membered Ring Systems: Furans and Benzofurans
197
The seven-membered oxa-tricyclic core of ()-englerin A was synthesized with modest diastereoselectivity by a Davies rhodium-catalyzed [4 þ 3] cycloaddition between a furan and a chiral diazo ester, as depicted below h10OL3708i. Another approach to the core of englerin A relied on a [5 þ 2] cycloaddition between a 3-oxidopyrylium species, derived from an Achmatowicz rearrangement of a furfuryl alcohol, and acrylate as described in a total synthesis of this guaiane sesquiterpene h10JA8219i. The adduct obtained from [5 þ 3] cyclodimerization of the 3-oxidopyrylium ion, first reported by Hendrickson in 1980, was reinvestigated as a rigid scaffold for the synthesis of cyclooctanoid derivatives h10S320i. O t-BuMe2SiO
O
+
O
O O O
N2
O
Rh2(Ooct)4 (2 mol%)
O
O
hexane reflux 90% d.r. = 3 : 1
O OSit-BuMe2
An intramolecular Diels–Alder reaction between a furan ring and an isoquinoline-derived iminium salt was demonstrated for the first time h10TL6822i. The cycloaddition proceeded slowly at room temperature. A catalytic asymmetric Diels–Alder reaction between furans and allenoates was achieved by using a chiral oxazaborolidinium catalyst. An application of this reaction to the synthesis of a subunit of laurenditerpenol is shown below h10OL1836i. O
H Ph Ph N+
Tf2N– H
O
H
catalyst (5 mol%) O +
OCH2CF3
B 2-Tol
Catalyst
O
PhMe –63 °C, 2.5 h 95% d.r. = 87 : 13 87% ee
O CH2CF3
Furan readily participated in a [4 þ 2] cycloaddition with methylenechlorophosphine pentacarbonyltungsten complex to give a mixture of two cycloadducts that could be converted to a phosphinine in three steps h10OL3384i. O
O
H2C = PCl
+ O
W(CO)5
P
23 °C, 2 h
Cl
P W(CO)5
+
W(CO)5
24%
Cl
71%
Furans trapped benzynes derived from CsF/AgF-promoted decomposition of 2-(trimethylsilyl)iodobenzene h10TL6608i. Reaction with the corresponding triflates was also reported h10CC5154i. A benzyne-initiated bis-Diels–Alder cycloaddition of 1,8-difurylnaphthalene was used to synthesize perylene derivatives for potential molecular electronics applications h10CEJ9736i. 2-Substituted furans
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bearing either electron-withdrawing or -donating groups underwent highly regioselective Diels–Alder cycloaddition with borylbenzynes that were generated from 2-boryl-6-iodophenyl triflates, as illustrated below h10AGE5563i. Reaction with 3-methylfuran was also regioselective.
O O
O B
+ OTf
SiMe3
I
O B
i-PrMgCl.LiCl
O
Et2O –78 °C, 30 min 91% >98 : 2
O
SiMe3
High regioselectivity was also observed in the Diels–Alder cycloaddition of 2-substituted furans with 6,7-indolynes compared to 4,5- and 5,6-indolynes h10OL96i. Furans bearing electron-donating groups provided the contra-steric adduct predominantly as illustrated below, while those with electron-withdrawing groups exhibited the opposite selectivity. Density functional studies showed that the C6C7 bond was highly polarized with the C6 carbon more electropositive, thus inducing substantial asynchronicity to the bond-forming steps. The calculations also predicted that reaction with 6,7-arynes of benzofuran and benzothiophene would show similar regioselectivity. Ph
Ph
n-BuLi (1.2 equiv.)
Et +
O (5 equiv.)
N Me
Br Br
Et2O –78 °C to rt 90% 84 : 16
N Me
O Et
A benzotriazole gold(I) complex performed as a stable catalyst for the cycloisomerization of furan-yne to provide phenol in up to 95% yield with 1 mol% catalytic loading h10OL344i. As depicted below, intramolecular Diels–Alder-like cyclization between furan and an unactivated trisubstituted alkene proceeded under UV irradiation and in the presence of 9,10-dicyanoanthracene (DCA) as a catalyst h10TL1273i. Interestingly, 2-phenylfuran as substrate gave a mixture of tricyclic and spiro-bicyclic products.
CO2Et O
CO2Et
hn DCA (5 mol%) C6H6 rt, 84 h 79%
H O
CO2Et CO2Et
Silver-catalyzed Mannich reaction of 2-trimethylsilyloxyfuran with fluorinated aldimines using a BINOL-based phosphine-oxazoline ligand provided the
Five-Membered Ring Systems: Furans and Benzofurans
199
trans-isomer of di- and trifluoromethyl-containing g-butenolides with ee up to 81% h10TA943i. Vinylogous Mukaiyama aldol addition of 2-tert-butyldimethylsilyloxyfuran with benzaldehyde derivatives occurred in a mixture of brine and methanol under ultrasound irradiation h10JOC8681i. The related addition of 2-trimethylsilyloxyfuran with benzaldehydes could be catalyzed by an imidazolium carbene to provide the anti-adduct as the major isomer h10SL2513i. The first example of a generalized anti-selective asymmetric vinylogous aldol addition of various 2-trimethylsilyloxyfurans with aryl, alkenyl, and alkyl aldehydes was achieved by using a trifluoroacetic acid salt of a thiourea derivative of quinine, as a catalyst. h10JA9558i. High levels of diastereomeric ratio and enantiomeric excess could be obtained, as shown by the following prototypical example. Vinylogous Mukaiyama–Michael additions of silyloxyfurans to cyclic enones and a,b-unsaturated oxo-esters were catalyzed by SnCl4 and Cu(OTf)2, respectively h10EJO5471i. – O F3C
HN O
OH
OMe S
O
HN N H
Ph
+
O + H OSiMe3
N
H Catalyst
catalyst (10 mol%) Et2O/CH2Cl2 (1 : 1) –20 °C, 96 h 94% d.r. = 95 : 5 95% ee
Ph O O
Silyl methide Lewis acid Tf2C(SiR3)CH2CHTf2, generated in situ from Tf2CHCH2CHTf2 and alkylsilyloxyfuran, catalyzed the vinylogous Mukaiyama–Michael 1,4-addition of various alkylsilyloxyfurans to a,b-unsaturated ketones h10JOC1259i, and the corresponding anti-selective addition of 3-bromo-2-alkylsilyloxyfuran to a,b-unsaturated aldehydes h10CC8728i. The acidity of this type of silyl catalyst was high enough to catalyze the addition of 2-(tert-butyldimethyl)silyloxyfuran to sterically hindered and less reactive 2,2-dimethylcyclohexanone as depicted below h10JOC5375i. O O O OSiMe2t-Bu
+
Tf2CHCH2CHTf2 (2 mol%)
t-BuMe2SiO
O
CH2Cl2 –24 °C, 3–4 h 53% single isomer
N-Boc-furylimine, employed as a masked a-amino acid group, participated in Mannich additions using proline-derived catalysts, as exemplified below, to furnish 4-hydroxyisoleucine derivatives after subsequent chelation-controlled methyl Grignard addition and oxidative cleavage of the furan ring to the acid h10JOC2745i.
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200
Ph Ph
N H
OSiMe3
O
O
(10 mol%) + H
O
O 2 steps
HO
O
H2 O 4 ⬚C, 16 h 75% d.r. = 97 : 3 99% ee
NBoc
NHBoc
NH2
OH
In a transformation initiated by a copper-catalyzed (TpBr3 ¼ hydrotris(tribromopyrazolyl)borate) furan aziridination, two molecules of a mono- or dialkyl substituted furan were incorporated into a bicyclic product which then ring-opened to a 1,2-dihydropyridine, as exemplified below h10JA4600i. O
O
TpBr3Cu(NCMe) Phl = NTs
O
CH2Cl2 20 °C, 20 h
TsN
TsN O
O
The scope and limitation of a previously reported ring opening of N-acylated furfurylamine via lithiation were studied. Substrates with a phenyl or an electrondonating substituent on the amide carbonyl, provided N-acyl-5-aminopenta2,4-dienals, as illustrated by the example shown below h10JOC4311i. 1. LDA THF –78 to –45 °C
O Bn N
O N H
O O
2. 1 N HCl 74%
N H
Bn N
Rearrangement of furfuryl alcohols to trans-4-hydroxy-5-substituted 2-cyclopentenones could be performed in subcritical water under microwave irradiation without the need for the acid used in conventional conditions h10SL2037i. As represented below, a dysprosium(III) triflate-catalyzed rearrangement of aryl- or alkyl-substituted furfuryl alcohols in the presence of anilines provided a novel entry to trans-4-amino-5-substituted cyclopentenones h10AGE9484i. O
NH2 OH O Ph
Ph
Dy(OTf)2 (5 mol%) +
MeCN 80 °C 92%
N H
l
201
Five-Membered Ring Systems: Furans and Benzofurans
2-Furoic acid can be photooxidized to 5-hydroxy-5H-furan-2-one in high yields by photoactive porous monolithic polymers composed of Rose Bengal grafted to the surface of a highly cross-linked polystyrene-divinylbenzene polymer h10TL3360i. Oxidation of 2-furylethanols to produce 3-keto-tetrahydrofurans, by photo-oxygenation as reported in 2009, can also be performed under the acidic conditions of Jones oxidation h10TL720i. An example is depicted below. O
Jones reagent O
O
acetone 0 ⬚C 64%
OH
O
5.3.2.2 Di- and Tetrahydrofurans A chiral 2,3-dihydrofuran derivative, as depicted below, underwent a Ferrier-type rearrangement with chiral or achiral allenylsilanes to generate 2,5-trans-disubstituted 2,5-dihydrofurans with high diastereoselectivity h10OL4624i. OAc
CO2Me
H
+ SiMe2Ph
O OAc
MeO2C
Me3SiOTf MeCN –40 °C 41% d.r. = >20 : 1
O H
OAc
An isothiourea-catalyzed diastereoselective acylation of silyl ketene acetals with anhydrides or benzoyl fluoride provided 3-acyl-3-arylfuranones, as shown below h10OL2660i. N N Ph
Et
O
(10 mol%) S Ph
(MeCO)2O (1.3 equiv.) OSiMe3
CH2Cl2 –78 °C to rt, 24 h 78% d.r. = 98 : 2
O Et
O
O
Sulfonic acid derivatives of carbohydrates, cellulose and starch, catalyzed the coupling between anilines and two molecules of 2,3-dihydrofuran to form furotetrahydroquinoline derivatives via an aza-Diels–Alder pathway reported previously h10TL517i. The arylation of 2,3-dihydrofuran with phenyl triflate to form 5-phenyl-2,3-dihydrofuran was found to proceed with higher enantiomeric excess and conversion using BINAP catalysts with xylyl groups on phosphorus and 3,30 -substituents on the binaphthalyl scaffold compared to BINAP and its 3,30 -disubstituted derivatives h10TL5724i. A rhodium-catalyzed hydroformylation of 2,3- and 2,5dihydrofurans using xanthene-based hybrid phosphine-phosphonite ligands furnished
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3-formyltetrahydrofuran in ee of up to 91% h10CC1244i. An interesting methylaluminoxane (MAO)-mediated Michael–aldol cyclization process between 2,3-dihydrofuran and 2-trifluoroacetamidoacrylate furnished an amino acid derivative of 2-oxabicyclo[3.2.0]heptane, as depicted below h10JOC545i. O
+
H N
F3C
H CO2Me
NHCOCF3
CH2Cl2 -20 ⬚C, 17 h 75% d.r. = 81 : 19
O
CO2Me
O
MAO
H
5-Oxanorbornene-2-carboxylate was subjected to a ring-opening metathesis polymerization using Grubbs’ catalyst to generate poly(5,6-dihydrooxanorbornane carboxylic acid) as a polysaccharide mimic h10JA15887i. The ring opening of the oxacycle in elaborated [5,7,6]-tricyclic carbon skeletons with dialkylaluminum chloride occurred in a regioselective manner, creating an all-carbon quaternary center in the major isomer, as illustrated below h10OL488i. O
CO2Et
O Et
Et2AICI (2.5 equiv.) O
CH2Cl2 -78 ⬚C, 4 h 94% d.r. = 10 : 1
t-BuMe2SiO H
CO2Et OH
t-BuMe2SiO H
An Ir/(R)-xylyl-PHANEPHOS-catalyzed [2 þ 2] cycloaddition between 7-oxabenzonorbornadienes and terminal alkynes proceeded in high yield and enantiomeric excess of up to 99% h10OL304i. Another Ir/(S)-p-Tol-BINAP complex catalyzed the ring opening of 7-oxabenzonorbornadienes with anilines and N-substituted piperazines h10OM3477i. A Rh/PPF-P(t-Bu)2-catalyzed regiodivergent resolution of a methoxy-substituted 7-oxabenzonorbornadiene by ring opening with amines and alcohols provided regioisomeric tetralins in high enantioselectivity h10OL5418i. As illustrated below, a highly regioselective gold-catalyzed ring opening of unsymmetrically substituted 1,4-disubstituted-1,4-epoxy-1,4-dihydronaphthalenes provided allylnaphthalenes h10SL2151i. Only substrates containing electrondonating groups proceeded regioselectively, indicative of the involvement of a benzyl cation intermediate.
O MeO
+
AuCl3 (2 mol%) SiMe3 (2 equiv.)
CH2Cl2 -40 ⬚C, 0.5 h 88%
MeO
A trisubstituted tetrahydrofuran derivative, as shown below, underwent an aldol reaction with ethyl diazoacetate to generate an intermediate adduct which transformed into the D4-oxocene core of (þ)-laurencin via an intramolecular oxocarbenoid insertion followed by b-silyl fragmentation/ring expansion h10OL4712i.
Five-Membered Ring Systems: Furans and Benzofurans
H BnO
O
N2
SnCl2
O
EtO
CO2Et BnO
N2
BnO O
OH
CO2Et
O
CH2Cl2 23 ⬚C 20–25%
SiEt3
O
203
OH SiEt3
Tetrahydrofuran was ring-opened by 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one, in the presence of a Lewis or Br nsted acid, to form a trifluoromethyl ether h10JOC1779i. The enolate of acetaldehyde, derived from the ring opening of tetrahydrofuran using n-BuLi at room temperature, reacted with benzynes and unsaturated esters (or dihydroisoquinolines) in a three-component coupling to form 1,2,3,4-tetrahydronaphthalen-1-ol derivatives h10T569i. The tetrahydrofuranyl radical could be generated from unstabilized THF using atmospheric oxygen as an initiator and allyl chloride (or benzyl chloride) as a propagator and underwent addition to imines and alkynes h10TL5980i. Moreover, the 2-chlorotetrahydrofuran intermediate formed reacted with alcohols to provide tetrahydrofuranyl ethers. As shown below, 2-tetrahydrofuranyl radical also reacted with fluoro(silyl)acetylenes and fluoro(stannyl)acetylenes, generated in situ by lithiation of 1,1-difluoroethylene, to provide the (E)-isomers as the major products h10JOC8326i. O + F
SiMe2Ph
O
-78 ⬚C to rt 78% E : Z = 84 : 16
SiMe2Ph F
Tetrahydrofurans can be oxidized at the a-carbon to form g-lactones by hydrogen peroxide in the presence of a chiral iron catalyst Fe(PDP). This transformation is highly selective in the presence of other secondary and tertiary C H bonds as illustrated by the example shown below h10SCI566i.
O
H2O2 (3.6 equiv.) AcOH (1.5 equiv.) Fe(R,R-PDP) (15 mol%)
O O
MeCN 25 ⬚C 80%
5.3.3. SYNTHESIS 5.3.3.1 Furans The synthesis of several furan-containing natural products were reported in 2010 h10SL2875, 10T2492, 10T8605i, including the synthesis of 2,3,5-trisubstituted furan-containing nakadomarin A h10OL1800i. Furan 2-carboxylic acid was converted into thieno[3,4-b]furan through a series of conventional procedures h10TL2089i. The syntheses of phenathrene-tethered furan-containing cyclophenes
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K.-Sun Yeung et al.
were also reported h10JOC4591i. A sequence of tandem Knoevenagel condensation–cyclization of a-epoxy aldehyde with a b-keto ester to form polysubstituted furans was used in the synthesis of furanocembranoid macrocycles h10TL5044i. Cross-coupling reactions continue to show utility in the synthesis of arylsubstituted furans h10TL2657, 10EJI1798, 10OL4022i, and direct arylation at the 5-position of 2-acylfurans using a Pd-catalyst was also reported h10S3927i. Functionalization at the 3-position of furan was realized via the reaction of 3-furyllithium with Ti(i-OPr)3Cl at 78 C in THF to give [(3-furyl)Ti(i-OPr)3]2, addition of which to carbonyl compounds in the presence of catalytic BINOL provided the corresponding optically active carbinols in high yields and high ee h10OL48i. A palladium-catalyzed oxidative Heck reaction of 3-fluoro-substituted furans with alkenes was developed to afford tetrasubstituted furans in moderate to good yields h10T8387i. 3-Alkyne-1,2-diols were used by many authors in 2010 as versatile starting materials for the synthesis of multi-substituted furans. A previously reported procedure for Ag-catalyzed 5-endo-dig cyclization of 3-alkyne-1,2-diols was adopted to prepare 5-substituted 2-furylacetic acids h10TL717i. Furan-3-carboxylates were produced when 3-alkyne-1,2-diols underwent Pd-catalyzed direct oxidative carbonylation reactions h10TL1663i. CuCl2 was also used as a catalyst in the reaction of 3-alkyne-1,2-diols to afford 2,3,5-trisubstituted furans h10TL3565i. A Au(I)-catalyzed hydration of symmetric and unsymmetric 1,3-diynes to 2,5-disubstituted furans was described h10OL2758i. A procedure for the synthesis of highly substituted furans in good yields using 1,3-dicarbonyl compounds and b-nitro-a,b-unsaturated carboxylates in the presence of acidic Al2O3 was developed h10SL2468i. g-Hydroxyketones, synthesized from a Cu-catalyzed three-component reaction, were converted into polysubstituted furans h10CC2865i. Polysubstituted 3-trifluoromethylfurans were prepared from 2-trifluoromethyl-1,4-diketones, which were obtained from Pummerer reactions of 2-(2,2,2-trifluoroethylidene)-1,3-dithiane-1oxide with ketones h10AGE2340i. Fluorine-containing polysubstituted furans were also synthesized by Rh-catalyzed [3 þ 2]-cycloadditions of fluoracetyl-containing diazo compounds with aromatic alkynes h10T1261i. A three-component reaction involving isocyanides, acetylene dicarboxylates, and aldehydes (instead of carboxylic acids as previously used) gives tetrasubstituted furans h10S2069, 10S2571i. Similarly, coupling of aldehydes, isocyanides, and active methylene species (including 5,5dimethylcyclohexane-1,3-dione, N,N0 -dimethylbarbituric acid and cyclohexane1,3-dione) produced highly substituted furans in high yields h10HCA2189i. Several examples of the use of carbohydrates as starting materials in the synthesis of furans were reported in 2010. As depicted below, functionalized a-cyanomesylates, derived from D-allose, D-arabinose, or D-threose, reacted with TMSN3 and Bu2SnO to provide polyhydroxylated furans via a cascade of reactions h10T736i. Stereoselective synthesis of furyl amino acids using D-aldopentose h10EJO3110i was used in the preparation of a C3-symmetric furyl-cyclopeptide h10EJO4049i. The conversions of glucose into 5-hydroxymethylfurfural by enzymatic methods
205
Five-Membered Ring Systems: Furans and Benzofurans
h10CC1115i and fructose into the liquid fuel 2,5-dimethylfuran using formic acid h10AGE6616i were also reported. O O
TMSN3 Bu2SnO
O OMe NC OMs
O
O
HO
O
+
toluene, 100 ⬚C
O
OH 28%
O
23%
O
Heterogeneous catalytic hydrogenation of unsaturated 1,2,4-trioxanes using Lindlar catalyst in MeOH provided 2,5-disubstituted furans in good yields h10TL804i. O O O
H2 (1 atm.) Lindlar catalyst O
MeOH 70%
O
A 2,3-disubstituted furan was obtained when a furanyl-substituted ynone was treated with Echavarren’s Au(I)-catalyst, as shown below h10CC5483i. t-Bu t-Bu P Au
O O
Au(I) (1 mol%)
O
DCM, 18 ⬚C quantitative yield
O
+
–
SbF6 NCMe
Ph Au(I)
As illustrated below, a short synthesis of furo[2,3-b]indoles using 2-aryl-4-pentanals as starting materials via oxidation–reduction steps was achieved h10TL4494i. CHO 1. O3, dry DCM, Me2S
O
2. Na2S, NaHCO3 MeOH, reflux, 12 h 83%
NO2
N H
A computation-designed regiodivergent Au-catalyzed cycloisomerization reaction of propargyl and allenyl ketones affords silyl furans in high yields h10JA7645i. OMe
SiMe3
O
SiMe3 Ph3PAuSbF6 (5 mol%) 0.05 M in DCM, rt 91%
O OMe
3,30 -Bis(pyrrol-2-yl)-2,20 -bifurans were obtained from a single-electron oxidative coupling of the corresponding pyrrolyl furans using ammonium cerium nitrate h10EJO823i.
K.-Sun Yeung et al.
206
O
O
E
CAN -25 ⬚C, 0.5 h 54%
N PMP O
PMP
E N
N
PMP
E = CO2Me
E
Successive treatment of ketal-functionalized nitroalkanes with Amberlyst A21 and Amberlyst 15 provided 2,5-disubstituted furans in good yields h10CC6165i. 1. Amberlyst A21 AcOEt, rt
O O
O
+ NO2
OBu
H
OBu O
2. Amberlyst 15 AcOEt, 50 ⬚C 78%
O
O
An efficient Cu-catalyzed intramolecular O-vinylation of ketones was developed for the synthesis of multi-substituted furans h10TL3678i. CuI (10 mol%) L (20 mol%)
O Ph
L:
CsCO3 (200 mol%) dioxane, reflux 58%
Br
O
Ph
N
N
Preparation of 3,4-disubstituted furans was realized using Pd-catalyzed coupling/ cycloisomerization of 1,6-enynes with aryl halides h10JOC582i. Ph O
+
CO2Et
Pd(O Ac)2/PPh3
CO2Et O
DMF, Bu3N, 140 ⬚C 75%
Br
Ph
When bis-propargyl ethers with S- or Se-functional groups were treated with a sodium alkoxide, 2,3,4-trisubstituted furans were produced in high yields h10OL4192i. PhS
PhS
OMe
NaOMe OMe O
dioxane, rt 99%
O MeO
Optically active trisubstituted 2-aminoalkylfurans were obtained from a,b-unsaturated aldehydes in one pot via enantioselective aziridination using a chiral pyrrolidine as a catalyst and subsequent condensation with 1,3-dicarbonyl compounds in the presence of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) as a base h10JA17886i. 2-Hydroxyalkylfurans were synthesized in the same manner through epoxidation.
207
Five-Membered Ring Systems: Furans and Benzofurans
1. Catalyst (2.5 mol%) TsNHOTs AcONa DCM, rt, 24 h
CO2Me
O
2. MeCOCH2CO2Me MTBD
NHTs
OSiMe3
Ar = 3,5-(CF3)2C6H3
68% yield 95% ee
DCM, rt 3. TFA, DCM, rt
Ar
N H
Pr
O
Pr
Ar
catalyst
Regioselective synthesis of trisubstituted furans with an alkoxy group at the 2-position, from transition metal-catalyzed ring opening reactions of cyclopropene derivatives, was developed. 2,3,4-Trisubstituted furans were produced using a copper catalyst, while 2,3,5-trisubstituted furans were obtained if a ruthenium catalyst was used h10CAJ2415i. MeO2C
Bu
RuCl2(PPh3)3
MeO2C
THF, rt 95%
Bu
MeO2C
OMe
O
Trisubstituted furans were also obtained by Cu-catalyzed coupling of 3-iodoprop-2-en-1-ols with 1-alkynes followed by cyclization h10CAJ74i. Ph
Ph Ph
CuI/L-proline
+ I
OH
Cs2CO3, dioxane 80 ⬚C 83%
Ph
O
Pt-catalyzed reaction of b-cyano-a,b-unsaturated ketones with propargyl carboxylates produced a-alkylidene-N-furylimines in moderate to good yields h10CC3366i. EtO2C
Et O2C
OAc
Pt Cl2 (10 mol%)
+
Ph
NC
Ph
O
toluene, 70 ⬚C 58%
N
Ph
O
Ph
OAc
Tandem rearrangement–nucleophilic substitution of a-acetoxy alkynyl oxiranes using a Au-catalyst led to highly substituted furans in high yields h10EJO1644i. OAc O
C6H13
MeOH Ph3PAuSbF6 (5 mol%) CH2Cl2, rt 95%
OAc O
C6H13
Reaction of electron-deficient alkynes with 2-yn-ols in a one-pot cascade fashion using a nano-CuO2 catalyst provided fully substituted furans h10CEJ10553i.
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K.-Sun Yeung et al.
CO2Et
1. PBu3, CH2Cl2, rt + Ph
EtO2C
2. nano-C uO2 DMF, 50 ⬚C 67%
OH
Ph
CHO
O
2,5-Diaryl-substituted 3-fluorofurans were generated by a Ph3AuCl/AgOTf-catalyzed cyclization of 2-mono-fluorobut-3-yn-1-ones, prepared from the fluorination of 1,4-disubstituted tert-butyldimethylsilyl but-1-en-3-yn-1-yl ethers using Selectfluor h10ASC2761i. The utility of 2-yne-enones in the efficient synthesis of polysubstituted furans having different structural features was further demonstrated by several groups in 2010. As shown below, a Rh-catalyzed domino heterocyclization–[(3 þ 2) þ 2]carbocyclization was developed to construct fused tricyclic furans based on the previous Rh-catalyzed domino nucleophilic addition–bicyclization of diyne-enones with alcohols h10CC7816i. When alcohols instead of aryl acetylenes were used, 2,3-fused bicyclic furans were obtained in good yields h10CC4384i. O
Ph O
Ph
NTs
+
Ph
[RhCl(CO)2]2 (5 mo l%)
NTs Ph
CO/N2 (1/4, 1 atm.) DCE, 60 ⬚C 45%
Ph
Ph
Fully substituted furans were formed using yne-enones as starting materials and the carbophilic IPrAuOTf as a catalyst h10CC6593i. Tetrasubstituted furans were also synthesized via a three-component domino reaction in high yields and under mild reaction conditions by using a Pd/Cu cocatalyst system, as exemplified below h10CC8839, 10TL3417i. O
Ph
Pd(OAc)2 (5 mol%) CuI (10 mol%) Ph2I+ PF6-
Ph MeO
MeOH/DMSO (1/10) 35 ⬚C 72%
Ph
Ph
O
Ph
Related reactions of the same yne-enone substrates with a,b-unsaturated imines using a Au-catalyst produced highly substituted furo[3,4-c]azepines in high yields h10CEJ456i. Ph O
Ph
N
+ Ph
Ph
Ph N
Ph3PAuOTf (5 mol%) CH2Cl2, 4 Å MS 85%
Ph
Ph O
Ph
Five-Membered Ring Systems: Furans and Benzofurans
209
Polysubstituted furans were produced in good yields from Au- or Pd-catalyzed reactions of 4-alkyn-2-ene-1,6-diols, which were obtained through Sonogashira reactions of 3-iodoalk-2-en-1-ols with terminal propargyl alcohols h10JOC2589i. Ph
C5H13
Au(PPh3)Cl (2 mol%) AgOTf (2 mol%)
Ph
CH2Cl2, 25 ⬚C 81%
HO
C5H13
O
HO
Cu-catalyzed reactions of 1,3-dicarbonyl compounds with alkynoates produced tetrasubstituted furans via an addition-oxidative cyclization process h10JOC966, 10SL1071i. SnCl2/CuI (10 mol%) DDQ (200 mol%)
CO2Et O
O
+
toluene, 100 ⬚C, 4 h 80%
CO2Et
EtO2C EtO2C
O O
Reactions of electron-deficient alkynes and 2-yn-ols in a one-pot manner under iron catalyzed conditions provided highly substituted furans in good yields h10JOC5347i. O
1. PBu3, DABCO CH2Cl2, rt
OEt
+ 2. Fe(ClO4)3˙xH2O DMSO, 80 ⬚C 57%
Ph HO
EtO2C Ph
O
CHO
A three-component cascade using a nucleophilic carbene for the synthesis of fully substituted furans was reported. Imidazo[1,5-a]pyridine carbenes reacted with aldehydes and acetylenedicarboxylates or allenoates to provide tetrasubstituted furans in moderate yields h10JOC6644i. MeO2C CO2Me
O N Bn + H – Cl
+ Cl
NBn
NaH/DBU
+
N
CH2Cl2, -20 ⬚C CO2Me
CO2Me CO2Me
N
42%
O
CO2Me
Cl
An intramolecular Wittig reaction was developed to synthesize tetrasubstituted furans. When Michael acceptors reacted with acid chlorides in the presence of Bu3P and Et3N, fully substituted furans were obtained in good to excellent yields h10OL3066i.
210
K.-Sun Yeung et al.
NC
Bu3P (1.1 equiv.) 4-ClC6H4COCl (1.1 equiv.)
COPh
CN
Et3N (1.3 equiv.) THF, rt 84%
O
Ph
Cl
A photoredox-promoted direct intermolecular C2-H functionalization of furan with diethyl bromomalonate was achieved using the visible light-induced reductive quenching pathway of Ru(bpy)3Cl2 h10OL3104i.
CO2Et O
Ru(bpy)3Cl2•6H2O (0.01 equiv.) 4-MeOC6H4NPh2 (2 equiv.) visible light
CO2Et
Br
+
CO2Et
O
DMF, rt, 24 h 67%
CO2Et
5.3.3.2 Di- and Tetrahydrofurans An asymmetric total synthesis of trilobacin, an annonaceous acetogenin with potent anticancer activities, featured a novel organoselenium-mediated oxonium ion formation/SiO2-promoted fragmentation protocol for the construction of the erythro-bis (2,20 )-tetrahydrofuran core in high stereoselectivity h10JA12226i.
OBn PMBO H BnO
O H H
R2
R1 R1 = n-C10H21 R2 = (CH2)5OBn
PhSeCl SiO2 K2CO3 CH2Cl2 rt, 24 h 83%
Cl
H OBn
BnO H
O H HO
H
R1
R2
The bridged tetrahydrofuran moiety of the cortistatin core was created by a regioselective opening of an epoxide to an allylic alcohol intermediate that underwent subsequent oxidative dearomatization/cyclization h10T4696i. OMe
Me
Et3SiO O H
OSiMe2t-Bu
1. n-BuLi THF, 0 ⬚C 2. PhI(OAc)2 CH2Cl2, i-PrOH CF3CH2OH,−78 ⬚C 57% (2 steps)
OMe
Me
O
OSiMe2t-Bu
O H
A formal synthesis of eurylene was achieved where both cis- and trans-tetrahydrofuran fragments were prepared using diastereo- and chemoselective permanganatemediated oxidative mono-cyclizations of trienes h10OL2468i. The tandem oxidative reactions mediated by hypervalent iodine(III) reagents were presented as attractive methods for the synthesis of tetrahydrofuran ring-containing natural products
211
Five-Membered Ring Systems: Furans and Benzofurans
h10T5863i. The reaction of furan with the very electrophilic phenoxenium species, generated using (diacetoxyiodo)benzene, proceeded via a formal oxidative [2 þ 3] cycloaddition process to furnish terahydrofuran-containing tricyclic compounds, as exemplified below h10T5893i. OH
O
O PhI(OAc)2
+ −H
O H +
CF3CH2OH rt
61%
t-Bu
O t-Bu
O
t-Bu
A remarkable double [3 þ 2] photocycloaddition reaction, which occurred in a sequential manner via a meta photocycloadduct, resulted in the formation of the hexahydrofuro[2,3-b]furan-containing fenestrane h10JA4i. H
H O
H
hv (254 nm)
O
O
hv (254 nm)
O MeO
cyclohexane 16 h 38%
H OMe
cyclohexane 4h 8% (isolated)
O H O
H OMe
H
H
hv (254 nm) cyclohexane, 18 h 8%
The densely substituted tetrahydrofuran tricyclic core of punctaporonin C was regio- and diastereoselectively synthesized via a pivotal intramolecular [2 þ 2] photocycloaddition between a vinylic double bond and a photoexcited tetronate h10CEJ6015i. O
O AcO
O
AcO
1. hv, i-PrOH, −75 ⬚C 2. K2CO3, MeOH −20 ⬚C, 60%
O (i-Pr)3SiO
O
(i-Pr)3SiO
OMe OH
A new method for the synthesis of the tetrahydrofuran ring involved ozonolysis of a diene and subsequent ring closing by a free hydroxy group. The cyclization event was rationalized through the formation of a Criegee carbonyl oxide h10TL4079i. OH O3 NaBH4 (work-up) OH
CH2Cl2 0 ⬚C to rt 60%
O
212
K.-Sun Yeung et al.
A method for the diastereoselective synthesis of the core 2,3-cis-THF ring system of cordigol, a fungicidal polyphenol from the stem bark of Cordia goetzei, through an SnBr4-promoted oxonium-Prins pathway driven by the preference of a styrenyl alkene to ring close via a benzylic cation was described h10OL900i.
OH
+ Ph
H
SnBr4 Me3SiBr
CHO
Ph
O H
CH2Cl2, −78 ⬚C 92%
Polycyclic products containing a 12-oxatricyclo[6.3.1.0]dodecane moiety with either a trans or a cis relative configuration of the oxacyclic bridge and cis angular substituents were formed stereospecifically by Prins-pinacol cyclization of a-dithianyl acetals h10JOC455i. Me CHO
S SnCl4
S MeO
O
O
CH2Cl2, 0 ⬚C 81%
Me OSi(i-Pr)3
S H
S
Treatment of the aldehyde shown below under Marson-type cyclization conditions achieved the synthesis of a brussonol analogue in a tandem fashion h10TL686i. OSiMe3
OMe OMe
MeO
SnCl4 or BF3•Et2O
O
CH2Cl2 −78 to 0 ⬚C 90–95%
O
OMe
H
H
a-Mono- or a-dialkylated aldehydes underwent cyclotrimerization in the presence of dibromotriphenylphosphorane (PPh3Br2) to afford tetrasubstituted tetrahydrofuran derivatives via a tandem aldol dimerization/Prins cyclization in good yields h10EJO966i. Me O
Me
CH2Cl2, r t H
Me Me
PPh3Br2
70%
OH
Me O
Me
Me Br Me
The first platinum-catalyzed enantioselective preparation of 8-oxabicyclo[3.2.1] octane derivatives via an asymmetric [3 þ 2]-cycloaddition reaction of a platinumcontaining carbonyl ylide generated from alk-4-yn-1-ones was described h10JA8842i.
Five-Membered Ring Systems: Furans and Benzofurans
i-Pr O
PPh2
PtCl2-Walphos AgSbF6
+
OBn
213
O i-Pr
P(3,5-xylyl)2 Fe
CH2Cl2, rt 89% 90% ee
Me
BnO Me Walphos
A new AuCl3-catalyzed cascade reaction based on an initial cycloisomerization reaction of enynol or enynamine derivatives to form 1,3-butadiene derivatives that then underwent an in situ Diels–Alder cycloaddition reaction with dienophiles was described. This process afforded interesting fused or spirocyclic tetrahydrofuran compounds, as illustrated below h10CEJ7110i. OH
NC
CN
NC
CN
+
AuCl3 (3 mol%)
NC O
ClCH2CH2Cl reflux 80%
Me
CN CN CN
Me
A 2,3-trans-substituted tetrahydrofuran intermediate for synthesis of (þ)-varitriol was constructed using a key threo-diastereoselective Pd(II)/Cu(II)-catalyzed intramolecular bisalkoxylation of unsaturated triol, followed by exo-regioselective ring opening of bicyclic dianhydroalditol h10T5244i. BnO
PdCl2, CuCl2 AcONa
HO OH
BnO
Me3SiCl, TBAI HCl
O
AcOH rt,12 h 83%
O
HO
OBn I
CH2Cl2 rt, 3 days 76%
O
Two asymmetric total syntheses of ()-englerin A were achieved via a key transformation involving a gold-catalyzed alkyne/alkene/carbonyl cyclization of 1,6-enynes bearing a carbonyl group to form a bridged tetrahydrofuran, as exemplified below h10AGE3513, 10AGE3517i. Me Me
Me
Me
Me AuCl
Me O
OH
CH2Cl2 rt 48%
Me
O
OH
H Me
The core oxygen-bridged ring system of ()-englerin A was also generated via a Rh2(OAc)4-catalyzed stereoselective 1,3-dipolar cycloaddition of a cyclic carbonyl ylide as depicted below h10OL3418i. A related enantioselective intermolecular 1,3-dipolar cycloaddition of a six-membered cyclic formyl-carbonyl ylide derived from tert-butyl 2-diazo-5-formyl-3-oxopentanoate with phenylacetylene dipolarophiles was achieved by using Rh2(S-TCPTTL)4 as a chiral catalyst h10JOC6039i.
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K.-Sun Yeung et al.
CO2Et
Me N2
O CO2Et
+
CO2Allyl
O O
Me
Rh2(OAc)4
H Me
toluene 100 ⬚C, 1 h 80%
O
CO2Allyl
H Me
A number of new methods reported in 2010 for the synthesis of tetrahydrofurans relied on the formation of C3 C4 bond from propargylic ether substrates via transition metal-catalyzed intermolecular or intramolecular processes. These include a diastereoselective samarium diiodide-promoted intramolecular coupling reaction of bromoalkynes with a,b-unsaturated esters to provided highly functionalized tetrahydrofuran analogs h10OL3026i. An intramolecular Pauson–Khand-type carbonylation method that used primary alcohols as a CO source and [{Rh(CO)Cl(dppp)}2] as a catalyst h10AGE5138i. An interesting Pd-catalyzed multicomponent intramolecular cycloaddition reaction between alkylidenecyclopropanes (3C), alkynes (2C), and alkenes (or a terminal alkyne, 2C) moieties proceeded diastereoselectively to provide tetrahydrofuran-containing [5,7,5] tricyclic systems, as shown below h10CC270i. H
O O
t-Bu
L=
Pd2(dba)3, L
O
CO2Et dioxane, 90 ⬚C 60%
CO2Et H
t-Bu
O
P 3
O
A cationic rhodium(I)/(R)-H8-BINAP complex catalyzed the asymmetric reductive cyclization of oxygen-linked 5-alkynals with heteroatom-substituted acetaldehydes to afford 3-methylenetetrahydrofuryl species h10JA1238i. PhO
O
O H
(CH2)3Ph
+
O
[Rh((R)-H8-BINAP)]BF4 H
PhO
H O
Ph(H2C)3
O
CH2Cl2, rt, 16 h 66%, >99% ee
O
A method to construct highly functionalized tetrahydrofurans with high diastereoselectivity from gold-catalyzed reactions of allylic acetates with propargylic alcohols was developed. The reaction involved intermolecular allylation and intramolecular enyne cycloisomerization h10OL3468i. O
OAc Ph
Me + Me
OH
Au(PPh3)NTf2 CH2Cl2, 30 ⬚C 65%
Ph O
A domino cyclization of 1,6-enyne with 2-bromoarylaldehyde followed by intramolecular aldol condensation under Pd-catalyzed conditions resulted in [5,7,6] tricyclic ring systems h10TL317i.
Five-Membered Ring Systems: Furans and Benzofurans
Pd(OAc)2 NaOAc, LiCl Bu4NBr
CHO
DMF, 100 ⬚C 77%
O
CHO
OH
+ Br
O
215
Highly substituted 3,4-dihalogenated 2,5-dihydrofurans were readily prepared in moderate to excellent yields by electrophilic cyclization of 1,4-butyne-diol derivatives using halogen electrophiles, for example, I2, IBr, and ICl h10JOC5670i. As illustrated below, a copper-catalyzed stereoselective vinyl oxirane ring expansion was performed to access a 2,5-cis- or a 2,5-trans-disubstituted 2,5-dihydrofuran product by using trans- and cis-epoxide starting materials, respectively. The reaction could be rendered enantioselective using certain chiral catalysts and was utilized to accomplish an asymmetric synthesis of goniothalesdiol h10AGE1648i. O
n-Bu
n-Bu
Cu(hfacac)2 (5 mol%) toluene 150 ⬚C, 8 h, 86%
n-Bu
O
n-Bu
A new palladium-catalyzed reaction of propargylic carbonates with 2-substituted cyclohexane-1,3-diones yielded substituted tetrahydrobenzofuran derivatives having a quaternary carbon stereocenter in a highly diastereoselective manner h10T2675i. O OAc
Me
+ Ph
O
Pd2(dba)3•CHCl3 dppf (20 mol%), K3PO4
O
Me
DMSO, 120 ⬚C 85%
Ph O
The first Ag(I)-mediated 1,3-dipolar cycloaddition reaction of N-propargylamides, in which the alkyne functioned as a formal 1,3-dipole, was developed to form furo[3,2b]-b-lactams in a regiospecific and highly diastereoselective manner h10CC1269i. Me
Me Ag2O, DBU
O
H
CH3CN N
Me
61%
N O
O
Me
O
An efficient oxidative cyclization mediated by the combination of iodosobenzene with tetra-(n-butyl)ammonium iodide in aqueous medium provided functionalized fused dihydrofuran derivatives in moderate to high yields with high diastereoselectivity h10JOC1760i. Ph
O
O Ph O
O
Ph
PhIO, Bu4NI H2O, 30 ⬚C,16 h 85%
O O
Ph
216
K.-Sun Yeung et al.
A one-pot cascade synthesis of substituted dihydrofurans through a Lewis basecatalyzed three-component cascade condensation between nitroalkenes, aldehydes, and 1,3-dicarbonyl compounds was developed h10OL2064i. OMe CHO
O
Me
+
+
O
O
DMSO, rt 83%
O2N
O
OMe
proline (5 mol%) K2CO3
O O
Dihydroindenofurans were synthesized from Baylis–Hillman adducts via a cascade of Pd-catalyzed 5-endo-trig-carbopalladation and enolate O-alkylation as a key step. This represented the first example of enolate O-alkylation with a C(sp3)bound palladium intermediate to form a dihydrofuran ring h10TL4648i. Me MeO2C
MeO2C H
Pd(OAc)2, PPh3 Cs2CO3
O CO2Me Br
Me O
toluene reflux, 22 h 81%
CO2Me
A 3-carbonyl-2,5-dihydrofuran derivative, as shown below, was synthesized by FeCl36H2O-catalyzed intramolecular cyclization of alkynyl aldehyde under mild conditions h10CEJ9264i. Ph O CHO
O
FeCl3.6H2O acetone, 50 ⬚C 90%
Ph O
5.3.3.3 Benzo[b]furans and Related Compounds Cross-coupling/cyclization between 2-halophenols and alkynes continued to be utilized in benzo[b]furan synthesis, including a Pd/hydroxyterphenylphosphine-catalyzed one-pot coupling of 2-chlorophenols with alkynes h10JOC5340i, and synthesis of 2-substituted benzo[b]furans from the reaction of 2-iodophenols and arylacetylenes catalyzed by palladium nanoparticles h10EJO6067i or copper triflate h10T2077i. Acetylenic 8-quinolinols, generated in situ by the Sonogashira cross-coupling reaction, were converted into furo[3,2-h]quinolines by microwave-assisted, copper-catalyzed intramolecular cyclization in the presence of basic alumina h10S486i. New conditions for the intramolecular cyclization of 2-alkynyl phenols to benzo[b]furans continue to be developed. Examples in 2010 include a highly active heterogeneous Pd-nanoparticle catalyst h10JA16771i, an electrophilic platinum nanoparticles/hypervalent PhICl2 system h10NC36i, rhodium(I) catalysts h10T6468i, and a heterogeneous gold-catalyzed system for the formation
Five-Membered Ring Systems: Furans and Benzofurans
217
of 3,30 -bisbenzofurans h10SL2443i. An interesting copper iodide-promoted biscyclization, a key step in a synthesis cytotoxic bis(benzo[b]furan derivative laetirobin, is shown below h10CAJ342i. CuX (X ¼ I, Br, Cl, CN)-induced cyclization of 2alkynyl phenol derivatives to give 3-halo- or 3-cyanobenzofurans was also described h10JOC3412i. Methods involving iodocyclization using 2-alkynylanisoles h10JOC1652i and their applications in the synthesis of furo[2,3-b]pyridin-4-ones and furoquinolinones under microwave irradiation h10S1741i, and by cyclization using PTSA in EtOH h10T3775i and FeCl3 h10JOC5701i, were also reported. O
O
O
O
CuI Et3N
OH
HO
HO OH
DMF 60 ⬚C, 2 h
OH
OH O
O OBn
75%
OBn
Highly substituted furans were generated from 3-(1-alkenyl)-2-alkenals-1-al through a copper(I) chloride-catalyzed addition of water followed by oxidation and cyclization to a naphthofuran under mild conditions h10TL273i. O
Ph Ph
CuCl (10 mol%) H2O CHO
MeO
O
+
O
DMF, air
MeO
Ph
MeO 65%
20%
As shown below, 2,3-bis(arylamino)benzofurans and 2,3-bis(arylimino)2,3-dihydrobenzofurans were prepared via a boron trifluoride etherate-catalyzed reaction of 2-hydroxybenzaldimines with aryl isocyanides h10S666i. N Ph
NHPh N
Ph
cat. BF3.Et2O
+ OH NC
CH2Cl2 0 ⬚C
NH
work up [O]
O 58%
N O
As shown below, 3-acyl-5-hydroxybenzofurans were generated via a copper(II) triflate-catalyzed cyclization of unactivated 1,4-benzoquinones with 1,3-dicarbonyl compounds h10TL2136i. Unsymmetrical 1,4-benzoquinones proceeded with complete regioselectivity. The construction of a fully substituted benzo[1,2-b:4,5-b0 ]difuran was accomplished by a base-catalyzed double annulation of 2,5-diiodo-1,4-benzoquinone with malononitrile h10JOC3350i. A BF3-mediated dehydrative cyclization reaction of benzoquinones with stilbene oxides provided 2,3-diaryl-5-hydroxybenzofurans and 2,3-diaryl-5-hydroxydihydrobenzofurans h10TL955i. A cyclization between CuBr2-activated ketene dithioacetals having a-electron-withdrawing groups and BF3-activated 1,4-benzoquinones also provided benzofurans h10ASC884i.
218
K.-Sun Yeung et al.
OH
O O
+
O
Cu(OTf)2 (5 mol%)
Ph
Ph
O
PhMe, reflux, 10 h
Ph
O
95%
O
Ph
A highly regioselective protocol for the synthesis of 3-acyl benzofuran derivatives involved a gold(III)-catalyzed tandem condensation/rearrangement/cyclization reaction of o-arylhydroxylamines with 1,3-dicarbonyl compounds h10JOC6300i. ONH2
O
O
AuCl3/3AgSbF6 (3 mol%)
O
+
CH3NO2, 90 ⬚C
O
82%
Reaction of various perfluorinated heteroaromatic substrates, such as tetrafluoro4-cyanopyridine, tetrafluoropyrazine, and tetrafluoropyridazine, with 1,3-dicarbonyl systems provided the corresponding furo-fused derivatives h10T3222i. O F
N
F
O
NaH, THF
O
+ F
N
reflux, 1 day 71%
OEt
F
F
N
F
N
OEt
O
5-Substituted 3-(1,3-dimethyl-2,3-dihydro-1H-benzimidazol-2-yl)-2-furanamines (masked 2-amino-3-furancarboxaldehydes) reacted with malononitrile to give 2-substituted 6-aminofuro[2,3-b]pyridine-5-carbonitriles h10S1009i. Ph
N O
N
CH2(CN)2 cat. NH4Cl
NC
69%
H 2N
H 2N
N
O
Application of a palladium-catalyzed intramolecular direct arylation/isomerization sequence to phenol derivatives provided access to a broad range of substituted benzofurans, as exemplified below h10AGE7958i. Benzo[4,5]furo[3,2-b]pyridine compounds could be generated via a similar approach h10SL77i.
MeO
Br O
1. Pd(OAc)2 (10 mol%) X-Phos (20 mol%), K2CO3 DMA, 80 ⬚C, 1.5 h 2. PTSA (10 mol%) CH2Cl2, rt, 3 h, 86%
MeO O
Decarboxylative homocoupling of benzofuran-2-carboxylic acids using a Pd/Ag catalysis system furnished symmetrical dibenzofuran derivatives, as depicted below h10CC8276i.
Five-Membered Ring Systems: Furans and Benzofurans
Pd(TFA)2 ( 7.5 mol%) Ag2CO3 (1.0 equi.) CO2H O
219
O
DMF/DMSO, 120 ⬚C 78%
O
Synthesis of ()-frondosin B was achieved by employing a Stille–Heck sequence on 2-chloro-5-methoxybenzo[b]furan-3-yl triflate with 2-(3-butenyl)-3-(trimethylstannyl)cyclohex-2-enone, leading to the racemic natural product in 34% overall yield h10OBC1290i. As depicted below, 2,3-diarylbenzofurans containing two different aryl groups were prepared from 2,3-dibromobenzofuran by sequential addition of two different boronic acids in a one-pot regioselective palladium-catalyzed cross couplings h10TL2420i. 1. 4-MeC6H4B(OH)2 (1 equiv.) Pd(PPh3)4 (5 mol%) aq. K2CO3 (2.0 M) dioxane, 70 ⬚C, 6 h
Br Br O
F
2. 4-FC6H4B(OH)2 (1 equiv.) 70 ⬚C, 6 h 79%
Me O
A concise enantioselective total synthesis of (þ)-frondosin B was achieved starting from an organocatalytic enantioselective conjugate addition of (5-methoxybenzofuran-2-yl)boronic acid to crotonaldehyde to install the sole stereogenic center of the molecule h10CS37i.
MeO O
OH B OH
Me
O
crotonaldehyde catalyst (20 mol%) HF (1.0 equiv.)
N
O
Me Me N Me H .DCA
MeO EtOAc, 23 ⬚C 84%, 93% ee
O
Me
N Bn
catalyst
A total synthesis of diptoindonesin G was completed via a dehydrative cyclization/intramolecular Friedel–Crafts acylation/regioselective demethylation sequence from an aryloxyketone using BCl3 to construct the tetracyclic skeleton in one pot h10OL5314i. HO
OMe
O MeO
O
OMe
OMe
O
BCl3 (5 equiv.)
CO2Me
CH2Cl2, rt 95% MeO
O
A variety of phenols were directly converted into the corresponding 2-methylthio-3-trifluoromethylbenzo[b]furans by triflic anhydride-mediated Pummerer annulation reactions with trifluoromethylketene dithioacetal monoxide h10JA11838i.
220
K.-Sun Yeung et al.
O
OH
+
O SMe
Tf2O (2 equiv.)
SMe
n-Bu
CF3
CH2Cl2, 0 ⬚C, 30 min 89%
SMe n-Bu
CF3
When 3-bromomollugin was thermally activated, a retro-oxa-6p pericyclic reaction occurred to form the interesting isopropenylfuromollugin h10JOC2274i. OH
OH
O OMe
O
Br
2 M NaOMe (3 equiv.) CuI (5 mol%) MeOH, heat, 56 h 50%
O OMe
O
Flash vacuum pyrolysis (FVP) of aryl 2-(allyloxy)benzoates produced dibenzofurans, with para-substituted substrates proceeding more efficiently, leading to 2-substituted analogs h10OBC2961i. O FVP O O
650 ⬚C 62%
O
2-Methylene-2,3-dihydrobenzofuran-3-ols reacted with thiol derivatives, including alkyl thiols, thiophenol, and thioacetic acid, leading to 2-thiomethylbenzofurans. The allylic substitution process was catalyzed by acid or promoted by a radical initiator h10EJO3459i. DME:H2SO4 (9 : 1) 90 ⬚C, 81% OH
DME, AIBN, 74%
O
O
SPh
DME, BP, 80%
A phosphine-catalyzed reaction of allylic carbonates, which served as 1,1-dipoles, with salicyl N-thiophosphinyl imines gave substituted trans-2,3-dihydrobenzofuran skeletons with high diastereoselectivity h10OL3768i. 2,3-Dihydrobenzofurans containing a quaternary C2 center were generated from Pd(hfacac)2-catalyzed oxidative intramolecular oxyalkynylation of nonactivated 2-(2-methylallyl)phenol using (triisopropylsilyl)acetylenyl benziodoxolone-derived hypervalent iodine as an alkyne transfer reagent h10OL384i. A synthesis of trans-dihydrobenzofurans was achieved from
221
Five-Membered Ring Systems: Furans and Benzofurans
o-aminophenols and phenylpropenes via a one-pot diazotization and diastereoselective Pd-catalyzed oxyarylation, as shown below h10OL1976i.
O
+
1. NOPF6 (1 equiv.) CH3CN, 0 ⬚C, 2 h
H2N
O 2. Pd2(dba)3 (5 mol%) ZnCO3 (2 equiv.) rt, 20 h, 83%
O HO
OMe
O
OH
O
OH
MeO
Reaction of 1,3-dienes with o-iodoaryl acetates under palladium-catalyzed annulation conditions led to dihydrobenzofurans with good regioselectivity and stereoselectivity h10JOC4131i. A phosphine-free annulation of 3-alkyl-1,2-dienols with o-iodophenols was exploited to generate 2,3-dihydrobenzofurans, as shown below h10OBC2020i. Me
OH
+ OCH2OEt
I
Me
Pd(OAc)2 NaOAc, TBAB DMSO, 110 ⬚C, 1 h
OCH2OEt
93%, E/Z = 90/10
O
Arenediazonium salts were employed for the synthesis of a series of dihydrobenzofuran acetic acid derivatives via a domino Heck–Matsuda coupling–carbonylation reaction h10TL2102i.
NaOAc, MeCN, rt 56%
N2BF4
Cl
O
Pd(OAc)2 (10 mol%) Mo(CO)6 (1.5 equiv.)
O
Cl CO2H
An asymmetric synthesis of a hexahydrodibenzofuran core structure with a quaternary stereogenic center was achieved using a Pd-catalyzed intramolecular Heck reaction, as shown below h10OBC4831i. This method was also applied in a total synthesis of ()-morphine h10CAJ2192i. O
H
Pd(OAc)2 (cat.) Ag2CO3, PPh3 O BnO
I
PhMe, 80 ⬚C, 16 h 95% d.r. = 14 : 1
BnO
As shown below, the annulation of 2-(1-hydroxy-3-arylprop-2-ynyl)phenols, that led to key intermediates for the formation of aurones, was catalyzed by silver nanoparticles or carbon black-supported silver nanoparticles (CSNs) and in the presence of a phosphine ligand in a toluene-water mixed solvent system h10TL6722i.
222
K.-Sun Yeung et al.
CSNs (10 mol%) i-Pr2NEt (10 mol%) Ph3P (10 mol%)
OH Br
OH
Br
O
toluene : water (1 : 3) rt, 2 h
OH
90%
A Pd(II)-catalyzed CH activation/C O cyclization reaction as directed by a proximate hydroxyl group was developed to construct dihydrobenzofuran rings, including spirocyclic analogs h10JA12203i. Pd(OAc)2 (5 mol%) Li2CO3 (1.5 equiv.) PhI(OAc)2 (1.5 equiv.) H
OH
C6F6, 100 ⬚C, 36 h
O
88%
Boron enolates, generated from a gold-catalyzed intramolecular addition of boronic acids to the alkyne moiety of ortho-alkynylbenzeneboronic acids, underwent aldol reaction with aldehydes to give cyclic boronate esters which could be converted into dihydrobenzofurans, as shown below h10JA5968i. OH B(OH)2
PrCHO PPh3AuNTf2 (0.5 mol%)
B
O O
CH2Cl2 rt,3 h
Bu
Cu(OAc)2.H2O (5 mol%) Pr
O
Bu
Pr
MeOH, 40 ⬚C, 10 h 75%, trans : cis = 79 : 21
O
Bu
5.3.3.4 Benzo[c]furans and Related Compounds A Cu(OTf)2-catalyzed regioselective 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol furnished functionalized phthalan in high yields h10TL4767i. A [Rh(cod)Cl]2/cationic 2,20 -bipyridyl system catalyzed the [2 þ 2 þ 2] cycloaddition between a,c-diynes and alkynes in water and under air to give benzofurofuran derivatives h10T7136i. An novel Rh(I)-catalyzed formal [2 þ 2 þ 2] cycloaddition between 1,6-diynes and potassium (Z)-(2-bromovinyl)trifluoroborates provided an access to highly substituted benzo[c]furan derivatives, as demonstrated below h10CC3800i. Ph
Ph
+
Bu O
Br O
Ph
Rh(OH)(cod) PPh3, CsF
Bu BF3K
dioxane/H2O 5 h, 70%
Ph
Five-Membered Ring Systems: Furans and Benzofurans
223
The first Rh(I)-catalyzed [3 þ 2 þ 1] carbonylative carbocyclization reaction of ene- and yne-cyclopropene systems demonstrated the use of the highly strained cyclopropene ring as a three-carbon component to provide polysubstituted benzo [c]furan structures h10OL3082i. H O Ph
CO [Rh(CO)2Cl]2
OH O Ph
ClCH2CH2Cl, 80 ⬚C Ph
78%
Ph
Formal intermolecular or intramolecular thermal [2 þ 2 þ 2] cycloadditions involving propargylic ene reaction/Diels–Alder cascade reaction formed functionalized benzo[c]furan compounds, as demonstrated by the intermolecular example shown below h10JA11039i. CO2Me
Bu
+
O H
CO2Me
Bu DBU toluene, 160 ⬚C 21 h, 75%
CO2Me O CO2Me
A sequence of reductive ring opening of benzo[c]furan, followed by reaction of the dianionic intermediate with chiral aldimines, provided amino-alcohols, as shown below. Cyclization of the amino-alcohols gave substituted tetrahydroisoquinolines with high enantiomeric purity h10EJO2893i. Li, DTBB; ZnMe2 (0–20 ⬚C) PhCH = NS(O)t-Bu O
Ph HN
−65 ⬚C, 12 h 78%, d.r. = 86 : 14
OH
S
O
tBu
ACKNOWLEDGEMENTS The authors thank Prof. Henry N. C. Wong for advice and assistance. X. L. H acknowledges with thanks support from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. K. S. Y. thanks Dr. Nicholas A. Meanwell for support.
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Five-Membered Ring Systems: Furans and Benzofurans
10EJO4049 10EJO5471 10EJO6067 10HCA169 10HCA272 10HCA698 10HCA746 10HCA870 10HCA920 10HCA1101 10HCA2189 10JA4 10JA1238 10JA4600 10JA5968 10JA7645 10JA8219 10JA8842 10JA9558 10JA11039 10JA11838 10JA12203 10JA12226 10JA15887 10JA16771 10JA17886 10JNP51 10JNP83 10JNP123 10JNP127 10JNP221 10JNP263 10JNP541 10JNP563 10JNP598 10JNP644 10JNP806 10JNP835
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CHAPTER
5.4
Five-Membered Ring Systems: With More than One N Atom Larry Yet Albany, NY, USA
[email protected]
5.4.1. INTRODUCTION The synthesis and chemistry of pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, and tetrazoles were actively pursued in 2010. No attempt was made to incorporate all the exciting chemistry and biological applications that were published in 2010.
5.4.2. PYRAZOLES AND RING-FUSED DERIVATIVES Hydrazine additions to 1,3-difunctional groups are the most common method for the preparation of pyrazoles. A series of 5-substituted-1H-pyrazoles 2 were efficiently synthesized from the reaction of b-dimethylaminovinylketones 1 and hydrazine sulfate in solid state on grinding in the presence of p-toluenesulfonic acid or in refluxing ethanol h10TL3193i. The reaction of ethyl 5-acetyl-3,4-dihydropyridine-1(2H)-carboxylate 3 with diverse aliphatic and aromatic monosubstituted hydrazines resulted in the regioselective formation of N-substituted-3-methylpyrazoles 4 h10S1781i. 1,10-Carbonyl-bis[3-aryl(heteroaryl)-5-trihalomethyl-1H-pyrazoles] were synthesized in one-pot method from the reaction of 4-methoxy-4-aryl(heteroaryl)-1,1,1-trihalobut-3-en-2-ones with 1,3-diaminoguanidine monohydrochloride h10JHC1073i. b,b-Dibromoenones 5 were converted to 1,3,5-trisubstituted pyrazoles 6 via a tandem hydrazine condensation/Suzuki–Miyaura cross-coupling reaction h10SL602i. Reaction of trifluoroacetylated enol ethers with hydrazines in the presence of diethylaminosulfur trifluoride (DAST) was applied in the dehydration, intramolecular cyclization, and mono- and difluorination reactions of some 5-trifluoromethyl-1H-pyrazoles h10TL3759i. A small molecule library of alkyl, sulfone, and carboxamide functionalized pyrazoles was developed via a rapid sequential condensation of various a-acylketene dithioacetals with hydrazine hydrate, followed by oxidation of sulfide to sulfone using water as the reaction medium h10JCO176i. A one-pot method for the synthesis of N-(1,3-diphenyl-1H-pyrazol-5-yl)amides was developed by cyclization of benzoylacetonitrile and phenylhydrazine in neat conditions followed by acylation h10JHC831i. Two simultaneous publications showed that treatment of b-ketofluoroacetonitriles 7 with hydrazine yielded 3-amino-4-fluoropyrazoles 8 h10OL4648, 10SC2547i. Trifluoromethyl-substituted pyrazoles were prepared from 1-aryl3,4,4,4-tetrafluoro-2-buten-1-ones and hydrazines h10H81349i. Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00008-5
#
2011 Elsevier Ltd. All rights reserved.
231
232
L. Yet
O NMe2
R
NH2NH2.H2SO4 p-TsOH, grinding, solventfree or EtOH, reflux 60–91% R = Me, Ar, 2-thienyl, 2-furyl
1
Me2NNH2 (2 eq.) PhB(OH)2 (2 eq.) Pd(PPh3)4 (5%)
Br
O
Br
R
5
K3PO4 (3 eq.) THF, 65 °C 59–76%
Me
O RNH2NH2 ethylene glycol R
N H
N
Ph
NHCO2Et
3
4 F
O
Me N N R
120 ⬚C 72–86%
N CO2Et
2
N N R
CN
R
EtOH, 80 ⬚C
H2N
F
NH N
8
7
6
R
NH2NH2.H2O
Diazo compounds can be employed as precursors in the preparation of pyrazoles and indazoles. A simple and completely regioselective one-pot Knoevenagel condensation/formal 1,3-dipolar cycloaddition reaction which generated 5-phosphonylpyrazoles 10 through the formation of two CC bonds and one CN bond using aldehydes, cyanoacetic acid derivatives, and Bestmann-Ohira reagent 9 was published h10AG(E)3196i. Similarly, base-mediated reaction of the Bestmann-Ohira reagent with various nitroalkenes such as b-substituted, a,b-disubstituted, and nitroethylene that are part of a carbocyclic or heterocyclic ring provided functionalized phosphonylpyrazoles through a one-pot regioselective reaction at room temperature h10JOC2197i. 2-Thio-3-chloroacrylamides underwent 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles h10OBC2735i. Pyrazoles 13 were prepared from 1,3-dipolar cycloaddition of ethyl diazoacetate 12 with acetylenes 11 in refluxing toluene h10TL5915i. O P(O)(OMe)2
Me N2
9
R1CHO, R2CH2CN KOH, MeOH, 25 ⬚C 78–95%
R1
R2 R1 = Ph, Ar, vinylic R2 = CN, CONHR, CO2Me
P(O)(OMe)2 R NH N
10
N2CHCO2Et 12 toluene, reflux 11–81% R = Ar, pyridyl,
11 (CH2)nOH, CO2R
R EtO2C
N N H
13
Syndones are useful intermediates in the preparation of pyrazoles and indazoles. A review titled, “Recent Developments in the Chemistry of Syndones,” showed reactions of syndones with alkynes leading to pyrazoles and indazoles h10T553i. The [3 þ 2] dipolar cycloaddition of arynes 14 and sydnones 15 provided a rapid and efficient synthesis of 2H-indazoles 16 h10OL2234i. The cycloaddition of 4iodosydnones 17 with terminal alkynes 18 proceeded with excellent regiocontrol to provide 5-iodo pyrazoles 19, which participated smoothly in subsequent CC and C-heteroatom bond forming processes h10JOC984i.
Five-Membered Ring Systems: With More than One N Atom
TMS
N
+ OTf
N
14
N 16
O
R
xylenes, 140 ⬚C 30–99% +
I
N
N Ar
R2 = H, Ar, i-Bu, vinyl, 2-thienyl, 2-pyridyl
O O 15
O N
R
TBAF, THF, 25 ⬚C 63–95%
R
Ar
233
N
R
R = n-Bu, cyclopropyl, TMS, Ph, Bn, Ar
18
Ar
I
N Ar 19
17
Multicomponent reactions were used in the synthesis of pyrazoles. Dialkyl 5-(aryl)-1-phenyl-1H-prazole-3,4-dicarboxylates 21 were prepared regiospecifically from the one-pot four-component reaction of trimethyl phosphite, acetylenic esters 20, and aroyl chlorides with phenylhydrazine in refluxing toluene h10T9835i. A one-pot three-component copper-catalyzed synthesis of N-aryl pyrazoles 25 from boronic acids 22, di-tert-butylazodicarboxylate 23, and 1,3-dicarbonyl compounds 24 was reported h10TL5005i. ArCOCl, P(OMe)3, PhNHNH2 toluene, reflux
CO2R
RO2C
70–85% R = Me, Et
20
CO2R
RO2C N
Ar
N Ph
21 R2 N ArB(OH)2
22
+ Boc
Boc +
N
23
O
O
R1
R3 R2
24
Cu(OAc)2 (5%), H2O HCl, dioxane
R1
32–83% R1 = H, Me; R2 = H,Cl, Br, Ar; R3 = H, Me, Ar
Ar
N
R3 N
25
The regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles 28 was achieved by the Huisgen cyclization of hydrazonyl chlorides 27 with a trisubstituted bromoalkene 26 h10TL1341i. The copper-catalyzed reaction of enaminoesters 29 with nitriles afforded fully functionalized pyrazoles 30 via an oxidative C C/NN bond formation cascade process h10AG(E)7790i. Reagent-controlled iodocyclization of propargylic hydrazides 31 led to either dihydropyrazoles 32 or pyrazoles 33 h10OL3506i. Acetoacetanilide was trilithiated with excess lithium diisopropylamide to form a reactive trianion-type intermediate which was followed by a regioselective Claisen-type condensation with a variety of aromatic esters to afford new C-acylated intermediates, 3,5-diketopentane-carboxanilides, that were not isolated but immediately condensed–cyclized with hydrazine to afford the NH-pyrazoleacetanilides, 5-aryl-1H-pyrazole-3-acetanilides h10JHC147i.
234
L. Yet
Ph
Ph Br
CHO HN
Ph
N
Ph
Cl
N
R
Ar
29
N
CO2i-Pr
R2
30
N
R1
N
CH2Cl2, 0 ⬚C 0–99%
R2
32
R3
N
CO2i-Pr NIS, BF3•OEt2
R1
R2
I
N
CO2i-Pr
CH2Cl2, 25 ⬚C 23–100%
R4
R1
R1= Ph, Ar R2= Me, Et, Ph, Ar R3= CO2R; R4 = H, Me, Et, Ph
HN
I(coll)2PF6
CO2i-Pr
N
R3
28
27
CO2i-Pr 1
R1HN
70–86% Ar
26
N
OHC
Et3N, CH2Cl2
N
+
R2CN, Cu(OAc)2 air, 110–120 ⬚C 35–92%
R4
R2
I 33
31
Several approaches were investigated in the preparation of indazoles. A general two-step synthesis of substituted 3-aminoindazoles 37 from 2-bromobenzonitriles 34 involving a palladium-catalyzed arylation of benzophenone hydrazone 35 to give 36 followed by an acidic deprotection/cyclization sequence was described h10JOC2730i. Cyclization of Z-tosylhydrazones 38 to furnish 3-substituted indazoles 39 was accomplished with copper(I) iodide and DMEDA in aqueous ethanol at ambient temperature h10T8854, 10TL3613i. Palladium-catalyzed cyclization of halophenyl hydrazones 40 and aryl isocyanates provided a convenient synthesis of 1-arylamide-1H-indazoles 41 h10OBC4827i. Iron(II) bromide catalyzed the transformation of aryl and vinyl azides with methyl oxime substituents into indazoles, or pyrazoles through the formation of a NN bond h10OL2884i. 1,3-Dipolar cycloaddition of nitrile imines 43 to benzyne 42 afforded N(1)-C(3) disubstituted indazoles 44 h10OL3368i. A variety of N-aryl-1H-indazoles were synthesized from arylamino oximes in the presence of 2-aminopyridine and methanesulfonyl chloride h10OL4576i. Microwave-assisted double Sonogashira coupling of 3,4-diiodo-1-trityl and 1-phenylpyrazole with terminal acetylene afforded dialkynylpyrazoles which was followed by heating at 240 C in the presence of 1,4-cyclohexadiene to obtain 2H-trityl and 2-phenylindazoles, respectively h10H(81)1651i. H2N
Br R
+ Ph
CN
R2
p-TsOH MeOH
Ph
H N N
R
65 ⬚C 73–90%
TMS
Cl + R1
N
43
NHR2
R2 I
N N Ts
ArNCO, Pd(OAc)2 (5%) PPh3 (20%), K2CO3 CH3CN, microwave NNH2
R
39
40
O NHAr N N
80 ⬚C 9–89% R = Me, Ph, n-C5H11
R
41 R1 N N
CsF (3.5 eq), 18-cr-6 (4.5 eq.) CH3CN, 25 ⬚C 49–79% R1 = Ph, 2-MeC6H4 Ar, 2-thiophenyl
R2 = Ph,
NH2
37
36
N R1 54–100% NHTs Br R1 = H, OMe, OCH2CH2O R2 = H, amino derivatives 38
42
N
CN
CuI (10%), DMEDA (30%) Na2CO3 (2.2 eq.), EtOH H2O, 25 ⬚C
OTf
Ph
H N R
100 °C 84–99%
Ph
35
34
R1
Pd(OAc)2, BINAP Cs2CO3, PhMe
N
R2
44
235
Five-Membered Ring Systems: With More than One N Atom
CH arylation reactions of pyrazole or indazole derivatives appeared in the literature. The first study of intermolecular direct arylation of indazoles 45 to give 3-arylated indazoles 46 in water was developed h10OL224i. 4-Chloro-1-methylpyrazole 47 underwent regioselective palladium-catalyzed arylation to give 5-arylpyrazoles 48 h10OL4924i. Palladium-catalyzed direct arylation of 1,3,5-trisubstituted pyrazoles to give 4-arylpyrazoles with aryl bromides in the presence of potassium acetate in DMAC was disclosed h10S127i. Ar2
Ar2X PdCl2(dppf)•CH2Cl2 (5%) N Ar1
R
PPh3 (10%), Ag2CO3 H2O, 50 °C 49–96%
N
45
Cl
N Ar1
R N
46
Cl
ArBr, Pd(OAc)2 (1%) DavePhos (2%) N Bu4NAc, isobutyric acid N NMP, 100 ⬚C CH3 13–94%
Ar
47
N N CH3
48
There were several reports of cross-coupling reactions of pyrazoles. 3-Bromo5-iodo-PMP-protected pyrazole 49 underwent sequential one-pot Suzuki cross-coupling reactions to deliver 3,5-di(hetero)arylpyrazoles 50 h10OL3328i. 4-Aryl-1H-pyrazoles 52 were obtained by Suzuki–Miyaura cross-coupling of 4-bromo-1H-1-tritylpyrazoles 51 with arylboronic acids h10H(81)1509i. The first Suzuki–Miyaura reactions of N-protected tribromopyrazoles in which their reaction with three, two, or one equivalents of arylboronic acids afforded 3,4,5-triarylpyrazoles, 3,5-diaryl-4-bromopyrazoles, or 5-aryl-3,4-dibromopyrazoles, respectively, were reported h10SL1923i. 1,3-Diarylsubstituted indazoles 54 were prepared from a two-step Suzuki cross-coupling/deprotection/N-arylation sequence starting from the 3-iodo-N-Boc indazole derivative 53 h10TL3796i. Br I
N N PMP
Ar2(Het)
Pd(PPh3)4 (10%) K3PO4, DMF, H2O 1. (Het)Ar1B(OH)2 2.
(Het)Ar2B(OH)2
49 I MeO
53
N N Boc
(Het)Ar1
ArB(OH)2 Ar Pd(OAc)2 (5%)
Br
N N PMP
N Tr
50
51
N
1. Ar1B(OH)2, Pd(PPh3)4, 2N Na2CO3, microwave, 120 ⬚C 2. Ar2I, CuI, K3PO4, trans-1,2-bis(N-aminomethyl) cyclohexane, PhMe, 110 ⬚C
PPh3, K2CO3 THF, reflux 35–92%
N Tr
N
52 Ar1
MeO N N 2 54 Ar
N-Alkylation and N-arylation of pyrazoles appeared in several reports. A series of 1-substituted-3-aminopyrazoles 56 were prepared via Chan–Lam copper-catalyzed cross-coupling of 3-pyrrolyl-pyrazoles 55 with potassium trifluoroborate salts h10TL6799i. N-Arylation of 3,5-dimethylpyrazole with halothiophenes with copper(II) fluoride catalyst in the presence of 1,10-phenanthroline and potassium carbonate was reported h10TL5052i. Under the conditions of Pd2(dba)3/xantphos/ sodium carbonate, 4-chloroquinazolines 57 underwent selective amination with the cyclic secondary amino group of 3-amino-1H-pyrazoles 58 to give 60, whereas
236
L. Yet
4-chloroquinazolines were exclusively aminated with the primary group of 3-amino1H-pyrazoles 58 via SNAr substitution in the presence of HCl to yield 59 h10OL552i. Copper-catalyzed N-arylation of 3-alkoxypyrazoles with pyridyl halides predominately afforded 3-alkoxy-1H-pyrazol-1-yl pyridine h10T2654i. Catalyst 6(1H-pyrazol-1-yl)nicotinic acid L-CuCl behaved as a very active promoter of the N-arylation reactions of pyrazoles h10T9141i. A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane was developed h10SL219i. H N
R1
N
R2 N
R2BF3K, Cu(OAc)2, bipy Na2CO3, ClCH2CH2Cl, 70 ⬚C 0–99%
N
R1 = H, Me, cyclopropyl R2 = Me, cyclopropyl, vinylic
N
N
56
55
R3
N NH R3
Cl
HN HCl
N
R1 N
59
R2
R1
dioxane
H N N
N
R1
+ R2
N
N
Pd2(dba)3 (0.5%) xantphos (1.5%) Na2CO3, dioxane
H2N
57
R3
70 ⬚C
58
R1
N N
N
NH2
R2
60
A chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide successfully catalyzed the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives which were stereoselectively converted to anti-2,3-difunctionalized b-lactams h10JA15550i. A novel reaction between 3- and 3,5-substituted pyrazoles with selenium dioxide proceeded with formation of bis(3R,5R0 -1H-pyrazol-4-yl)selenides h10T8772i. Reaction of 6-chloroN,N0 -bispyrazolyl-[1,3,5]triazine-2,4-diamines with 4-aminobenzylamine under microwave irradiation produced pyrazolyl bistriazines h10T121i. Sulfoximines bearing pyrazolylmethyl and aryl substituents and their corresponding sulfilimine intermediate were prepared from sulfide precursors by either iron-catalyzed nitrogen transfer reactions or metal-free imination procedures h10ASC309i. 3,4,5-Trinitro1H-pyrazole was prepared according to several appropriate synthetic methods h10AG(E)3177i. Silica-bonded S-sulfonic acid (SBSSA) was employed as a recyclable catalyst for the condensation reaction of aromatic aldehydes with 3-methyl-lphenyl-5-pyrazolone to give 4,40 -alkylmethylene-bis(3-methyl-5-pyrazolones) in ethanol at reflux h10TL692i. Novel bulky pyrazolylphosphine ligands 61 were employed in the Stille, Kumada, and Hiyama cross-coupling reactions h10T5451i. Me N
R N R = Me, t-Bu
PPh2
61
Five-Membered Ring Systems: With More than One N Atom
237
Table 1 Pyrazole-Fused Ring Systems. Pyrazole-Fused Ring Types References
Pyranopyrazoles
h10SC257, 10SC2930i
Pyrazolopyridines
h10H(81)2075, 10JCO600, 10JHC287, 10JHC861, 10OL516, 10TL2967, 10TL4717, 10TL4755i
Pyrazolopyrimidines
h10H(81)73, 10JCO807, 10JHC1259, 10JHC1379, 10S2767, 10SC1539, 10T5112i
Pyrazoloisoquinolines
h10ASC2050, 10OL4856, 10TL3980, 10T8242i
Thienopyrazoles
h10EJO6440i
Pyrazolooxacines
h10EJO6454i
Pyrazolotetrazines
h10JCO69i
Bicyclic- or tricyclic-fused pyrazoles
h10ASC2041, 10H(81)2617, 10JHC629, 10JOC502, 10OL2524, 10SC135, 10SC877, 10SC2130, 10TL478, 10TL970i
Larger-fused pyrazoles
h10JHC1283, 10SC1057, 10SC1123i
Many methods for the preparation of pyrazole-fused ring systems were published. The different structural types are listed in Table 1.
5.4.3. IMIDAZOLES AND RING-FUSED DERIVATIVES A review titled “Regioselective Functionalization of the Imidazole Ring via Transition Metal-Catalyzed CN and CC Bond Forming Reactions” was published h10ASC1223i. A review titled “1H-Benzimidazole-2-acetonitriles as Synthon in Fused Benzimidazole Synthesis” was reported h10JHC243i. The kinetics of the reactions of some imidazoles and benzimidazoles with benzhydrylium ions (diarylcarbenium ions) was studied photometrically in DMSO, acetonitrile, and aqueous solution at 20 C h10OBC1929i. Various methods were reported for the synthesis of imidazoles. One-pot microwave-assisted 1,5-electrocyclization of azavinyl azomethine ylides 62 in the presence of amines and aldehydes led to the synthesis of imidazole-4-carboxylates 63 h10EJO4312i. A methodology to generate 2-thio- and 2-oxoimidazoles 65 through an addition–cyclization–isomerization reaction of propargylcyanamides 64 with thiol and alcohol nucleophiles was described h10JOC261i. A library of 4,5disubstituted-2-aminoimidazoles 67 was synthesized using a nitroenolate route with 66 h10OBC2814i. 3-(a-Aminobenzyl)-1,2,4-oxadiazole imines 68 underwent Boulton–Katritzky-type rearrangement to give 4(5)-acylaminoimidazoles 69 in the presence of strong base h10OL3491i. Bisimidoyl chlorides reacted smoothly with (2,2-dimethoxyethyl)amine to give bisamidines which were subsequently cyclized to give the corresponding bisimidazoles with formic acid h10S1311i.
238
L. Yet
The reaction of allylindium reagents and N-(cyanoalkyl)amides afforded fully substituted 4-alkenylimidazoles via the In-mediated Barbier-type allylation of nitrile and the following dehydrative cyclization cascade h10TL5922i. 2
1. R NH2, CH3CN 2. R CHO 3. microwave, 150 °C
CH3
1
R O
N
N
Y
62
O Ph
( )m
R
1
2
R O
57–87% 1 2 R = Me, Et; R = H, Bn, 3 allyl; R = H, Ph, Et, n-Pr, CH2CO2Me; Y = CO2Et, CONH2
CH3 1. H2, Pd/C, EtOH, HCl ( )n H N 2. NH2CN, EtOH 2 NO2 m = 2–4, n = 0–4
66
CH3 R 2
R
4
R XH (X = O,S) DIPEA, i-PrOH, 120 °C 3 R 53–97%
1
O
3
O
N
N N
N R
3
4
KOt-Bu PhOCHN DMF
N N
67
O
65
R = Et, Ph, Ar
Ph
Ph
4
XR
R = Ph, PMB
64
CH3 ( )n ( )m Ph
N R1
2
R = H, Bn, pBnOBn
3
63
N
N
1
R = Me, Bn, PMB
3
R
H N
2
R
Ar N
52–80%
N
Ph
N H
68
Ar
69
A simple highly versatile and efficient synthesis of 2,4,5-triarylimidazoles 71 was achieved by three-component cyclocondensation of benzil 70, aromatic aldehydes and ammonium acetate under various conditions.
Ar1
O Ar2
Ar1
N
Conditions + Ar3CHO + NH4OAc
Ar 3 N
Ar 2
O
H (R)
70
71
Conditions
References
FePO4, EtOH, 80 C
h10H(81)2313i
h10SC1134i
Microwave, 120 C, solvent free RNH2, p-TsOH, or MCM-41, 140 C
h10SC1270i
[(CH2)4SO3HMIM][HSO4], solvent free, 120 C
h10SC1998i
RNH2, [(CH2)4SO3HMIM][HSO4], solvent free, 140 C
h10SC2588i
PEG-400, reflux
h10SC2667i
ArNH2, Cu(NO3)2-zeolite, 80 C
DABCO, t-BuOH, 60 C
h10TL3018i h10TL5252i
Benzimidazoles were prepared from different precursors. 2-Nitroanilines 72 were reduced with iron powder in the presence of ammonium chloride and formic acid in isopropanol to deliver benzimidazoles 73 h10SL2759i. 2-Fluoro-5-nitroaniline 74, primary amines, and substituted aldehydes were melted together in one-pot to generate a variety of 1-alkyl-2-aryl-5-nitrobenzimidazoles 75 under solvent-free
239
Five-Membered Ring Systems: With More than One N Atom
conditions h10TL4459i. Acid-catalyzed rearrangement proceeding via a novel ring contraction of 3-(b-2-aminostyryl)quinoxalin-2(1H)ones led to the synthesis of 2benzimidazol-2-ylquinolines h10TL6503i. Electrophilic activation of bisamides 76 with trifluoromethanesulfonic anhydride and 2-chloropyridine led to polysubstituted-benzimidazoles 77 h10T1208i. The regiospecific synthesis of 3-alkyl-4-hydroxybenzimidazoles as intermediates for an expedient approach to potent EP3 receptor antagonists was reported h10TL1380i. A variety of N-aryl-1H-benzimidazoles were synthesized from arylamino oximes in the presence of methanesulfonyl chloride and triethylamine h10OL4576i. NO2
N
Fe powder, NH4Cl
R
R
HCO2H, i-PrOH, 80 °C 73–98%
NH2
N H
73
72 R2
O NH2
O2N
F
74
ArCHO, RNH2
O2N
NH
N Ar
140 °C 0–77%
75
N R
Tf2O, 2-ClPy
R1
O
77
2
R
R2
N
CH2Cl2, reflux 51–66%
NH
76
N
R1
R2
O
Many similar methods were published for the synthesis of 2-substituted-benzimidazoles 79 from o-phenylenediamines 78 and they are shown in Table 2. Transition metal-catalyzed methods were utilized in the preparation of 2-substituted benzimidazoles. 1,2-Disubstituted-benzimidazoles 82 were prepared with high Table 2 Preparation of 2-Substituted Benzimidazoles from o-Phenylenediamines. NH2
Conditions
R1
N R1
R2
NH2
78
79
N H
Conditions
References
ROH, hv, Pt at TiO2, nitrogen, 303 K
h10AG(E)1656i
2-Chloroquinoline-3-carbaldehyde, 70% HOAc, 110 C
h10EJO317i
ArCHO, CuOTf, CH3CN, 80 C
h10JHC153i
2RCHO, [(CH2)4SO3HMIM][HSO4], H2O, 25 C
h10SC1216i
RCHO, KI, DMF, air, microwave
h10SC1963i
ArCHO, FeCl3, PANI, EtOH, 25 C
h10SC2686i
ArCHO, Phl(OAc)2, solvent free, 25 C
h10SC2880i
RN¼¼C¼¼Se, DMF, 25 C
h10SL901i
ArCHBr2, KOt-Bu, I2, benzoyl peroxide, pyridine, DMF, reflux
h10TL6493i
240
L. Yet
regioselectivity from aryl halides 80 and amidines 81 by copper-catalyzed reactions h10EJO680i. The copper-catalyzed one-pot three-component cascade reaction of sulfonyl azides 83, alkynes 84, and 2-bromoanilines 85 to give functionalized benzimidazoles 86 was developed h10ASC347i. Palladium-catalyzed reaction of 2-nitroaniline 87 with aromatic aldehydes in the presence of p-toluenesulfonic acid and hydrogen gas afforded 2-arylbenzimidazoles 88 h10SC1743i. Cobalt(II)-complex catalyzed efficiently the intramolecular CN cross-couplings of Z-N0 -(2-halophenyl)-N-phenylamidines 89 to afford 2-substituted-benzimidazoles 90 in the presence of potassium carbonate and 1,10-phenanthroline h10OBC5692i. Diarylcarbodiimides were converted to 1,2-disubstituted-benzimidazoles via addition/intramolecular CH bond activation/CN or CC in a one-pot cascade bond forming reaction using copper(II) acetate/oxygen as the oxidant at 100 C h10ASC2905i. NH
I +
R1 Br
CuI (15%), DMEDA (30%) R2HN
80
R3
Cs2CO3, NMP, 150 ⬚C
NH2
83
87
R3
0–56%
81
R1SO2N3 + R2
N R1
+
84
NO2
ArCHO, Pd(TMHD)2 (5%), p-TsOH
NH2
EtOAc, H2 65–82%
R3
82
N R2
1. CuI, Et3N, DMSO 2. CuI, L-proline, K2CO3, DMSO 43–78% R1 = Me, Bu, Ar n-Bu, Ph, Ar
Br
85
R1 = Cl, Me, CF3, CN, NO2 R2 = Me, i-Pr, Ph, Ar R3 = Me, Ph, Ar
N R3
R2 = TMS,
N
N Ar N H
88
R1 Br
89
R2 NHAr
86
R2 N SO2R1
Co(acac)2•H2O (10%) 1,10-phenanthroline (20%) K2CO3, PhMe, 110 ⬚C 84–97% R1 = H, Br, Cl, Me R2 = alkyl, Ph
N R2
R1
90
N Ar
Cross-coupling reactions and direct CH arylations of imidazoles and benzimidazoles were disclosed. 2,5,6-Trisubstituted-benzimidazoles were prepared by Heck reactions of 2,4,5-tribromo-N-methylimidazole and 2-aryl-4,5-dibromo-N-methylimidazoles and subsequent 6p-electrocyclization/dehydrogenation reactions h10SL1779i. 3,6-Di- and 2,3,6-trisubstituted imidazo[1,2-b]pyridazines were prepared from 6-chloroimidazo[1,2-b]pyridazines by a microwave-assisted, one-pot, two-step Suzuki cross-coupling/palladium-catalyzed arylation process h10EJO862i. A general approach to complex arylated imidazoles via regioselective sequential arylation of all three CH bonds and regioselective N-alkylation enable by SEM-group transposition was disclosed h10JOC4911i. 2,5-Dibromo-1-methylimidazole was monoarylated regioselectively by the use of a selective palladium catalyst h10JOC1733i. Several reports of N-arylation and N-alkylation of imidazoles were published. A facile and efficient Cu(I)-catalyzed microwave-assisted cross-coupling method was reported for the preparation of N-alkynyl or N-bromoalkenyl heteroarenes from bromoalkynes in the presence of poly(ethylene glycol) 400 h10JOC980i. Regioselective N1-alkylation of 3-(1H-imidazol-4-yl)pyridine using bromoacetaldehyde
Five-Membered Ring Systems: With More than One N Atom
241
diethyl acetal in the presence of cesium carbonate was reported h10SC81i. Recyclable copper(II) oxide nanoparticles catalyzed the vinylation of imidazole with vinyl halides under ligand-free conditions h10TL3181i. Oxidative iron-catalyzed N-alkylation of pyrazoles 91 with ethers 92 afforded pyrazole derivatives 93 h10OL1932i. R1 N
H +
N H 91
R2
R1 N
FeCl3•6H2O (2.5%) TBHP (3–5 eq.) O
92
R3
DCE or EtOAc, 80 ⬚C 54–95%
N R2
O
R3
93
A library of oligomeric compounds was synthesized based on the imidazole-4,5dicarboxylic acid scaffold along with amino acid esters and chiral diamines derived from amino acids h10JCO248i. A novel three-component reaction between 1-substituted imidazoles 94, aldehydes 95, and electron-deficient acetylenes 96 proceeded under mild conditions (rt, no catalyst, solvent free) to form an unknown family of C2-functionalized imidazoles 97 h10EJO1772i. These exact same conditions were published where water was employed as the solvent h10S2421i. Highly enantioenriched 2-acylimidazoles, prepared by palladium-catalyzed decarboxylative asymmetric allylic alkylation of 2-imidazolo-substituted enol carbonates, were converted to the corresponding carboxylic acid, ester, amide, and ketone derivatives with complete retention of the enantiopurity h10JA8915i. A series of N-substituted 2,4-dinitroimidazoles, 4,5-dinitroimidazoles, and 2-methyl-4,5-dinitroimidazoles were selectively reduced to the corresponding aminonitroimidazole derivatives, using iron dust in glacial acetic acid at room temperature h10JHC1049i. Reactions of imidazo [1,5-a]pyridine carbene-derived zwitterions with ethyl propiolate and dimethyl acetylenedicarboxylate gave densely functionalized pyrroles and thiophenes, respectively h10JOC2382i. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was found to catalyze the amidation of acyl imidazoles h10OL324i. Peptidomimetics based on the imidazole scaffold were prepared from amino acid esters h10OL4928i. 2-(Trifluoroacetyl)-1,3-azoles reacted with 3-aminopyrazoles to give the corresponding trifluoromethyl-substituted alcohols h10S1195i. The synthesis and reactivity of imidazo[1,2] hetarylglyoxylates were disclosed h10S1692i. Novel 1-methyl-2-(2-substitutedoxazol-4-yl)-1H-benzimidazole derivatives were obtained from treatment of 2-benzimidazolyl esters with acetamide in the presence of boron trifluoride-etherate h10SC414i. 2,4-Dinitroimidazole 98 was converted to the potassium salt, followed by reaction with O-mesitylenesulfonylhydroxylamine (MSH) to give 1-amino2,4-dinitroimidazole 99, and further reaction with nitronium tetrafluoroborate afforded 1-nitramino-2,4-dinitroimidazole 100 and its sodium salt 101 h10TL399i. Highly functionalized heterocycles were synthesized in one-pot reactions of 2-alkylimidazoles or 2-methylbenzimidazoles with 1,3-diacid chlorides h10TL1139i. Preparation of bis(1-tert-butoxycarbonyl-2-benzimidazolylmethyl) amines from N-tert-butoxycarbonyl-protected 2-chloromethylbenzimidazole was described h10SL423i.
242
L. Yet
N + N R1
R4CHO + R2
95
R3
96
N
neat 31–74%
N R1
94
O R4
R1 = R4 = alkyl; R2 = H,
R3
Ph; R3 = CO2Me, CN
R2
97
O2N N N H
98
O 2N 1. KOH, MeOH NO2 2. MSH 45%
N NO2 N NH2
99
NO2BF4
O2N
O2N
N
N
neat O2N
N NH
NO2
100 (25%)
O2N
NO2 N NNa
101 (15%)
Imidazole-containing compounds were utilized as reagents for various synthetic transformations. An in situ generated catalyst from RuH2(PPh3)4, N-heterocyclic carbene (NHC) precursor 102, sodium hydride, and acetonitrile was shown to have high activity for the amide synthesis directly from either alcohols or aldehydes with amines h10JOC3002i. Homoenolates generated from a,b-unsaturated aldehydes by catalysis with 102 underwent facile addition to conjugated sulfonimines followed by methanolysis to afford protected GABA derivatives h10OBC761i. Nucleophilic heterocyclic carbene 102 was employed in the cyclopropanation of ethyl cyanocinnamates with phenacyl bromide by Michael-initiated ring closure h10OBC941i. A rhodium-catalyzed amination reaction of aryl halides with amines was developed with the use of carbene 102 h10OL1640i. A facile reaction of aromatic aldehydes with carbon dioxide to give carboxylic acids was mediated by ligand 102 h10OL2653i. g-Substituted allylic chlorides reacted with alkyl Grignard reagents in the presence of imidazolium salt 102 to give substitution products via an SN20 selective fashion h10TL5704i. An imidazole-catalyzed protocol for monoacylation of symmetrical diamines was developed h10OL4232i. Isoquinoline-based ligand 103 catalyzed conjugate borylation of various a,b-unsaturated amides in good yields and enantioselectivities h10CC7525i. Chiral bicyclic imidazole nucleophilic catalysts 104 were successfully applied in an asymmetric Steglich rearrangement with good to excellent yield and enantioselectivity at ambient temperature h10JA15939i. The facile three-component reactions of imidazo[1,5-a]pyridin-3-ylidenes 105 with aldehydes and DMAD or allenoates led to the synthesis of fully substituted furans h10JOC6644i. 2-Pyridin-2-yl-1H-benzimidazole 106 was discovered to be a versatile bidentate N-donor ligand suitable for the copper-catalyzed formation of vinyl CN and CO bonds h10OL464i. Imidazole carbamates and ureas 107 were found to be chemoselective esterification and amidation reagents of carboxylic acids h10OL4572i. Chiral six-membered annulated N-heterocyclic copper complex of ligand 108 catalyzed the b-borylations of a,b-unsaturated esters with high yield and enantioselectivities h10OL5008i. A cyclobutene-1,2-bis (imidazolium) salt 109 was an efficient catalyst precursor for the one-pot tandem Suzuki–Miyaura/dehydrobromination reactions for the synthesis of alkynes starting from 1,1-dibromoalkenes, palladium(II) acetate, aryl boronic acids, and potassium tert-butoxide in toluene h10S2621i. N-Heterocyclic 110 carbene-catalyzed cross-coupling of aromatic aldehydes with Baylis–Hillman bromides provided easy access to a-arylidene-g-keto esters h10S2649i. NHC-catalyzed transformation of 4-formylbenzoates
Five-Membered Ring Systems: With More than One N Atom
243
with a,b-unsaturated aldehydes to cyclic hemiacetals proceeded smoothly in the presence of imidazolium salt 111 h10T8922i. Direct asymmetric a-amination of aldehydes with azodicarboxylates with imidazolium L-proline catalyst 112 gave excellent enantioselectivities and high yields h10TL6105i.
Ph i-Pr
N
N
Cl N Ar
N
Cl i-Pr
N
102
N
N
N
104 R
Cl
105
103
N
N
N
N
107
110
Cl
N Ph
N
Cl 109
N
N Cl
N
Cl
2BF4
Ph
108
Ph
N
N
N
N
Y Y = alkoxy, MeNOMe
106
Cl
N O
H N
N
N
SO3
Ph
N
OTf
N
111
CO2H
112 H
Many methods were developed for the synthesis of imidazole fused ring systems. The different structural types are listed in Table 3.
Table 3 Imidazole-Fused Ring Systems. Imidazole-Fused Ring Types References
Fused 5,5-rings
h10JHC1287, 10SC173i
Imidazopyridines
h10AG(E)2743, 10H(81)185, 10H(80)439, 10TL284, 10OL412, 10SL1606, 10SL2299, 10T519, 10T9745, 10TL828, 10TL4605, 10TL4755i
Pyridimobenzimidazoles
h10JCO225, 10JHC26i
Imidazotri(tetra)zines
h10JCO604, 10TL3899i
Benzimidazoquinolines
h10S2794i
Imidazoiminosugars
h10S4051i
Hexahydrobenzimidazoles
h10S3934i
Tricyclic-fused pyrazoles
h10EJO4832, 10JHC524, 10JHC543, 10JOC992, 10JOC4604, 10OL3704, 10S2828, 10SC111, 10SL1469, 10T128, 10T8231, 10TL6082i
Larger-fused pyrazoles
h10JCO222, 10T1937, 10T4542i
244
L. Yet
5.4.4. 1,2,3-TRIAZOLES AND RING-FUSED DERIVATIVES A perspective called “Regioselective Syntheses of Fully Substituted 1,2,3-Triazoles: The CuAAC/CH Bond Functionalization Nexus” was published h10OBC4503i. A highlight entitled “Copper-Catalyzed Azide–Alkyne Cycloaddition: Regioselective Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles” was reviewed h10AG(E)31i. An entire issue of Chemical Society Reviews with 13 review articles on “Click Chemistry” was published h10CSR1221i. The relative stabilities of the tautomers between the 1- and 2-N-(a-aminoalkyl)-1,2,3-triazole forms were studied by 1H and 13C NMR spectroscopy h10H(82)479i. Click chemistry includes a range of reactions that proceed in high yield under ambient conditions, preferably in water, with regioselectivity and a broad tolerance of functional groups. The copper-catalyzed 1,3-dipolar cycloaddition reaction of azides and acetylenes to give 1,2,3-triazoles is known as the “cream of the crop” of all click reactions. 1,4-Disubstituted 1,2,3-triazoles containing a pentafluorosulfanylalkyl group were synthesized in good to excellent yields by the click cycloadditions of in situ generated SF5-alkyl azides with aromatic and aliphatic alkynes h10TL6951i. Light was used as an activator for the in situ generated copper(I)-catalyzed click reaction between azides and alkynes without adding reducing agents h10TL6945i. A wide variety of 1-monosubstituted 1,2,3-triazoles 114 and 115 were synthesized efficiently via a copper-catalyzed click reaction between azides 113 and acetylene gas, generated in situ from CaC2 with the addition of H2O or D2O h10TL6275i. Formation of 5-iodo-triazoles 118 with copper(I) iodide-promoted cycloadditions between alkynes 117 and azides 116 was controlled by DMAP and low alkyne concentrations h10TL550i. A methodology for the direct use of trimethylsilyl-protected alkynes 119 in the copper(I)-mediated alkyne–azide cycloaddition reaction without the need of a previous deprotection step to give 1,2,3-triazoles 120 was reported h10SL1873i. An efficient room-temperature method for the synthesis of 1-sulfonyl-1,2,3-triazoles 122 from in situ generated copper(I) acetylides and sulfonyl azides 121 was described h10OL4952i. Similarly, [Tpm*,BrCu (NCMe)]BF4 efficiently catalyzed the [3 þ 2] cycloaddition between alkynes and N-sulfonylazides under mild conditions h10OBC536i. 1,5-Diarylsubstituted-1,2,3triazoles 124 were formed in high yield from aryl azides and terminal alkynes 123 in DMSO in the presence of catalytic tetramethylammonium hydroxide h10OL4217i. A microwave-assisted, one-pot, three-step Sonogashira cross-coupling-desilylation-cycloaddition sequence was developed for the convenient preparation of 1,4-disubstituted-1,2,3-triazoles 126 starting from a range of aryl halides 125, trimethylsilyl acetylenes, and azides h10OL4936i.
245
Five-Membered Ring Systems: With More than One N Atom
R N H
N
CuI (5%), CaC2
N H
H2O, Et3N, 55 ⬚C
R N3
57–92%
113
114
CuI (5%), CaC2 D2O ,Et3N, 55 ⬚C 42–91%
R N D
N
N D
115
R = CH2Ar, CHMePh, 4-OMeC6H4, alkyl
R 117 CuI, DMAP
ArCH2N3
CH3CN, rt, 3d
116
37–78% R = i-Pr, Ph, Ar
R1SO2N3
121
BnN3, CuBr (15%) Et3N, DMF, 100 ⬚C
I Ar
N N N
R
118
N
75–94%
122
TMS
119
R2 CuTc (10%), PhMe R1O S 2 or H2O, rt N N R1 = alkyl, Ar, Bn
R
R2
Ar1
N N
57– 94% R = alkyl, Ar, TIPS, CO2Et
N Bn
R
120
Ar2N3, NMe4OH (10%) DMSO, rt
Ar2
37–92%
Ar1
123
N N
N
124
R2 = Ph, OEt
TMS, PdCl2(PPh3)2 (5%), CuI (10%),
1. Ar
X
125
DIPEA, MeOH 2. TBAF 3. CuI (10%), RN3, MeOH, microwave, 120 ⬚C
N N R N
Ar
126
81–98%, R = Bn, Ar
Unsymmetrically 1,10 -disubstituted-4,40 -bis-1H-1,2,3-triazoles were prepared from 4-ethynyl-1,2,3-triazoles and azides h10OL1584i. An ultrasound or ultrasound/microwave-enhanced, efficient, and sustainable metallic copper-catalyzed Huisgen 1,3-dipolar regioselective cycloaddition of azides and alkynes was developed h10JCO13i. Terminal di-, tri-, tetra-, and pentaynes substituted with a variety of functional groups react with benzyl azide in the presence of CuSO45H2O and ascorbic acid to give derivatives of 4-ethynyl-, 4-butadiynyl-, 4-hexatriynyl-, and 4-octatetraynyl-1,2,3-triazoles in moderate to good yields h10JOC8498i. The investigations of the use of carboxylic acid-promoted copper(I)-catalyzed azide–alkyne cycloadditions were published h10JOC7002i. The copper-catalyzed cycloaddition of organic azides with dialkylaluminum acetylides enabled regioselectively a rapid access to 1,4,5-trisubstituted triazoles h10AG(E)2607i. A series of 1-allylated and 1-benzylated 1,2,3-triazoles with varying substituents at the 4-position were prepared using a two-step one-pot click transformation h10S3339i. Sol–gel precursors containing one or multiple triethoxysilyl groups were prepared from the copper-catalyzed azide–alkyne cycloaddition h10CC8416i. Imidazole derivatives substituted by a normal alkyl group are shown to be efficient as a ligand for the copper(Ι)-catalyzed azide–alkyne cycloaddition reaction h10OL4988i. New copper catalysts were reported for some click reactions. A structurally welldefined dinuclear complex copper(I) acetate was developed as a highly practical and efficient catalyst for the copper(I)-catalyzed azide–alkyne cycloaddition
246
L. Yet
h10ASC1587i. New supported catalysts for the Huisgen’s [3 þ 2] azide–alkyne cycloaddition were prepared by immobilization of copper species on commercially available polymeric matrixes incorporating the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) template h10ASC1179i. A novel form of polyvinylpyrrolidone-coated copper(I) oxide nanoparticle was used to catalyze azide/alkyne click reactions in water under aerobic conditions h10ASC1600i. Polymeric dinuclear alkynylcopper(I) complexes were employed in the interaction of terminal alkynes with copper(II) salts in acetonitrile h10CC2274, 10CEJ6278i. Copper nanoparticles were found to catalyze the 1,3-dipolar cycloaddition of azides and alkynes h10EJO1875i. Cu(I)-doped zeolites were heterogeneous catalysts for the [3 þ 2] cycloadditions of alkynes with azides h10S1557i. In addition to copper, zinc impregnated with carbon catalyzed the cycloaddition of organic azides and alkynes to provide the corresponding 1,4-disubstituted- and 1,4,5-trisubstituted-1,2,3-triazoles h10EJO5409i. Organic azides can also be generated in situ and reacted with alkynes in one-pot reactions. A convenient and efficient one-pot sequence was developed for the synthesis of C-carbamoyl-1,2,3-triazoles 128 from alkyl bromides 127 using sodium azide, followed by methyl propiolate and copper iodide, and finally with amines, zirconium tert-butoxide, and 1-hydroxybenzotriazole, under microwave irradiation h10TL3691i. An efficient, one-pot, regioselective synthesis of 1,4-diaryl-1H-1,2,3triazoles 130 was described via the copper(I)-catalyzed reaction of diaryliodonium salts 129, sodium azide, and terminal alkynes h10S1687i. 1,2,3-Triazole-appended azetidines and pyrrolidines were prepared from iodine-mediated cyclization of homoallyl amines at room temperature to cis-2,4-azetidine or upon heating cis2,5-pyrrolidines followed by displacement of iodine with sodium azide and cycloadditions with alkynes h10OL5044i. Nonafluorobutanesulfonyl azide efficiently converted primary amines 131 to azides followed by copper-catalyzed 1,3-dipolar cycloaddition with alkynes 132 in a one-pot regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles 133 h10ASC2515i. A base- and metal-free three-component reaction of ynones, sodium azide, and alkyl halides was developed for the regioselective synthesis of 2,4,5-trisubstituted-1,2,3-triazoles h10SL1617i. Orthogonally Nprotected-4-(1,2,3-triazol-4-yl)-substituted-3-aminopiperidines were prepared from a piperidine building block by a sequence of nucleophilic aziridine ring opening with sodium azide and subsequent copper-catalyzed Huisgen 1,3-dipolar cycloaddition with alkynes h10EJO1745i. O R1R2NH (6 eq.) Zr(Ot-Bu)4 (20%)
OMe Ph(CH2)nBr n = 1–3
NaN3, DMA
CuI (10%), DIPEA
microwave, 120 ⬚C
microwave, 90 ⬚C
HOBt (0.4 eq.) microwave,100 ⬚C 72–93%
127
Ar 2 Ar1 2IX
129
NaN3, CuI PEG 400, rt
Ar1N3
Ar 2 71–85%
N N N Ar1
130
R1–NH2
N N ( )n N
H2O, rt
62–83%
NR1R2
128
R 2 132 1. NfN3, CuSO4•5H2O, NaHCO3, Et2O, MeOH,
131 2. Sodium as corbate, rt
O
Ph
R2
R1
N N
R1 = Bn, Ar R2 = Ph,
N
133
(CH2)5CH3
Five-Membered Ring Systems: With More than One N Atom
247
Other methods of 1,2,3-triazole synthesis were also published. Ethyl diazoacetate 134 was treated with aryl imines 135 in the presence of DBU to provide ethyl 1-(4methoxyphenyl)-5-aryl-1H-1,2,3-triazole-4-carboxylates 136 h10CAJ328i. 2-Azidothiazoles 137 underwent base-catalyzed condensation reactions with activated methylene compounds 138 to yield new 1-(1,3-thiazol-2-yl)-1H-1,2,3-triazole-4carboxylic acids 139 h10SC391i. A one-pot Cu(II)-catalyzed aza-Michael addition of trimethylsilyl azide to 1,2-diaza-1,3-dienes and Cu(I)-catalyzed 1,3-dipolar cycloaddition of in situ generated a-azidohydrazones with alkynes provided a useful protocol for the synthesis of novel pyrazolone-triazole derivatives h10OL468i. Aromatic propargylated aldehydes, different azides, 2-aminobenzophenone derivatives, and ammonium acetate were condensed in the presence of catalytic amounts of acidic ionic liquid, 1-methylimidazolium trifluoroacetate, ([Hmim]TFA), and Cu(OAc)2/ sodium ascorbate to afford triazolyl methoxyphenylquinazolines h10JCO638i. Substituted 1H-1,2,3-triazole-4-carboxylic acids were synthesized by a three-component reaction of aryl azides, ethyl 4-chloro-3-oxobutanoate, and either O- or S-nucleophiles in the presence of sodium methylate h10SC1932i. A one-pot regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles from homoallyl alcohols was reported h10TL4037i. 4-Aryl-1H-1,2,3-triazoles 141 were synthesized from anti-3-aryl-2,3dibromopropanoic acids 140 and sodium azide by using copper(I) iodide as the catalyst in dimethyl sulfoxide h10S4256i. Similarly, 4-aryl-1H-1,2,3-triazoles 141 were synthesized from the palladium-catalyzed reaction of anti-3-aryl-2,3-dibromopropanoic acids 140 and sodium azide by a one-pot method in the presence of xantphos h10S283i. N2 N
EtO
Ar
O
+ S
N3
R3
137
Br CO2H
140
CH3CN
N O
64–95%
135
O
N
Br
N N EtO
PMP
Ar
136 R1
R1
Ar
DBU (3 eq.)
H
134
R2
PMP
H +
O
42–87%
OEt
R2
DMSO, N2, 110 ⬚C 53–95%
N
S
139
138
NaN3, CuI, sodium ascorbate, Cs2CO3
NH Ar
CO2H
Ar Br
141
CO2H
N N
NaN3, Pd2(dba)3 xantphos, DMF
Br
N N
R3
N
NaOMe, MeOH
140
N N NH
110⬚C 55–71%
Ar
141
1,2,3-Triazoles could be converted to other structures. 4-Aryl-1,2,3-triazoles 142 was selectively CH arylated with ruthenium catalysis to give biaryl-1,2,3-triazoles 143 which underwent palladium-catalyzed dehydrogenative direct arylation to give annulated phenanthrenes 144 h10OL2056, 10S2245i. The regioselective N-alkylation of 1,2,3-triazoles of 4,5-dibromo- and 4-bromo-5-trimethylsilyl1,2,3-triazoles gave good to excellent N-2 selectivity and high chemical yields for
248
L. Yet
N-2-substituted-4,5-dibromotriazoles h10OL4632i. Substituted propargyl alcohols 146 underwent FeCl3-catalyzed triazole propargylation with 145 to give propargyl triazoles 147 h10OL3308i. A palladium-catalyzed alkenylation of 1,2,3-triazoles with terminal conjugated alkenes by direct CH functionalization was developed in the presence of Cu(OAc)2 and dioxygen h10EJO1227i. Treatment of 1-sulfonyl-1,2,3triazoles with a catalytic amount of 4-dimethylaminopyridine in acetonitrile gave rearrangement to 2-sulfonyl-1,2,3-triazoles h10H(80)177i. Cl
R2 N
+
N N R1
[RuCl2(p-cymene)]2 (2.5%) MesCO2H (30%) K2CO3, PhMe, 120 ⬚C 64–89%
R3
142
R2
R2
Pd(OAc)2 (5%) Cu(OAc)2, PhMe
N N N R1
143
PivOH, 140 ⬚C, air 65–96%
N N N R1
144
R3
R3
R1 = hex, oct; R2 = Me, OMe, 4-R(O)CC6H4 ; R3 = Me, Ph, CO2Et R1
R1 N
HO N
R2
N H
145
N
FeCl3 (10%), CH3CN, 90 ⬚C 64–96% R4
+ R3
146
R1 = R2 = H, Ph or benzo R3 = Ph, Ar, alkyl R4 = n-Bu, TMS, Ph
N R2
N R4 R3
147
Several syntheses of substituted benzotriazoles and applications of benzotriazolemediated methodology to different synthetic transformations were reported. N-Imidoylbenzotriazoles were obtained by the reaction of ketoximes with methanesulfonyl chloride and subsequently with benzotriazole as a one-pot process via a Beckmann rearrangement h10T6097i. A facile and high-yielding protocol for diverse benzotriazoles through intramolecular N-arylation of different o-chloro-1,2,3-benzotriazenes using CuI/cesium carbonate was developed h10TL5740i. An efficient and highly versatile method for the synthesis of diverse regiospecific 1-arylbenzotriazoles by the copper(I)-catalyzed intramolecular N-arylation of diazoaminobenzenes of 2haloaryldiazonium salts in PEG-water was developed h10OBC4720i. Benzotriazol1-yl-sulfonyl azide, a new crystalline, stable, and easily available diazotransfer reagent provided N-(R-azidoacyl)benzotriazoles convenient for N-, O-, C- and S-acylations h10JOC6532i. Benzotriazole esters formed in situ were found to be efficient intermediates in the esterification of tertiary alcohols using DMAP as the base h10S4261i. N-Nitro-benzotriazole reacted with various C-nucleophiles in tetrahydrofuran at room temperature to afford either o-nitramidophenylazo compounds or o-nitramidophenyl hydrazones h10SC3046i. 3-Aryl-1,2,4-benzotriazines were formed unexpectedly by the treatment of 1,l-bis(benzotriazol-1-yl)methylarenes with allylsamarium bromide h10TL6763i. N-Alkylation of benzotriazoles with alkyl halides was accomplished in basic ionic liquid [Bmim]OH under solvent-free conditions h10SC2525i. “Click” chemistry was very active in many fields this year, and these applications are reflected in Table 4.
Five-Membered Ring Systems: With More than One N Atom
249
Table 4 Application of Click Chemistry in Different Fields. Click Chemistry Field References
Amino acids, peptides, and peptidomimetics
h10AG(E)976, 10AG(E)5378, 10CC5307, 10CC8142, 10CC8407, 10EJO1445, 10EJO4194, 10JOC3938, 10JOC5385, 10OBC2941, 10T3599, 10TL4357i
Biological systems
h10CC7557, 10CC8335, 10EJO2759, 10H(80) 1249, 10JCO491, 10JCO609, 10OBC1749, 10OBC3874, 10OL2578, 10OL4256i
Carbohydrates
h10JOC3097, 10S828, 10T2141, 10T9475, 10TL1022, 10TL4328i
Electronics/electrochemical systems
h10CEJ5416i
Fluorescent probes
h10JA12172, 10JOC1756, 10JOC4039, 10OBC4051, 10TL1152i
Nanomaterials
h10CEJ5544, 10S3021, 10EJO5090i
Nucleotides and nucleosides
h10JOC6806, 10JOC8693, 10S3710i
Polymers
h10CC7542, 10CC8719i
Supramolecular systems
h10CEJ1592, 10CSR1536, 10OL1776, 10OL3630i
Triazole-containing reagents found some applications. A modular sugar-based pyrrolidine 148 was found to be a highly enantioselective organocatalyst for the asymmetric Michael addition of ketones to nitrostyrenes h10ASC2571i. Novel 1,3-dialkyl-1,2,3-triazolium ionic liquids 149 were efficient reaction media for the Baylis–Hillman reaction h10JOC4183i. Active and selective catalysts for the asymmetric reduction of ketones, under transfer hydrogenation conditions, were obtained by combining [RhCl2Cp*]2, with a series of L-amino acid thioamide ligands functionalized with 1,2,3-triazoles h10OBC4536i. The E-a-haloenones were prepared through a triazole–Au complex (TriA–Au) 150 catalyzed propargyl acetate rearrangement and sequential allene halogenation h10OL2088i. Trifunctional thioureas bearing a 1,5-disubstituted triazole tether were useful asymmetric catalysts for Michael addition of nitrostyrene with cyclohexanone h10TL2737i. An ionic liquid-supported TEMPO 151 was used in the oxidation of alcohols to aldehydes and ketones h10TL4501i. Novel dicationic azolium salts 152, with an imidazolium and 1,2,3-triazolium unit, were developed as NHC precursors for ligands in palladium-catalyzed Suzuki–Miyaura couplings of aryl chlorides, iodides, and triflates h10S2609i.
250
L. Yet
O O
O
O X
O N
N H
N
O
N
N
N
N
X
X = I, NTf2, OTF, PF6, BF4
148
150
149
O N BF 4 O
N N N
151
PPh3 R N N N Au R = H, Me; X = OTf, BF
N
N
R N
Me N 2X
N N Me ( )n
N
R = n-Bu, Bn; n = 1, 3, 9; X = I, BF4
152
Some fused-1,2,3-triazole systems were reported. A convenient synthesis of 1,2,3-triazole-fused isoindolines (n ¼ 0) and dihydroisoquinolines (n ¼ 1) 153 from easily available terminal alkynes and (2-haloaryl)alkylazides was reported h10T8846i. 3,5-Disubstituted-6H-pyrrolo[1,2-c][1,2,3]triazoles 154 were obtained from the Morita–Baylis–Hillman adducts of propargyl aldehydes h10T3490i. Intramolecular 1,3-dipolar cycloaddition between an alkyne and an azide led to a series of 1,2,3-triazolofused-1,4-benzodiazepines, 1,2,5-benzothiadiazepines, pyrrolobenzodiazepines, and pyrrolobenzothiadiazepines h10TL4859i. 2-Azido-3-(2-iodophenyl)acrylates reacted with terminal alkynes in the presence of a copper(II) catalyst without ligands to give a wide range of [1,2,3]triazolo[5,1-a]isoquinolines 155 h10T80i. Novel N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines 156 were prepared from 2-chloro-5-nitropyrimidin-4-yl thiocyanate via N2,N4-substituted-5-nitropyrimidine-2,4-diamines h10S689i. A highly modular approach to various fused 1,2,3-triazoles was developed featuring a one-pot procedure combining copper(I) catalyzed azide–alkyne cycloaddition and palladium-catalyzed CH bond functionalization h10OL5092i. Enantioenriched allenylsilanes were used in the three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contained an imbedded azide which then underwent thermally induced intramolecular 1,3-dipolar cycloaddition reactions to give unique fused ring systems containing 1,2,3-triazoles h10OL336i. An expedient and facile route for the general synthesis of 3-arylsubstituted-1,2,3-triazolo[1,5-a] [1,4]benzodiazepin-6-ones and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones was published h10OBC4971i. Novel 3-substituted-1,2,3-triazolo[1,5-a]quinazolinones were synthesized from anionic hetero-domino reaction of appropriate substituted 2-azidobenzoates prepared from isatins and acetonitriles activated by 1,3-thiazole, 1,3-benzothiazole, 1,3,4-oxadiazole, and 1,2,4-oxadiazole rings h10JHC415i. Novel tricyclic 4-(trifluoromethyl)-[1,2,3]triazolo[1,5-a]quinoxalines were readily prepared from N-(o-haloaryl)alkynylimines and sodium azide via copper(I)-catalyzed tandem reactions h10ASC1296i.
251
Five-Membered Ring Systems: With More than One N Atom
( )n
R1
N N
CO2Et
R2
N N
R1
N
N N
N
R n = 0, 1; R = Ar, alkyl
R2
154
N
N R1
N
N N R2
N
N H
156
155
153
5.4.5. 1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES A review titled “Synthesis of 3,4,5-Trisubstituted-1,2,4-Triazoles” was published h10CR1809i. Various synthetic protocols were available for the preparation of 1,2,4-triazoles and derivatives thereof. Four-component palladium-catalyzed reaction of aryl iodides 157, amidines 158, carbon monoxide, and hydrazines delivered 1,3,5-trisubstituted1,2,4-triazoles 159 h10AG(E)325i. Reaction of 1,2,4-oxadiazoles 160 with excess hydrazine afforded 3-amino-1,2,4-triazoles 161 through a reductive ANRORC rearrangement h10JOC8724i. The first quinolyl substituted 1,2,4-triazole, 3,5-bis (2-quinolyl)-1,2,4-triazole was synthesized from 2-cyanoquinoline with hydrazine in acetic acid h10JHC210i. A convenient method for the synthesis of 1,2,4-triazolines 163 using oxazolones 162 and diethyl azodicarboxylate, followed by subsequent treatment with sodium hydroxide to give 1,2,4-triazoles 164, was reported h10JOC4330i. Heating of N,N-dimethylformamide azine dihydrochloride {N0 [(dimethylamino)methylene]-N,N-dimethylhydrazonoformamide dihydrochloride} with anilines in the absence of a solvent gave a range of 4-aryl-1,2,4-triazoles by direct transamination h10S2278i. Protected oxamide/oxalate derivatives 165 reacted with N,N-dimethylformamide diethyl acetal 166 to deliver amidines 167 which were condensed with hydrazine hydrochloride salts to give functionalized 1,5-disubstituted-1,2,4-triazoles 168 h10JOC8666i.
ArI + H2N
157
R1
CO, Pd(OAc)2 (5%) xantphos (5%), Et3N, DMF, 80 ⬚C;
R1
R2 NHNH 2 , HOAc
NH
158
N Ar
41–79%
159
R1 = R2 = alkyl, Ar
Ar
DEAD, CH3CN rt
O O
N
N
50–100% R = Me, i-Pr, Bn
R
162
HO2C
N N R2
X O
PG
O
+
Me
N Me
166
OEt
50 ⬚C 90–96%
Me
N
Ar N
reflux 74–83%
NH
164 R
O PG
O
X = N, O; R = Ar, alkyl PG = Bn, t-Bu, PMB, allyl
167
N
NaOH, EtOH
X
N
Me
N H
161
O EtOAc
N
Ar
DMF, rt 71–93%
160
CO2Et N N CO2Et R
OEt
H 2N
N
Ar
NH2 N
NH2NH2
163
O
165
Ar
Cl N
RNHNH2•HCl
N
HOAc, 50 ⬚C
N N
72–99%
X PG R
168
252
L. Yet
A two-step procedure for the synthesis of 1,2,4-triazoles 170 was achieved from primary amides 169 and phenylhydrazine via an oxidative process h10SL1771i. Substituted 4-amino-1,2,4-triazol-3-ones were synthesized from aldehyde hydrazones and azodicarboxylates in the presence of triphenylphosphine h10T2427i. 3-(Trifluoromethyl)-4H-1,2,4-triazole 172 was prepared in a single step from trifluoroacetylhydrazide 171 with formamidine acetate in low yield h10S1075i. 5-(5-Aminoimidazol-4-yl)-1,2,4-triazol-3-ones were obtained from 5-amino-4(N-ethoxycarbonyl)cyanoformimidoyl imidazoles and hydrazine in a rapid onepot reaction h10SL2792i. The reaction of 3,6-diaryl-1,2,4,5-tetrazines 173 and 2-arylsubstituted acetonitriles, under basic conditions, led unexpectedly to 3,5-disubstituted-1,2,4-triazoles 174 in moderate yields h10TL1654i. Thioamides 175 reacted with benzylhydrazide in the presence of silver(I) benzoate and acetic acid to give 1,2,5-trisubstituted-1,2,4-triazoles 176 h10TL2660i. Heterocyclic carbohydrazides were employed as precursors for the preparation of 1,2,4-triazole-5-thiones and derivatives thereof h10H(81)917i.
O Ar
N H
169
R
Ph
1. (COCl)2, CH2Cl2, 2, 6-lutidine
N
N
2. PhNHNH2, DMF, O2
N
Ar
30–66%
R
170
S
N
N N Ar
173
N N
RCH2CN, DBU THF, reflux 43–66%
Ar
N H
174
R1 R
formamidine acetate
N H
175
R2
N N
MeOH, rt
171
Ar
N
CF3CONHNH2
172
BnCONHNH2 AgOBz, HOAc CH2Cl2, rt 43–90% R1 = R2 = Ar, alkyl
CF
N H
25%
N N R1
N R2
Bn
176
There were some literature reports on the reactions of 1,2,4-triazoles. The Michael addition of a,b-unsaturated ketone with 1,2,4-triazole was efficiently catalyzed by the primary amine thiourea catalyst to give the products in high yields with moderate to excellent enantioselectivities h10SL2357i. 5,5-Dibromo-1,2,4-triazole 177 was selectively cross-coupled to only the 5-substituted triazoles 178 in which the carboxyl group acted as a tunable directing group h10JOC6965i. 3,5Dibromo-1,2,4-triazole 179 reacted with stannyl derivatives under microwave irradiation at 110 C to afford 5-aryl-1,2,4-triazoles 180, which were elaborated to 3,5-diaryl-1,2,4-triazoles 181 with the same catalyst systems h10SL55i. A Biginellilike three-component condensation using 3-amino-1,2,4-triazole as urea component resulted in an unexpected alternative direction of the tetrahydropyrimidine ring formation h10TL2095i.
253
Five-Membered Ring Systems: With More than One N Atom
ArB(OH)2, Pd(OAc)2 (3%) PPh3, (6%), Na2CO3
CO2H N N Br
NMP/H2O (1:2), 80 ⬚C
Br
N
Br Br
Ar2SnBu3 PdCl2(PPh3)2/LiCl or
N N N Me
Ar1
PdCl2(PPh3)2/CuI microwave, 130 ⬚C 41–88%
Ar
N 178
Br
Ar1SnBu3 PdCl2(PPh3)2/LiCl or
N N Me 179
Br
45–64%
177
N
CO2H N N
PdCl2(PPh3)2/CuI microwave, 130 ⬚C
Ar2 N Ar1
68–83%
180
N N Me 181
The use of 1,2,4-triazole reagents in synthetic operations were described. A highly enantioselective and diastereoselective cyclopentene forming reaction that employed catalytic amounts of Lewis acids and NHC 182 was developed h10JA5345i. An efficient strategy for the carbon–carbon bond formation between aldehyde and nitrile intramolecularly using an NHC catalyst 183 to give 3-aminochromone derivatives was reported h10OL352i. Intramolecular redox amidation for the synthesis of functionalized lactams with NHC catalyst 184 was reported h10OL5708i. Chiral NHC 185 was found to be efficient catalysts for the formal [4 þ 2] cycloaddition reaction of alkyl(aryl)ketenes and 3-alkylenyloxindoles to give the corresponding 3,4-dihydropyrano[2,3-b]indol-2-ones in excellent yields with good diastereo- and enantioselectivities h10JOC6973i. NHC 186 was employed in the direct synthesis of a-protio, a-deuterio, a-chloro-, and a-fluoro carboxylic acids h10JA2860i. 1,10 -Dithiobis(1H-1,2,4-triazole) 187 reacted with alkenes to form the corresponding thiiranes h10TL4110i. NHC of triazolium salt 188 catalyzed the oxidation amidation/azidation of aldehydes h10OL1992i and oxidation of aldehydes to esters h10JA1190i. Bifunctional NHCs bearing a (thio)urea moiety as hydrogenbond donor group were active catalysts in the benzoin reaction h10SL881i. O N
N
N BF4 N
N R
182 R = 2, 6-diEt-Ph 183 R = 2, 6-diF-Ph
BF4
BF4
N
N
N R2 N
N Ph
N
N N S S N N
R1
184 R1 = H, R2 = C6F5 185 R1 = C(3, 5-(CF3)2
186
187
I
N N
N
188
C6H3)2OH, R2 = Ph
Structurally unique 1,2,4-triazole fused ring systems were reported. 1,2,4-Triazolopyridines were prepared from the palladium-catalyzed coupling of aldehydederived hydrazones h10AG(E)8395i. Palladium-catalyzed addition of hydrazides to 2-chloropyridine followed by dehydration in acetic acid under microwave irradiation afforded [1,2,4]triazolo[4,3-a]pyridines 189 h10OL792i. N-Triazolide imidates reacted with 1,2,4-triazole-3,5-diamine to give regioselectively 5-substituted-2amino[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-ones 190 was described h10S1645i. The reaction of 4-amino-3-mercapto-5-phenyl-s-triazole with aromatic or aliphatic
254
L. Yet
ketones containing active a-hydrogens in acetic acid afforded s-triazolo[3,4-b][1,3,4] thiadiazines 191 h10S2636i. Three-component, one-pot synthesis of the [1,2,4]triazolo/benzimidazolo quinazolinones was achieved by condensation of 2-amino benzimidazole or 3-amino-1,2,4-triazole with dimedone and aldehydes in the presence of sulfamic acid in acetonitrile h10SC677i. Efficient syntheses of 1,2,4-triazolo[3,4-b] [1,3,4]thiadiazine derivatives were reported h10SC2421i. Microwave irradiation was used to accelerate the cyclocondensation of isoflavones and 3-amino-1,2,4-triazoles in the presence of sodium methoxide to produce 6,7-diaryl[1,2,4]-triazolo[4,3a]pyrimidines 192 h10SL1825i. An efficient one-pot microwave approach for the synthesis of novel [1,3]oxazolo[3,2-b][1,2,4]triazoles 193 was described h10TL3907i. The synthesis of 9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxalines 194 was described h10TL2262i. New triazolopyrrolopyrazine ring systems were prepared from 1,3-dipolar cycloaddition reactions h10SL2067i. The synthesis of 2-alkoxy(aralkoxy)5-chloro[1,2,4]triazolo[1,5-a]quinazolines was reported h10H(81)1843i. Reaction of 1-substituted 3,5-diamino-1,2,4-triazoles with b-keto esters followed by rearrangement led to 3-amino-2H-[1,2,4]triazolo-[4,3-a]pyrimidin-5-ones 195 h10T3301i. 2-Aryl2H-[1,2,4]triazoloquinolin-3-ones 196 were derived from a-chloroformylarylhydrazines hydrochloride h10T930i. Dimroth rearrangement of [1,2,4]triazolo[4,3-c]pyrimidines afforded highly functionalized 2-substituted [1,2,4]triazolo[1,5-c]pyrimidines 197 h10SL2179i. O N N
N N
HN
N
N
R
R
189
Ph
R1
N
NH2
N
R2
191 R1
N
N
N N
194
N
N
Ar2
192
193
NH2
O
195
Cl
N
N NH2
R1 N N R2
Br
N N
R2
O
N Br
N
R
Ar1
R3
N
R
N N
S
190
N
N N
N
N N
196
N
O Ar
N N
R
197
5.4.6. TETRAZOLES AND RING-FUSED DERIVATIVES An NMR study of the tautomeric behavior of N-(a-aminoalkyl)tetrazoles was published h10JOC6468i. The most common preparation of tetrazoles is the reaction of nitriles with azides. Pyridine hydrochloride was a good catalyst in the preparation of 5-substituted 1Htetrazoles 199 from aromatic nitriles 198 and sodium azide h10SC2624i. Treatment of nitriles 200 with sodium azide in the presence of iodine or the heterogeneous catalyst, silica-supported sodium hydrogen sulfate, afforded 5-substituted-1H-tetrazoles 201 h10SL391i. Mesoporous ZnS nanosphere was a novel heterogeneous catalyst for synthesis of 5-substituted 1H-tetrazoles from various nitriles and sodium azide h10CC448i. 5-Substituted-1H-tetrazoles were prepared from aromatic nitriles with
255
Five-Membered Ring Systems: With More than One N Atom
sodium azide, catalyzed by montmorillonite K-10 or kaolin clays in water or DMF h10JHC913i. An efficient method for preparation of 5-arylamino-1H-tetrazoles and 1-aryl-5-amino-1H-tetrazole derivatives 203 and 204 in various ratios from aminonitriles 202 was reported using FeCl3–SiO2 as an effective heterogeneous catalyst h10SC3159i. Similarly, arylaminotetrazole derivatives were synthesized efficiently by the reaction of arylcyanamides and sodium azide in the presence of zinc(II) chloride under aqueous conditions at reflux h10T3866i. NaN3, pyridine hydrochloride Ar
CN 198
(0.2 eq.), DMF, 100–120 ⬚C
Ar
79–96%
N N NH N
R CN
199
DMF, 110 ⬚C 73–77%, 0.4–1.9 ratio
202
2-butanone 120 ⬚C or 75 ⬚C
200
HN N
RHN
N
N
R
201
79–92%
NaN3, FeCl3-SiO2 (cat)
(ArHN) H2N CN
NaN3, NaHSO4-SiO2 or I2, DMF or
N N
N N NH N 203
+
H2N
N 204 R
Amides 205 were converted to 1,5-disubstituted tetrazoles 206 in the presence of diisopropyl azodicarboxylate, diphenylphosphoryl azide, and diphenyl-2-pyridyl phosphine h10TL1404i. The reaction between 1,1-difluoroazides 207 and primary amines 208 was reported to be an efficient synthetic approach to 1,5-disubstituted fluorinated tetrazoles 209 h10TL4205i. 5-Aroyl-1-aryltetrazoles were prepared from a four-component Ugi-like multicomponent reaction h10S4107i. A mild and general one-pot procedure for the conversion of cyanoethyl amides 210 to cyanoethylprotected tetrazoles 211 with azidotrimethylsilane via the imidoyl chlorides generated in situ was disclosed h10TL2010i. DIAD, DPPA (2-pyridyl)PPh2
O R1 205
NHR2
THF, 45 ⬚C
R1 N N R2 N N
30–85%
206
R1 = Ar, Bn; R2 = alkyl
O R
CN 210
R2 R1CF2N3 + R2NH2 207
208
EtOH or THF rt or reflux R1F2C 40–80% R1 = amides; R2 = Bn, alkyl, cycloalkyl
1. PCl5, pyridine, CH2Cl2, reflux
N N
2. TMSN3, rt
N N
N
N N N 209
R CN
73–86% 211
Reactions of tetrazoles were reported in the literature. Inverse electron demand Diels–Alder reactions of 5-(1-nitrosovinyl)-1-phenyl-1H-tetrazole, generated in situ from the corresponding bromooxime, with electron rich alkenes and heterocycles, provided tetrazolyl-1,2-oxazines and -oximes h10TL6756i. The one-pot regioselective preparation of 5-aryl/alkyl-2-vinyl-2H-tetrazoles 213 from 5-substituted tetrazoles 212 via a very simple procedure using 1,2-dibromoethane and triethylamine without
256
L. Yet
catalyst was described h10TL1411i. Ga(OTf)3 catalyzed the direct displacement of alcohols 214 with phenyltetrazole 215 to give thiotetrazole 216 h10OL5780i. Various 1,5-disubstituted tetrazoles 218 were prepared from palladium/copper-catalyzed direct arylation of 1-substituted tetrazoles 217 in the presence of tris(2-furyl)phosphine (TFP) and cesium carbonate h10JOC241i. An efficient procedure for transferring an oxygen atom to the 1- or 2-substituted 5-alkyl or aryl tetrazole 219 to give corresponding N-oxides 220, was developed using HOFCH3CN h10JOC3141i. 1,4-Additions of 5-phenyltetrazole derivatives to a,b-unsaturated enones were accomplished with salts of 9-amino-9-deoxy-epiquinine h10EJO2073i. The first anionic tetrazole-2N-oxide was prepared by mild aqueous oxidation of easily prepared 5-nitrotetrazole with oxone h10JA17216i. Various pyrido-, quinolino-, pyrazino-, and quinoxalinotetrazoles 221 were azide components in Cu-catalyzed click reaction with alkynes to give N-linked-1,2,3-triazole derivatives 222 h10OL2166i. Tetrazolo[1,5-a]pyrimidines are capable of serving as masked azides in copper-catalyzed Huisgen cyclization with a variety of terminal alkynes, providing a simple protocol for the generation of novel 40 -substituted 2-(10 ,20 ,30 -triazol-10 -yl)pyrimidines h10JHC887i. N N
Ph
N
R
BrCH2CH2Br, Et2N (4 eq.), CH3CN, reflux
N N N NH
N
N N
R
212
OH
N N
53–88% R = alkyl, Ar
SH Ga(OTf)3 (10%)
R2
R1
213
215
N N N
ClCH2CH2Cl, 75 ⬚C
214
N
S R2
R1
52–94%
F2, H2O, CH3CN ArI, Pd(OAc)2 (5%) TFP (10%), CuI
N N N
N R
Cs2CO3, CH3CN, 40 ⬚C 26–87%
217
Ar N N N
N R
R2
N N N N
218
X R1
N N
Cu(OTf)2•PhH (10%) N PhMe, reflux X = C, N
221
R2
N N N N R1
R1 = R2 = alkyl, Ar
219
R2 N
O
HOF•CH3CN 85–95%
R1
Ph
216
220
X R1 N
N
R2
N N
222
Nitro-containing tetrazoles and bis-tetrazoles are highly energetic materials. Highdensity energetic mono- and bis(oxy)-5-nitroiminotetrazoles 223 and 224, respectively, were reported h10AG(E)7320, 10JA15081i. Energetic salts based on monanions of N,Nbis(1H-tetrazol-5-yl)amine 225 and 5,50 -bis(tetrazole) 226 were disclosed h10CEJ3753i. N N MeO N N
R R
N NO2 R = NH4, NH2NH3
223
O2N N N N N ( )n N N N N R O O N N NO 2 n = 1, 2
224
H N N M N N N N NH N N
225
N N N N H
N M N N N
226
257
Five-Membered Ring Systems: With More than One N Atom
Some fused tetrazole ring systems were published this year. Iodine catalyzed onepot multicomponent synthesis of a library of compounds containing tetrazolo[1,5-a] pyrimidine cores 227 was reported h10JCO35i. Organocatalytic two-step synthesis of diversely functionalized tricyclic tetrazoles 228 was published h10OBC4527i. A method for the synthesis of previously unknown heterocyclic systems 4-{(5(difluoromethoxy)-1H-benzo[d]imidazol-2-ylthio)methyl}tetrazolo[1,5-a]quinolines derivatives 229 was developed h10JHC441i. Tetrazolo[1,5-a][1,4]benzodiazepines 230 were obtained by a facile azide Ugi five-center four-component reaction (U-5C-4CR) using ketones, sodium azide, ammonium chloride, and corresponding isocyanide h10OL3894i. The synthesis of a variety of annulated tetrazoles from differently substituted allyl azides, afforded from the Baylis–Hillman adduct of acrylates, using intramolecular cycloaddition approach was described h10S2731i. Isonitriles from the Baylis–Hillman adducts of acrylates were viable precursors to tetrazolofused diazepinones via post-Ugi cyclizations h10TL510i. OCHF2
O
O R1 N
N CN
R2
N N N
R2 R1
S
R1 N H
N N N N
R3
227
228
R2 R3
NH N H
R1 N N
N N N N
229
R2 R3
N N
230
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Five-Membered Ring Systems: With More than One N Atom
10JOC6468 10JOC6532 10JOC6644 10JOC6806 10JOC6965 10JOC6973 10JOC7002 10JOC8498 10JOC8724 10JOC8666 10JOC8693 10OBC536 10OBC761 10OBC941 10OBC1749 10OBC1929 10OBC2735 10OBC2814 10OBC2941 10OBC3874 10OBC4051 10OBC4503 10OBC4527 10OBC4536 10OBC4720 10OBC4827 10OBC4971 10OBC5692 10OL224 10OL324 10OL336 10OL352 10OL412 10OL464 10OL468 10OL516 10OL552 10OL792 10OL1584 10OL1640 10OL1776 10OL1932 10OL1992
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10OL2056 10OL2088 10OL2166 10OL2234 10OL2524 10OL2578 10OL2653 10OL2884 10OL3308 10OL3328 10OL3368 10OL3491 10OL3506 10OL3630 10OL3704 10OL3894 10OL4217 10OL4232 10OL4256 10OL4572 10OL4576 10OL4632 10OL4648 10OL4856 10OL4924 10OL4928 10OL4936 10OL4952 10OL4988 10OL5008 10OL5044 10OL5092 10OL5708 10OL5780 10S127 10S283 10S689 10S828 10S1075 10S1195 10S1311 10S1557
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Five-Membered Ring Systems: With More than One N Atom
10S1645 10S1687 10S1692 10S1781 10S2245 10S2278 10S2421 10S2609 10S2621 10S2636 10S2649 10S2731 10S2767 10S2794 10S2828 10S3021 10S3339 10S3710 10S3934 10S4051 10S4107 10S4256 10S4261 10SC81 10SC111 10SC135 10SC173 10SC257 10SC391 10SC414 10SC677 10SC877 10SC1057 10SC1123 10SC1134 10SC1216 10SC1270 10SC1539 10SC1743
263
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264
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10SC1932 10SC1963 10SC2130 10SC2421 10SC2525 10SC2547 10SC2588 10SC2624 10SC2667 10SC2686 10SC2880 10SC2930 10SC3046 10SC3159 10SL55 10SL219 10SL391 10SL423 10SL602 10SL881 10SL901 10SL1469 10SL1606 10SL1617 10SL1771 10SL1779 10SL1825 10SL1873 10SL1923 10SC1998 10SL2067 10SL2179 10SL2299 10SL2357 10SL2759 10SL2792 10T80 10T121 10T128 10T519 10T553 10T930 10T1208
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Five-Membered Ring Systems: With More than One N Atom
10T1937 10T2141 10T2427 10T2654 10T3301 10T3490 10T3599 10T3866 10T4542 10T5112 10T5451 10T6097 10T8231 10T8242 10T8772 10T8846 10T8854 10T8922 10T9141 10T9475 10T9745 10T9835 10TL284 10TL399 10TL478 10TL510 10TL550 10TL692 10TL828 10TL970 10TL1022 10TL1139 10TL1152 10TL1341 10TL1380 10TL1404 10TL1411 10TL1654 10TL2010 10TL2095 10TL2262 10TL2660
265
J. Koubachi, S. Berteina-Raboin, A. Mouaddib, G. Guillaumet, Tetrahedron 2009, 66, 1937. M.A. Ameen, S. Karsten, J. Liebscher, Tetrahedron 2009, 66, 2141. Y. Su, Z. Jiang, D. Hong, P. Lu, Y. Wang, X. Lin, Tetrahedron 2009, 66, 2427. S. Guillou, F.J. Bonhomme, D.B. Chahine, O. Nesme, Y.L. Janin, Tetrahedron 2009, 66, 2654. V.M. Chernyshev, A.V. Astakhov, Z.A. Starikova, Tetrahedron 2009, 66, 3301. S.P. Park, S.-H. Ahn, K.-J. Lee, Tetrahedron 2009, 66, 3490. L. Kiss, E. Forro, R. Sillanpaa, F. Fulop, Tetrahedron 2009, 66, 3599. D. Habibi, M. Nasrollahzadeh, A.R. Faraji, Y. Bayat, Tetrahedron 2009, 66, 3866. M.F. Proenc¸a, M. Costa, Tetrahedron 2009, 66, 4542. M.-H. Wu, J.-H. Hu, D.-S. Shen, P. Bremond, H. Guo, Tetrahedron 2009, 66, 5112. A. Pal, R. Ghosh, N.N. Adarsh, A. Sarkar, Tetrahedron 2009, 66, 5451. H.-J. Pi, L.-F. Liu, S.-S. Jiang, W. Du, W.-P. Deng, Tetrahedron 2009, 66, 6097. M. Ghandi, N. Zarezadeh, A. Taheri, Tetrahedron 2009, 66, 8231. H. Ren, S. Ye, F. Liu, J. Wu, Tetrahedron 2009, 66, 8242. M. Seredyuk, I.O. Fritsky, R. Kramer, H. Koz1owski, M. Haukka, P. Gu¨tlich, Tetrahedron 2009, 66, 8772. V. Fiandanese, G. Marchese, A. Punzi, F. Iannone, G.G. Rafaschieri, Tetrahedron 2009, 66, 8846. T. Kylmala, A. Hamalainen, N. Kuuloja, J. Tois, R. Franze´n, Tetrahedron 2009, 66, 8854. M. Yoshida, N. Terai, K. Shishido, Tetrahedron 2009, 66, 8922. H.-Y. Liu, Z.-T. Yu, Y.-J. Yuan, T. Yu, Z.-G. Zou, Tetrahedron 2009, 66, 9141. V. Aragao-Leoneti, V.L. Campo, A.S. Gomes, R.A. Field, I. Carvalho, Tetrahedron 2009, 66, 9475. V.A. Mamedov, N.A. Zhukova, T.N. Beschastnova, A.T. Gubaidullin, A.A. Balandina, S.K. Latypov, Tetrahedron 2009, 66, 9745. A. Alizadeh, T. Firuzyar, L.-G. Zhu, Tetrahedron 2009, 66, 9835. V.S. Arvapalli, G. Chen, S. Kosarev, M.E. Tan, D. Xie, L. Yet, Tetrahedron Lett. 2010, 51, 284. R. Duddu, P.R. Dave, R. Damavarapu, N. Gelber, D. Parrish, Tetrahedron Lett. 2010, 51, 399. M.J.L. Rivilli, E.L. Moyano, G.I. Yranzo, Tetrahedron Lett. 2010, 51, 478. M. Nayak, S. Batra, Tetrahedron Lett. 2010, 51, 510. N.W. Smith, B.P. Polenz, S.B. Johnson, S.V. Dzyuba, Tetrahedron Lett. 2010, 51, 550. K. Niknam, D. Saberi, M. Sadegheyan, A. Deris, Tetrahedron Lett. 2010, 51, 692. A. Zhang, X. Zheng, J. Fan, W. Shen, Tetrahedron Lett. 2010, 51, 828. D.C. Beshore, R.M. DiPardo, S.D. Kuduk, Tetrahedron Lett. 2010, 51, 970. G.R. Pereira, L.J. Santos, I. Luduvico, R.B. Alves, R.P. de Freitas, Tetrahedron Lett. 2010, 51, 1022. S. Chatterjee, G. Ye, C.U. Pittman, Jr., Tetrahedron Lett. 2010, 51, 1139. L. Du, N. Ni, M. Li, B. Wang, Tetrahedron Lett. 2010, 51, 1152. S. Dadiboyena, E.J. Valente, A.T. Hamme, Tetrahedron Lett. 2010, 51, 1341. W. Zeller, A.S. Kiselyov, J. Singh, Tetrahedron Lett. 2010, 51, 1380. G.M. Schroeder, S. Marshall, H. Wan, A.V. Purandare, Tetrahedron Lett. 2010, 51, 1404. J. Roh, K. Vavrova, A. Hrabalek, Tetrahedron Lett. 2010, 51, 1411. M.J. Haddadin, E.H.G. Zadeh, Tetrahedron Lett. 2010, 51, 1654. L.J. Kennedy, Tetrahedron Lett. 2010, 51, 2010. N.Y. Gorobets, Y.V. Sedash, K.S. Ostras, O.V. Zaremba, S.V. Shishkina, V.N. Baumer, O.V. Shishkin, S.M. Kovalenko, S.M. Desenko, E.V. Van der Eycken, Tetrahedron Lett. 2010, 51, 2095. A. Unciti-Broceta, M.J. Pineda-de-las-Infantas, M.A´. Gallo, A. Espinosa, Tetrahedron Lett. 2010, 51, 2262. M. Bibian, A.-L. Blayo, A. Moulin, J. Martinez, J.-A. Fehrentz, Tetrahedron Lett. 2010, 51, 2660.
266
L. Yet
10TL2737 10TL2967 10TL3018 10TL3181 10TL3193 10TL3613 10TL3691 10TL3759 10TL3796 10TL3899 10TL3907 10TL3980 10TL4037 10TL4110 10TL4205 10TL4328 10TL4357 10TL4459 10TL4501 10TL4605 10TL4717 10TL4755 10TL4859 10TL5005 10TL5052 10TL5252 10TL5704 10TL5740 10TL5915 10TL5922 10TL6082 10TL6105 10TL6275 10TL6493 10TL6503 10TL6756 10TL6763 10TL6799 10TL6945 10TL6951
K. Takasu, T. Azuma, Y. Takemoto, Tetrahedron Lett. 2010, 51, 2737. A. Rahmati, Tetrahedron Lett. 2010, 51, 2967. K. Sivakumar, A. Kathirvel, A. Lalitha, Tetrahedron Lett. 2010, 51, 3018. V.P. Reddy, A.V. Kumar, K.R. Rao, Tetrahedron Lett. 2010, 51, 3181. K. Longhi, D.N. Moreira, M.R.B. Marzari, V.M. Floss, H.G. Bonacorso, N. Zanatta, M.A.P. Martins, Tetrahedron Lett. 2010, 51, 3193. T. Kylma¨la¨, S. Udd, J. Tois, R. Franze´n, Tetrahedron Lett. 2010, 51, 3613. D. Yang, M. Kwon, Y. Jang, H.B. Jeon, Tetrahedron Lett. 2010, 51, 3691. H.G. Bonacorso, L.M.F. Porte, G.R. Paim, F.M. Luz, M.A.P. Martins, N. Zanatta, Tetrahedron Lett. 2010, 51, 3759. J.M. Salovich, C.W. Lindsley, C.R. Hopkins, Tetrahedron Lett. 2010, 51, 3796. D.S. Werner, H. Dong, M. Kadalbajoo, R.S. Laufer, P.A. Tavares-Greco, B.R. Volk, M.J. Mulvihill, A.P. Crew, Tetrahedron Lett. 2010, 51, 3899. C. Ball, D.K. Dean, O. Lorthioir, L.W. Page, C.L. Smith, S.P. Watson, Tetrahedron Lett. 2010, 51, 3907. J.R. Mali, U.R. Pratap, D.V. Jawale, R.A. Mane, Tetrahedron Lett. 2010, 51, 3980. P.S. Reddy, V. Ravi, B. Sreedhar, Tetrahedron Lett. 2010, 51, 4037. Y. Sugihara, K. Onda, M. Sato, T. Suzuki, Tetrahedron Lett. 2010, 51, 4110. A.G. Polivanova, S.V. Shkavrov, A.V. Churakov, A.S. Lermontov, S.A. Lermontov, Tetrahedron Lett. 2010, 51, 4205. M.A. Ameen, S. Karsten, R. Fenger, J. Liebscher, Tetrahedron Lett. 2010, 51, 4328. E.K. Singh, L.A. Nazarova, S.A. Lapera, L.D. Alexander, S.R. McAlpine, Tetrahedron Lett. 2010, 51, 4357. F.A. Romero, R. Moningka, Tetrahedron Lett. 2010, 51, 4459. A. Fall, M. Sene, M. Gaye, G. Go´mez, Y. Fall, Tetrahedron Lett. 2010, 51, 4501. P. Liu, L.-s. Fang, X. Lei, G.-q. Lin, Tetrahedron Lett. 2010, 51, 4605. J. Quiroga, J. Trilleras, D. Pantoja, R. Abonia, B. Insuasty, M. Nogueras, J. Cobo, Tetrahedron Lett. 2010, 51, 4717. R. Ducray, P. Boutron, M. Didelot, H. Germain, F. Lach, M. Lamorlette, A. Legriffon, M. Maudet, M. Menard, G. Pasquet, F. Renaoud, I. Simpson, G.L. Young, Tetrahedron Lett. 2010, 51, 4755. C.S. Chambers, N. Patel, K. Hemming, Tetrahedron Lett. 2010, 51, 4859. R.E. Beveridge, D. Fernando, B.S. Gerstenberger, Tetrahedron Lett. 2010, 51, 5005. P. Arsenyan, E. Paegle, A. Petrenko, S. Belyakov, Tetrahedron Lett. 2010, 51, 5052. S.N. Murthy, B. Madhav, Y.V.D. Nageswar, Tetrahedron Lett. 2010, 51, 5252. S. Okamoto, H. Ishikawa, Y. Shibata, Y.-i. Suhara, Tetrahedron Lett. 2010, 51, 5704. R.R. Kale, V. Prasad, H.A. Hussain, V.K. Tiwari, Tetrahedron Lett. 2010, 51, 5740. K.M.J. Cheung, J. Reynisson, E. McDonald, Tetrahedron Lett. 2010, 51, 5915. Y.M. Kim, S. Lee, S.H. Kim, K.H. Kim, J.N. Kim, Tetrahedron Lett. 2010, 51, 5922. V. Gaumet, E. Moreau, A. Taleb, F. Leal, J. Neyts, J. Paeshuyse, C. Lartigue, O. Chavignon, A. Gueiffier, J.-C. Teulade, J. Me´tin, J.-M. Chezal, Tetrahedron Lett. 2010, 51, 6082. X. Ding, H.-L. Jiang, C.-J. Zhu, Y.-X. Cheng, Tetrahedron Lett. 2010, 51, 6105. Z. Gonda, K. Lorincz, Z. Nova´k, Tetrahedron Lett. 2010, 51, 6275. C. Siddappa, V. Kambappa, A.K.C. Siddegowda, K.S. Rangappa, Tetrahedron Lett. 2010, 51, 6493. V.A. Mamedov, D.F. Saifina, A.T. Gubaidullin, V.R. Ganieva, S.F. Kadyrova, D.V. Rakov, I.Kh. Rizvanov, O.G. Sinyashin, Tetrahedron Lett. 2010, 51, 6503. S.M.M. Lopes, A. Lemos, T.M.V.D.P. Melo, Tetrahedron Lett. 2010, 51, 6756. Z. Zhong, R. Hong, X. Wang, Tetrahedron Lett. 2010, 51, 6763. N. Ji, E. Meredith, D. Liu, C.M. Adams, G.D. Artman, III, K.C. Jendza, F. Ma, N. Mainolfi, J.J. Powers, C. Zhang, Tetrahedron Lett. 2010, 51, 6799. M.A. Tasdelen, Y. Yagci, Tetrahedron Lett. 2010, 51, 6945. Y. Huang, G.L. Gard, J.M. Shreeve, Tetrahedron Lett. 2010, 51, 6951.
CHAPTER
5.5
Five-Membered Ring Systems: With N and S (Se) Atoms Yong-Jin Wu*, Bingwei V. Yang** *Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492-7660, USA
[email protected] **Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543-4000, USA
[email protected]
5.5.1. INTRODUCTION This review chapter focuses on the syntheses and reactions of five-membered heterocyclic ring systems containing nitrogen and sulfur (or selenium) (reported during 2010). The importance of these p-rich heterocycles in medicinal chemistry and natural products is also covered.
5.5.2. THIAZOLES 5.5.2.1 Synthesis of Thiazoles The Hantzsch reaction discovered in 1889 remains one of the most reliable routes to thiazoles. For example, a novel series of thiazole-containing cyclopeptides 5 is prepared by means of the Hantzsch reaction followed by intramolecular thioalkylation macrocyclization reaction h10JOC7939i. The resin-bound orthogonally protected Fmoc-Cys-(Trt)-OH 1 undergoes standard repetitive Fmoc-amino acid coupling to yield the linear tripeptide 2 with N-terminal free amine. This amine is treated with Fmoc-isothiocyanate to give thiourea 3 after Fmoc deprotection. Exposure of thiourea 3 to 1,3-dichloroacetone brings about Hantzsch reaction to give the resin-bound chloro methyl thiazolyl peptide 4. The Trt group is deprotected under acidic conditions, and the free thio undergoes base-induced SN2 intramolecular cyclization to give thiazolyl thioether cyclic peptide 5 after resin cleavage.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00009-7
#
2011 Elsevier Ltd. All rights reserved.
267
268
Y.-J. Wu and B.V. Yang
Solid-phase peptide synthesis
O FmocHN
N H
FmocNCS; piperidine
O
H N
N H
O Trt-S
Trt-S
1
NH2
2
O H N
O N H
O Trt-S NH2
HN S
O
H N
Cl
Cl
N H
O Trt-S HN
3
S
4
Cl
O
H N
TFA, t-Bu3SiH; Cs2CO3; HF, anisole
N
NH2
O S N
HN
S
5
Other applications of Hantzsch reaction include the diversity-oriented synthesis of N-aryl-N-thiazolyl compounds h10TL4797i and orthogonally protected thiazole diamino acids h10CEJ9002i. Dirhodium tetrakis(heptafluorobutyramide)-catalyzed reaction of 4-bromothiobenzamide 6 with methyl 2-diazo-3-oxobutanote 7a affords thiazo-4-carboxylate 8a in 47% yield. This approach complements the Hantzsch synthesis of thiazole-4carboxylates from halopyruvates h10JOC152i. The diazophosphonate 7b and diazosulfone 7c also react with 6 to afford a range of thiazole-5-phosphonates 8b and -sulfones 8c, respectively, in modest to excellent yields. Z NH2
Br
S
6
+
Rh2(NHCOC3F7)4 (2 mol%)
N2 O
N
Me
S
Z
Br
Me 35–88%
7a/b/c
8a/b/c
a: Z = CO2Me; b: Z = PO(OMe)2; c: Z = Ts
A recent total synthesis of ()-bacillamide C makes use of a one-pot, four-component Ugi reaction to form methyl 2-(1-(N-(2,4-dimethoxybenzyl)acetamido)ethyl)thiazole-4-carboxylate 13 h10OBC529i. Treatment of isonitrile 9, 2,4-dimethoxybenzylamine, acetaldehyde, and thioacetic acid in methanol gives the Ugi reaction product 13 in good yield. In this Ugi-type reaction, a benzylamine instead of ammonia is required, as ammonia displays poor reactivity. The
Five-Membered Ring Systems: With N and S (Se) Atoms
269
2,4-dimethoxybenzyl protecting group is removed under acidic conditions to give 14, which is converted to ()-bacillamide C, an algicidal natural product. ArCH2NH2 + MeCHO MeO2C
N
9
C
Me H
MeO2C
N
N
MeO2C
N H S O N Me Me Me 10
26
NMe2 HS Me
Ar
Me
Ar
O
Me
H N
Ar
N S N Me O Me Me 11
Ar = 2,4-dimethoxybenzyl Me N
O
S
N
Me
N H
MeO2C
Me
TFA 58%
Me
N
MeO2C
Me Ar
O
-Me2NH
MeO2C
N
N SH N O Me Me Me 12
60%
S
Ar
13
14
A series of trisubstituted thiazole derivatives 20 have been prepared from propargylic alcohols 15 h10OBC3259i. Tertiary propargylic alcohols 15 undergo cycloaddition with thioamides 16 in the presence of silver triflate as the catalyst to give substituted thiazoles 20 with complete regioselectivity. This reaction is in contrast to the corresponding scandium-catalyzed version where the substrates are limited to the secondary aromatic propargylic alcohols. The reaction pathway involves the propargylic cation 17 or the allenyl cation 18, which is attacked first at the g position by the sulfur atom of the thioamides to give intermediate 19. This intermediate cyclizes in the 5-exo-dig mode, leading to the thiazole 20. OH R1 2
R
AgOTf (10 mol%)
S +
R3
R4
R1 R2
NH2
R4 1
HN ..
R
C
2
R
Ag
19
R3
C 3 b g R
18
R2 R1
S R3
R1 R2 a
17
16
15
a b g
N
42–89% R3
S
R4
20
R1, R2 = aryl, alkyl, together cyclopentyl; R3 = H, alkyl, aryl, TMS
Cycloadditions of secondary propargylic alcohols 21 with thioamides have also been investigated h10OBC3259i. Reaction of alcohol 21 with benzothioamide proceeds smoothly to give thiazole 23 as a single product. However, in the case of secondary propargylic alcohol 24, a 29 : 71 mixture of thiazoles 30 and 31 is obtained in 87% overall yield. Presumably, both the instability of the allenyl cation intermediate 26 and the steric effect of the trimethylsilyl group make nucleophilic attack (by the sulphur atom of benzothioamide) at the a position more favorable than that at the g position, thus providing 31 as the major product.
270
Y.-J. Wu and B.V. Yang
OH
S
AgOTf (10 mol%)
Ph
87%
n-Bu
N
+
Ph
n-Bu
Ph
NH2
21 OH
AgOTf (10 mol%)
S +
Ph 24
S 23
22
Ph
TMS
Ph
Ph a b g 25
NH2 22
R1 = aryl; R3 = TMS, H
TMS
Ph
C a b g TMS 26 Ph
Ph
HN ..
NH ..
S
Ph
Ph Ag
TMS
27
TMS 28
Ag
R1 Ph
S [Ag]
N Ph
S
C
TMS
Ph
N H
Ph
S 31
N
TMS
Ph
S 30
29
Substituted thiazoles 36 are also synthesized from propargylic alcohols 32 through a sequence of propargylation, sulfuration, and cyclization h10OBC3259i. Thus, propargylic alcohol 32 is treated with thioamide 16 and 10 mol% ferric chloride, and the resulting crude product 34 is subjected to Lawesson’s reagent to furnish the substituted thiazole 36 in moderate yield. OH
(1) FeCl3 (10 mol%) (2) Lawesson's reagent
O
Ph
+
Ph
R4
R3
32
16 R4
33 R4
O
Ph S
HN
N
HN 3
3
R Ph
R3
a b g
NH2
34
R Ph
35
41−51%
R3
S
R4
36
R3 = Ph, TMS, n-Bu; Ph; R4 = aryl, n-Pr
A new cycloaddition reaction of the 3-sulphanyl and 3-selanylpropargyl alcohols 37 with thioamides has been developed for the synthesis of multifunctionalized thiazoles 41 h10T7975i. The reaction presumably proceeds through the propargyl cation 38, which isomerizes to the propadienyl cation 39 which is stabilized by either the adjacent sulphur or selenium. Reaction of the propadienyl cation 39 with thiobenzamide gives the propadienylimine intermediate 40, which undergoes a 5-exo-trig ring closure to form thiazole 41. In this reaction, tetrabutylammonium hydrogensulfate serves as a scavenger to remove the eliminated hydroxyl group. Both the sulfanyl and selanyl are versatile functional groups for further chemical manipulations.
Five-Membered Ring Systems: With N and S (Se) Atoms
PhC(S)NH2; Sc(OTf)3 (5 mol%), n-Bu4NHSO4 (0.2 eq.)
XPh Ar OH
XPh
XPh
Ar
Ar
271
C
39
38
37
PhC(S)NH2
X = S, Se XPh
XPh
Ar Ar N
C
48–100%
S
S HN
Ph
Ph
40
41
Oxidation of thiazolines represents another approach to thiazoles. For example, treatment of thiostrepton derivative 42 (which contains one thiazoline ring and four thiazole rings) with bromotrichloromethane and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) brings about remarkably selective oxidation of the thiazoline moiety to give penta(thiazole) analog 43 in excellent yield h10AG(E)3317i. O
NH2
N H
S
O
N O S
Me HO
N
O
N H
N S
O
H N Me
Et H Me
OH
O
NH
CBrCl3, DBU
N
S HN
O
91%
O
O
Me
N H
N Me O Me
NH
HN
O
H N
N
N
H N
Me
OH
S Me
O Me HO
O
OH
NH2
N
42
H
S
O
N O S
Me HO
N
O
N Me
N H
S
Me
O
O
N
H N
N
Me
H N
O
O
HN
O Me
N H
N
S HN
NH
O
H N
N
S
O Me
43
Me
HO
Me OH
OH
OH
O Et H NH
Me
272
Y.-J. Wu and B.V. Yang
Oxidation of thiazolines to thiazoles is typically carried out with activated manganese dioxide, nickel oxide, and bromotrichloromethane/DBU. These reagents are effective, but excessive manganese dioxide and nickel oxide are generally required and bromotrichloromethane is harmful to the environment. Recently, it has been shown that molecular oxygen can effect this transformation h10TL1751i. For example, treatment of thiazoline 44 with potassium carbonate in the presence of air and molecular sieves in DMF at 80 C affords thiazole 47 in excellent yield. Ph
air, K2CO3, DMF, MS
S
Ph
N
44
Ph
S N
CO2Et
45 Ph
S N
OOH CO2Et
46
OH CO2Et
S
91%
N CO2Et
47
5.5.2.2 Synthesis of Thiazolines Various 2-phenylaminothiazolines 50 have been prepared from the corresponding N-(2-hydroxyethyl)-N0 -phenylthioureas 49 under mild conditions using either 1,10 -carbonyldiimidazole (thio-CDI) or 1,10 -carbonyldiimidazole (CDI) to promote the cyclization h10OL5526i. X N
N H2N
OH
R1
HN
R
R1
48
N PhHN
OH
PhNCS
2
N
S
PhHN
S
X = S, O 71–88%
R2
R2
N R1
50
49
Pattenden’s approach to thiazolines, first reported in 1993 h93T5359, 95T7321i, has been applied to the synthesis of largazole analogs h10OL3018i. Cyclocondensation of 2-methylcysteine 52 with nitrile 51 in the presence of diisopropylethylamine (DIPEA) results in thiazoline acid 53 in good yield. Compound 53 is converted to the marine peptide bisebromoamide in just one step. Me
Me
SH
H2N BocNH
CN
Me
52
N BocNH
DIPEA, EtOH
N Me
Me
CO2H Me
O O
48%
S
N Me
O O
OH
51
Br
OH
53
Br
Me CO2H
Five-Membered Ring Systems: With N and S (Se) Atoms
273
5.5.2.3 Reactions of Thiazoles and Fused Derivatives N-Heterocyclic carbene gold(I) complex (Ipr)AuOH 56 has been shown to be an effective catalyst for the carboxylation of aromatic C-H bonds including thiazoles h10JA8858i. Under optimized catalytic conditions, the gold(I)-mediated C-H activation of thiazole exhibits moderate selectivity and affords 2.3 : 1 mixture of C2/ C5 regioisomers 54 and 55. In the case of benzothiazole, a good yield is obtained as there is no regioselectivity issue. N
(IPr)AuOH (1.5 mol%), KOH, THF
+ CO2
N
N CO2H
S
+
S
HO2C
54 (81%)
N
55 (27%) i-Pr
(IPr)AuOH (1.5 mol%), KOH, THF
i-Pr N
N CO2H
78%
S
S
S
57
N
Au i-Pr i-Pr OH 56 (IPr)AuOH
Direct carboxylation of benzothiazoles without a metal catalyst is also possible h10OL3567i. Reaction of 58 with cesium carbonate in the presence of carbon dioxide (1.4 atm.) in DMF at 125 C furnishes methyl benzo[d]thiazole-2-carboxylate 59 after esterification with methyl iodide. N S
R
58
Cs2CO3, CO2, DMF; MeI
N R
S
R = Me, 91% CO2Me R = CN, 90% R = C(O)Ph, 68%
59
The palladium-catalyzed C-H arylation of thiazoles and benzothiazoles using lithium tert-butoxide as the base has been disclosed h10JOC6998i. Treatment of benzothiazole with 4-bromotoluene in dioxane at 100 C affords the coupling product 60 in excellent yield. Surprisingly, no coupling reaction is observed when DMF is employed as the solvent. The subtle solvent effect has been judiciously applied to the synthesis of 2,5-diarylthiazole derivatives via a one-pot 2-arylation followed by 5-arylation of thiazole. In a representative example, arylation of thiazole with 4-bromotoluene occurs selectively at the 2-position to give 61 when the reaction is performed in dioxane at 100 C for 5 h. Exposure of this crude reaction mixture with DMF, additional lithium tert-butoxide, and 4-bromoanisole provides 2,5-diarylthiazole 62 in 56% overall yield.
274
Y.-J. Wu and B.V. Yang
Pd(Pt-Bu3)2 (2 mol%), LiOt-Bu (1.2 eq.)
N Me
Br
+ S
N Br
+
Me
N Me
96% (in dioxane) trace (in DMF)
Pd(Pt-Bu3)2 (2 mol%), LiOt-Bu (1.2 eq.), dioxane
S
60 N Me S
S
61 Pd(Pt-Bu3)2 (2 mol%), LiOt-Bu (1.2 eq.), DMF Br
56%
OMe N Me S MeO
62
Direct C-H bond arylation of thiazoles with arylboronic acids involves manganese acetate and microwave heating h10S1166i. Presumably, arylboronic acids undergo the single electron oxidative decomposition by manganese acetate to generate the aryl radicals, which couple with thiazoles to give substituted thiazoles. Interestingly, conventional heating in place of microwave irradiation does not provide sufficient C-H activation for thiazoles. N + (HO)2B
Mn(OAc)3 EtOH, mW 52%
S
N + (HO)2B S
N
Mn(OAc)3 EtOH, mW 54%
S
N S
The nickel–copper-catalyzed direct alkylation of thiazoles and benzothiazoles has been developed h10AG(E)3061i. The optimized conditions include nickel complex 63 as the active precatalyst (5 mol%), copper(I) iodide (5 mol%) as the cocatalyst, and tert-butyl lithium as the base in dioxane at 140 C. Under these conditions, various 2-alkylated thiazoles 64 and 65 are obtained in good yields. The mechanism of the coupling reaction might parallel to those of nickel/copper- and copper-catalyzed direct arylation and alkynylation of aromatic heterocycles. The copper cocatalyst is not necessary for the coupling reaction, but it is required to achieve satisfactory yields.
Five-Membered Ring Systems: With N and S (Se) Atoms
R-X (1.2 eq.), 63 (5 mol%), CuI (5 mol%), t-BuOLi (1.4 eq.), dioxane
N
NMe2 N R
S
275
N Ni Cl
S
n-butyl iodide, 78% 5-bromopent-1-ene, 74% PhCOO(CH2)6I, 72%
64
NMe2
63
Me
N
Me
S
Ph(CH2)3Cl (1.2 eq.), 63 (5 mol%), t-BuOLi (1.4 eq.), dioxane
Me
N
Me
S
(CH2)3Ph
76%
65
Decarboxylative cross-coupling of thiazole-2-carboxylic acids with aryl halides has been studied h10OL4745i. Under a bimetallic system of catalytic palladium and a stoichiometric silver carbonate, a variety of 5-arylthiazoles 67 are prepared in good yields. Surprisingly, no cross-coupling is observed in the presence of stoichiometric copper carbonate, a reagent that has also been used for decarboxylation (vide infra). In contrast, addition of stoichiometric silver carbonate proves effective, affording the arylated thiazoles in good yields. The triphenylphosphine ligand is not essential, but it does generally improve efficiencies. A somewhat similar silver–palladium-catalyzed decarboxylative cross-coupling of aryl triflates 69 with thiazole carboxylate salts 68 has appeared h10CEJ3906i.
Ph
PdCl2 (5 mol) PPh3 (10 mol%) Ag2CO3 (1 eq.)
N Me
S
+ Ar-X 59–91%
CO2H
Ph
N Me
S Ar
X = Br, I
67
66
R Me
N Me +
KO2C
Me
N Me S
S
68
Ag2CO3 (5 mol%) PdCl2 (3 mol%) Ph3P (9 mol%) 2,6-lutidine (20 mol%)
OTf
69
80% (R = Cl) 75% (R = Me)
R
70
Decarboxylative C-H cross-coupling of thiazoles with oxazoles provides easy access to the bis(azole) compounds. These coupling reactions are typically performed with copper carbonate (base), palladium acetate (catalyst), and bis(dicyclohexylphosphino)ethane (dcpe) (ligand) in dioxane at 140 C in a sealed vial h10AG(E)2768i. Mechanistically, thiazole acids undergo decarboxylation in the presence of copper carbonate to give cuprate 76, which intercepts the C-2 palladated oxazole intermediate 77 (derived from oxazole via deprotonation followed by palladation). Transmetallation of 77 with cuprate 76 affords the palladium intermediate 78 which reductively eliminates palladium(0) to produce the coupled product 73.
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Y.-J. Wu and B.V. Yang
Ph
N Me
S
N
R1
Me N
45–82%
S
Ph
Me
74 CO2Cu
O
R2
N
R1
O
R2
N
R1
73
72
N S
R2
+ H
71 CO2H Ph
O
Pd(OAc)2 (5 mol) dcpe (5 mol%) CuCO3 (3 eq.)
75 Me
Ph
N Me + Pd
S
O N
76
Cu
R2 N R1
S
Ph
77
O
R2
N
R1
Pd
78
Reaction of 5-isobutylthiazole with olefins 79 in the presence of palladium acetate (10 mol%, catalyst) and silver acetate (3 equiv., oxidant) in propionic acid at 120 C leads to direct oxidative allenylation to give 5-alkenylated thiazoles 80 in good yields h10JOC5421i. The choice of propionic acid as a solvent appears to be critical to the efficiency of this type of reactions. Pd(OAc)2 (5 mol%), AgOAC (3 eq.), EtCO2H
N + i-Bu
R
S
79
64–85%
N i-Bu
R
S
80 R = CO2t-Bu, CONMe2, aryl, etc.
Functionalized thiazolyl amines are made by the oxidative coupling of polyfunctional zinc amidocuprates using (diacetoxyiodo)benzene (PhI(OAc)2) as oxidant h10S2313i. The required organozinc reagent 82 is obtained by direct zincation of 2,4-dibromothiazole with TMP2Zn2MgCl22LiCl (TMP ¼ 2,2,6,6-tetramethylpiperidyl). This zinc reagent is treated with the THF soluble complex CuCl2LiCl and LiN(TMS)2 to afford the corresponding zinc amidocuprate 83. Subsequent oxidation of 83 with (diacetoxyiodo)benzene furnishes the heterocyclic amine 84 in 82% yield. Amines 85 and 86 are obtained from the zinc reagent 82 when lithium morpholin-4-ide and lithium diisopropylamide are used, respectively.
Five-Membered Ring Systems: With N and S (Se) Atoms
Br TMP2Zn•2MgCl2•2LiCl (0.6 eq.)
N Br
Br
) Zn
S
81
2
82 Br
S 83
Br
PhI(OAc)2 (1.1 eq.)
TMS N Cu TMS ZnX
N Br
CuCl•2LiCl (1.1 eq.); LiN(SiMe3)2 (2 eq.)
Br N
S
277
N Br
82%
S
84
TMS N TMS
(1) CuCl•2LiCl Br Br
) Zn
S
2
(2) PhI(OAc)2
82
N Br
Br
2
(2) PhI(OAc)2
82
O
85 Br
(1) CuCl•2LiCl, LDA
) Zn
S
N
S
80%
N Br
Br
N Li
O
N
N Br
S
86
65%
i-Pr N i-Pr
The functionalized organozinc halides can also be converted to primary amides h10OL3648i. Thus, organozinc chloride 87, which is readily prepared by halogen–magnesium exchange and subsequent transmetalation with zinc chloride, reacts with trichloroacetyl isocyanate to give the corresponding primary amide 89 after hydrolysis under basic conditions. O N Br
ClZn
S
Cl3C
N
Mg, ZnCl2, LiCl
S
87 K2CO3, MeOH 82%
NCO Cl3C
ClZn N
N S O
O
88
N H2N
S O
89
The arylation of thiazoles in 4- and 5-position has been investigated in detail, and several guidelines have been developed for selecting reaction conditions for the arylation of various thiazoles h10T8051i. Dibromothiazoles undergo catalyst-controlled regioselective Suzuki couplings h10JOC1733i. Bisaryl phosphite-thiazole ligands have been employed in asymmetric radium-catalyzed hydrogenation of alkenes h10CEJ4567i. Thiazoles as synthetic intermediates have been reviewed h10OBC3366i.
5.5.2.4 New Thiazole-Containing Natural Products Grassypeptides A–C, a group of closely related bis-thiazoline containing cyclic depsipeptides, have been isolated from extracts of the marine cyanobacterium Lyngbya
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Y.-J. Wu and B.V. Yang
confervoides h10JOC8012i. Other thiazoline natural products include publicatins A–E from cone snail-associated bacteria h10JNP1922i (structures not shown). New thiazole-containing natural products from a water bloom of the cyanobacterium Microcystis sp. include 10 microcyclamides, MZ602 and MZ568 h10TL6602i, GL616, GL582, GL614A, GL-614B, GL-614C, GL546A, GL546B, and GL628 h10T2705i (all structures not shown). Two related peptide metabolites, hoiamide B and hoiamide C, were isolated from two different collections of marine cyanobacteria obtained from Papua New Guinea h10JNP1411i. Me N
Bn
S Me
i-Pr N
O
O O O
Me HN Me
O
28
Me O O
HO
Me N
S
N N Me
i-Bu
NH
Et
H N Et
OH
O
O
n-Pr
O H
Me
Grassypeptide A: R = Et, 28R Grassypeptide B: R = Me, 28R Grassypeptide C: R = Et, 28S S Me
Me O
Me
NH
S
MeO O
R
Me O
N
Me
HO
O
N
S N
N
Me
Bn
S
O
H
Et
Me O
Me
Me
OH
Hoiamide B
S N
N
NH
N
Me
S
Me
HO
MeO O
Me O
OH
Me Et
O
H CO2Et N H HO Me
n-Pr Me
Me
OH
Hoiamide C
5.5.2.5 Synthesis of Thiazole-Containing Natural Products Total syntheses of the thiopeptides amythiamicin C and D have been reported h10CEJ14083i. The first total synthesis of bisebromoamide has been completed, and this synthetic work has resulted in a revision of the stereochemical assignment on the thiazoline methyl group h10OL3018i. The total syntheses of ()-bacilloamide C has been disclosed h10OBC529i.
Five-Membered Ring Systems: With N and S (Se) Atoms
279
R S
N
Amythiamicin C O
N
S
N S
N
N i-Pr
O
N O
HN
R=
O
S
HN O
O O O
NH
O
NH
H
MeHN S
Me
Amythiamicin D R = CO2Me
N
N
N
S
i-Pr
R1
Me N NH2 Me
S
N
Me
O
Me
O i-Bu N H Me
O
O O O
N
Et
N Bn
OH Br
Revised structure of bisebromoamide
5.5.2.6 Pharmaceutically Important Thiazoles BILN 2061 is the first inhibitor of the hepatitis C virus (HCV) NS3 protease under clinical studies for the treatment of HCV infections h10JMC6466i. However, the development of this compound was discontinued because of the observation of cardio toxicity in high-dose monkey toxicology studies. To this end, significant structural modifications have been carried out to resolve this cardiotoxicity issue, and these efforts have culminated in the discovery of several second-generation HCV NS3 inhibitors, including BMS-650032, TMC-435350 h09JMC7014i, RG-7227/ ITMN-191, MK-7009 h10DF803i, and BI 201335. The initial 4-week antiviral results for BI 201335 are promising in both treatment-naı¨ve patients and patients who failed previous treatment with current gold-standard therapy. BI 201335 is now being evaluated in phase IIB clinical trials and could become the first noncovalent linear NS3 protease inhibitor available for the treatment of HCV patients.
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Y.-J. Wu and B.V. Yang
O i-Pr HN
i-Pr
HN
N
N
S
N
i-Pr N
S
N
N Br
O MeO
Me
O
O NH
NH
CO2H
O N H
O
N
O
NH
O
O
MeO
MeO O
S
CO2H
O NH
t-Bu O
Me
N
O
O O N S H
O
O
BILN 2061
TMC435350 phase II Tibotec/Medivir
BI 201335
5.5.3. ISOTHIAZOLES 5.5.3.1 Synthesis of Isothiazoles A facile synthesis of 3-substituted benzisothiazoles 91 starting from readily available o-mercaptoacylphenones 90 has been developed h10OL752i. The key cyclization step features a mild S-nitrosation and its succeeding intramolecular aza-Wittig reaction to construct the isothiazole ring. Nitrosation of the o-mercaptoacylphenone 90 leads to the unstable S-nitroso 92, which is immediately treated with ethyl diphenylphosphine generating an azaylide intermediate 93, the precursor for the aza-Wittig reaction. O
O
O R
i-pentylONO (3 eq.), 0 °C
EtPPh2(2 eq.) 0 °C to rt
R
SH
R
92
90
O R
P(Et)Ph2
S N
94
93
O P(Et)Ph2
R
95
R
37–85%
O N
S
P(Et)Ph2
S N
SNO
P(Et)Ph2
N S O P(Et)Ph2
91
R = Ph, substituted Ph, n-Bu, s-Bu
Saccharin 97 is prepared via a new approach involving a TiCl4-catalyzed intramolecular N-acylation of sulfonamide with carboxylic ester h10TL5834i. Noteworthy is the use of carboxylic ester as an N-acylating agent for making N-acylsulfonamides.
Five-Membered Ring Systems: With N and S (Se) Atoms
O SO2NH2
O S
TiCl4, TCE
NH
115 °C CO2Et
281
82%
O
96
97
TCE = 1,1,2,2-tetrachloroethane
5.5.3.2 Reactions of Isothiazoles The NHC gold(I) hydroxide complexes 56 has shown to be an effective catalyst for the carboxylation of isothiazole 98 with high regioselectivity at the most acidic C-H bond position, in analogy to the carboxylation of thiazole and benzothiazole which are described in Section 5.5.2.3 h10JA8858i. 1. CO2 N
H S
[(IPr)AuOH] 56 (1.5 mol%) KOH, THF 2. aq. HCl
98
84%
N
COOH S
99
1,2-Diamines are not commonly conceived in a direct manner, but rather through a combination of several synthetic steps. Recently, a direct oxidative transformation of terminal alkenes 100 to vicinal diamines 103 has been reported h10AG (E)8109i. The reaction employs saccharin 101 and bistosylimide 102 as two nitrogen sources and proceeds under the palladium-catalyzed oxidation condition with high chemoselectivity and complete regioselectivity. When working with terminal alkene 100 in the presence of iodobenzene dicarboxylate as oxidant, saccharin is an efficient nitrogen source for aminopalladation. Bistosylimide 102 selectively incorporates into the thus-formed intermediate. Deprotection of the two amino groups in 103 is carried out under acidic condition. The free diamine is converted to bisbenzoylamide 104 for the purpose of structural confirmation.
R
100
Pd(NCPh)2Cl2 (5 mol%) Saccharin 101 NHTos2 102 PhI(t-BuCOO)2, DCM 35–94%
1. TMSI, 75 °C 2. HBr, HOAc, 75 °C NHCOPh O S O 3. PhCOCl, TEA, N O NHCOPh 0 °C to rt R NTos2 R = n-hex R 104 68% 103
R = n-alkyl (C6−C12), substituted alkyl, c-hex
The CuI/1,3-di(pyridin-2-yl)propane-1,3-dione catalyst system, first developed by Chen h08T4254i, has demonstrated its utility in the synthesis of N-aryl sultams 107 h10TL360i. Particularly noteworthy is that this catalytic system affords modest to excellent yields of coupling products between 3-bromopyridine and various primary and secondary sulfonamides, while 3-bromopyridine is usually a poor substrate for such coupling reactions.
282
Y.-J. Wu and B.V. Yang
HN
Ar Br +
S O O
105
CuI (0.2 eq.) ligand (0.2 equiv.) K2CO3, DMF, 120 °C
O
O
Ar N
S O O
N
107
106
N
108 ligand
Ar=2-pyridine (85%), 3-pyridine (70%), 4-pyridine (60%), 4-MeO-Ph (40%), 4-Me-OCO-Ph (83%), 4-amino-3-methyl-5-nitro-Ph (79%)
A series of cis trisubstituted sultam-fused aziridines 111 and 116 containing a quaternary carbon center have been prepared with exclusive cis-selectivity (cis/ trans > 99/1) by a one-pot protocol that combines allylic ylide aziridination and Pd (0)-catalyzed isomerization reaction h10OL504i. The aziridination reaction between allylic sulfur ylide 109 and cyclic N-sulfonyl imines 110 initially generates a trans/cis mixture of vinylaziridine 111. In the subsequent Pd(0)-catalyzed isomerization, the equilibrium between trans-111 and cis-111 is established through p-allyl palladium complexes 112 and 113, in which cis-configured aziridine cis-111 dominates because of its higher thermodynamical stability. The aziridine moiety of 111 can further react with nucleophile NaN3 stereospecifically, and the ring-opening compound 114 is obtained as the only product. O O S N
+
S
Ph
Br
O
109
O
R
111
Ph
R
trans-111
cis-111 Pd(PPh3)4
Pd(PPh3)4 O
O Ph
PdL2 R
113
115
Ph
Ph
Ph N3
114
S
+
Ph
Br
Ph
109
1. t-BuOK, THF, 0 °C 2. Pd(PPh3)4 (10 mol%)
82%
O O S N
O S N
S N
112
96% R = Ph
H
H
PdL2
Ph
O
R
R
H
O O S N
S N
S N
O
O NaN3 O BF3•Et2O S NH DMF
O S N
cis/trans = >99/1
Ph
O
O
78–84% R = Ph, n-C6H13
R
110
1. t-BuOK, THF, 0 °C 2. Pd(PPh3)4 (10 mol%)
Ph
H Ph
116 cis/trans = >99/1
Five-Membered Ring Systems: With N and S (Se) Atoms
283
5.5.3.3 Isothiazoles as Auxiliaries and Reagents in Organic Syntheses The Oppolzer camphor sultam and its derivatives continue demonstrating great versatility in asymmetric synthesis. A modified Brookhart and Templeton’s aziridination employs a-substituted N-a-diazo-acyl (2R)-camphorsultam 117 and N-alkoxycarbonyl imines 118 for the synthesis of a variety of trisubstituted aziridines 119 in a highly stereodefined manner h10OL1668i. The chiral auxiliary of the so-obtained aziridine could be easily removed by treatment with tetrabutylammonium hydroxide and hydrogen peroxide. Further, the acid-catalyzed rearrangement of N-Boc aziridines 119 proceeds with the retention of the configuration at the b-carbon, affording the trisubstituted trans-oxazolidin-2-one 121 as an essentially single isomer. R3 N
O
O
N S O
118
O
2
R1
R
N2
CF3SO3H (20 mol%) DCM, -78 °C
X
117
N R3
XR R1
50–74% R
1. Bu4NOH H2O2, -15 °C
R2
119
trans/cis >20/1 dr >20/1 (trans)
O O HN
O H
X R Me
Ph
121
CF3SO3H (20 mol%) DCM, -40 °C 69%
2. TMSCH2N2 R1 = Me R2 = Boc R3 = Ph
O
Boc N Ph
MeO Me
120 98% ee 83% yield
R1 = Et, Me R2 = Boc, Cbz R3 = Ph, substiuted Ph; naphthyl
An acid-catalyzed ring expansion has engaged N-a-diazoacetyl (2S)-camphorsultam 122 as a means to provide functionalized seven-membered ring systems 124 and 127 in almost enantiomerically pure form h10CC6810i. The proposed model assumes the formation of intermediate 125 via the equatorial attack of 122, while the chiral auxiliary shields one prochiral face of the diazo carbon. From intermediate 125, whereas its bulky carbonyl moiety oriented in an axial position, migration of the alkyl group occurs through inversion of the chiral center at the diazonium carbon. As such, symmetrically substituted cyclohexanones would be converted to homologated chiral cycloheptanones 124 with a kinetically stabilized a-hydrogen, while additional stereogenic center(s) are created due to the desymmetrization of the residual substituents. The ring expansion of TBS-protected dihydrotestosterone 128 with 122 renders the seven-membered ring derivative 129 as a single isomer.
284
Y.-J. Wu and B.V. Yang
O
O BF3•OEt2 DCM, -78 °C
O N2
+ R3
N S
H
O
R3
R1
R2 R3
123
XS
122
R1 = alkyl, H, Ph, PhthN, vinyl R2 = H, OTMS, OTBS R3 = H
XS
R3
40–81%
R2
R1
O
H O
124 dr = >20/1/1/1
When R3 = Me O BF3
BF3 O
COXS
N2
R3
1
R
H
N2
R3 R2
122
O R3 R1
H
125
123
Y = CH 2, 73% Y = O, 86%
122 BF3•Et2O DCM, -78 °C XSOC
H H
H
H
128
H O XS
H
70%
O
O
OTBS
OTBS H
Y
126
R3 R2
COXS
H
O
Y
H
127
129
Using Oppolzer’s sultams as enantioresolution agents is exemplified by the synthesis of conformationally constrained b-proline mimics, that is, the optically active bridgehead-substituted 7-azabicyclo[2.2.1]heptane-2-endo-carboxylic acids 135 h10JA14780i. To separate the enantiomers of precursor 131-endo, a (2R)-camphorsultam group is introduced as a chiral auxiliary. After removal of the PMB group, alcohol 132 is suitable for large-scale and reproducible separation by silica gel column chromatography to give enantiopure (R)-133 and (S)-133. Methylation of the hydroxy group and hydrolysis convert 133 to the b-amino acid oligomer 135.
Boc 1. a.(COCl)2 N CH OPMB DMF 2 b. NaH, (92%)
Boc N CO Me 2 10 steps
HO
COOH
Boc N CH OH 2
O
Boc N CH OH 2
+ (S) R
X
(R)-133
Boc N CH2OH
NH
O O XR
2. DDQ, DCM (99%)
separation O
X
R
131-endo
130
(R)
S
O
R
X
(S)-133
132
Boc N CH OMe 2
TMSCH2N2, aq. HBF4, DCM (R): 72% (S): 79%
* O
R
X
134
LiOH H2O
(R): 85% (S): 84% O
Boc N CH OMe 2 * OH
135
Five-Membered Ring Systems: With N and S (Se) Atoms
285
Other applications of Oppolzer’s sultams include asymmetric Diels–Alder reaction of 1,2-dihydropyridine derivatives with N-acryloyl (2R)-camphorsultam in preparations of chiral isoquinuclidines h10T7618i, diastereoselective aldol reaction in the synthesis of (-)-dictyostatin h10EJOC2148i, asymmetric alkylation in the synthesis of discodermolide h10CEJ485i, and the enantioresolution of racemic aromatic alcohols using (2R)-camphorsultam dichlorophthalic (CSDP) acid method h10EJOC6372i.
5.5.3.4 Pharmaceutically Interesting Isothiazoles Several biologically active isothiazoles and their saturated and/or oxygenated analogs were reported in 2010. Isothiazolidinone and isothiazolone have been incorporated into antibacterial agents 136 h10BMC3053i and 137 h10EJMC19i, respectively, and isothiazole into inhibitor of brassinin oxidase 138 h10BMCL2456i. Benzosultam 139 has been identified as a selective CRTh2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) antagonist h10BMCL3287i. O
Cl
O
S N
N
N O
O
Ph Cl
136
N H
O R
O S O N
COOBn
N
O
O N
138
N O
N S N COOH
139
S
137 R = H, F
5.5.4. THIADIAZOLES AND SELENODIAZOLES 5.5.4.1 Syntheses of Thiadiazoles Novel N-(Cbz-aminoacyl)thiosemicarbazides 142 undergo concurrent cyclization and deprotection with retention of chirality to give 2,5-disubstituted 1,3,4-thiadiazoles 143 h10JOC6009i. The primary amine group in 143 couples with diverse acylbenzotriazoles under microwave irradiation to give chirally pure thiadiazolyl amino acids 145 or dipeptides 147. This method represents a promising route to the preparation of various thiadiazole-substituted peptides.
286
Y.-J. Wu and B.V. Yang
N N N
R1 Cbz
N H
R1
S H2N
+
N H
N H
Cbz mW, THF N 70 °C, 2−4 h H 38–79%
R2
O
140
141
R1 S
H2N
N N
N N N 144 mW, 70 °C R3
R2
N H
S
H2SO4
N
R2
N H
142 H
53–73%
O
H N
Cbz
O HN
Cbz
R1
O
H N
S
N H
R3
60–62%
143
N H
N N
R2
145
Cbz
N H
5
R
N N
R4
O
H N
Cbz
O
146
mW, 70 °C
143
R5
N N H
R1
O
H N O
R
S
N H
4
N N
N H
R2
147
57–67%
R1 = Me, Bn, i-Pr; R2 = i-Pr, c-hex; R3 = Bn, i-Pr, CH2-Indolyl; R4 = Bn, 2-methylthioethyl; R5 = Me, i-Pr
2-Amino-1,3,4-thiadiazoles 150 can be conveniently synthesized by a one-pot green procedure employing readily prepared dithiocarbamates 148 and acid hydrazides 149 in water h10TL790i. The reaction of triethylamine with water gives a mild basic media in which thiosemicarbazide 151, the intermediate from initial condensation, can be converted into anion 152. Its intramolecular cyclization via nucleophilic attack of sulfur at the carbonyl leads to intermediate 153. Aromatization of 153 proceeds with elimination of water.
N H
Et3N H2O reflux
O
S R1
S
R2
+ H2N N H
148
R3
O
S R1
40–96%
N H
N N H H
Et3N + H2O
H N R1
O R3 N NH S
153
R3
H N
H2O R1
OH R3 N NH S
−H2O
N N H
N H
151
149
O
S R1
R3
152 OH + Et3NH
N N
R1
OH
N H
S
R3
150
R1 = Ph, substituted Ph, n-Bu, PhCH2, (R)-1-phenylethyl, adamantyl R2 = −CH2CH2CN, Et; R3 = Ph, substituted Ph, PhCH2, 4-pyridine
A one-pot microwave-assisted reaction facilitates the synthesis of a series of 1,2,4thiadiazoles 157 from 1,3,4-oxathiazol-2-ones 155 and ethyl cyanoformate
Five-Membered Ring Systems: With N and S (Se) Atoms
287
h10T7192i. 1,3,4-Oxathiazol-2-ones 157 are readily prepared from the corresponding carboxamides 154 by treatment with chlorocarbonylsulfenyl chloride. The microwave technique has demonstrated its effectiveness on generation of nitrile sulfides 156 via the decarboxylation of 155 and the subsequent 1,3-dipolar cycloaddition. In comparison, the formation of 157 (when R ¼ Ph) completes quantitatively within 10 min at 160 C under microwave irradiation, while the same reaction provides the thiadiazole with 62% yield in refluxing p-xylene after 18 h. solvent mW, 160−200 ºC 10−30 min
R O ClCOSCl R
NH2
O N
154
S
R R
O 42–96%
155
N
NCCO2Et
N S
N
156
R = Ph, substituted Ph, 2-thienyl, Me, CH2Cl, CHCl2
S
CO2Et
157
Solvent: THF, EtOAc, DCE, toluene
The conversion of a mono-protected 1,2-dianiline 159 to benzothiadiazole 2,2dioxides (benzosulfamides) 161 is accomplished upon treatment with sulfamide 160 in hot diglyme h10TL5306i. Sequential alkylations of the two nitrogens in 161 provide a flexible route to a diverse range of N,N0 -disubstituted benzosulfamides. O O2N
CN 1. PMB-NH , 80 °C 2 2. cat. Pd/C, 65 °C
Cl
HN PMB
80% 158
R1X, K2CO3, DMF, 80 °C 54–100%
R1 N
O O
H2N
CN
S
CN
159
H2N
O S
NH2 160 diglyme, 160 °C
1. TFA, reflux, 100% 2. R2Y, K2CO3, DMF, 80 °C, 42–65% R1 = Me
O
N PMB
Me N
O
CN
S
59%
O
N PMB
H N
O
161
CN
S N R2
162
163
R1 = Me,i-Pr, allyl, CH2CO2Et, 4-Br-PhCH2H, 4-CO2Me-PhCH2; X=OTs, Br, I. R2 = 3-Cl-PhCH2, i-Pr, ; Y = Br, Cl;
5.5.4.2 Reactions of Thiadiazoles and Selenodiazoles The chiral cyclosulfamide (S)-2-benzyl-4-isopropyl-1,2,5-thiadiazolidine 1,1-dioxide 166 is designed as a chimera of Evans and Oppolzer chiral auxiliaries, which appears to be very effective for the stereocontrolled synthesis of chiral building blocks 169 and 172 through asymmetric aldolization and alkylation reactions h10TA2361i.
288
Y.-J. Wu and B.V. Yang
O O S N H N
OH
p-TsCl KOH
BnNH2 DMSO N S
82%
O
O
HN
S
O
68%
165
164
1. TiCl4, DIPEA, -78 ⬚C 2. RCHO, -78 to 0 ⬚C
O
Ph N
91%
N
R
N
OH O O
OH OH O
169
168
Ph N O
N
1. base, -78 ⬚C 2. R1X 170, -78 to 0 ⬚C
Ph
167
N S
O O
30–78% dr > 99 : 1
O
N
R1
S
O
O
R
93–96%
O
S
167 LiOH THF, H2O
S
N
O O
166
Ph
87–93% dr > 99 : 1 R = i-Pr, Ph, n-Pr, c-Hex
Ph EtCOCl Et3N
N
LiOH THF, H2O
OH
R1 O
91–96%
O
172
171
Base = NaHMDS, LiHMDS; R1 = Bn, Allyl; X = Br, Cl.
New approach to selenadiazoloquinolones 178 based on 4-aminobenzoselenadiazole derivative involves a Gould-Jacobs reaction h10T8169i. Amino-benzoselenadiazole 175 is conveniently prepared from readily available 4-nitrobenzothiadiazole 173 via reduction with SnCl22H2O to afford triaminobenzene 174 followed by treatment with aqueous SeO2. Nucleophilic vinylic substitution of activated enol ethers 176 with 175 gives benzoselenadiazole derivatives 177, which are converted to selenadiazolo[3,4-h]quinolones 178 by thermal cyclization under Gould–Jacobs conditions. Hydrolysis of the ethyl ester results in acid 179. N S
68–88%
N NO2
NH2
173
174
N Se N H
1. SeO2, H2O NH2 2. NaOH, H2O •2HCl NH2 97%
SnCl2•H2O HCl, reflux, 5 h
N Y
H
X 177
Se N NH2
OR X 176 ROH, reflux 65–90%
175
N
Ph2O, 250 ⬚C 78–93% Y = CO2Me, CO2Et
Y
N
Se
O X
N NH
N
HCl, reflux 98% X = CO2Et
178
R = Me, Et; X = H, CO2Me, CO2Et, CN, COMe; Y = CO2Me, CO2Et, CN, COMe; X,Y = CO-O-C(CH3)2-O-CO
Se
O HOOC
N NH
179
289
Five-Membered Ring Systems: With N and S (Se) Atoms
5.5.4.3 Pharmaceutically Interesting Thiadiazoles 1,2,5-Thiadiazolidin-1,1-dioxide derivative WYE-103231 has been identified as a selective norepinephrine reuptake inhibitor h10JMC4511i. 1,3,4-Thiadiazoles are incorporated into the potential allosteric substrate competitive inhibitor of c-Jun N-terminal kinase BI-90H9 h10BMC590i and SGLT2 (sodium-dependent glucose cotransporter) inhibitor 180 h10BMC2178i, and 1,2,5-thiadiazole into LAL (lysosomal acid lipase) inhibitor 181 h10JMC5281i. NHMe
HO
N
N N
MeO N H
S
S
NO2 S N
BI-90H9 N N
O
O
Cl
OH
F
181
N N S
HO
N
O
O
WYE-103231
N
N
O S
S
O
OH
180
OH
5.5.5. SELENAZOLES The reaction of N,N0 -diarylselenoureas 184 with phenacyl bromide in reflux EtOH allows access to selenazol-imines 186 h10HCA395i. In analogy to the Hantzsch thiazole synthesis, nucleophilic substitution of Br in phenacyl bromide by the Se-atom of selenourea 184 leads to the isoselenourea derivative 185, which undergoes a cyclocondensation to give 186. The cyclization proceeds selectively via the more nucleophilic N-atom, bearing 4-OMe-, 4-NMe2-, or 4-Me-phenyl group. R2 NH2
R2
R2
NCSe +
toluene HN
R1
R2
182
183
1. PhCOCH2Br EtOH, reflux Se
80–92% HN
2. NH3, H2O 73−92%
N
R1 = Br, OMe, NMe2, Me; R2 = Br, Cl
R1
O
Se N
Ph
Ph
R1
184
N
Se
HN
R1
185
186
290
Y.-J. Wu and B.V. Yang
REFERENCES 08T4254 93T5359 95T7321 09JMC7014 10AG(E)2768 10AG(E)3061 10AG(E)3317 10AG(E)8109 10BMC590 10BMC2178 10BMC3053 10BMCL2456 10BMCL3287
10CC6810 10CEJ485 10CEJ4567 10CEJ3906 10CEJ9002 10CEJ14083 10DF803 10EJMC19 10EJOC2148 10EJOC6372 10HCA395 10JA8858 10JA14780 10JMC4511
10JMC5281 10JMC6466
10JNP1922
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Five-Membered Ring Systems: With N and S (Se) Atoms
10JNP1411 10JOC152 10JOC1733 10JOC5421 10JOC6009 10JOC6998 10JOC7939 10JOC8012 10OBC529 10OBC3259 10OBC3366 10OL504 10OL752 10OL1668 10OL3018 10OL3567 10OL3648 10OL4745 10OL5526 10S2313 10S1166 10T2705 10T7192 10T7618 10T7975 10T8051 10T8169 10TA2361 10TL360 10TL790 10TL1751 10TL4797 10TL5306 10TL5834 10TL6602
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CHAPTER
5.6
Five-Membered Ring Systems: With O and S (Se, Te) Atoms R. Alan Aitken*, Lynn A. Power** *School of Chemistry, University of St. Andrews, St. Andrews, Fife, United Kingdom
[email protected] **IOTA NanoSolutions, Liverpool, United Kingdom
[email protected]
5.6.1. 1,3-DIOXOLES AND 1,3-DIOXOLANES Bismuth triflate is effective in catalyzing reaction of aldehydes with the bis(trimethylsilyl) ether of ethanediol to give 2-substituted 1,3-dioxolanes h10S2771i, and a rhenium oxo complex is effective in catalyzing reaction of aldehydes with either epoxides or 1,2-diols to give dioxolanes, the study focusing particularly on biorenewable compounds such as furfural and glycerol which react to form dioxolane 1 h10IC4741i. An improved synthesis of benzodioxole avoiding any use of dihalomethanes has appeared, involving treatment of catechol with diethoxymethane in the gas phase over a heterogeneous catalyst such as titanium silicalite h10MI72i. Reaction of dibenzoylethyne with ethanediol and Ph3P affords the dioxolane 2 together with Ph3PO h10MI188i. Treatment of the hydroxy cyclohexadienone 3 with aromatic aldehydes and catalytic DMAP leads to ring-fused dioxolanes 4 with a diastereomeric ratio between 90 : 10 and 80 : 20, and the X-ray structure of the product for Ar ¼ 4-O2NC6H4 was reported h10OL568i. A new zinc salen complex is effective in catalyzing reaction of epoxides with CO2 to form 1,3-dioxolan2-ones 5 h10CC4580i, and the use of metal salen complexes for this reaction has O O
OH
O
O
t-BuO
O O
O
CH2Cl2 –78 ⬚C
5 R1
6
R3
OH
cat. DMAP
Me
R
R2 R1
7
H
O
Ar
4
O O
O
Me
3
O IBr
R2
ArCHO
O
2
O
R
H
O
O
Ph
Ph
1 O
O
OH
O
OH
t-BuOI CO2
O O
I
I
8
R3
O t-BuOI CO2
R OH
O
#
O
R I
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00010-3
O
R
2011 Elsevier Ltd. All rights reserved.
9
293
294
R.A. Aitken and L.A. Power
been reviewed h10AGE9822i. A new method for the synthesis of dioxolanone 5 (R ¼ CH2OH) from glycerol involves selenium-catalyzed carbonylation with CO in the presence of K2CO3 in DMF followed by oxidation of the intermediate selenocarbonate using oxygen h10HAC541i. Cyclization of the allylic carbonates 6 occurs readily upon treatment with IBr to give the bicyclic dioxolanones 7 h10SL368i, and both allylic and propargylic alcohols react with tert-butyl hypoiodite and CO2 gas under mild conditions to give iodinated dioxolanones 8 and 9, respectively h10AGE1309i. A review of palladium-catalyzed oxaheterocyclizations includes several examples of carbonate-containing allylic alcohols cyclizing to afford vinyl 1,3-dioxolan-2-ones h10JMOA(319)1i. A study of the conformations of 1,3-dioxole and 1,3-dioxolane using computational methods has found that the hydrogen atoms play a key role in explaining the observed nonplanar structures h10CPL(488)17i. New X-ray structures of dioxolanes include the alcohol 10 which shows a strong hydrogen bonding interaction h10AXEo225i and the spiro oxindole dioxolane 11 h10AXEo1305i. X-ray structures have been reported for bis(N-oxides) such as 12, derived from Pseudomonas putida oxidation of 2-chloroquinoline and useful as catalysts for asymmetric allylation of aldehydes h10OBC1081i. The conformation of alkaloids 13 and 14 has been examined using X-ray diffraction and NMR methods h10HCA25i. A mixture of calcium and zinc oxides is effective in catalyzing the room temperature transesterification of 1,3-dioxolan-2-one with methanol to give dimethyl carbonate and ethanediol h10CSUC575i. The asymmetric phase-transfer catalyzed alkylation of dioxolanone 15 has been reported using a chiral biaryl ammonium salt as catalyst and either benzyl bromides with KOH to give products 16 or methyl vinyl ketone and Cs2CO3 to give the Michael addition products 17 h10CC7593i. O
H
O
Ph Ph
O
O Me
O
O
N H
10
O
Me
O
Ph
N O
Me
11 Ph
O N
O
O
O Me
O
H NMe O
Ph
Me
15
O
ArCH2
Me
O Me
16
O
13 O
O *
O
or
O
O
Me Me
O
O
12
O
Me Me
Me
H NMe
O Me
O
O O
14
17
A compound released by the triatomine insect has been identified as a 4 : 1 mixture of enantiomers 18 and 19 h10OL5601i. The diacid 20 has been introduced as a chiral derivatizing agent to determine the absolute configuration of chiral primary amines h10OL880i. The TADDOL-type compound 21 is the chiral catalyst in the key deracemization step leading to a total synthesis of (R)-a-lipoic acid h10S2931i. Deprotonation of the salt 22 leads to a chiral bis(N-heterocyclic carbene) ligand of value in catalytic asymmetric hydrogenation h10CC3001i. The spiro dioxolane 23
295
Five-Membered Ring Systems: With O and S (Se, Te) Atoms
has been identified as the resting state of the catalytic system in the N-heterocyclic carbene-catalyzed acyloin reaction and characterized spectroscopically h10AGE7120i. Et
O
Et
Me
O
Et
Et
O
Et
Me
O
Et
Ph Ph
19
18
CO2H
O O
HO
O
HO
O
Ph Ph
CO2H
21
I Me
O
Me
O
N N
N Ar
H
N Ar
O
N H H O
I
22
N
Ph N N O Ph
N Ph
23
Et
O
O Ph O
O
O O
MeO N
O O
Me Et
R
20
O
N
Ph
O Ph
26 R = H 27 R = OH
25
24
A dioxolanone-containing methacrylate 24 has been used in conjunction with imidazolium salts to form conductive ionic polymer gels h10CC1488i. The adrenergic and serotoninergic activity of dioxolane structures such as 25 containing lactam or cyclic imide functionality has been examined h10EJM3740i. An efficient asymmetric synthesis of the pharmacologically active compound dexoxadrol 26 has been reported h10SL1775i, and synthesis and evaluation of the NMDA antagonist activity of various analogues has been described, including an X-ray structure determination of 27 h10MCC87i.
5.6.2. 1,3-DITHIOLES AND 1,3-DITHIOLANES Acetylenic carbonyl compounds 28 react with ethane-1,2-diol in the presence of molecular sieves and DMSO by a double Michael addition to give the dithiolanes 29 h10TL290i. The reaction between epoxides 30 and CS2 in the presence of Bu4NBr and an aluminium salen complex gives both 1,3-oxathiolane-2-thiones 31 and 1,3-dithiolane-2-thiones 32 with the ratio depending on the substituents present and the conditions. A careful mechanistic and kinetic study has revealed several structural misassignments in the literature in this area, with spectra due to 31 having been assigned to 32 h10SL623, 10JOC6201i. X-ray structures have been reported for 33–35 h10JOC6201i, as well as for 36 h10JCX501i and the macrocyclic compounds 37 h10AXEo1335i and 38 h10AXEo1044i.
296
R.A. Aitken and L.A. Power
O
O
R1
R1
R2
R1
S R2
R2
33 R = Ph 34 R = CH2OPh
R2
S
R1 and/or S R2
O O
S
S S
32 O
S
S
S
S
S
S
35
S
31
S
S
S
O
S
S
S
S
R1
30
S
S
CS2 O
29
28 R
S
O O
37 36
O
MeS
S
S
S
MeS
S
S
S
O O
38
Hydrolytic cleavage of 2-substituted 1,3-dithiolanes to give the corresponding aldehydes or ketones is efficiently achieved using catalytic iodine on alumina in either water or aqueous ethanol h10TL2862i. The fluorinated benzodithiole tetraoxide 39, for which an X-ray structure was reported, acts as a synthetic equivalent of FCH2 for fluoromethylation of aldehydes, RCHO, to give RCH(OH)CH2F by deprotonation, addition, and subsequent cleavage with SmI2 h10AGE1642i. The key step in a synthesis of the antitumor and immunosuppressive agent ()-triptolide is a cationic cyclization of dithiolane 40 to afford 41 brought about using trimethylsilyl triflate and involving S-silylation and ring opening of the dithiolane h10CC5778i. Oxidation of the 1,3-dithiolane derived from camphor with m-CPBA gives the sulfoxide sulfone 42 and the disulfone 43, and X-ray structures of both products were reported h10RJO363i. O2 S F
39
i-Pr
i-Pr
Me
Me
S
S
40
.. O S
OMe
OMe
S O2 S
Me
Me
Me
Me
Me O2S
SH
41
42
Me O2S
SO2
43
Reaction of 1,3-dithiole-2-thione-4,5-dithiolate with substituted 1,4-bis(bromomethyl)benzenes gives access to a range of thiamacrocycles with 20- to 60-membered rings h10S4169i. The tetramethylammonium salt of a cadmium complex of the same dithiolate 44 has been prepared, characterized crystallographically, and examined as a two-photon absorption material h10SM1535i. SOMO–HOMO energy level conversion leads to the nitroxyl complexes 45 cyclizing in methanol to form products 46 h10AGE529i. Depending on the nature of R and Ar, the compounds 47 are cyclized with base to give either five- or six-membered ring products, exemplified by 48 and 49 for which X-ray structures are reported h10OL244i. The compound 50 containing both 1,3-dithiole and 1,2-dithiole-3-one rings acts as an effective sensor for Hg2þ h10CAJ1692i. A range of biradicals have been reported containing both nitroxyl and triarylmethyl radical sites with the latter stabilized by three bulky benzodithiolyl substituents 51 h10CC628i.
297
Five-Membered Ring Systems: With O and S (Se, Te) Atoms
S
S S Cd S S
S S
Me Me
S S
Me Me
44
Me4N
S
N
S
Me
S
S
S M S 2
MeO S
O
S
Et
O
N Me
S
N
S S
O
50
49
48
S S
N
S
S
MeO S
S O
46 O
O
47 Me
N
S
O
HN R
M S 2
S
O
S Ar
S
45 M = Au, Ni
Br O
S
O N
S
Me Me Me Me
S
Me Me
CO2H
51
A review of nonplanar push–pull chromophores has appeared including many based on tetrathiafulvalene (TTF) and derivatives h10CC1994i. Copper complexes of pyridylTTF derivative 52 h10SM713i and the bis(pyridine N-oxide) TTF 53 h10CC4947i have been prepared and characterized structurally and electrochemically. The X-ray structure, conductivity, and magnetic properties of the TTF donor 54 and its salt (54)2þ FeCl4 have been reported h10SM2413i. A series of new Nheterocycle-containing TTF derivatives have been prepared as exemplified by 55–57 h10SM361i, and synthesis and conductivity properties have been reported for dibenzoTTF salts 58 h10SM575i. The diiodoTTF derivative 59 forms a twodimensional chiral organic metal with camphorsulfonic acid, and its X-ray structure shows the importance of halogen bonding h10CC3926i. N MeS
S
S
MeS
S
S
S O
S
S
S
HN
52 O
S
S
O
S
S
NH N
N
53
S
O
N S
MeS MeS
55 S S
S S
56
N
S
S
S
S
N
S
S
S
N
S S
58
Se
O
Me S
Se
54
S S
O
O
57
NH3 X
S
S
S
S
S
I
S
I
59
A dual signaling anion receptor selective for phosphate is based on the diindolylquinoxalinoTTF 60 h10CC7745i, while three diquinoxalinoTTF derivatives 61 have been synthesized, had their X-ray structures determined, and are found to show differing field-effect transistor activity depending on R with n-type activity for
298
R.A. Aitken and L.A. Power
R ¼ CF3, p-type for R ¼ Me and no activity for R ¼ F h10SM2323i. The synthesis, structures, and electrochemistry of extended TTF analogues 62 and 63 have been described h10SSS391i, while the triazine-functionalized donor 64 forms twisted nanofibers, nanoribbons, and other interesting quaternary structures with N-dodecylcyanuric acid h10AGE9876i. N
R
PrS
S
NH
N
S
S S
N
61 PrS
S
S
N
2
MeS
S
MeS
S
NH
N
60
S
S
SMe
S
SMe
62 BuS
N
S
S S
S
S
S N
63
S
S
NH2 N
BuS
S
S
BuS
S
S
N
S
S N
65
NH2
S S S
BuS
S
S
BuS
S
S
64 S
S
SBu
S S
S
S N
S
S
CN
S
S
CN
SBu
BuS
66
The trisTTF-fused dehydro[12]annulene 65 has been prepared and exhibits multi-redox behavior and solvatochromism h10H(80)909i. The thiacrown etherfused TTF 66 has been prepared, its X-ray structure determined, and it has been converted into a magnesium porphyrazine which forms a charge-transfer complex with tetrafluoro-TCNQ h10H(81)717i. A TTF-containing calixarene has been prepared and its structure and electrochemistry were examined h10H(81)1661i.
5.6.3. 1,3-OXATHIOLES AND 1,3-OXATHIOLANES Reaction of carbonyl compounds with 2-mercaptoethanol to give 2-substituted 1,3oxathiolanes proceeds efficiently using aluminium-containing helical mesoporous silica h10CC5163i and using sulfonic acid-functionalized carbon prepared by heating polyvinyl alcohol with hydroxyethanesulfonic acid at 180 C h10SSS1270i, the latter catalyst being easily filtered off and reused. The spiro oxindole epoxides 67 react with thioacetamide and LiBr under either microwave or ultrasound irradiation to give spiro oxathiolanes 68 h10MI399i. Iodine in the ionic liquid [bmim] BF4 is an effective catalyst for condensation of aromatic aldehydes with mercaptoacetic acid to form the 1,3-oxathiolan-5-ones 69 h10TL6108i. The X-ray structure of a
299
Five-Membered Ring Systems: With O and S (Se, Te) Atoms
hemihydrate of the oxathiolane-containing drug lamivudine 70, which is in clinical use as a reverse transcriptase inhibitor, has appeared h10AXCo329i. Hydrolytic cleavage of 2-substituted 1,3-oxathiolanes to give the corresponding aldehydes or ketones is efficiently achieved using catalytic iodine on alumina in either water or aqueous ethanol h10TL2862i. The oxathiolanone 71 reacts with epoxides via a ring-opening ring-closure sequence with loss of acetophenone to give a-mercaptog-lactones 72 h10SL1797i. Me NH2 O
COAr O
R
NH2
S
O
COAr O
R
N H
S O
N H
67
N
Ar O
69
68
S
O Ph
S
Me
O
70 O
R
O
– PhCOMe
71
Me
72 O
MeO2C HO
HO
HS
O
+
N
O
O
Et2NH
O
73
R
O O
HOO
OOH Me
75 O
MeO2C H O O H
74
O
O O O
76
5.6.4. 1,2-DIOXOLANES Treatment of homoallylic hydroperoxide 73 with diethylamine results in cyclization to afford the dioxolane 74 h10T157i. The dihydroperoxy-1,2-dioxolane 75 is readily prepared from acetylacetone, hydrogen peroxide, and catalytic SnCl2 in acetonitrile and brings about efficient epoxidation of substituted chalcones in a mixture of aqueous KOH and DME h10SL2755i. The spiro 1,2-dioxolane-3,5-dione (“malonyl peroxide”) 76 is effective in metal-free 1,2-dihydroxylation of alkenes h10JA14409i.
5.6.5. 1,2-DITHIOLES AND 1,2-DITHIOLANES A series of 5-aryl-1,2-dithiole-3-thiones have been examined as potential cyclooxygenase inhibitors for use as anti-inflammatory agents, and good activity was obtained for compounds such as 77 h10AJC946i. Air oxidation of the caesium salt of 1,3dithiole-2-thione-4,5-dithiolate 78 results in rearrangement and coupling to form the dimeric 1,2-dithiole system 79 h10ICA4074i. The 1,2-dithiole-3-thione-4-thiolate ligands 80 have been prepared by treatment of ArCCH with BuLi and CS2 followed by sulfur and used to form ruthenium and molybdenum complexes
300
R.A. Aitken and L.A. Power
h10ICA173i. An improved synthesis of the 1,2-diselenolane diol 81 has been described, and its X-ray structure as well as metal complexation behavior is reported h10EJI74i. The 1,2-benzodiselenole 82 has been formed in low yield as a byproduct and its X-ray structure determined, showing a significant NO to Se interaction h10EJI637i. t-Bu S
S
S
S
S S t-Bu
HO
Se
HO
Se
Se Se
81
O S
S
S S
S S
86
87
S
S
S 80
S Cs
O
O O
83 O S
S
S
S
79
O
SPh
82
S
S S
S S Cs
78
NO2
77
S Cs
Ar
S
S
S
MeO
S
Cs
O
N H
N
NH
85
O O
84
5.6.6. 1,2-OXATHIOLES AND 1,2-OXATHIOLANES 3-Propyl-1,2-oxathiolane 83 has been detected in Sauternes wine, and both it and cis and trans isomers of its S-oxide, the sultine 84, have been prepared and spectroscopically characterized h10JFA10606i.
5.6.7. THREE HETEROATOMS A further series of over 30 spirocyclic 1,2,4-trioxolanes such as 85 have been prepared and evaluated as antimalarial agents h10BML563i. Flash vacuum pyrolysis has been used to study the thermal decomposition of 1,2,4-trithiolane 4-oxide 86 and the isomeric 2-oxide 87 with IR and UV spectroscopic identification of the matrix-isolated products showing sulfine, thiosulfine, thioformaldehyde, and a trace of 1,2-dithiirane to be formed in the first case, and dithioformic acid, sulfine, and thioformaldehyde in the second h10EJO2132i.
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CHAPTER
5.7
Five-Membered Ring Systems with O and N Atoms* Stefano Cicchi, Franca M. Cordero, Donatella Giomi Dipartimento di Chimica “Ugo Schiff”, Universita` degli Studi di Firenze, Sesto Fiorentino (FI), Italy
[email protected];
[email protected]
5.7.1. ISOXAZOLES The isoxazole ring is a common structural fragment in biologically active molecules, such as natural products and marketed drugs. 1,2-Benzisoxazoles, for instance, possess potent pharmacological properties thanks to their isosteric relationship with the indole core. Efficient protocols for the synthesis of a range of 1,2-benzisoxazoles using improved 1,3-dipolar cycloadditions (1,3-DC) of nitrile oxides and benzyne have been described. The simultaneous in situ generation of the reactive nitrile oxide and benzyne reactants is the key to the procedure. Thus, room temperature addition of TBAF to a premixed solution of o-(trimethylsilyl)phenyl triflate and hydroximoyl chloride derivatives (as benzyne and nitrile oxides precursors, respectively) in THF produces 1,2-benzisoxazoles 1 in high yields in only 30 s h10CC1272i. Compounds 1 were efficiently obtained by microwave irradiation (mw) at 120 C of hydroximoyl chlorides in the presence of anthranilic acid, as benzyne precursor, t-BuONO and K2CO3 in MeCN for 10 min h10OBC2537i. The above reactions are tolerant of a variety of substituents on the aromatic ring of the hydroximoyl chlorides, including alkyl, electron-withdrawing, and electron-donating groups, and were also extended to less stable aliphatic nitrile oxides. Yields were significantly improved with respect to previous methods. TMS
HO
TBAF (2.4 equiv.)
N
+ OTf
Cl
Ar
THF, rt 30 s 50–99%
O N
1
Ar
t-BuONO (2.0 equiv.) K2CO3 (1.5 equiv.) CH3CN, mw 120 °C, 10 min 51–96%
HO
NH2
N
+ CO2H
Cl
Ar
Ar = Ph, 1-naphthyl, 2-naphthyl, 2,6-Me2C6H3, 2-MeOC6H4, 4-MeOC6H4, 2-EtC6H4, 2-O2NC6H4, 4-O2NC6H4, 4-i-PrC6H4, 4-PhC6H4, 3-BrC6H4, MeCHPh
This procedure was also applied by Larock to various o-(trimethylsilyl)aryl triflates and aryl-, heteroaryl-, alkyl-, and alkenyl-substituted chlorooximes operating with CsF as F source in MeCN at room temperature for 2.5 h, leading to variously substituted 1,2-benzisoxazoles in satisfactory yields (36–93%) h10OL1180i. Analogous results were obtained by Browne h10TL2271i. A novel synthesis of new fused *Dedicated to Prof. Alberto Brandi in occasion of his 60th birthday. Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00011-5
#
2011 Elsevier Ltd. All rights reserved.
303
S. Cicchi et al.
304
bicyclic isoxazoles has been reported from 2-nitro-1,1-ethenediamines 2, readily prepared from commercial acetylenic alcohols or amines. Compounds 3 were isolated in high yields likely formed via acid-mediated intramolecular 1,3-DC. The best results were obtained with concentrated sulfuric acid in acetonitrile with microwave irradiation at 140 C for 5 min h10TL3388i. NO2 ()
()
n
n
N H
X
X = OH, NH2
2 HO
CO2Et
NHMe
CH3CN, mw 140 °C, 5 min
n = 1–3
O N
3
51–90%
Ar
N
Cl
() N n
H2SO4 (2 equiv)
NHMe
CO2Et H N
N
Ar
NH
O NEt3, CH2Cl2, rt, 18 h
4
5 56–69%
Ar N
Ar = Ph, 2,6-Cl2C6H3, 2,4-Cl2C6H3, 2-O2NC6H4
OH
Reactions of alkylidenepyrrolidine 4 and hydroximoyl chlorides gave polyfunctionalized isoxazoles 5, presumably by cycloaddition/elimination processes h10OBC4978i. Thermally promoted 1,3-DC between alkynyl iodides and nitrile oxides allowed an excellent regioselective synthesis of highly decorated 4-iodoisoxazoles 6. The process offers a broad scope with respect to both the iodo-alkynes and chlorooximes. Further functionalization was achieved via Suzuki cross-coupling h10JOC5414i. N R1
OH Cl
R2
I
DME, reflux, 24 h Na2CO3 0.25 M in H2O via syringe pump
N O
R2
R1 I 6 48–91%
R1 = Mes, 4-ClC6H4, 3-O2NC6H4, 4-MeOC6H4, 2-Cl,6-FC6H3, 5-methylthien-2-yl R2 = TMS, c-Pr, CH2NMe2, n-Bu, (CH2)3Cl, 4-MeO2CC6H4,
O O N N R1O
N
O
O
R2CHNHOH chloramine-T
R 1O
N
O
NaHCO3, EtOH, rt, 1 h
O
O
N
R2
O
O 1
7
R = CPh3, H R2 = Ph, 1-naphthyl
O R2
N
8
78–87 %
An efficient, catalyst-free, nitrile oxide-alkyne click cycloaddition chemistry was exploited to conjugate nucleosides and nucleotides with isoxazoles. The protocol involved chloramine-T as reagent to induce nitrile oxide formation and alkyne partners, attached to the sugar residue and/or the nucleobase, reacting in very mild conditions (room temperature, atmospheric conditions, aqueous environment). For instance, two 1,3-DC processes allowed the conversion of compounds 7 into
305
Five-Membered Ring Systems with O and N Atoms
isoxazole derivatives 8 h10OBC391i. Boronic acid catalysis (BAC) was applied for the activation of unsaturated carboxylic acids in 1,3-DC with azides, nitrile oxides, and nitrones for the synthesis of pharmaceutically interesting triazoles, isoxazoles, isoxazolines, and isoxazolidines. For instance, nitrile oxides reacted with alkynoic acids under BAC with o-O2NC6H4B(OH)2 under very mild conditions leading to isoxazoles 9 and 10 with a free carboxylic acid functionality in much improved yields and regioselectivities compared with the corresponding thermal, uncatalyzed reactions. Unsubstituted alkynoic acids led to isoxazoles 9 as single products, while 3-substituted dipolarophiles gave compounds 10 as the major regioisomers h10CEJ5454i. NO2 OH B
R1 N O (1.1 equiv.)
OH R1 (5 mol%)
N
R1
O
+ R2
N
O
+ ClCH2CH2Cl
CO2H (1 equiv.)
R2
rt, 2–24 h
R2
Ph
Yield (%) 9 : 10 ratio
H
87
>98 : 2
PhCH = CH H
71
>98 : 2
PhCH2CH2 H
73
>98 : 2
R2
CO2H HO2C
9
R1
10
Ph
Me
78
1 : 16
Ph
Ph
69
1:6
Click end-capping reactions exploiting 1,3-DC of nitrile N-oxides for rotaxane synthesis have been described. Pseudorotaxanes possessing various dipolarophiles at the axle termini were studied, and satisfactory results were obtained with stable nitrile oxides such as 12. Reaction of acetylene 11 with 12 led to the isoxazole-containing [2]rotaxane 13 as single product in high yield h10OL3828i. O O
O
O O
O H H O N O O O O
12 CH2Cl2 reflux, 2 h
PhSO2NHOH FeCl3 (2.5 mol%)
OH Ar R
CH2Cl2, reflux, 2 h
98%
PhO2S
N
NEt3 or DMAP (3 equiv.)
OH
R
OMe
O MeO
PF6
13
Ar 15
O N
O
O H H O N O O O O
MeO
PF6–
11
14
OMe
N
N
OH N O
Ar 16
R
R Ar 17 56–95%
Ar = Ph, 4-FC6H4, 4-BrC6H4, 4-MeOC6H4, 4-MeC6H4. 2-thienyl R = n-Bu, t-Bu, i-Pr, c-Pr, Ph
The same procedure was applied to the synthesis of main-chain-type polyrotaxanes by a click polymerization of diethynyl-functionalized rotaxanes with unstable and stable homoditopic nitrile N-oxides according to rotaxanation and polymerization protocol. The process efficiently proceeded without catalyst to afford highly functionalized polyrotaxanes with a polyisoxazole backbone in high yields h10MM4070i. A versatile iron-catalyzed protocol for the one-pot synthesis of isoxazoles and isoxazolines from propargyl alcohols 14 has been described. The use of
306
S. Cicchi et al.
N-sulfonyl-protected hydroxylamines as binucleophiles in iron(III)-catalyzed propargyl substitution allowed the selective in situ formation of propargyl hydroxylamines 15 converted into propargyl oximes 16 by base-induced b-elimination. Thermal cyclization of 16 led to isoxazoles 17 in high yields h10CEJ12207i. Alkynyl oxime ethers 18 underwent a gold-catalyzed domino reaction involving cyclization and subsequent Claisen-type rearrangement to afford trisubstituted isoxazoles 20 in a direct, efficient, and regioselective manner h10OL2594i. However, gold-catalyzed cyclizations of O-propioloyl oximes 21 via CN bond formation followed by intermolecular arylidene group transfer afforded 4-arylideneisoxazol-5(4H)-ones 22 in high yields and diastereoselectivities, under mild conditions h10OL2453i. Recent synthetic methodologies toward the synthesis of valdecoxib, as well as other 3,4-diarylisoxazoles as COX-II inhibitors, have been reviewed h10EJM4697i. Reactions of electrophilic 4-alkylidene isoxazolones with isocyanides led to branched 3-alkynylamides via nitrosative cleavage of the heterocyclic ring. N-Iodosuccinimide induced ring closure in the presence of nucleophiles allowed the formation of new iodopyrrolinones. For instance, isoxazolone 23 gave derivative 24 converted into the alkynylamide 25. Subsequent treatment with N-iodosuccinimide in the presence of allyl alcohol afforded iodopyrrolinone 26 in satisfactory yield. The procedure was successfully applied to variously substituted starting materials and different nucleophiles h10OL416i.
N
N O
O
R1
N O
R2
AuCl3 (5 mol%) R1
DCE, reflux, 2 h
R2
R1 [Au]
R2 19
18
20 53–99%
Ar N O
R
O
N Au(PPh3)NTf2 (5 mol%)
O
O
CH3CN, rt
Ar
R 21
R = Ar, n-Pr, t-Bu, Cy
22 50–94% de 84–98%
N O Ph
HN O O
t-Bu-NC H2O
Ph
NaNO2 O
AcOH FeSO4
O N O
t-Bu
23
NH 24 100% I
H2NO2S Valdecoxib
Ph
N OH
HN 25 92%
t-Bu
O
O
NIS O
Ph 26 72%
t-Bu
307
Five-Membered Ring Systems with O and N Atoms
5.7.2. ISOXAZOLINES Some enantioselective organocatalytic syntheses of isoxazolines have been reported. Trifluoromethyl-substituted 2-isoxazolines 29 were prepared by an enantioselective hydroxylamine/enone cascade reaction catalyzed by ammonium salts such as 28 derived from Cinchona alkaloids. The process, consisting of a conjugate addition/ 5-exo-trig cyclization/dehydration sequence, afforded 29 in good chemical and optical yields. A likely rationalization of the accelerating effect and stereoselectivity induced by 28 was proposed h10AGE5762i.
R1 F3C
28 (10 mol%) HONH2 (aq. 50%, 3 equiv.) CSOH (3.3 equiv.)
O R
2
CHCI3 -10 to -30 ⬚C, 11–22 h
27
O
R1 F3C
HO
MeO
N R2
29
N+ H
Ar Br-
80–99%, 82–94% ee
N 28 Ar = 3,5-(CF3)2C6H3; 9-anthracyl
(16 examples)
5-Hydroxy-2-isoxazolines 30 were obtained in good yields from a,b-unsaturated aldehydes or ketones and N-hydroxy-4-toluensulfonamide under mild conditions by a domino process consisting of conjugate addition/extrusion of TsOH/cyclization. Treatment of 30 with LiAlH4 afforded b-hydroxy oximes 31 as single diastereoisomers. Beckmann rearrangement of 31 validated the shown configuration h10JOC1961i. 3 2 1
1
3
2
-
4
2
1 1
2
30
R
O
N
-
2
31
85-102 °C, mw, 10-20 min
2
2
-
OH
DBU (25 mol%) EtOH
32
2
R
N
33
88-96% (7 examples)
3-Unsubstituted 2-isoxazolines 32 were synthesized in both racemic and enantioselective manner from a,b-unsaturated aldehydes and oximes in the presence of an amine as organocatalyst and an acid as cocatalyst h10CEJ11325i. Compounds 32 were then converted into b-hydroxynitriles 33 by heating in the presence of a catalytic amount of a base such as DBU. Under these reaction conditions, optically active isoxazolines underwent the base-catalyzed isomerization with full conservation of the absolute configuration h10JOC6712i. Iperoxo base 36, precursor of the muscarinic superagonist iperoxo, was obtained in good yield and with high reproducibility by nucleophilic substitution of 3-nitro-2-isoxazoline 35 with butynol 34 h10TL3470i.
S. Cicchi et al.
308
2 2
34
2 2
3
2
36
35 3
2
38 3
2
1
1
-
37
-
3
39
38
-
Nitrile oxides smoothly add to styrene-modified DNA affording exclusively 3,5-disubstituted isoxazolines. This Cu-free click reaction allows the high-density functionalization of DNA directly on the DNA solid support and in solution h10CEJ6877i. The asymmetric reactions of nitrile oxides and nitrones with acrylamides h10CSR845i and the use of a multinucleating system in the presence of tartaric acid esters to induce enantioselectivity in 1,3-DC reactions of the same dipoles with allylic alcohols have been reviewed h10CRE173i. Isoxazoline N-oxides 39 were prepared through a highly enantioselective organocatalytic [4 þ 1] annulation between 2-nitroacrylates 37 and racemic a-iodo-aldehydes. Comparable results were obtained regardless of the double bond geometry of the nitroacrylate, probably because 37 isomerizes under the reaction conditions. It was proposed that the enamine generated from the aldehyde and pyrrolidine 38 adds in a conjugate fashion to 37. Then, the intermediate Michael adduct evolves into the final product through an intramolecular SN2-type O-alkylation followed by hydrolysis of the iminium moiety with release of the catalyst h10OL5402i. Optically active isoxazoline N-oxides 42 were synthesized through a three-component domino process. In the first step, a diene is generated by pyrrolidine-catalyzed condensation of nitroalkene 40 with an aldehyde. Then the diene intermediate undergoes conjugate addition by the camphor-derived sulfur ylide 41 followed by intramolecular cyclization with release of the chiral auxiliary. Under the reaction conditions, ester exchange occurred and isoxazolines 42 were obtained as single trans-isomers in good chemical and optical yields h10CEJ8605i. 2
2 2
2
-
3
1 2
3
40
-
41
3
ee
2
1
42
3 3 3
44
2
44
1
3
1
2
2
1
2
2
2
2
2 2
2
43
-
45
-
ee
H
2
-
44 ee
2
309
Five-Membered Ring Systems with O and N Atoms
The chiral complex 44Cu(NTf2)2 catalyzes the enantioselective 1,3-DC of nitrones with propioloylpyrazole and acryloylpyrazole derivatives, affording the corresponding 4-isoxazolines 43 and isoxazolidines 45, respectively. The adducts 43 were then converted into b-lactams via reductive cleavage of the NO bond using SmI2 h10JA15550i. Strain-promoted nitrone–cyclooctyne cycloaddition affords bicyclic 4-isoxazolines 46 with exceptionally fast reaction kinetics and was studied as a rapid metal-free, thermal bioconjugation reaction h10CC931, 10AGE3065, 10AGE9422i. van Deft et al. applied this methodology in the site-specific labeling of peptides and proteins. 1 1 2 2
2 3 4
2
2
– –
–
2 2
–
2
N-Phenylsulfonyl-4-isoxazolines 47 were obtained in good yields from propargylic alcohols and N-hydroxybenzenesulfonamide as binucleophile by iron and gold catalysis. Under heating, isoxazolines 47 undergo a diastereoselective Baldwin rearrangement to cis-N-phenylsulfonyl-2-acyl-aziridines 48 h10CEJ12207, 10JOC6050i. An experimental and theoretical study on the thermal rearrangement of 4-isoxazolines prepared by 1,3-DC of nitrones generated from allenoates indicates that the isomerization to pyrroles occurs via 2-acylaziridine intermediates h10T6078i. The synthesis and reactivity of 4-isoxazoline have been reviewed h10EJO3363i. A Pd complex with the spiro bis(isoxazoline) ligand ()-50 promoted the 5-endotrig cyclization of b,g-unsaturated carboxylic acids and amides 49 affording, respectively, g-butenolides and 3-pyrrolin-2-ones 51 in good yields h10CC9064i. The synthesis of novel spiro bis(isoxazoline) and spiro (isoxazole-isoxazoline) ligands in enantiopure form was accomplished using an enantiomerically pure alkenyl alcohol as building block h10TA379i. 2
–
p – 2
2
–
i i
i i
310
S. Cicchi et al.
5.7.3. ISOXAZOLIDINES Isoxazolidines are useful intermediates in the synthesis of complex organic molecules. Several research groups exploited the chemistry of isoxazolidines in new syntheses of natural products and analogues. Some improvements of practical procedures leading to more general, efficient and selective syntheses of these heterocycles have been developed. The total synthesis of perhydrohistrionicotoxin 54 was accomplished on gram scale by employing both conventional batch chemistry and microreactor techniques by Holmes et al. The key step, involving the conversion of intermediate 52 into the tricyclic isoxazolidine 53 by dipolar cycloreversion and 1,3-DC, transferred into flow mode afforded the product with yield and purity comparable to the standard method h10CEJ11471i. A. toluene/EtOH NC 184 °C, mw 50 min C5H11
N O
52
C5H11 or B. 10 mL steel coil 500 μL min–1 250 psi toluene, 190 °C
Ph
t
N O
CN
C5H11
N H
C4H9
HO
53 A. 70%
54
B. 62%
3
2 2
2
2
5 3
n
n
n
The enantioselective synthesis of cocaine analogues 57 having a C-1 bridgehead substituent was accomplished through a highly stereoselective intramolecular 1,3-DC of nitrones 55 catalyzed by Al(Ot-Bu)3 which allowed the control of the cis orientation of the substituents at C-2 and C-3 positions in the tropane skeleton. A similar approach was applied to the synthesis of (S)-cocaine h10OL4118i. A formal stereoselective synthesis of the alkaloid halichlorine in racemic form was achieved through the reaction of oxime 59 with 1,3-butadiene 58. The formation of the bicyclic isoxazolidines 60 arises from conjugate addition of 59 to 58 to afford a transient nitrone that undergoes an intramolecular 1,3-DC. Stepwise reductive cleavage of the N O bond and of the sulfonyl group afforded lactam 61 that was further elaborated to an advanced intermediate previously used in halichlorine synthesis h10JOC1992i. An analogous cascade sequence involving conjugate addition/intramolecular 1,3-DC was applied to a total synthesis of the alkaloid ()-cylindrine C h10T3643i.
Five-Membered Ring Systems with O and N Atoms
n 2
311
3
2
BnO
OBn
Y Y
N O
OBn +
XOC COX
H
O N
Y
OBn OBn
HO
H N
O 65
62 63 64 OBn X = NMe2, Y = H; X = OMe, Y = CO2Me; X = OEt, Y = SiMe2Ph
OBn OBn OBn
Some analogues of the iminosugar casuarine were synthesized through a general approach based on the stereocontrolled cycloaddition of the tribenzyl D-arabinose derived nitrone 62 with a suitable dipolarophile 63 followed by a reductive ringopening/cyclization cascade sequence to pyrrolizidinone derivative 65 h10EJO5574i. Isoxazolidine 66 was prepared by 1,3-DC of N-D-gulosyl C-iso-propyl nitrone and N-acryloyl camphor sultam followed by sequential removal of the two auxiliary groups, N-Fmoc protection and construction of the thiazoline group. The synthesis could be performed on a multigram scale, and both the enantiomeric forms were available by using D- or L-gulose-derived nitrone. Reductive cleavage of the N O bond of 66 and removal of the Fmoc group afforded the methyl ester of the nonproteinogenic amino acid tubuvaline 67 that was used in the syntheses of some potent antitumor tetrapeptides of the tubulysin family h10CEJ11678i. 6 3
2
2 2
2 3
4¢ 1¢ 2
Alsmaphorazines A and B (68 and 69) are two novel alkaloids with a skeleton consisting of a 1,2-oxazinane and an isoxazolidine unit; they were isolated from the leaves of Alstonia pneumatophora (Apocynaceae) and structurally characterized. Compound 68 was found to inhibit the NO production in J774.1 cells h10OL4188i. The C-40 -truncated phosphonated carbocyclic 20 -oxa-30 -azanucleosides ()-70 were found to inhibit the reverse transcriptase of different retroviruses at concentrations in the nanomolar range, whereas the corresponding trans-isomers
S. Cicchi et al.
312
()-71 were completely inactive h10JOC2798i. Synthetic approaches to isoxazolidinyl and isoxazoline nucleosides have been reviewed h10CRV3337i. Tetrahydronaphthalene isoxazolidines 74 were prepared from nitroolefin acrylates 72 and aldehydes through an organocatalytic one-pot sequential Michael addition/nitrone formation/intramolecular [3 þ 2] nitrone-olefin cycloaddition in aqueous media using pyrrolidine 73 as catalyst h10CEJ3842i. Optically active indeno[2,1-c]isoxazolidines were obtained through an analogous sequential process involving Michael addition of bis(phenylsulfonyl)ethylene/nitrone formation/intramolecular [3 þ 2] nitrone-olefin cycloaddition catalyzed by 73 h10CC7611i. 2
2 2 2
1 2 2
– –
1
ee t t
t
t
Enantiopure pyrroline N-oxide 75 reacts with multiwalled carbon nanotubes 76 affording highly functionalized materials 77 with ca. one cycloadduct every 161 carbon atoms. The organic functionalized nanotubes 77 have a solubility in DMF that is close to 10 mg/mL h10CC252i. Functionalized isoxazolidines such as 78 were prepared by a three-component one-pot cycloaddition of a-diazo ester, nitroso benzene, and an electron-deficient alkene in the presence of a catalytic amount of HOTf. The products were obtained in good yields and with high diastereoselectivity (16 examples, 63–95% yield, dr ¼ 8–30 : 1) h10CC2504i. 2 2
2
2
2
2
2 2
2 2
2
2
ee
p
Five-Membered Ring Systems with O and N Atoms
313
Optically active 3-vinyl-isoxazolidines such as 80 were prepared by enantioselective hydroxylamine hydroamination of allenes catalyzed by enantiopure biarylphosphine gold(I) complexes. Isomeric 5-vinyl-isoxazolidines were obtained starting from N-linked hydroxylamine by hydroalkoxylation of allenes in the presence of catalytic amounts of chiral silver salts and gold(I) complexes h10AGE598i. An experimental and theoretical study on the competitive formation of b-enaminones and 3-amino-2(5H)-furanones from 3-alkoxycarbonyl-4-acyl- and 3,4-dialkoxycarbonyl-substituted isoxazolidines by treatment with a mild base such as tetrabutylammonium fluoride has been reported h10EJO5897i.
5.7.4. OXAZOLES An expedient method for the direct conversion of aldehydes into 2,4-disubstituted oxazoles relies on the oxidation of an oxazolidine formed from the condensation of serine with an aldehyde and proceeds through a 2,5-dihydrooxazole intermediate. In contrast to standard methods that start from carboxylic acids, the use of aldehydes as starting materials does not require intermediate purification and affords the oxazoles under relatively mild conditions. The reaction is wide in scope and can be performed stepwise, with isolation of the intermediate oxazolidine, or one-pot to obtain the oxazole 82 directly h10OL3614i. 1. Ser-OMe .HCl (1 equiv.), K2CO3 (2 equiv.), rt, 12 h 2. BrCCl3 (3 equiv.), DBU (3 equiv.), 0 °C to rt, 12 h
O
MeO2C N
Ph
O R
Ph
O
81
82 79%
R1
CO2Me DABCO, NCS
HO
83 R = Alk R1 = H, Me
NH2
84
CH2Cl2, 0 °C
R1
O R
O
NBS, K2CO3
N
CO2Me 85 82–96%
DCE, reflux
R1
R N
CO2Me
86 70–97%
R2MgBr THF –78 °C O
R1
R N
R2
DCE, reflux
R1
R
R2
N O
O R = n-C5H11
87
R1 = H, Me R2 = Me, Ph
O
NBS, K2CO3
88 74–99% 81–92%
S. Cicchi et al.
314
A novel two-step method for the syntheses of oxazole-4-carboxylates was optimized. The method involves a one-pot condensation–oxidation of aliphatic aldehydes and serine methyl ester (84 R1 ¼ H) (or threonine methyl ester, 84 R1 ¼ Me) to afford the intermediate oxazolines 85 that are subsequently oxidized to the oxazole derivatives. This procedure also offers the chance to transform the 3-isoxazoline-4-carboxylate, by reaction with Grignard reagents, into the corresponding 4-keto-derivatives 87 which are, finally, oxidized to 4-keto-oxazoles 88 h10OL3456i. a-Chloroglycinates 89 are useful substrates for a straightforward synthesis of 5-aminooxazole-4-carboxylates in a reaction catalyzed by aluminumbased Lewis acids. The use of isonitriles afforded N-substituted derivatives 91, while cyanide ion gave N-unsubstituted 5-aminooxazole-4-carboxylates 90 h10OL3942i. Oxazole-4-carboxylates were also obtained through a mild treatment with a dilute solution of DBU in acetonitrile of N-acyl-b-halodehydroaminobutyric acid derivatives 93, in turn obtained, in a multistep synthesis, from N-acylthreonine derivatives 92 h10T8672i. The compounds synthesized in this work were inserted into short oligopeptide chains for fluorescence studies. R2 O
NH 2 Et2AlCN
O R
CO2Et
THF, rt
R1
N H
N
1
NH
Cl CO2Et
C N R2 THF, rt Me2AlCl
89 R1 = Alk, Ar
90 36–86 %
O
CO2Et N
R1
91 52–85 %
R2 = Alk
H N
R O
CO2CH3 OH
92 R = Ar
CO2CH3
H N
R
CO2CH3
O
X
93
N
DBU 2% CH3CN
R
O
94 84–91%
A complete and detailed study dealing with Au(III) and Au(I) catalysis for the synthesis of oxazoles was published h10CEJ956i. Starting from propargylic amides 95, catalysis using Au(III) afforded only substituted oxazoles, like 97, while Au(I) gave methylenedihydrooxazoles 96. The number of substrates analyzed is proof of the wide scope of the reaction.
Five-Membered Ring Systems with O and N Atoms
O
O
[P(Ph)3Au]NTf2
R
CH2Cl2
N
R
N H
AuCl3
O
CH3CN
N
97 45–99%
Pd(OAc)2, ligand 101 K2CO3, pivalic acid
O Ph X +
Ph
O
16 h, 110 °C
N
O N
98
Ph N
99
X = Cl X = Br X = OTf X=I ligand =
R
95
96 30–95%
315
100 1 : 100 1 : 100 1 : 27 1 : 14
77% 75% 76% 82%
101
i-PrO
PCy2 Oi-Pr
Pd(OAc)2, ligand 104 K2CO3, pivalic acid
O Ar
X +
Ar
16 h, 110 °C
N
O
O N
98
Ar N
102
103 >12 : 1
ligand =
58–85%
P
104
Two complementary palladium-catalyzed methods for direct arylation of oxazole 98 with high regioselectivity at both C-5 and C-2 were described. The former is the first general method for C-5 selective arylation of oxazoles and could be of great importance for the synthesis of the many natural compounds that contain this heterocycle h10OL3578i. 2-Phenylsulfonyloxazole 105 is an efficient starting material for the synthesis of 2,5-disubstituted-1,3-oxazoles. Deprotonation by LDA affords a C-5 carbanion that can react with a variety of electrophiles to afford 106. In a second step, the sulfonyloxy group is displaced by a nucleophile affording the 2,5-disubstituted oxazole 107 h10OL808i. 1. LDA, THF -78 °C H 2. Electrophile
N S O O 105
O
N
E
O S O O Electrophile = ketones aldehydes 106 72-91% Bu3SnCl NBS alkyl halides
N
RLi THF, 0 °C R = Alk Ar
R
E O
107 69-90%
S. Cicchi et al.
316
t-BuS
t-BuS
BocHN
BocHN
O
O N
Br
N
N
Pd(OAc)2 (10 mol%) S-PHOS (20 mol%)
R
N
O
O
N
N O
O
O
108
MeO
O
109 R = Ar, Alk
MeO
62–80%
A decarboxylative cross-coupling of aroyl carboxylic acids with aryl halides was described using the catalysis of PdCl2 and in the presence of a stoichiometric amount of Ag2CO3. This procedure converts oxazole-5-carboxylic acids into the corresponding 5-aryl (or heteroaryl) substituted oxazole h10OL4745i. A library of derivatives containing a tris-oxazole moiety was obtained through a Pd-catalyzed coupling of the bromooxazole precursor 108 with the aim of a structural diversification of natural products containing a 2,4-concatenated tris-oxazole h10TL1674i. Several studies aimed at the discovery of new synthetic pathways for the production of known natural compounds were published h10TL4882, 10T6483i as well as the discovery of new oxazole-containing natural compounds h10T2705i. A straightforward spectroscopic method was described for the structural determination of oxazoles and imidazoles h10T1465i. The 2-acyl-5-aminooxazoles obtained by reaction of acyl chlorides with a-isocyanoacetamides can be easily hydrolyzed by concentrated HCl solutions to afford the corresponding a-ketoamides h10OL820i. Benzo- and naphtha-condensed oxazoles were used as protecting groups removable by photolysis h10T8189i.
5.7.5. OXAZOLINES A new convenient one-pot synthesis of 2-oxazolines 111 via boron esters of N-(2hydroxyethyl) amides 110 has been reported. The procedure involves thermolysis of the boron esters at 240–260 C in the presence of solid CaO as an acid scavenger h10TL5313i. O O R
110
N H
O B 3
Δ CaO
R = Alk, Ar, Het
HN
N R
O
Ph E1
R E2
111 75–94%
112
PhIO (1.5 equiv) Bu4NI (0.5 equiv) THF, rt, 10 min
Ph N
O
+ E1 R 2
Bz N
E1
E2 R E E1 = E2 = COMe R = Ar, Pr 113 42–78% 114 8–19%
An efficient oxidative cyclization of amidoalkylation adducts of activated methylene compounds 112 mediated by iodosobenzene and a catalytic amount of tetrabutylammonium iodide under neutral conditions provided oxazolines 113 as major products when E1 ¼ E2 ¼ COMe, together with minor amounts of N-benzoyl
317
Five-Membered Ring Systems with O and N Atoms
aziridines 114 h10TL453i. A bromotriphenylphosphonium salt was exploited to promote tandem one-pot cyclization of chiral 2-aminoalcohols with various aromatic acids to give optically active 2-aryl-1,3-oxazolines in moderate to excellent yields h10EJO4227i. A base-catalyzed tandem Michael addition/intramolecular isocyanide [3 þ 2] cycloaddition of ethyl isocyanoacetate and Michael acceptors with tethered carbonyl groups 115 allowed the diastereoselective synthesis of fused oxazolines 116 under very mild conditions h10CC3357i. O CN R2 R1
S
S
CO2Et
NaOH (10 mol%)
R1 EtO2 C
R2
S
S
C
THF, rt R2 = Ar, Me
R1 = Ar, Het
115 O
116 68–96%
O cat. DBU Cl3CCN
O
O
O
O
85% O
4-epi -osmundalactone
OH
O
SiO2
CH3CN, –45 °C OH
R2 O
R1 EtO2 C N
O
N
S
S
O
O O
NH
NHBz
N O
(two steps)
OH CCl3
117 CCl3
118
119
Trichloroacetimidates prepared from osmundalactone and its epimer underwent intramolecular conjugate addition during silica gel chromatography leading to oxazolines in good yields. Synthetic elaboration of oxazoline 118, from trichloroacetimidate 117, allowed a novel synthesis of N-Bz-protected D-daunosamine 119 h10EJO2206i. Carbanions of L-serine and L-threonine esters protected in the form of oxazolines 120a,b add selectively to the unsubstituted para-position of nitroarenes leading to sH adducts 121a,b. Then, oxidation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) or dimethyldioxirane (DMD) afforded, respectively, p-nitroaryl or p-hydroxyaryl derivatives of the protected racemic serine 122a and 123a and optically pure D-allo-threonine 122b and 123b, easily hydrolyzed to give amino acid derivatives 124a,b and 125a,b. In the case of threonine, the carbanion addition was a highly stereoselective process controlled by the second stereocenter h10EJO4218i.
N
E
Ph R
120a R = H 120b R = Me E = CO2Et
DDQ or DMD –78 °C to rt
t-BuOK Z
+ O
G
NO2–
NO2
H
Z THF/DMF –78 °C
H EN
R O
121a,b Ph Z = F, Cl, OMe, Me, CN
25–91%
E N
G Z HCl aq. R THF or EtOH reflux O
Ph
E
69–80%
122a,b G = NO2 123a,b G = OH
HN Bz
Z R OH
124a,b G = NO2 125a,b G = OH
318
S. Cicchi et al.
O
N
Nu
126
O 1. RLi, ligand 2. (MeS)2
DMF O mw, 120 °C 127 38–99% 20 min
O
N
H Nu N N
N
OPr
OPr
OPr OPr
N
A
24–95% de 2–90%
OPr
B
OPr
OPr OPr
128 ligand = TMEDA: A = H, B = SMe
129
ligand = diglyme: A = SMe, B = H
Various nucleophiles (thiolates, alkoxides, amines, iodide, and cyanide) react with oxazolino[3,2-b]indazole 126 under microwave conditions to give 2-substituted 1H-indazolones 127 in satisfactory yields h10OL2524i. The use of a chiral oxazoline as an ortho-lithiation directing group allowed the synthesis of inherently chiral calix[4]arenes 129 from compound 128. The diastereoselectivity of the reaction can be tuned by the choice of the ligand h10OL4600i. Iridium complexes of chiral oxazoline-based P,N-ligands were applied in asymmetric hydrogenation of minimally functionalized terminal olefins h10CEJ14232i, of imines h10CEJ4003i, and of the C¼¼C bond of exocyclic a,b-unsaturated carbonyl compounds h10ASC1841i. A new generation of air-stable chiral cationic (P,N)-iridium catalysts, such as 130, has been developed and applied to the asymmetric isomerization of primary allylic alcohols to aldehydes h10CEJ12736i. t-Bu P N t-Bu Ir
O
R Ar
(COD)
130
R
130 (7.5 mol%) O OH H , then degassed Ar 2 12–87% THF, 35 °C, 22 h 80–99% ee
OMe R6
O
O
B(OH)2
N R5
R1
R4
R2 R3
R
131
+
[Rh(C2H4)2Cl]2 131 (1.1 mol%) dioxane, H2O KOH
O R4
R1 N
N S
50–97% 30–93% ee
R5
N
R2 O
132 R3
Chiral biaryl phosphite-oxazoline ligands have been efficiently applied to asymmetric Pd-catalyzed Heck reactions of several substrates and triflates under thermal and microwave conditions h10CEJ3434i. Palladium-catalyzed asymmetric allylic alkylation has been accomplished using chiral phosphaalkene-oxazoline ligands h10OL4667i. The cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of chiral branched allylic esters via SN20 displacement of (Z)-allylic trichloroacetimidates has been investigated h10JA15185, 10JA15192i. A three-step procedure allowed the synthesis of the new highly modular family of olefin-
319
Five-Membered Ring Systems with O and N Atoms
oxazoline [OlefOx] ligands 131, successfully applied in the Rh-catalyzed conjugate addition of arylboronic acids to cyclic enones h10AGE1143i. Novel chiral S,N-heterobidentate thiourea-oxazoline ligands 132 with axial chirality have been synthesized and applied to Pd-catalyzed enantioselective bis(methoxycarbonylation) of terminal olefins h10ASC1955i. Applications of bis(oxazoline) (Box) ligands in enantioselective oxidative cross-coupling reactions of 3-indolylmethyl C H bonds h10AGE5558i and asymmetric Kumada reactions of alkyl electrophiles h10JA1264i have been reported. A highly enantioselective carbonyl-ene reaction of trifluoropyruvate catalyzed by a recyclable In(III)-Pybox complex in ionic liquid afforded trifluoromethyl-containing tertiary homoallyl alcohols with excellent yields (up to 98%) and enantioselectivities (up to 98% ee) h10ASC2085i.
O R
O N
R
Phebox
N H
N H
R
N
O
N
N
O
O
N
O
R R R Bopa
Ph
N
O N
Ph Ph Ph trans-DPBO
N
O
N
N N
133
The preparation of transition metal bis(oxazolinyl)phenyl (Phebox) complexes and their potent activities for asymmetric catalysis in conjugate reductions, reductive aldol reactions, direct aldol reactions, and hydrogenation reactions have been reviewed h10CC203i. New chiral Phebox-Ru(II) complexes showed high catalytic activity and excellent enantioselectivities for trans-selective cyclopropanations of alkenes with tert-butyl a-diazoacetate h10CEJ4986i and asymmetric direct alkynylation of aldehydes h10OL3860i. Chiral bis(oxazolinylphenyl)amines (Bopa) proved to be efficient ligands for iron- and cobalt-catalyzed asymmetric hydrosilylation of ketones and enones h10CEJ3090i. A diphenylamine-linked bis(oxazoline) ligand with trans-diphenyl substitution on the oxazoline rings (trans-DPBO) has been immobilized onto one- to three-generation Fre´chet-type dendrimers and a C3-symmetric core structure. The catalytic activities and enantioselectivities of these new ligands were tested in the asymmetric Friedel–Crafts alkylation reactions of indole derivatives with nitroalkenes h10EJO2121i. Base-functionalized aza-bis(oxazoline) ligands, such as 133, were prepared to explore the concept of dual activation through the Lewis acid and a tethered tertiary amine base. The catalytic activity of the Cu complex was tested in the asymmetric Henry reaction h10JOC6424i. The zwitterionic cyclopentadienyl-bis(2-oxazolinyl)borate diaminozirconium(IV) complex 134 has been exploited as precatalyst for the cyclization of aminoalkenes to fiveand six-membered nitrogen rings under mild conditions h10CC339i. A mechanistic investigation has been performed with coordinatively saturated tris(4,4-dimethyl-2oxazolinyl)phenylborato (ToM) Mg(II) compounds, such as 135, suggesting concerted C N and CH bond formation for intramolecular hydroamination h10JA17680i. Chiral tris(oxazoline)–Cu(II) complexes (Tox/CuX2) behave as highly efficient catalysts in asymmetric Nazarov reactions h10AGE4463i.
S. Cicchi et al.
320
O Ph
O
Ph
B
Zr
NMe2 NMe2
N O N
O
N B
Mg
135 (10 mol%)
H2N
N O N
HN
R
C6D6, 50 °C
R R
R
134
135
O O N O
O
CO2Me
Tox/CuX2 (5–20 mol%)
O O CO2Me
O N
t-BuOMe, HFIP
R
N
R E = CO2Me
dr >99:1 up to 98% ee yield up to 96%
Tox
A tetradentate tripodal ligand containing 2-aminooxazoline moieties (TAO) has been developed. This system can tautomerize upon chelation to a metal ion and form flexible cavities via intramolecular hydrogen bonds h10CC2584i. O N (
NH2 )3
74% (two steps)
N
NH O O HN NH N Zn N N N O
N O
NH HN NH
O
N
O
Zn(OAc)2 MeOH
N
O
TAO O R
R H2N
R
R R = CO2H
OH
DMF, reflux 10 h, 92%
O
N N
N O
136
O
a, b
O N
Ar
R
OH Ar
81–94% R 86–99% ee
a: 136 (1 mol%), CuF2, H2SiPh2, CH2Cl2 b: HCl aq.
A one-pot synthesis of a novel D2-symmetrical chiral tetraoxazoline ligand 136 from 1,2,4,5-benzenetetracarboxylic acid and L-valinol has been reported. Asymmetric hydrosilylation of aromatic ketones was carried out in the presence of the corresponding Cu(II)-catalyst leading to optically active secondary alcohols with high enantioselectivities (up to 99% ee) h10ASC1119i.
5.7.6. OXAZOLIDINES A very straightforward method for the synthesis of oxazolidines involves the reaction of olefins 137 with N-substituted oxaziridines catalyzed by Fe(acac)3. Although affording mixtures of stereoisomers, the method is wide in scope and efficient h10JA4570i.
Five-Membered Ring Systems with O and N Atoms
O N
Ar
Ns Fe(acac)3 (5 mol%)
R Ar
H
CH3CN 0 °C
137 R = Ar, Alk
O
+ BEt3
138
52–93%
141 BEt2 Ar
140
PhCHO Ph
Ar N
142 O B
Et Et
Ar N
Ph
Et N
Ar N C BEt3
139
NH
R
Ar Ar N C
143
PhCHO
Et
N
Ph
Et Et
O Ph
Et
144
Et
Ts N
O O HO
321
Ts Pd(dba)2, dppe Ph
O
N Ph
145
THF, 50 °C
147
146
O 87% dr > 98:2
A new multicomponent reaction, involving aldehydes, isocyanides 139, and trialkylboron reagents, affords good yields of substituted oxazolidines. The reaction is wide in scope and works also with BBu3 h10CEJ7904i. Carbonic acid ethyl 4-hydroxy-but-2-enyl ester (145) and aromatic N-sulfonylimines 146 were the substrates for a Pd-catalyzed reaction that afforded 4-vinyloxazolidine derivatives h10TL5131i. A new multicomponent reaction for the production of chiral oxazolopiperidine was developed with the catalysis of Rh(CO)2acac. The starting materials are butenoic acid 148 and 1,2-aminoalcohols 149 h10T3749i. H2 /CO, Rh(CO)2acac biphephos
NH 2 OH O
THF, mw 75 °C, 90 min
R2
148
150
N Ph Ph Cl +
R2 = Alk
152
R2
BF4–
N
Ph
153
(10 mol%) CsCO3 (10 mol%)
O NTs
R2 R1
R2
151 R1 = Ar
N
O
several examples 46–70%
OTMS
O NTs
C R1
R1
149
O
N
O
OH
R1
154
Cl
O
79–94% ee yield 15–36%
S. Cicchi et al.
322
Ceria nanoparticles were revealed as an efficient and reusable catalyst for the transformation N-alkyl ethanolamines into N-alkyl 1,3-oxazolidin-2-ones by atmospheric CO2 fixation h10CC4181i. A variation of a procedure developed for the preparation of cyclic carbonates was applied to the synthesis of oxazolidin-2-ones. Treating an allylamine with m-CPBA, Br3CCO2H, and DBU resulted in the desired cyclic carbamate h10JOC7745i. A novel enantioselective formal [3 þ 2] cycloaddition of ketenes 151 and oxaziridines 152 for the synthesis of oxazolidin-4-ones has been described. The reaction was catalyzed by an N-heterocyclic carbene produced in situ from 1,2,4-triazole 153 and CsCO3. The reaction is wide in scope and affords high levels of enantioselection h10AGE8412i. Atropisomeric benzoylformamides 155 undergo photochemical type II reaction leading to cis- and trans-oxazolidin-4one photoproducts maintaining the high enantiomeric excess of the starting material h10CC4791i. O O
O Ph
hn
N O t-Bu
155
Ph
MeOH–1 N HCl (9:1 v/v)
Ph
N
N O t-Bu
O t-Bu cis
conversion 40%
trans
156
69 : 31 99% ee
157 99% ee
O OMe Boc N
MeO
158 R = Alk, Ar
R
TFA (2 equiv.) CH2Cl2 reflux, 2 h
O
N R
MeO 159 81–92%
Rather unexpectedly when treating compound 158 with trifluoroacetic acid, the product obtained was the corresponding oxazolidin-2-one 159. The transformation proved to be general and efficient h10T5161i. The use of NH4I as catalyst allowed an easy and regioselective conversion of unactivated aziridines into the corresponding oxazolidin-2-ones h10TL4552i. A simple approach for easy synthesis of 5-aryl-2-oxazolidinones from aziridines under compressed CO2 conditions was developed, requiring no catalyst and using an organic solvent h10SL2159i. A novel class of chiral oxazolidine organocatalysts 160 found application in the enantioselective Diels–Alder reactions of 1,2-dihydropyridines with acroleins to afford chiral isoquinuclidines h10CC4827i.
323
Five-Membered Ring Systems with O and N Atoms
Ph Ph O
R HN 160
XCO2H
O + HN N
R = t-Bu, i-Pr, Bn, Ph X = CF3, CCl3, CBr3
O
164 Ph
O
162
N
Bn N Ph
O
toluene quant.
165
Ph
O
163 99% 1. CpZr(H)Cl 2. TMSOTf
Bn OH
N
N
OTs
161
BnHN
O
[Pd(dba)2 ] (3 mol%) DPPF (3 mol%) K2CO3
166 92%
OH
A number of N-heteroaryl isoxazolidin-2-ones 163 were accessed through a Pd-catalyzed reaction with heteroaromatic tosylates 161 h10CEJ5437i. A mild method for the synthesis of N-acyl oxazolidin-2-ones using acyl fluorides and tertiary bases such as i-Pr2NEt or NEt3 was described h10OL4102i. 2-Butenyloxazolidine 165 was the substrate for a tandem hydrozirconation/Lewis acid-mediated cyclization sequence that afforded trans-2-substituted cyclopentylamines 166. The marked trans selectivity was justified on the basis of the transition state geometry h10OL5128i. The oxazolidin-2-one ring was used as a scaffold for the construction of a bicyclic system through a palladium-catalyzed carboamination reaction between aryl bromides and 4-(but-3-enyl)-substituted oxazolidin-2-ones 167. The resulting bicyclic product 168 was easily transformed into polysubstituted pyrrolidine derivatives h10OL2322i. H N Cl
H
NH2 NH
H
O O
NH
PhBr, [(allyl)PdCl]2 RuPhos, NaOt-Bu
O
Br
Ph
O N
O
O
toluene, 90 °C
167
168 92%
Br
169
NH
O H synoxazolidinone A
A new protocol was developed for oxidative amidation reactions between oxazolidin-2-ones with activated olefins, conducted under Pd/Cu catalysis, using air as a terminal oxidant h10EJO5181i. Trifluoromethyl group containing oxazolidines (Fox) were synthesized by condensation of serine esters with trifluoroacetaldehyde hemiacetal or trifluoroacetone. These compounds are completely configurationally and hydrolytically stable and can be considered as proline surrogates h10JOC4135i. A series of racemic pentafluorophenyl esters were resolved using an equimolar amount of (S)-4-phenyloxazolidin-2-one. The levels of diastereocontrol were found to be good (80–96% de) at a 40% conversion h10TL5892i.
S. Cicchi et al.
324
A 4-oxazolidinone ring, rarely seen in natural products, is the characteristic moiety of some new natural products isolated from sub-arctic ascidians. The structure of synoxazolidinone A 169 is reported h10OL4752i.
5.7.7. OXADIAZOLES A novel Ugi-4CR/aza-Wittig method has been developed for the synthesis of 2,5disubstituted 1,3,4-oxadiazole derivatives. Using (N-isocyanimino)triphenylphosphorane 170, a secondary amine, a carboxylic acid, and an aromatic aldehyde in CH2Cl2 at ambient temperature, compound 171 is obtained in high yields without using any catalyst or activation h10OL2852i. Ph Ph
O Ph
Ph N H
O Ph
Ph N N OH (Ph3 )P
170
N N
R2
Br O
R1
CH2Cl2, rt, 2 h
N N
N
O Ph
CuI/phen (5 mol%) LiO-t-Bu toluene, rt
171 93% N N
R1
172 R1, R2 = Ar, Alk
(Ph3)P = O
Ph
R2
O
173 50–79%
1,3,4-Oxadiazoles can be directly alkynylated at room temperature using the catalysis of CuI and 1,10-phenanthroline. This method gave direct access to oxadiazole core p-conjugated systems 173 h10JOC1764i. A series of 2,5-diaryl substituted 1,3,4-oxadiazoles were used as ligands for metallic ions and found application in molecular logic gates and switches h10CEJ5794i. The 1,3,4-oxadiazole derivative 174 characterized by oligoyne chains found application in a study for the energy transfer process h10CEJ1470i. N N O t-Bu Ph
174 n = 1–4
n
N Ph
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Five-Membered Ring Systems with O and N Atoms
10OL3456 10OL3578 10OL3614 10OL3828 10OL3860 10OL3942 10OL4102 10OL4118 10OL4188 10OL4600 10OL4667 10OL4745 10OL4752 10OL5128 10OL5402 10SL2159 10T1465 10T2705 10T3643 10T3749 10T5161 10T6078 10T6483 10T8189 10T8672 10TA379 10TL453 10TL1674 10TL2271 10TL3388 10TL3470 10TL4552 10TL4882 10TL5131 10TL5313 10TL5892
327
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6.1
CHAPTER
Six-Membered Ring Systems: Pyridines and Benzo Derivatives Philip E. Alford Dartmouth College, Hanover, NH 03755, USA
[email protected]
6.1.1. INTRODUCTION The pyridine moiety has found a function in almost all aspects of organic chemistry, as a solvent, base, ligand, functional group, and molecular scaffold. As a structural element, pyridine is considered a privileged pharmacophore in medicinal chemistry. Each containing an intact pyridine moiety—TakepronÒ, NexiumÒ, Singulair, and Actos produced billions of dollars in revenue in 2010 (Scheme 1). Countless other pharmaceuticals and industrial processes are certain to have involved pyridine as a reagent, ligand, solvent, or synthon. Modern CH activation methods have confirmed pyridine as an essential functional group with unique directing and activating utility. Me MeO
OMe
H N
Me S
N
Et
S
N
O
N O
Nexium®
O
O
NH
Actos®
Scheme 1
The crucial chelating ability of pyridine has given the molecule an important role in metal organic frameworks and other supramolecular structures hJA10756, JA14457, JA15814, CC8752i. Pyridinium salts are versatile reagents and important cationic structures in nanodevices hCSR2203, EJO92i. Well into the 21st century, the fundamental physical organic chemistry of this heterocycle continues to be studied, and novel methods are discovered which rely on the unique utility of pyridine. Pyridines have found applications in organoelectronic materials hCEJ2392i, organic light-emitting diodes technology hOL5534i, herbicides hJHC171i, and molecular sensors hJA8544, CEJ1480i. Even as the forefront of nano- and biotechnology calls on chemists to prepare innovative pyridine-derived structures, novel alkaloids containing the pyridine moiety continue to be uncovered in nature.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00012-7
#
2011 Elsevier Ltd. All rights reserved.
329
330
P.E. Alford
H N
O –O C 2
+ N
HO
Polyaxibetaine
Cl Me
H HN
HH H N
H
Phantasmidine
H N
O
Lycoposerramine R
Scheme 2
Polyaxibetaine (Scheme 2) is a modified tyrosine that contains a pyridine moiety hJNP620i. Isolated from the skin of the poison arrow frog Epipedobates anthonyi, phantasmidine is a tightly wound knot of fused ring systems containing a chloropyridine, dihydrofuran, pyrrolidine, and cyclobutane hJNP331i. Dedicated to the late John Daly, this novel ring system shows activity as a nicotinic acetylcholine receptor agonist but with different selectivity than Daly’s epibatidine hT9231i. Last year, John Daly was honored with a special issue in the Journal of Natural Products hJNP306i. Lycoposerramine is a member of the pyridine-containing lycodine family of alkaloids and was recently synthesized for the first time in 2010 hOL2551i. MeO
HN
N
H2N N N
O
N
Aplidiopsamine A
HO
N
N
N
N
Eucophylline
Lakshminine
NH2
Scheme 3
Isolated from the Australian colonial ascidian Aplidiopsis confluata, aplidiopsamine A contains a fused pyrrolo[2,3-c]quinoline linked to an adenine residue (Scheme 3). The compound shows significant anti-plasmodial activity even against chloroquineresistant parasites hJOC8291i. Eucophylline, a rare example of a vinylquinoline alkaloid, was isolated from the latex-yielding plant Leuconotis eugenifolius hJNP1727i. Many natural products occur in quantities that are too small to adequately investigate potential biological activity. For instance, the oxoisoaporphines occur only in two species of flowering plant; the most recently isolated of these compounds, lakshminine was isolated in 2 mg from over 4 kg of poisonous Strychnos toxifera. A recent synthesis of this compound has allowed it to be screened as an antiproliferative against human cancel cell lines hJNP1951i.
6.1.2. PYRIDINES 6.1.2.1 Preparation of Pyridines Cyclocondensation-based syntheses have historically been the most commonly used preparations of pyridine hT5432, JHC287, H(82)867i. Although cyclocondensations
331
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
like the Bohlmann–Rahtz synthesis hSL2251i are arguably more versatile, the multicomponent Hantzsch synthesis in particular has found especially widespread use since its introduction in 1881. Recent methods have focused on green and aqueous conditions (Scheme 4) hTL1187i. Variations on the Hantzsch synthesis have also been reported which directly access the pyridine hS4228i or substitute any of the starting materials for synthetically equivalent reagents hT5161i. For Hantzsch syntheses that require oxidation of the 1,4-dihydropyridine, many new oxidation methods are reported each year hTL3859, JHC1429i. The Hantzsch ester itself is also a useful synthetic reagent; these compounds can be considered synthetic equivalents to NADH, and many Hantzsch esters have found use as hydride transfer agents hCEJ4895i. Me
R2
R2 H O
R2CHO
H2O
(NH4)2CO3
55–60 ⬚C
+
2 eq. O R1O
R1O
R1
2C
CO2
Me
N H
[ox]
R1O
Me
CO2R1
2C
Me
Me
N
Hantzsch ester up to 99%
Scheme 4
Worldwide, novel multicomponent couplings were a popular research focus for many groups in 2010. Efficient single-step conversion of simple starting materials to highly functionalized pyridines promises both economic and environmental advantages. One novel multicomponent cyclocondensation incorporates four separate building blocks over two steps to produce tetra-substituted pyridines hJOC726i. Initial nucleophilic addition of the allenyllithium to a nitrile produces an electro-deficient allene that undergoes attack by a trifluoroacetate anion; acyl transfer from oxygen to nitrogen results in a cyclizable 1,5-ketoamide that produces a 4-hydroxypyridine. The authors go on to functionalize the hydroxypyridine as a nonaflate—a common strategy used to furnish easily handled pyridine building blocks for palladium-based chemistry (Scheme 5). Several closely related cyclizations were also reported last year hEJO2555, S2129i.
OR1 Li
1. Et2O, ⫺40 ⬚C 2. R2-CN 3. F3CCO2H 4. TMSOTf, Et3N CH2Cl2, D 5. NfF, NaH, THF
R3
ONf OR1 F3C
N
R2
26–62%
R3-B(OH)2 Pd(OAc)2, PPh3 K2CO3, DMF, 70 ⬚C
OR1 F3C
N
R2
69–99%
Scheme 5
Another reported cyclization involved an unusual defluoronation sequence to furnish polysubstituted 3-fluoropyridines hOL4376i. Various fluoroalkyl alkynylimines undergo hydroamination with benzylamine before cyclization as shown in Scheme 6.
332
P.E. Alford
HN
Ph
N +
F 3C
H2N
F
Cs2CO3 2.5 eq.
Ph
97%
THF, 80 ⬚C
Ph
Ph via:
N
Ph
Base Ph
H Ph F
Ph
N
–
N
C F2
Ph –HF
F2C N
Ph
Ph
Ph F –
F
N
F Ph
N
Ph
N–
p.t. Ph
F
N –HF
HN
Ph
Ph
Ph
Scheme 6
A particularly curious cyclocondensation was reported that utilizes a Curtius rearrangement to produce reactive isocyanates that react with acetic acid, then cascade and dimerize to form substituted pyridines. Observation of the trimeric side-product suggests that the mechanism is far more complicated than one would initially expect; the authors propose more than 20 possible intermediates in this process (Scheme 7) hJOC6625i.
O N3
AcOH, 10 eq. +
DMSO, 150 ⬚C, 4 h
N 62%
N 12%
Scheme 7
Inspired by the cyclocondensation of 1,5-dialdehydes with hydroxylamine, actinidine was synthesized by treatment of a 1,8-dialdehyde with hydroxylamine. This reaction is proposed to proceed first via a highly diastereoselective [4 þ 2] enamine/enal cycloaddition before presumably undergoing ring opening and cyclocondensation to the N-hydroxypiperidine, which dehydrates to the pyridine core of actinidine (Scheme 8) hOL1408i. via:
Me O O Me
Me
NH2OH, TsOH
Me NH2OH, TsOH
O
THF Me
NHOH
N
THF Me
Actinidine
Scheme 8
333
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Aza-Diels–Alder approaches to pyridine offer simultaneous formation of multiple bonds in one pot. These [4 þ 2] approaches rely on a subsequent elimination or oxidation step. In many cases, the initial diene and dienophile are equipped with the necessary leaving groups to furnish a fully aromatized pyridine core hT8095i. For the example shown below, a-ketohydrazones are condensed with a secondary amine to produce an azoenamine that undergoes a [4 þ 2] aza-Diels–Alder cycloaddition with diethyl acetylenedicarboxylate (Scheme 9) hTL6186i. Several other examples of these reactions were reported in 2010 hT947i, including one apparent enzyme-catalyzed [4 þ 2] cycloaddition reported in the synthesis of the pyridine core of thiocillin antibiotics hJA12182i.
N
CO2Et
Me
EtO2C H
+ N
CO2Et
NPh
N
+
DIPEA (0.2 eq.)
CO2Et
NHPh
N
[4 + 2]
H
toluene, reflux
EtO2C
50% N
N
CO2Et
Scheme 9
Another aza-Diels–Alder was used in a recent method reported by Danheiser et al. for the synthesis of pyridines hJA13203i. This elegant method generates its reactive diene by an ene reaction mechanism which intramolecularly cyclizes in one pot to the end product (Scheme 10). Danheiser et al. describe their method as a metal-free formal [2 þ 2 þ 2] cycloaddition—conversion of a dialkenyl nitrile into a pyridine ring is a process that generally requires a metal catalyst.
H H ene reaction O
N
[4 + 2]
O
160 ⬚C toluene
H
N
160 ⬚C toluene
O
71% N
H
Scheme 10
Metal-catalyzed [2 þ 2 þ 2] cyclotrimerization reactions have been extensively employed to generate pyridines from tethered dialkynes hEJO3407, S2071, SL2314i. One such cobalt-catalyzed [2 þ 2 þ 2] cyclotrimerization was used to generate part of the spiro-cyclic core found in the citrinadin alkaloids hOL1288i. In this case, use of a functionalized nitrile allows the possibility for further nucleophilic annulation at the pyridine nitrogen (Scheme 11).
334
P.E. Alford
OH NC
OH MW, CpCo(CO)2 toluene
HN
N HN
83% O
O
Scheme 11
A chiral cobalt catalyst was used to functionalize naphthalenes with a sterically demanding pyridine (Scheme 12). The resulting axially chiral biaryl is produced with high enantiomeric excess hJOC3993i. Such systems have applications as chiral auxiliaries and ligands in catalytic systems. Ph N [Co⬘], hv
OMe
OMe
PhCN
86% yield, 93% ee
Scheme 12
Some of the most creative syntheses rely on rearrangement reactions to furnish the pyridine ring system. Okuda et al. performed a novel pyridine synthesis via a Truce–Smiles rearrangement hTL903i. This impressive rearrangement generates two fused rings in one pot, though yields and generality could be improved (Scheme 13). Cl
CN + O
NC O
–
H
DMF CN
CN
O
K2CO3
CN
O
CN :base
CN
– CN
N C O
CN
O
O
O–
H+ C N
N –
N NH
N NH2
Scheme 13
Lastly, the oxidation of piperidines continues to be a well-traveled path for the introduction of pyridine moieties. For a clever [3 þ 2] preparation of 5-azaindoles, SeO2 provides excellent yields, whereas many other common oxidation conditions result in no reaction or decomposition (Scheme 14) hOL3168i.
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
CO2Et
H CO2Et
TsN
MeCN
TsN
CO2Et SeO2
Me
TMSOTf OMe 95%
335
N
Me
dioxane
N H
N H 92%
Scheme 14
Waters et al. reported a mild room temperature oxidation of tetrahydro-b-carbolines as part of a total synthesis of eudistomin U. For this aromatization, Waters investigated hypervalent iodine reagents ultimately settling on IBX and TBAB (Scheme 15) hOL4086i. CO2Me
CO2Me NH N H
IBX (2 eq.) TBAB (0.25 eq.) MeCN, rt, 2 h
N H 75%
NAc
N
N N H NAc
NH
eudistomin U
Scheme 15
6.1.2.2 Reactions of Pyridines Pyridine finds many roles in synthetic chemistry: as a Lewis base, functional group, synthon, solvent, and biologically active molecular framework. As a base, pyridine has been a central component of several organic “superbase” systems hOL5242, JOC2651i. As an electron- withdrawing group—when joined with a trifluoroacyl group—pyridine aids in the creation of a “superelectrophilic” ketone hJA3266i. At times, these many roles can clash. For instance, pyridine and dichloromethane are commonly used together in a variety of different systems; a recent paper by Wamser et al. reveals that dichloromethane and pyridine readily, albeit slowly, react via an SN2 process to produce methylene bispyridinium dichloride. These authors advise caution when using pyridines in dichloromethane—particularly when using DMAP and when reactions times are on a timescale of days or longer (Scheme 16) hJOC4292i. 1 atm., rt N DCM, days
+ N CH2 N + Cl– Cl–
Scheme 16
As shown above, pyridine is capably nucleophilic at nitrogen. However, some simple pyridines such as pyridone are ambident nucleophiles, reacting at either the nitrogen or oxygen. Mayr et al. rigorously investigated the nucleophilicity of various pyridones using benzylhydrylium electrophiles. In this chapter, experimental results
336
P.E. Alford
are compared to theoretical calculations. Even though the thermodynamic advantage of amides over imidates is lessened when the imidate is contained within an aromatic pyridine ring, the N-alkylated amide-type product is favored in systems where alkylation is reversible hJA15380i. This regioselectivity is also demonstrated in a recent total synthesis of cyfusine (Scheme 17) hSL2789i. E+
E+ N
O
N –
E
O
O–
N
N
O
E
favoured O–
O
O
O
E
E+
E+ N
N
N –
E
N
Scheme 17
The nucleophilicity of pyridine at nitrogen allows facile formation of pyridiniums, which are important oxidizable cationic frameworks in supramolecular chemistry and medicinal chemistry. Reagents and reactants derived from pyridinium salts will be discussed in Section 6.1.2.3. Due to the valuable bioactivity of many pyridine derivatives, novel methods for the functionalization of pyridine are immensely important—particularly at the relatively inert carbon centers. After more than a century of investigation, a well-defined classical reactivity of pyridine has been identified. As a p-deficient heterocyclic aromatic system, pyridine is highly resistant to electrophilic substitution yet notably vulnerable to nucleophilic attack. This reactivity has long been exploited in pyridine methodologies; even today, many new methods of SNAr-type mechanism to functionalize pyridine are known hS2111, S4273, T3452i. Another mechanism by which nucleophilic substitution takes place is via addition–oxidation. Maes et al. report that substitution of hydrogen on pyridine via oxidative alkylamination has made significant progress since the introduction of AgPy2MnO4. However, KMnO4 sometimes, but unpredictably, works equally well (Scheme 18). An in-depth investigation helps to explain this observation, and the results have identified an additive that reliably produces high oxidative yields with KMnO4 hJOC5126i. via: AgPy2MnO4 or KMnO4/TBACI
O2N + N
Scheme 18
N H
8–10 ⬚C
O2N
[ox] N H
N
O 2N N >90%
N
337
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
The capacity of pyridine capacity to undergo SNAr-type reactions has provided a unique new reagent for difluoroolefination. While investigating various means of difluoroalkylation using difluoromethyl sulfones, Hu et al. discovered that replacing a phenyl moiety with pyridine resulted in drastically different and improved reactivity hOL1444i. Typically, difluoroolefination using a difluoromethyl sulfone is a twostep process: nucleophilic 1,2-attack at the carbonyl followed by a desulfonylation procedure using sodium mercury amalgam. Difluoromethyl 2-pyridyl sulfone truncates this approach by following a Julia–Kocienski-type mechanism to install difluoromethylene in a single step (Scheme 19). O F F O S R1
O O O S CF2H N F O N
R1
O O F S F
R2
Base
N
O
F S
O
H+
R1 R2 O
R2
N –
R2 F
O–
O
R1
F O–
R1
O
F
S
+
NH R1 R2 O +
–SO2
R2
F
NH
Scheme 19
The lithiation of pyridine provides access to enormously useful nucleophilic pyridyl synthons. However, due to the natural tendency for pyridine to undergo nucleophilic attack, there have long been complications in this process: n-butyllithium is known to attack at C-2. While more sterically demanding bases are proven to be better choices for direct lithiation, Wamser et al. have noted that even LDA will nucleophilically attack 2,6-difluoropyridine (Scheme 20). This highlights the ease at which pyridine undergoes SNAr-type reactions as much as it highlights the difficulties associated with lithiation hJOC4292i. LDA F
N
F
THF, 0 ⬚C
F
N
N
Scheme 20
To achieve direct lithiation at C-2, the best results have been found using an n-butyllithium lithium aminoalkoxide mixed aggregate. These aggregates act as poorly nucleophilic superbases. It has recently been observed that some enantiomeric excess can be achieved by using a chiral aminoalkoxide, nBuLiLiPM (Scheme 21). To better explain the reactivity of nBuLiLiPM species, a joint experimental and theoretical study was carried out to observe the metalation of 2-substituted pyridines hJA2410i. In short, apolar solvents discourage nucleophilic addition by favoring formation of a highly basic tetrameric aggregate species over a more nucleophilic dimeric species.
338
P.E. Alford
Li
LDA
Orthometallation Cl
N
BuLi Cl Cl
Me
N
N Li
Li
H
Bu
Bu
N
Cl
Cl
N
* Ph
N Li PhCHO
O Cl
BuLi•LiPM
N
Li
OH
Scheme 21
Stoichiometric lithiation of pyridines can also be complicated by Tchitchibabintype 2,2-linked dimerizations. It is known that the strong Lewis acid BF3 activates pyridine toward mild metalation conditions using lithium and zinc reagents. Knochel et al. noted that BF3 activates pyridine toward a-lithiation using tmpMgCl hAG(I) 5451i. The frustrated Lewis pair tmpMgClBF3 also allows functionalization at C-2 through the equilibrium structure shown in Scheme 22. This reagent also demonstrates sterically selective lithiations that favor different sites than tmpMgCl does on many 3-substituted pyridines. Regioselective lithiation of pyridine derivatives was also the focus of other methodology papers hOL1984, JOC2227, JOC839i. via: tmpMgCl•BF3•LiCl N N
THF, –40 ⬚C, 10 min F
B F
H F
N
Mg Cl THF
N
+ THF Mg
– F B F F
E+ N
E
Cl
Scheme 22
Direct lithiation of other halogen-substituted pyridines results in quirky reactivity beyond nucleophilic displacement: the halogen dance rearrangement results in shuffled substituents and sometimes unexpected reactivities (Scheme 23). Snieckus et al. exploited this fascinating rearrangement to achieve a sequential double halogen dance with two substitutions and an iodine substituent that walks from the highly accessible 4-position to the 2-position hOL2198i.
339
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
OCONR2
OCONR2 CI
CI
LDA
N
TMSCI
N −
I
H+
I
N
TMS
– I
OCONR2
OCONR2 TMSCI
N −
LDA
CI
I
OCONR2
TMS
N
TMS I
CI
OCONR2
OCONR2 CI
CI
TBAF
N I
TMS
CI
N
THF
I
TMS
Scheme 23
Metalation with zinc and magnesium provides other useful nucleophilic sources of pyridine. Pyridyl Grignard reagents are useful for cross-coupling reactions hCEJ3300i and have recently been shown to aminate pyridine by reaction with N-chloramines hOL1516i. Pyridine organozinc reagents have utility in a variety of coupling reactions beyond the well-known Negishi coupling hJOC2131, T3135, TL357i. The excellent stability of these reagents is often underestimated by chemists; 2-pyridylzinc bromide is highly stable at room temperature showing virtually no decomposition after 12 months at room temperature hTL357i. The unique reactivity of pyridine extends out onto the side chains. a-Methylenes at the 2-position of pyridine display a relatively high acidity due to resonance stabilization of the resulting anion. Lutidine and 2-picoline anions are useful pyridinylation reagents in total synthesis. Taber et al. use laterally lithiated 2-picolines to undergo conjugate addition with enones to ultimately access senepodine G and cermizine C (Scheme 24) hJOC5737i. O
O nBuLi THF, 0 ⬚C, 1 h
N
+ N
CH2Li
CuBrSMe, –30 ⬚C, 2 h
81%
–78 ⬚C, 5 min; 2 h
N
Scheme 24
Just as picolyl lithium species are easily generated, 2-picolyl palladium species can be produced as well (Scheme 25). These laterally palladated picolines and lutidines undergo CH functionalization on the side chain; Xia et al. reported good yields for the palladium-catalyzed addition of 2-methyl azaarenes to N-tosyl imines hJA3650i. H + N
Scheme 25
Ph
N
Ts
Pd(OAc)2 (5 mol%) 1,10-phenanthroline THF, 120 aC
Ph N
82% NHTs
340
P.E. Alford
Palladium-catalyzed methods are immensely important tools for the functionalization of pyridine. Of all the palladium-catalyzed coupling methods, the Suzuki–Miyaura reaction is perhaps the most widely relied upon hS3637, T2624i. With respect to pyridine chemistry, however, the use of 2-pyridylboronic acids has been problematic. In recent years, new modifications have allowed improved, general, and high yield use of the Suzuki coupling with 2-pyridyl nucleophiles hOL2314i. Still, Suzuki coupling methods that involve 3-pyridyl boronates or where an aryl boronic acid is coupled to a pyridine acceptor are preferred if possible hH(80)359i. The versatility of the Suzuki reaction extends far beyond arylations to vinylations and alkylations as well hT1973i. Below, a novel Suzuki–Miyaura coupling allows facile synthesis of substituted Cbz-protected 2-aminoethyl pyridines (Scheme 26). 1. 9-BBN,
NHCbz THF, 0 ⬚C
Br
N
2. aq. NaOH, 0 ⬚C to rt 3. PdCl2(dppf), THF, 65 ⬚C
N H
N
Cbz 93%
Scheme 26
The Negishi cross-coupling provides an attractive alternative to Suzuki–Miyaura methods (Scheme 27). Luzung et al. suggest using Knochel conditions to produce 2pyridylzinc halides for their mild Negishi coupling procedure—this two-step sequence from 2-halopyridines to 2-arylpyridines involves no highly reactive metals or cryogenic conditions, making this the route particularly well suited for large-scale work hJOC8330i. Hiyama hTL3558i and Kumada–Corriu hCEJ3300i cross-couplings have also been demonstrated to be excellent options.
+ ArCl N
Pd2dba3 (2 mol%) X-Phos (8 mol%) THF, 65 ⬚C
ZnCl
up to 99% Ar
N
Scheme 27
A surprising recent report from Baran’s group shows that arylboronic acids directly couple with unsubstituted pyridines without the need for a palladium catalyst. Mechanistically disparate from any Suzuki reaction, this novel direct CH functionalization relies on a catalytic amount of silver nitrate in the presence of a co-oxidant and proceeds readily at room temperature in good yields (Scheme 28) hJA13194i. R
B(OH)2 +
N Me
Scheme 28
TFA (1 eq.) AgNO3 (0.2 eq.) K2S2O8 (3 eq.)
R
1:1 DCM:H2O rt, 3–24 h
N
R = t-Bu, 60% R = H, 45% + C4 arylation
Me
341
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Direct CH functionalization of pyridine has grown in leaps and bounds over the past few years hOL4277i. In a testament to the maturity of these processes, Sarpong et al. relied on a direct CH functionalization as the key step to join the two aromatic moieties of the lycodine dimer complanadine A. In this case, an iridium-catalyzed Hartwig–Miyaura boronylation functionalized C-5 in impressively high yield and selectivity (Scheme 29) hJA5926i. Me Me N
cat. [Ir(cod)(OMe)]2 [B(pin)]2 di-t-butylbipyridine THF, 80 ⬚C
N Boc
Me N N
N Boc
O B O
N Boc
H N
Complanadine A
75%
H
H Me
Scheme 29
Direct CH activation of pyridine has found success with other methods as well (Scheme 30). Below, Rh(I)-catalyzed direct arylation represents another approach; in this case, the heterocycle is used without requiring any prefunctionalization hJOC7863i. Me
Br
Me
[RhCl(CO)2]2 (cat.) N
R
Dioxane 175–190 ⬚C, 24 h
Me
N
R
R = H, 0% R = Me, 53% R = iPr, 78%
Me
Scheme 30
Direct CH functionalization of pyridine has also been observed using calcium reagents. When pyridine is mixed together with an organocalcium bis(allyl)calcium complex, an unusual pyridine insertion reaction occurs hAG(I)7795i. The initial transfer of the allyl groups to pyridine is proposed to proceed by a pericyclic mechanism. The allyl group then walks to the 4-position via a Cope rearrangement (Scheme 31).
via: Ca(C3H5)2
Scheme 31
acetyl chloride
pyridine 25 ⬚C
(py)nCa N
[3,3]
O N Me
342
P.E. Alford
Several other direct CH activation techniques reported last year preferably functionalized the 4-position of unsubstituted pyridine. In contrast to the many methods for CH activation which rely on directing groups, recent methods pioneered by Hiyama have utilized bifunctional reagents consisting of nickel and a Lewis acid (Scheme 32). The use of a highly bulky N-heterocyclic carbene ligand is important for inducing steric hindrance between the nickel and the Lewis acid at N-1; this interaction prevents ortho-substitution and reduces substitution at the meta position. N
HN t-Bu Pr
Pr
N Mes
Pr
Pr
Amino NHC ligand [Ni(cod)2] (0.1 eq.)
+ Pr
Pr
N
AIMe3
N
Pr Pr
N
N 59%
26%
0%
Scheme 32
Though the exact mechanistic details of these reactions remain unknown, Ong et al. have isolated for the first time the predicted bimetallic pyridine nickel aluminum complex that proceeds CH functionalization hJA11887i. To improve the C-4 selectivity of this process, Hiyama et al. have employed an exceptionally large aluminum Lewis acid. These conditions provide exclusive alkylation and alkenylation at C-4 (Scheme 33) hJA13666i. Me
t-Bu
t-Bu t-Bu O
AI
O Ph
Me + N
Pr
85% R
N
Ph
Me
t-Bu
N R
[Ni(cod)2] (0.05 eq.) toluene, 130 aC
+
N
Trace N
C-4 exclusive
Scheme 33
Direct CH activation strategies have traditionally been more successful at the more reactive 2-position of pyridine. A recent copper-catalyzed synthesis of indolizines from pyridine demonstrates substitution at this position hJA13200i. By alkylating at the nitrogen, C-2 becomes more receptive to the tethered vinylcuprate and undergoes attack; reductive elimination furnishes the indolizine in excellent yield (Scheme 34). Indolizines can also be accessed by a palladium- or gold-catalyzed cycloisomerization hOL5538, OL3242i.
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
CO2Et
Me CuBr (5 mol%)
CO2Et
+
Me
N
DCM, rt
N2
N
343
90%
via: + N
– CuBr
CuBr
N
CO2Et Me
CO2Et Me
Scheme 34
Pyridine plays an important role in the CH activation of other systems as well; the pyridine moiety is a unique functional group that directs and activates metal catalysts towards the site of functionalization hJOC2415i. Virtually any functional group can be integrated by CH activation at both sp2 and sp3 centers hJA3965, JA12249i. The advent of modern C H activation chemistry has been a major topic in recent years; this is an area which pyridine has found a central role. As the field matures, mechanistic details are further clarified and the abundance of synthetic transformations are organized and reviewed h10CR576, 10CR824, CR1147i. This past year, a special issue of Chemical Reviews covered the topic of CH activation hCR575i. Despite the wide acceptance of a Pd(II)/Pd(IV) catalytic cycle—a mechanism supported by Yu and Sanford—Ritter argues that the evidence for a palladium (IV) intermediate is not yet convincing. This past year, Ritter proposed a binuclear Pd (III) complex wherein simultaneous participation of both metals lowers the activation barrier for oxidative addition and reductive elimination hJA14530i. While the exact mechanistic details remain to be elucidated, new conditions for CH activation continue to be reported—some integrating functional groups from quite unusual sources hJA10272, JA12212, OL3464, JA3648i. Yu et al. have reported excellent conditions for the integration of CF3 groups via traditional CH activation with a palladium acetate directed by an ortho-pyrid-2-yl moiety (Scheme 35).
N H
TFA (10 eq.) Pd(OAc)2 (0.1 eq.) DCE
+ – S BF4 CF3 N
86%
CF3
Scheme 35
One of the major limitations of these methods is a reliance on the pyridine moiety itself. Generally linked to the substrate by strong covalent aryl–aryl carbon–carbon bonds, the pyridine moiety is difficult or impractical to remove. Gevorgyan et al. addressed this problem by tethering the pyridine moiety to the arene substrate via an easily modifiable silyl linkage (Scheme 36). It was reported that
344
P.E. Alford
a pyridyldiisopropylsilyl group provides an optimal combination of stability under CH activation conditions and mutability in subsequent steps hJA8270i. Less bulky groups on the silicon resulted in decomposition during C H activation. The pyridyldiisopropylsilyl arenes can be synthesized in two steps from the corresponding halopyridine and haloarene. After CH activation, the pyridylsilyl group can be easily removed by fluorine-induced desilylation or the silyl group can be replaced by a boronate, halide, alcohol, or aryl in excellent (> 90%) yields. B(pin) AcO
N
Si
Pd(OAc)2 (10 mol%) PhI(OAc)2 (2 eq.) AgOAc (1 eq.)
i-Pr i-Pr
1. BCl3 2. pinacol, TEA N
Si
Me
i-Pr i-Pr
94%
AcO
I
DCE, 80 ⬚C, 2 h
AgF Me
Me
AcO
NIS Me 100%
Scheme 36
While the pyridylsilyl group above works best for classic oxidizing CH activation conditions, pyridyldimethylsilyl groups have been stable enough to allow CH functionalization under other conditions hOL2838i. Nakamura et al. report the direct CH arylation of olefins with iron using a pyridyldimethylsilyl activating group. CH activation methodologies continue to be find success with a variety of metals in addition to palladium: iron hSL313i, copper hOL1644i, and ruthenium hOL5032i. While investigating CH activation conditions, Zhu et al. observed formation of pyrido[1,2-a]benzimidazoles in good yield. In this reaction, the pyridyl group acts as both a directing group and a nucleophile (Scheme 37). Mechanistic studies suggest that this ring closure proceeds as a Cu(III)-catalyzed SEAr process hJA13217i.
H N N
Cu(OAc)2 (0.5 eq.) Fe(NO3)3•9H2O (0.1 eq.) PivOH (5 eq.), O2 balloon DMF, 130 ⬚C
N N
88%
Scheme 37
Pyridine has also found a role as a directing group in azide–alkyne click chemistry hT2602, CEJ10202i. This popular copper-catalyzed reaction is known to be significantly accelerated when quinolyl and pyridyl azides are used. Zhu et al. investigated the effect of a range of azides that contain a chelating group (Scheme 38). Azides with auxiliary nitrogen donor ligands were more reactive than those containing oxygen and sulfur donor ligands. Further, the presence of donor ligands such as pyridine and quinoline may assist the reduction of Cu(II) to a highly catalytic Cu(I) species in addition to enhancing the electrophilicity of the azide group hJOC6540i.
345
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
OMe N
N3
N N N
N
t-BuOH, Cu(OAc)2 3h
99%
OMe
Scheme 38
6.1.2.3 Pyridine N-Oxides and Pyridinium Salts Pyridine N-oxides are highly versatile ambivalent species capable of reacting with both nucleophilic and electrophilic reagents. For substitution at C-2, pyridine N-oxides provide a highly effective alternative to typical SNAr chemistry hCC3384, TL5127i. An activating agent can simultaneously facilitate nucleophilic addition while serving to deoxygenate the pyridine ring. Novel variations on this strategy have been reported in 2010. Tosyl azole reagents, for instance, allow the coupling of triazoles, imidazole, and pyrazole with pyridine at C-2 (Scheme 39) hJOC2722i. Ts-triazole + N O
O O R S N
–
N
+ N
– N
OTs
N
H N
N
N
OTs
N
N
N
N
84%
N
N
N
Scheme 39
Chemists at Pfizer have reported a novel method for the preparation of 2-aminopyridines from pyridine N-oxides where a phosphonium salt, PyBroP, functions as the activating agent. Mechanistically, this approach is similar to other pyridine N-oxide activating strategies; however, the authors report that the alternative activating agents (Ac2O, Ts2O, TsCl, etc.) commonly produce a variety of problematic side reactions (Scheme 40) hOL5254i. via: + N
+
H
O–
N H
Me
PyBroP i-Pr2EtN DCM, 25 ⬚C
PyBroP = + N
H2N
OP(Py)3
Me –
Br
N N 83% H
Me
22 other examples
N
N P+ Br N – PF6
Scheme 40
An entirely new synthesis of pyridine N-oxides was reported which involves a tandem [2,3]-rearrangement followed by a 6-p-azatriene electrocyclization hJA7884i. Starting from O-propargylic a,b-unsaturated oximes, p-acidic copper becomes coordinated to the propargyl triple bond. A nucleophilic intramolecular attack by nitrogen on the triple bond is followed by CO cleavage, and reductive elimination furnishes a N-allenyl nitrone. Electrocyclization of this azatriene produces the polysubstituted pyridine N-oxide (Scheme 41).
346
P.E. Alford
O
PPh3 (0.1 eq.) CuBr(PPh3)3 (0.1 eq.)
N
DMSO, 120 ⬚C
Ph
O
Pr Ph
Pr
•
– O + N
– O + N
Pr
Ph
– Cu
Pr
Cu
– O + N
Pr
Ph
Ph
Pr
– O + N
+ O N
N
87%
Pr Ph
Ph
Scheme 41
Pyridine N-oxides have been favorable substrates for CH functionalization and arylation methods. Due in large part to the work of the late Keith Fagnou, pyridine N-oxides have found a valuable role in palladium-catalyzed methodologies over the past few years. In honor of Dr. Fagnou, chemists from the University of Ottawa have continued and expanded on this chemist’s work posthumously. Campeau et al. have investigated the mechanism of Fagnou’s palladium-catalyzed direct arylation of pyridine N-oxides. The order of each reaction component was scrutinized and competition experiments were performed, ultimately supporting a concerted metalation-deprotonation mechanism (Scheme 42). It was also found that Pd(OAc)2 plays a role as precatalyst as well as the source of the mechanistically necessary acetate base hJOC8180i.
Br
Pd(OAc)2 P(t-Bu)3•HBF4 K2CO3, PhMe 110 ⬚C
Ph
O
t-Bu3P Pd O O
+ N
+ N –
t-Bu3P Pd
H
O
O
O
– + N O
Me
Ph –
Me
Scheme 42
Lapointe et al. have further shown that palladium-catalyzed functionalization can be entirely site-selective depending on the conditions used hJOC749i. It is also interesting to note that in this case (Scheme 43), the presence of the pyridine N-oxide was necessary for each transformation—a free unoxidized pyridine coordinated the metal catalysts and prevented reaction. Conversion of the pyridine moiety to a pyridine N-oxide is similar in this way to a protecting group strategy.
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
347
Ar + N – O
Ar N Me
+ N – O
+ N – O
or N Me
51% Fagnou’s protocol
N
or N Me
55% Gaunt’s protocol
+ N – O
Ar N Me
53% Larrosa’s protocol
No reaction with these conditions N Me
Scheme 43
Pyridine N-oxides have also been shown to be excellent substrates for a range of other metal-catalyzed cross-couplings as well. You et al. have coupled unsubstituted thiophenes and furans with pyridine N-oxides, taking advantage of the relatively facile metalation of these heterocycles to report the first CH/CH heterocoupling hJA1822i. Charette et al. reported a ligand-free copper-catalyzed directed alkenylation of N-iminopyridinium ylides hAG(I)1115i. These substrates may offer some of the same benefits as pyridine N-oxides with the added benefit of a chelating effect; one possible mechanism for this transformation is shown below where the N-iminopyridinium ylide adds into the copper catalyst to generate a more reactive species (Scheme 44). via:
I
+ N
+
– NBz
I
CuBr2 (0.1 eq.) K2CO3 (2 eq.)
+ N
Cu
PhCl, 125 ⬚C, 16 h
N
O– Ph
reductive elimination
+ N –
mel, acetone, 75 ⬚C Zn dust, AcOH, rt
NBz 81%
N 81%
Scheme 44
As mentioned earlier, pyridinium salts are important cationic structures in supramolecular chemistry. Cyclobisparaquat and derivatives are commonly used as cationic macrocycles hJA4954i, and pyridiniums can be used as cationic stations on switches hCSR2203, OL1284i and receptors hCEJ1480, JOC2259i. N-Methyl pyridines and quinolines were used to enable a RCM macrocyclization. These azine salts engaged in supramolecular noncovalent p-cation/arene interactions—the resulting steric environment provides enough conformational control to result in good yields of [12]paracyclophanes (Scheme 45) hJA12790i.
348
P.E. Alford
Face-to-face pyridinium/arene interaction + N Me PF–6
PCy3 Cl Ru Cl Ph PCy3 (10 mol%)
O
MeO
DCM, reflux, 15 h
O 41%
MeO O O
O O
Scheme 45
Generated in situ, pyridinium salts can provide thermodynamic motivation for a variety of intramolecular rearrangements and intermolecular reactions hJHC569, SL2474i. Pyridinium salts are readily attacked by nucleophilic species in a SNAr manner or directly to produce a dihydropyridine hTL4218, SL1606, T8667, S1000i. The coenzyme NADþ is a pyridinium salt and is involved in many redox reactions in biological systems including humans. Synthetic variations have sought to replicate such systems in a laboratory setting hJA10547i. These compounds are also effective homogenous electrocatalysts for the conversion of CO2 to methanol hJA11539i. MeO2C
Br
MeO2C
+ N
K2CO3 O N Me
O
CH3Me, 80 ⬚C
N
MeO2C
–
O
N Me
86%
N Me
Scheme 46
For the synthesis of 3-spiroindolizine oxindole derivatives, authors describe a formal 6p-electron 1,5-electrocyclization—though other possible mechanisms are certainly possible (Scheme 46). This method provides a potential route to the secoyohimbane and heteroyohimbane natural products hOL2108i. Other spirocyclizations have been enabled by N-acylation of pyridine in the presence of a strong Lewis acid. Pigge et al. have prepared spiro-1,4-dihydropyridines by using Ti(OiPr)4 to activate a 4-substituted pyridine towards intramolecular nucleophilic attack from an enolizable side chain at C-4 (Scheme 47) hOL3434i. R2 R1O2C
O
O NR2
N
EtO2CCI Ti(Oi-Pr)4
O N
DCM 68–93%
R1O2C
R 1O
2C
NR2
Me N CO2Et
N CO2Et
Scheme 47
N-Acetylpyridinium salts can be polarized by coordination with tungsten to form an activated electrophilic metal–pyridinium complex. The tungsten–acetylpyridinium complex readily reacts with nucleophiles and hydride sources to produce
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
349
tungsten-complexed 2-substituted-1,2-dihydropyridines. This complex can be further substituted by treatment with triflic acid followed by addition of an appropriate nucleophile (Scheme 48) hJA17282i.
W
1. ZnEt2 N
+
1. ZnEt2, CuCN
+
W
N
O 2. TfOH
Me
N
2. O2
O
Me
Me O
Scheme 48
6.1.3. QUINOLINES 6.1.3.1 Preparation of Quinolines O H
aromatic substitution
condensation path a
NH2
N
path b
NH2
Scheme 49
The synthesis of quinolines most commonly proceeds from aniline and aniline derivatives; from these starting materials, the majority of historically important quinoline syntheses follow one of two basic reaction pathways (Scheme 49). From ortho-aminobenzaldehyde or other disubstituted anilines, annulation of the pyridine ring can proceed by way of a relatively facile condensation reaction (path a). From unsubstituted aniline, annulation requires a thermodynamically demanding aromatic substitution at C-2 (path b). The Friedla¨nder quinoline synthesis is one of the most successful and reliable preparations of quinoline. By relying on a condensation-based pathway, Friedla¨nder syntheses offer relatively mild reaction conditions compared to other quinoline preparations that may require aromatic substitution. Though the Friedla¨nder was first reported more than a century ago, this method continues to be popular and new improvements continue to be discovered. This past year, an enantioselective Friedla¨nder synthesis was reported which furnishes a remote stereocenter during condensation (Scheme 50). A proline-based catalyst was used to generate chiral quinolines, which were converted to enantioenriched tacrine derivatives hOL5064i. TBSO O Br
N H
CHO
CO2H (10 mol%)
Ph
Br
+ NH2 Br
Scheme 50
Ph
PhMe/pyridine (3:7) –25 ⬚C
N Br
76% yield 92% ee
350
P.E. Alford
Venkatesan et al. noticed a significant limitation in current Friedla¨nder methods: the synthesis of 2,4-unsubstituted quinoline-3-carboxylic acids hJOC3488i. Previously, only one example of this type of Friedla¨nder had ever been reported by using 3-oxo-propionic acid ethyl ester, though the overall yield was discouragingly low. Venkatesan et al. investigated the same Friedla¨nder reaction using a synthetically equivalent (under acidic conditions) diethyl acetal. Such diethyl acetals are commercially available and inexpensive. Finding success, the group demonstrated that a one-pot two-step tandem reduction-Friedla¨nder process maintained high yields, operational simplicity, and tolerance of functional groups (Scheme 51). EtO
OEt OEt O
F
CHO
(2.5 eq.)
O F
SnCl2•2H2O (4 eq.)
OEt
EtOH, reflux NO2
68%
N
Scheme 51
Even beyond the Friedla¨nder synthesis, condensation with an ortho-oxo functionality remains one of the most versatile routes for the preparation of pyridines. The Pfitzinger, Camps, and Neimentowski quinoline syntheses all involve a final condensation reaction with a carbonyl substituent adjacent to the amino substituent hHCA946i. As shown below, Cuny et al. use an amide enolate to condense with the reactive carbonyl of an a-ketoacid to form the quinoline portion of isaindigotidione; a subsequent lactamization step furnishes the fused piperidone system (Scheme 52) hOL4628i.
CO2H O NH
t-BuOK, DMF
MeO N Boc OMe
O
N
OMe
80 ⬚C, 4 h
O
BnO
N Boc
HO2C
N H
OBn
O OMe 55%
OMe N H
O
OH
OMe Isaindigotidione
Scheme 52
Lactamization is also a useful method for a ring-closure route to quinolines. For a novel synthesis of ammosamide B (Scheme 53), Fenical et al. used a Wittig olefination to incorporate a tert-butyl acetate adjacent to the amine at C-4 of an oxindole; lactamization produces the quinoline skeleton of the natural product hJA2528i.
351
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
H2N
O
OH NH2
PPh3
O
O2N
1. CO2t-Bu
O
H2N
O2N
O
O
N
Cl
N
2. TFA
N Me
N
N
Me
NH2
Me
Ammosamide B
Scheme 53
One of the most unique methods used for quinoline formation last year was an Ullmann-type coupling reaction (Scheme 54). This synthesis first relied on an aldol condensation to put an aryl halide in close proximity to a p-excessive N-heterocycle such as imidazole, benzimidazole, or pyrrole. Next, an intramolecular Ullmann reaction formed the final CN bond of the quinoline moiety in high yield—once again showing the utility of ortho-substituted benzaldehydes hOL1500i.
CHO +
N
I
N H
CN
CuI (0.1 eq.) proline (0.2 eq.) K2CO3 (2 eq)
N
CN
CN
N H
DMSO
N
N 91%
I
Scheme 54
2-Aminobenzaldehydes are particularly useful reagents for the synthesis of quinolines even beyond traditional Friedla¨nder chemistry. Patil and Raut developed a mechanistically novel strategy for the synthesis of 2-substituted quinolines (Scheme 55). Starting from 2-aminobenzaldehydes, these authors have effected a cascade reaction where a copper-activated terminal alkyne attacks a pyrrolidine-derived iminium. The resulting internal alkyne is then activated by copper iodide and undergoes amination to generate the quinoline ring system hJOC6961i. This process offers a modern alternative to Friedla¨nder-type reactions. CuI (0.1 eq.) pyrrolidine (0.25 eq.)
CHO + NH2
n-Hex
MeCN, 100 ⬚C
N 94%
n-Hex
Scheme 55
Alkyne-based methods have been exceptionally successful in recent years. Last year, novel methods for the synthesis of quinolines have involved the ring closure by isocyanides, azides, olefins, amines, enamines, and enolates hH(81)357, ARK(8) 160, ASC1582, ASC1896, HCA257i. Zhu et al. reported a DABCO-promoted cyclization that produced 2-alkoxy and 2-aryloxy quinolines hJOC7502i. DABCO
352
P.E. Alford
attacks the isocyanide to produce a nucleophilic ylide that attacks the adjacenet alkyne to produce the quinoline skeleton. A nucleophilic alcohol then attacks C-2 in a SNAr fashion to displace the catalytic DABCO (Scheme 56).
Ph DABCO (1 eq.) 2-hydroxypyridine
Ph 56%
DCM
NC
N
Ph
Ph –
+ – N C
O
N
N
N
+ N
Ph N
–
Ph HO
N
+ N
N
Ph
+ N
N
O
N
– O
N
Scheme 56
Other alkynes are used to induce cyclization via electrophilic activation. Once activated and substituted by an electrophilic reagent such as I2 or NBS, propynyl groups were rendered susceptible to attack from an adjacent azide. Upon attack, the resulting ring system aromatized to the quinoline by deprotonation and loss of nitrogen (Scheme 57). This new method by Yamamoto produces 3-halo-2-substituted quinolines in excellent yield hJOC1266i.
E
E+ N3
N –N2
E+
H E – N + N2
Scheme 57
E+ N + N2
E+ = I2, 69% ICI, 55% NIS, 82% Br2, 96% NBS, 84%
353
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Another approach to using alkynes for the synthesis of quinolines was demonstrated in a recent total synthesis of cleistopholine. An N-propargyl naphthoquinone was activated by in situ generated gold triflate before becoming susceptible to electrophilic attack from the adjacent enamine (Scheme 58). This method was used to synthesize a host of azaanthraquinones including several natural products hJOC4323i. While this method was used to excellent effect to synthesize azaanthraquinones, the strategic disconnects used in this method may be less successful if applied to a naphthalene or benzene rather than a quinone—the former of which are relatively inert aromatic systems that often require harsh conditions to effect this type of aromatic C H substitution. Me O
O
+ AuL
Me 60%
HOAc, 100 ⬚C, 1 h
N H
O
Me
O
AgOTf (0.1 eq.) Ph3PAuCl (0.1 eq.)
N
N H
O
O Cleistopholine
Scheme 58
Many traditional quinoline syntheses have relied on aromatic substitution of aniline derivatives. As described in Section 6.1.16.1.1, such a route (path b, Scheme 49) inherently requires disruption of the aromatic phenyl moiety. Many of these processes are thermodynamically demanding and require harsh reaction conditions. Perhaps the most maligned of these traditional syntheses is the Skraup method, described as both “a witches brew” and “notorious“ hTL3876i. Still, modern chemists have improved upon these old methods and applied them decisively toward the synthesis of complex targets. Cushman et al. reported an efficient synthesis of ammosamide B by way of an impressive Skraup–Doebner–Miller synthesis at its key step hOL3112i. By effecting three bond-forming reactions in one pot—imine condensation, amide formation, and electrophilic aromatic substitution—Cushman et al. furnish both the oxindole and quinoline moieties in one step (Scheme 59). MeO2C
H2N
O
O NH2 MeOC
BocHN NH2 NHBoc
TsOH, Cu(OAc)2 CHCl3, 8 h
N
HN
O BocHN
H2N N
CO2Me
O N
Cl
Me
NHBoc
NH2
50%
Ammosamide B
Scheme 59
Monosubstituted aniline derivatives can be also converted to quinolines via ring closure with a Friedel–Crafts reaction. Extending this concept to nitriles, Kobayashi
354
P.E. Alford
et al. have reported a Houben–Hoesch-type ring closure in their recent methodology for the synthesis of quinolines hJOC2741i. Normally, nitriles can be difficult to activate and are not electrophilic enough to undergo Houben–Hoesch reaction except with electron-rich arenes. Kobayashi et al. have identified an unusually electron-rich nitrile, which is readily activated via N-perfluoroacylation—the resulting adduct readily cyclizes to produce a 4-hydroxyquinoline derivative (Scheme 60). OH CN
(F3CCO)2O
CF3
DMF, rt, 24 h
O
N
O
Me
89%
O
N Me
O workup CF3
O + Me2N
H
O CF3
N
O O
CF3
N
C N
CF3
O
CN-activation
H
N
O
Me
Me
Scheme 60
The Povarov reaction has been a particularly efficient method for the synthesis of quinolines. As a [4 þ 2] cycloaddition, this method generates multiple bonds stereoselectively in one pot. When performed intramolecularly, the Povarov reaction is particularly facile—a characteristic that has found the Povarov at home in a variety of multicomponent reactions and tandem sequences hJHC1148i. Shown below, an enamine-based Povarov allows formation of 2-arylquinolines by an elimination–oxidation aromatization (Scheme 61). A closely related formal [4 þ 2] cycloaddition was reported that relies on a copper catalyst to produce tetrahydroquinolines hCJC443i. via: N
Me +
NH2
H
N O
O
BiCl3
O
Me
Me S8
MeCN N H
Ar
220 ⬚C
N
87%
Scheme 61
Electrocyclizations are another pericyclic pathway used for the synthesis of quinolines. Liang et al. reported that the Sonogashira coupling of benzimidoyl chlorides with propargyl ethers triggers a domino cascade to 2,4-substituted quinolines hJOC1305i. After Sonogashira coupling, the resulting alkynyl imine tautomerizes to an allene which readily undergoes 6p-electrocyclization (Scheme 62).
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
355
:A H
MeO MeO N Cl
Ph Ph
CuI, Et3N Pd(PPh3)2Cl2
Ph
+
80 ⬚C
N MeO
Ph
N
Ph
Ph MeO
MeO
H-A Ph
Ph
H electrocyclization
p.t. N
87%
Ph
N
Ph
Scheme 62
6.1.3.2 Reactions of Quinolines Several methods reported this past year have highlighted the unique reactivity of quinolines; others have focused on quinolines as substrates or targets. In most cases, the reactivity of quinoline mirrors the reactivity of pyridine. The dominant aromaticity of the benzene portion of quinoline results in a more reactive and less aromatic azine moiety. This heightened reactivity makes quinoline more receptive to nucleophiles and provides improved reactivity in SNAr reactions—a mechanism that has been used extensively for functionalizations last year. Demonstrating the enhanced reactivity at the azine ring, a small library 4-thioalkyl quinolines was synthesized by regioselective SNAr displacement of a halide (Scheme 63). These compounds were then screened for their ability to enhance monoclonal antibody production in mammalian cell cultures hT9461i. SMe
Cl Br
NaSR OMe
N
Br
DMF, rt 3h
OMe
N
O
85%
O
Scheme 63
Even displacement on the benzene moiety can be controlled due to resonance effects from the azine moiety (Scheme 64). This past year, Griffith et al. presented several methods for the synthesis of halogenated 5-hydroxyquinolines—such compounds are primed for further functionalization hTL3876i. Cl
N
NaOMe
Cl
N
MeOH relux Cl
Scheme 64
HBr
N
Cl
41% (two steps)
AcOH OMe
OH
356
P.E. Alford
Sequential substitution of halogens on quinoline and other electron-deficient heterocycles is of particular interest in organic synthesis and medicinal chemistry. A palladium-catalyzed Sonogashira coupling chemoselectively reacts with the iodine substituent and leaves the adjacent chlorine intact for further functionalization by SNAr or Suzuki–Miyaura cross-coupling (Scheme 65) hT8261i. Ph
Cl
N
Ph
Cl
I
CuI PdCl2(PPh3)2
Ph
NEt3
NHMe
Ph
H2N–Me N 74%
EtOH
Ph
N
Ph
68%
Scheme 65
While investigating palladium-catalyzed couplings, Skrydstrup et al. discovered a novel nucleophilic amidation procedure hCEJ5437i. Catalyzed by palladium, nitrogen nucleophiles react with tosylquinolines to produce the corresponding amidated product; for 2,4-ditosylates, reaction is regioselective at the 2-position—the favored position for many metal-catalyzed procedures (Scheme 66). OTs O HN
+ N
O
OTs
OTs
[Pd(dba)2] (3 mol%) DPPF (3 mol%) K2CO3
O
91%
dioxane, 100 ⬚C, 16 h
N
N
O
Scheme 66
Silylated dialkyl phosphite esters readily attack quinoline in acidic media. By silyl transfer, the phosphonium is converted to a phosphonate and the quinoline is reactivated for attack at C-2 (Scheme 67). This reductive, one-pot, diphosphonylation of quinolines proceeds in high yields hCC258i. Phosphonylated pyridines and quinolines have shown unique biological profiles and may find potential use for the treatment of stroke. via: MeO
P
OMe
TMSO + OMe P OMe
O P
OMe OMe
O
OMe P
OMe
OTMS N
H2SO4
N H
+ N TMS
N H
96%
O P OMe OMe
Scheme 67
Tetrahydroquinolines and dihydroquinolines are highly desirable substrates in their own right, particularly in the realms of natural product synthesis and medicinal chemistry. The tetrahydroquinoline (R)-sumanirole selectively stimulates
357
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
D2 receptors, which are believed to facilitate the restoration of motor function in victims of Parkinson’s disease hSL1473i. A new total synthesis of this compound begins with a reductive-amidation of a quinoline to a N-functionalized dihydroquinoline; a subsequent chiral epoxidation and directed nitration at C-8 allows preparation of sumanirole in twelve steps overall (Scheme 68). Cl
O N
O
O
NHMe
Ph
DIBAL-H DCM R
AI
N
61%
N
N
O
R
O N
N sumanirole
HN O
O
Ph
Scheme 68
Zhou et al. continued their work on the asymmetric hydrogenation of quinolines, thus achieving highly impressive chiral induction after examining a host of ligands and conditions. These optimal conditions employed iridium in preference over ruthenium- and rhodium-based catalysts (Scheme 69) hTL3014i. Alternately, providing a similar transformation with equally impressive enantiomeric excess, other groups have found success with other conditions hTA1549, ASC2441i. [Ir(cod)Cl]2 (R)-SegPhos TfoH•NC5H11 THF, 700 psi H2
Me
N
N H
95% yield 91% ee 10 other examples
Me
Scheme 69
One of the clear advantages quinoline has over tetrahydroquinoline is a distinctive sensitivity to ultraviolet light and a corresponding fluorescence hOL2318i. For this reason, quinolines are commonly integrated into sensors, indicators, and other nanodevices as fluorescent reporters hJA8232i. One quinoline-based sensor reported in 2010 relied on both the fluorescent p-conjugated system and metalophilic azine moiety of quinoline. In the presence of mercury, a hydrazine-linked diquinoline system becomes conformationally restricted, the resulting extended planar p-system is highly fluorescent (Scheme 70) hOL5406i. Highly fluorescent N N Free rotation
Scheme 70
Hg2+ N N
N
H2O
N H2O Hg N OH Retricted rotation
Hg N
OH
358
P.E. Alford
Cinchona alkaloids, such as quinodine, are naturally occurring nonracemic quinolines that are used extensively in organocatalysis and as chiral ligands in metal-catalyzed methods; in many cases, these catalysts can be synthetically altered to improve enantioselectively (Scheme 71) hOL1516, AG(I)9460i.
S Ph OH
N H
NH
N
N
H
N
N
H
Quinidine OMe
OMe
Unnatural quinidine-derived catalyst
Scheme 71
6.1.4. ISOQUINOLINES 6.1.4.1 Preparation of Isoquinolines As with quinoline, recent chemistry for the preparation of isoquinolines has relied heavily on cycloisomerization of ortho-substituted phenyl alkynes. These methods most often involve a formal 6-endo-dig cyclization of a nucleophilic nitrogen moiety, commonly furnished with a leaving group to ensure subsequent aromatization to the isoquinoline. The Larock isoquinoline synthesis uses a tert-butyl group which acts as a neutral leaving group and work by Zhang et al. has exploited aldehyde formation to provide a thermodynamic trap (Scheme 72). A recent novel approach taken by Wu¨rthwein et al. involves an N-indoline moiety, which eliminates as indole to allow formation of the fully aromatic neutral isoquinoline hEJO1787i. R R
Larock Ag+
N
+ N
R
N
Ag+ O
O
R
Zhang
+
N
H
R⬘
R R
Würthwein N
Scheme 72
N
Ag+
+ N
N H
R⬘
359
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Another means of stabilizing the resulting cyclized product is by means of a N-tosyl stabilized N-amino ylide hCC5238i. This zwitterionic species readily undergoes 1,3-dipolar cycloadditions with a suitable dipolarophile (Scheme 73). O Ph
N
N H
Ph
OEt AgOTf (5 mol%) Ts
Ph N
DCE/DMAc 60 ⬚C
+ N
[3 + 2]
N N
Ts EtO2C
Scheme 73
Using another 6-endo-dig cyclization, Li et al. enabled the cyclization of orthoalkynylbenzonitrile by use of a platinum catalyst commonly used for hydrolyzing nitriles to amides hTL6422i. Although this process produces a mixture of two 1,3-disubstituted products, the quinoline can be readily converted to the quinolone (Scheme 74). Me O N
H
Me P O
Me P Me OH Pt H
P
OEt
Me Me
N
EtOH, reflux
O
48%
NH
+
Ph
15%
Ph
Ph HBr, AcOH, 50 ⬚C 92% conversion
Scheme 74
A novel azide-based cyclization was reported which generates the isoquinoline moiety by way of a Huisgen 1,3-dipolar cycloaddition preceded in situ by alkynylation hT80i. The resulting 1,2,3-triazolo[5,1-a]isoquinoline readily expels molecular nitrogen to form 1,3-disubstituted isoquinolines (Scheme 75). Ph CO2Et CuCl (0.1 eq.) 2 I
N3
K2CO3, DMF 60 ⬚C, 4 h
CO2Et N
75% Ph
N N
CO2Et
AcOH N
reflux, 8 h
99% Ph
O
O
Scheme 75
For the synthesis of isoquinolinium salts, Cheng et al. applied their nickel-catalyzed procedure hCEJ282i. First furnishing an ortho-vinyl group before cyclization,
360
P.E. Alford
Cheng converted the salt to the isoquinolone as part of a total synthesis of oxyavicine—a feat achieved without the use of protecting groups and with impressive overall yield (Scheme 76). O
N
O
Br
+ Me N
O
Me O
[Ni(cod)2]/P(o-Tol)3
+
O
O
O
O
HO
OH O O
O N
K3[Fe(CN)6], CsOH
Me
O O
O
N
Me
oxyavicine O
O
O
O 67% overall (five steps)
OH
Scheme 76
Isoquinolines can be synthesized by formation of the benzene moiety in the presence of nickel. Sato et al. reported a nickel-catalyzed [2 þ 2 þ 2] cycloaddition involving 3,4-pyridyne and propargyl diols (Scheme 77) hH(80)917i. OMOM Et3Si 2 eq.
TfO
OMOM
Ni(cod)2
+ OMOM
MOMO
via:
N
CsF
72% N
N MOMO
OMOM
Scheme 77
Classic preparations of isoquinoline remain popular, particularly the Pictet– Spengler (Scheme 78) and the Bischler–Napieralski (Scheme 79) reactions. Capretta and Awuah performed an in-depth investigation for microwave-assisted preparations of 1,4-substituted isoquinolines (Schemes 78–79). Despite reporting excellent facile conditions for both the Pictet–Spengler and the Bischler–Napieralski, an alternate and simpler strategy of functionalizing 1-isoquinolines remained both faster and more economical hJOC5627i. Also reported in 2010 were several variations of the Pictet–Spengler hS587, S2949, TL1774, TL6356i and novel applications of the Bischler–Napieralski hCC7525, H(80)831i.
361
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
R3
R3 R3 R1
R1 NH2
TFA MW, 140 ⬚C
+
R2
R1 NH
R2
N
R2
10% Pd/C
toluene
R4
CHO R4
R4 R5
R5
R5
Scheme 78
MeO NH2
MeO MeO
+ CO2H R1
POCl3 MW, 140 ⬚C
MeO NH 10% Pd/C
MeO
N
MeO
R2
toluene
R2
R2 R1
R1
Scheme 79
As the final step in many isoquinoline syntheses, the oxidation of dihydro- or tetrahydroisoquinoline is an important route to the fully aromatic heterocycle. Shi et al. performed dozens of elimination–oxidation reactions to fully investigate this mild conversion of tetrahydroquinolines to isoquinolines hEJO6987i. In these reactions, base-catalyzed elimination of toluenesulfinic acid produces the dihydroquinoline, which readily aromatizes to isoquinoline in air (Scheme 80).
R4
R1
NTs
R2
NaOH, O2 air DMSO
R3
R1
R4 N
R2 R3
Scheme 80
6.1.4.2 Reactions of Isoquinoline In contrast to pyridine and quinoline, isoquinoline favors nucleophilic attack almost exclusively at the 1-position. Benefiting from both enhanced reactivity and highly specific regiochemistry, many SNAr-type methods and cross-couplings show impressive results when applied to isoquinolines (Scheme 81). When activated by ethyl chloroformate, this effect is especially notable and an organoindium species preferentially attacks C-1 over an aldehyde hEJO3650i.
362
P.E. Alford
O Cl
O
OEt
O
In(Cy)3 10% CuCl THF, CH3CN, 45 ⬚C
N
N
CO2Et
63% Cy
Scheme 81
Demonstrating the enhanced reactivity at C-1 for cross-coupling reactions, a Buchwald amination procedure provides high yields of coupled heterocycles— exclusively linked at C-1 of isoquinoline (Scheme 82) hTL4340i.
N Cl
N Pd2(dba)3/BINAP Na2CO3/Dioxane
N
N
110 ⬚C, MW, 45 min
90%
Cl
Cl
Scheme 82
As with the other azine species, due to the medicinal importance of the isoquinoline structure, highly selective sequential functionalizations can be valuable methodologies. Starting from commercially available 1,3-dichloroisoquinoline, ortho-lithiation regioselectively functionalizes C-4; from this species, three sequential Negishi reactions can be performed regioselectively to produce a diverse array of 1,3,4-trisubstituted isoquinolines as shown below (Scheme 83) hTL3524i.
R1
R1
R1 R3 Negishi N
N R2
R2
N Cl
Cl
Negishi
N Cl
Cl
ortho-lithiation
Scheme 83
Li Cl
Cl Negishi
commericially available
N Cl
363
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
Isoquinoline-based ylides, easily generated from isoquinoline and a benzyl halide, allow facile preparation of fused hetero[a]isoquinoline systems (Scheme 84) hS4007i. Undergoing [2 þ 3] dipolar cycloadditions, this 1,3-dipole reacts exclusively at C-2 with a variety of dipolarophiles hTL6439, S2794i.
O Cl O Cl Ph
Cl N
K2CO3
N
57%
O
+ –
1, 4-dioxane
O
N
Ph
Ph
Scheme 84
Isoquinoline-1,3,4-triones contain a reactive ketone at C-4 that undergoes [2 þ 2] cycloaddition with disubstituted alkynes under photochemical conditions hJOC2989i. The resulting oxetene rearranges to an enone that subsequently undergoes 6p-electrocyclization (Scheme 85).
N N
N
+
O O O N
hv N
[2 + 2] Me O
O
O
O
O 50%
Me
N
Me
O
Scheme 85
Furo[3.4-c]isoquinolines are remarkable fused heterocyclic systems which contain a trapped isoquinolino-3,4-quinodimethane moiety (Scheme 86). This results in a stabilized system, which still retains a reactive diene. Ghorai et al. report in situ generation of furo[3,4-c]isoquinoline by coupling o-alkynyl acyl isoquinolines with Fischer carbene complexes; the resulting intermediate is subsequently trapped with a suitable intramolecular or intermolecular dienophile hS3179i.
364
P.E. Alford
R
R
O
TMS
O OMe Cr(CO)5
+
N
reflux
OMe
TMS
N
THF
Ph
Ph HO R
R O OMe N
silica gel
O
TMS
N
Ph
TMS
R = H, 48% R = Ph, 55%
Ph
Scheme 86
Like pyridine, isoquinoline is also used in metal-directing/activating methodologies, sometimes offering different reactivity than seen with pyridine. For the directed CH functionalization of indole, 2-quinolylmethyl was investigated as a replacement for 2-pyridylmethyl as a N-substituted directing group hH(80)895i. When the isoquinoline is used, Brown et al. observed a rare example of C-7 functionalization in addition to functionalization at the 2-position (Scheme 87).
CO2Me
CO2Me N
N
10% Pd(OAc)2 Cu(OAc)2 1,4-dioxane, AcOH 70 ⬚C
N
N
40% CO2Me
Scheme 87
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JA3266 JA3648 JA3650 JA3965 JA4954 JA5926 JA7884 JA8232 JA8270 JA8544 JA10272 JA10547 JA10756 JA11539 JA11887 JA12212 JA12249 JA12790 JA13194 JA13200 JA13203 JA13217 JA13666 JA14457 JA14530 JA15380 JA15814 JA17282 JHC171 JHC287 JHC569 JHC1429 JOC726 JOC749 JOC839 JOC1266 JOC1305 JOC2131 JOC2227 JOC2259
M.J. O’Connor, K.N. Boblak, M.J. Topinka, P.J. Kindelin, J.M. Briski, C. Zheng, D.A. Klumpp, J. Am. Chem. Soc. 2010, 132, 3266. X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3648. B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am. Chem. Soc. 2010, 132, 3650. D. Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965. A.-M.L. Fuller, D.A. Leigh, P.J. Lusby, J. Am. Chem. Soc. 2010, 132, 4954. D.F. Fischer, R. Sarpong, J. Am. Chem. Soc. 2010, 132, 5926. I. Nakamura, D. Zhang, M. Terada, J. Am. Chem. Soc. 2010, 132, 7884. M. Rouffet, C.A.F. de Oliveira, Y. Udi, A. Agrawal, I. Sagi, J.A. McCammon, S.M. Cohen, J. Am. Chem. Soc. 2010, 132, 8232. N. Chernyak, A.S. Dudnik, C. Huang, V. Gevorgyan, J. Am. Chem. Soc. 2010, 132, 8270. J. Leblond, H. Gao, A. Petitjean, J.-C. Leroux, J. Am. Chem. Soc. 2010, 132, 8544. J. Kim, S. Chang, J. Am. Chem. Soc. 2010, 132, 10272. Y. Matsubara, K. Koga, A. Kobayashi, H. Konno, K. Sakamoto, T. Morimoto, O. Ishitani, J. Am. Chem. Soc. 2010, 132, 10547. Z. Shi, N. Lin, J. Am. Chem. Soc. 2010, 132, 10756. E.B. Cole, P.S. Lakkaraju, D.M. Rampulla, A.J. Morris, E. Abelev, A.B. Bocarsly, J. Am. Chem. Soc. 2010, 132, 11539. C.-C. Tsai, W.-C. Shih, C.-H. Fang, C.-Y. Li, T.-G. Ong, G.P.A. Yap, J. Am. Chem. Soc. 2010, 132, 11887. Q. Shuai, L. Yang, X. Guo, O. Basle´, C.-J. Li, J. Am. Chem. Soc. 2010, 132, 12212. K. Gao, P.-S. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc. 2010, 132, 12249. P. Bolduc, A. Jacques, S.K. Collins, J. Am. Chem. Soc. 2010, 132, 12790. I.B. Seiple, S. Su, R.A. Rodriguez, R. Gianatassio, Y. Fujiwara, A.L. Sobel, P.S. Baran, J. Am. Chem. Soc. 2010, 132, 13194. J. Barluenga, G. Lonzi, L. Riesgo, L.A. Lo´pez, M. Toma´s, J. Am. Chem. Soc. 2010, 132, 13200. T. Sakai, R.L. Danheiser, J. Am. Chem. Soc. 2010, 132, 13203. H. Wang, Y. Wang, C. Peng, J. Zhang, Q. Zhu, J. Am. Chem. Soc. 2010, 132, 13217. Y. Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J. Am. Chem. Soc. 2010, 132, 13666. W. Yang, A. Greenaway, X. Lin, R. Matsuda, A.J. Blake, C. Wilson, W. Lewis, P. Hubberstey, S. Kitagawa, N.R. Champness, M. Schro¨der, J. Am. Chem. Soc. 2010, 132, 14457. D.C. Powers, D.Y. Xiao, M.A.L. Geibel, T. Ritter, J. Am. Chem. Soc. 2010, 132, 14530. M. Breugst, H. Mayr, J. Am. Chem. Soc. 2010, 132, 15380. M.K. Bayazit, L.S. Clarke, K.S. Coleman, N. Clarke, J. Am. Chem. Soc. 2010, 132, 15814. D.P. Harrison, M. Sabat, W.H. Myers, W.D. Harman, J. Am. Chem. Soc. 2010, 132, 17282. Q. Ren, W. Mo, L. Gao, H. He, Y. Gu, J. Heterocycl. Chem. 2010, 47, 171. R.B. Toche, D.C. Bhavsar, M.A. Kazi, S.M. Bagul, M.N. Jachak, J. Heterocycl. Chem. 2010, 47, 287. A. Rouchuad, W.R. Kem, J. Heterocycl. Chem. 2010, 47, 569. P. Kumar, J. Heterocycl. Chem. 2010, 47, 1429. T. Lechel, J. Dash, P. Hommes, D. Lentz, H.-U. Reissig, J. Org. Chem. 2010, 75, 726. D. Lapointe, T. Markiewicz, C.J. Whipp, A. Toderian, K. Fagnou, J. Org. Chem. 2010, 75, 749. G. Bentabed-Ababsa, S.C.S. Ely, S. Hesse, E. Nassar, F. Chevallier, T.T. Nguyen, A. Derdour, F. Mongin, J. Org. Chem. 2010, 75, 839. Z. Huo, I.D. Gridnev, Y. Yamamoto, J. Org. Chem. 2010, 75, 1266. G.-L. Gao, Y.-N. Niu, Z.-Y. Yan, H.-L. Wang, G.-W. Wang, A. Shaukat, Y.-M. Liang, J. Org. Chem. 2010, 75, 1305. L. Melzig, A. Metzger, P. Knochel, J. Org. Chem. 2010, 75, 2131. A. Chartoire, C. Comoy, Y. Fort, J. Org. Chem. 2010, 75, 2227. A. Dorazco-Gonza´lez, H. Ho¨pfl, F. Medrano, A.K. Yatsimirsky, J. Org. Chem. 2010, 75, 2259.
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
JOC2415 JOC2651 JOC2722 JOC2741 JOC2989 JOC3488 JOC3993 JOC4292 JOC4323 JOC5126 JOC5627 JOC5737 JOC6540 JOC6625 JOC6961 JOC7502 JOC7863 JOC8180 JOC8291 JOC8330 OL1284 OL1288 OL1408 OL1444 OL1500 OL1516 OL1644 OL1984 OL2108 OL2198 OL2314 OL2318 OL2551 OL2838 OL3112 OL3168 OL3242 OL3434 OL3464 OL4086 OL4277 OL4376 OL4628 OL5032 OL5064 OL5242 OL5254 OL5406
367
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368 OL5534 OL5538 S587 S1000 S2071 S2111 S2129 S2794 S2949 S3179 S3637 S4007 S4228 S4273 SL313 SL1473 SL1606 SL2251 SL2314 SL2474 SL2789 T80 T947 T1973 T2602 T2624 T3135 T3452 T5161 T5432 T8095 T8261 T8667 T9231 T9461 TA1549 TL357 TL903 TL1187 TL1774 TL3014 TL3524 TL3558 TL3859 TL3876
P.E. Alford
P.K. Koech, E. Polikarpov, J.E. Rainbolt, L. Cosimbescu, J.S. Swensen, A.L. Von Ruden, A.B. Padmaperuma, Org. Lett. 2010, 12, 5534. Y. Xia, A.S. Dudnik, Y. Li, V. Gevorgyan, Org. Lett. 2010, 12, 5538. M. Wu, S. Wang, Synthesis 2010, 587. R.E. Beveridge, B.A. Arndtsen, Synthesis 2010, 1000. N. Nicolaus, H.-G. Schmalz, Synthesis 2010, 2071. M. Schlosser, R. Ruzziconi, Synthesis 2010, 2111. M.K. Bera, H.-U. Reissig, Synthesis 2010, 2129. B.-W. Zhou, J.-R. Gao, D. Jiang, J.-H. Jia, Z.-P. Yang, H.-W. Jin, Synthesis 2010, 2794. N. Chowdappa, B.S. Sherigara, J.K. Augustine, K. Areppa, A.B. Mandal, Synthesis 2010, 2949. G.P. Jana, S. Mukherjee, B.K. Ghorai, Synthesis 2010, 3179. J.R. Vyvyan, J.A. Dell, T.J. Ligon, K.K. Motanic, H.S. Wall, Synthesis 2010, 3637. H. Hu, K. Shi, R. Hou, Z. Zhang, Y. Zhu, J. Zhou, Synthesis 2010, 4007. J. Lio, C. Wang, L. Wu, F. Liang, G. Huang, Synthesis 2010, 4228. N.G. Norager, K. Juhl, Synthesis 2010, 4273. N. Yoshikai, A. Matsumoto, J. Norinder, E. Nakamura, Synlett 2010, 313. L. Jean-Ge´rard, F. Mace´, H. Dentel, A.N. Ngo, S. Collet, A. Guingant, M. Evain, Synlett 2010, 1473. M. Adib, A. Mohamadi, E. Sheikhi, S. Ansarai, H.R. Bijanzadeh, Synlett 2010, 1606. S. Kantevari, S.R. Putapatri, Synlett 2010, 2251. Y. Miclo, P. Garcia, Y. Evanno, P. George, M. Sevrin, M. Malacria, V. Gandon, C. Aubert, Synlett 2010, 2314. D. Coffinier, L. El Kaim, L. Grimaud, Synlett 2010, 2474. P. Durkin, P. Magrone, S. Matthews, C. Dallanoce, T. Gallagher, Synlett 2010, 2789. Y.-Y. Hu, J. Hu, X.-C. Wang, L.-N. Guo, X.-Z. Shu, Y.-N. Niu, Y.-M. Liang, Tetrahedron 2010, 66, 80. M.A. Terzidis, J. Stephanidou-Stephanatou, C.A. Tsoleridis, A. Terzis, C.P. Raptopoulou, V. Psycharis, Tetrahedron 2010, 66, 947. S. Roy, A.J. Zych, R.J. Herr, C. Cheng, G.W. Shipps, Tetrahedron 2010, 66, 1973. D. Urankar, M. Steinbu¨cher, J. Kosjek, J. Kosmrlj, Tetrahedron 2010, 66, 2602. M. Co´rdoba, R.R. Castillo, M.L. Izquierdo, J. Alvarez-Builla, Tetrahedron 2010, 66, 2624. S.-H. Kim, R.D. Rieke, Tetrahedron 2010, 66, 3135. S.J. Mountford, E.M. Campi, A.J. Robinson, M.T.W. Hearn, Tetrahedron 2010, 66, 3452. T. Sirijindalert, K. Hansuthirakul, P. Rashatasakhon, M. Sukwattanasinitt, A. Ajavakom, Tetrahedron 2010, 66, 5161. D.N. Bobrov, V.I. Tyvorskii, Tetrahedron 2010, 66, 5432. Q. Zhang, T. Fang, X. Tong, Tetrahedron 2010, 66, 8095. M.J. Mphahlele, Tetrahedron 2010, 66, 8261. S. Yamada, M. Abe, Tetrahedron 2010, 66, 8667. N. Houllier, M.-C. Lasne, R. Bureau, P. Lestage, J. Rouden, Tetrahedron 2010, 66, 9231. S.A. Kazi, G.F. Kelso, S. Harris, R.I. Boysen, J. Chowdhury, M. Hearn, Tetrahedron 2010, 66, 9461. V. Parekh, J.A. Ramsden, M. Wills, Tetrahedron Asymm. 2010, 21, 1549. B.M. Coleridge, C.S. Bello, D.H. Ellenberger, A. Leitner, Tetrahedron Lett. 2010, 51, 357. K. Okuda, N. Watanabe, T. Hirota, K. Sasaki, Tetrahedron Lett. 2010, 51, 903. F. Tamaddon, Z. Razmi, A.A. Jafari, Tetrahedron Lett. 2010, 51, 1187. R. Quevedo, E. Baquero, M. Rodriguez, Tetrahedron Lett. 2010, 51, 1774. D.-S. Wang, Y.-G. Zhou, Tetrahedron Lett. 2010, 51, 3014. H. Yang, E. Sjogren, Tetrahedron Lett. 2010, 51, 3524. F. Loue¨rat, P.C. Gros, Tetrahedron Lett. 2010, 51, 3558. X. Liao, W. Lin, J. Lu, C. Wang, Tetrahedron Lett. 2010, 51, 3859. J. Li, D.W. Kung, D.A. Griffith, Tetrahedron Lett. 2010, 51, 3876.
Six-Membered Ring Systems: Pyridines and Benzo Derivatives
TL4218 TL4340 TL5127 TL6186 TL6356 TL6422 TL6439
369
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CHAPTER
6.2
Six-Membered Ring Systems: Diazines and Benzo Derivatives Michael M. Miller, Albert J. DelMonte Bristol-Myers Squibb Company, Princeton, NJ, USA
[email protected]
6.2.1. INTRODUCTION This review provides an overview into the vast number of 2010 publications involving diazine chemistry with the idea that readers may be intrigued by a brief description, example transformation, or structure and decide to read the primary article. Due to the considerable volume of disclosures published throughout the year and the space limitations of this chapter, the authors regret that not all contributions to the field can be highlighted herein. Diazines are an important class of compounds and can be found in almost every area of chemistry. There have been numerous reports on the synthesis, reactions, and applications of diazines within 2010. In addition, there have been many computational investigations involving diazines h10JCPC2389, 10JPCB2549, 10JOC6595, 10JCTC370, 10OL132, 10JHC1259i. The aromaticity and stability of azines in comparison to benzene were explored, and it was found that substitution had minimal impact on the level of aromaticity h10OL4824i. In addition, several reviews covering this chemical motif and their use within the industry have appeared in the literature hB-10MI253, 10CHE905, 10CHE641i. Throughout this review, we will highlight recent advances in diazine chemistry and their applications to the chemical enterprise. While there is a wealth of rich applications that can be found in the patent literature, unfortunately these examples are considered outside the scope of this document. For the purposes of this summary, the three diazine systems (i.e., pyridazine, pyrimidine, and pyrazine) and their benzo analogs (i.e., phthalazine, cinnoline, quinazoline, pteridine, quinoxaline, and phenazine) will be described. N N
N
Pyridazine
N
N
N
Pyrimidine
Pyrazine
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00013-9
#
2011 Elsevier Ltd. All rights reserved.
371
372
M.M. Miller and A.J. DelMonte
N
N N
N
Phthalazine
N
N
N
N
N
N
N
N
Cinnoline
Quinazoline
N
N
Pteridine
Quinoxaline
Phenazine
6.2.2. PYRIDAZINES AND BENZO DERIVATIVES 6.2.2.1 Syntheses Construction of pyridazines ring systems bearing useful functionality for further modification was documented throughout 2010. Pyridazine difluoroboranes from N-heterocycle substituted tetrazines and alkynyl difluoroboranes were investigated h10OL160i. The resulting products could undergo further CC and CO bond forming reactions.
Me N
N R2
N N
N N
BF2 -N2
BF3Et4N
TMSCl CH2Cl2, rt, 10 min
R1
99%
N N
Me
N N R1
N N N
R2
N BF2
Ph DMPY
DMPY 10% PdCl2(PPh3)2 Ag2O, Na2CO3, PhI N N DME, H2O 80 ⬚C, 2 h, 60%
Ph Ph DMPY O B O
DMPY Pinacol, Na2CO3 N THF, reflux, 5 h, 68% N
Ph DMPY
A rapid synthesis for quinolino[2,3-c]cinnolines was described h10OL5502i. A similar approach was demonstrated in order to prepare neocryptolepines. O H NH2
NC + O2N
MeOK pyrrolidine MeOH
N
NO2 NH2
1. MeOK (5%), MeOH 2. Zn, warm AcOH or 1. Zn, AcOH, 10–15 min 2. KClO, MeOH, rt, 5 min
N
N
N
Cinnolines, including fused ring derivatives, have been synthesized in a chemoselective fashion using a modified Richter process in which a triazene acts as a masked diazonium ion h10TL6882i.
Six-Membered Ring Systems: Diazines and Benzo Derivatives
373
Br R2
aq. HBr, Acetone or MeSO3H, CH2Cl2. 1-(2-ethoxy-2-oxoethyl)pyridinium bromide
R2
R1
N
N
O 1
R
N
N
( )n
MeSO3H, CH2Cl2 N R1
R1 = H, OMe
N N n = 1, 2, 3 R2 = (CH2)nOH O
R2 = n-Pr, Ph, 4-MeOC6H4, (CH2)2-4OH, CH2O-(3-MeOC6H4)
R2
H2SO4 1:1 Acetone:H2O 50 ºC, 20 h
R1
N H
N
A series of cinnoline derivatives were furnished using a synthetically practical protocol which leverages a gold-catalyzed hydroarylation sequence h10JOMC37i. While the exact mechanism of this event is still not understood, the transformation is tolerant of a variety of different groups on the nitrogen atom and aryl substitution. Me
4 mol% (XPhosAu(NCCH3)SbF6) N N CO2Me MeNO2, 100 ⬚C, 4 h Ph 99%
cat p-TsOH N N CO2Me CHCl3, 60 ⬚C, 1.5 h 76% Ph
N N CO2Me Ph
6.2.2.2 Reactions Chlorophthalazine was effectively modified via metalation, using tmpZnCl–LiCl under microwave conditions, and treated with various electrophiles to produce novel phthalizine scaffolds (1) in a regioselective manner. Subsequent Negishi crosscoupling was shown to provide access to polyfunctionalized systems h10S1097i. O N
Ph
O PhZnCl·MgCl2·LiCl N cat. PEPPSI-iPr THF N 25 ⬚C, 30 min Cl 95%
O
tmpZnCl·LiCl, THF 45 min, 60 ⬚C, MW S I
N N N
N
Cl 86%
1
ZnCl·MgClBr·LiCl N N PEPPSI-iPr THF N 50 ⬚C, 5 min 92% S
O N N N
N
S
Several Lewis acid catalyzed inverse electron-demand Diels–Alder reactions with unsubstituted nonactivated phthalazine 2 were catalyzed by 5,10-dimethyl-5,10dihydroborane h10OL4062i. A bidentate complex was proposed and the mechanism explored.
374
M.M. Miller and A.J. DelMonte
5 mol% Me B
N N
+
B Me
( )n
N
n = 1, 2, 3
2
( )n
DIEA, Diglyme 55–80 ⬚C, 60 h 52–85 %
n = 1, 2, 3
A series of pyrrolo[2,1-a]phthalazines were produced in a one-pot three-component reaction from 2, 2-bromoacetophenones, and acetylenic dipolarophiles h10SL2407i. Reactions were performed in 1,2-epoxybutane as the solvent. Addition of MeOH allowed for direct isolation of crystalline product from the crude reaction stream and afforded the desired heterocycle in yields ranging from 61% to 80%. The mechanism below was proposed. O
O Br
N N
+
+
E
E
reflux, 12 h
2
N N
Et
E = CO2Et
MeOH, rt overnight
E
COPh E -2H
N N
N Br N COPh
E
E
N N
COPh
COPh
H E
E
A copper-catalyzed coupling reaction between organoindium reagents and nitrogen-containing heterocycles, including phthalazine (2), was reported h10EJO3650i. This mild transformation permits direct functionalization of heterocycles with a wide tolerance to functional groups. Et O N + + N EtO Cl
2
0.33 In(Et)3
O
10% CuCl THF/MeCN (1:1) 45 ⬚C, 16 h 65%
N N
OEt
Pyridazine-derived hydrazone 3 was utilized in catalytic asymmetric reactions, including allylations, crotylations, and cinnamylations h10OL688i. Exploration of the performance of 6-chloro-3-pyridazine hydrazone 3 in a one-pot cross-metathesis/cinnamylation protocol led to oxidized product 4. Release of 5 is easily achieved upon Pd(OH)2-catalyzed hydrogenation.
Six-Membered Ring Systems: Diazines and Benzo Derivatives
Cl
Ph
Ph Me (R,R)
3 mol% H Grubbs II
O +
Si N Cl Me
3
N HN
N N
N N Cl
CH2Cl2, 0 ⬚C; then 30% H2O2 62% (90% ee)
Ph CH2Cl2 reflux
375
Ph
N
4
1. 10 mol% Pd/C 1000 psi H2, EtOH
N
Ph
NH2
Ph
2. 10 mol% Pd(OH)2 1000 psi H2, HCl, EtOH 89%
Me Ph
5
The rich chemistry of 3-pyridazylnitrene and 3-pyridazylcarbene which involved ring expansion, ring opening, ring contraction, and fragmentation upon exposure to flash vacuum thermolysis or photolysis was investigated h10JOC1600i. Intermediates were identified spectroscopically and with the aid of theoretical calculations. H hu N N N
N2
N
N or FVT N 500–700 ⬚C 250 ⬚C
N N N N
H CH2 N
N3
N N
C + C CH2
N
FVT or hu
N
N
H
N
N
+
CN
+
NC
+
C
CN
6.2.2.3 Applications Pyridazine scaffolds have been incorporated into ligands of metal complexes. A series of phthalazinium halides were metalated with [Rh(ButO)(COD)]2 and [Ir(ButO) (COD)]2, and the carbene transition metal complexes (6) were characterized h10OM5941i. The synthesis and characterization of Cu and Ni complexes of phthalazine hydrazone 7 were reported h10RJGC493i. Phthalazine derivatives were also used as ligands in an investigation of central ring size and charge effects of dirhodium complexes h10OM6493i. Another paper reported the study of a fluorescent p-conjugated 3,30 -bipyridazine ligand (8) h10IC3991i. This compound was found to have pronounced solvatochromism and was capable of complexing metals (CuI, NiII, PtII, and IrIII). N N
N R
Me
[M] X HN
6
M = Rh, Ir X = Cl, Br, I
OH Me
N
Bu2N
N N N N
N N
7
NBu2
8
A large number of biologically active compounds have been described which contained pyridazine-based skeletons. Several papers described a series of phthalazine derivatives that exhibited anti-inflammatory activity. Several compounds including 9 had activity comparable to indomethacin h10EJM1267i, while 10 exhibited stronger anti-inflammatory activity compared to ibuprofen in the xylene induced ear edema
376
M.M. Miller and A.J. DelMonte
model in mice h10EJM4807i. The phthalazine-1-one derivative 11 was found to be a potent and selective S1P5 agonist h10CMDC1693i. This compound was selected for further biological studies with the goal of treating multiple sclerosis and other demyelinating diseases. Cinnoline templated PDE4 inhibitor 12 was synthesized to address solubility and metabolism issues and possessed improved pharmokinetics in monkeys h10BMCL137i, while cinnoline derivative 13 was synthesized and evaluated as a GABAA modulator h10BMC8374i. In another paper, imidazo[1,2-b] pyridazine analog 14 was highlighted for its ability to bind with amyloid plaques and demonstrated such a high binding affinity that the value of generating a PET radioligand was discussed h10AMCL80i. Lastly, a number of reports described chemical motifs that exhibited anticancer activity, including bis-cinnolines h10EJM5744i, triazolophthalazine 15 h10BMC2537i, indolizinophthalazine derivatives h10EJM3938i, and the pyridopyridazine-based Smo inhibitor 16 h10BMCL4607i. In addition to being a potent inhibitor of Smo, 16 was found to exhibit reduced PXR transactivation and good oral bioavailability in rats. Me
N N Cl N N
9
Me
H2N
Me O
N N
Me
O N
O O
10
Me
N N MeS
14
N
N
NH
N N
12
NH
13
O H2N
N N N
MeO2S
Me N
Me N Me N
HN
O Me
CONH2
Me NH
N
Me
CN
11
Me
N N
Me
O
N
N O N
F3C
N
N N
15
16
Me
6.2.3. PYRIMIDINES AND BENZO DERIVATIVES 6.2.3.1 Syntheses Versatile syntheses of substituted pyrimidines derivatives have appeared in the literature in 2010. A number of these involved one-pot multicomponent reactions. While strategies for the synthesis of dihydropyrimidinones and thiones which are not accessible through the traditional Biginelli reaction had been reviewed h10S3943i, the preparation of 20 in a one-pot synthesis from the condensation of aldehyde 17, cyclohexane-1,3-dione 18, and urea 19 utilized catalytic amounts of NiCl2 and potassium iodide h10JHC324i. A simple and practical one-pot ZnCl2 catalyzed, solvent-free reaction of acetylenes, orthoformate, and amines to afford pyrimidine skeleton 21 was described h10SL2311i. In another paper, condensation with acetoacetanilide 22, urea 24, and aromatic aldehyde 23 rapidly afforded pyrimidine carboxamide derivative 25 in a solvent-free system at 120 C h10CHE856i.
377
Six-Membered Ring Systems: Diazines and Benzo Derivatives
Additional studies provided various Biginelli-type products with utility h10JOC7954, 10JA16677i. OHC
10 mol% NiCl2 10 mol% KI
O +
+ (3 eq.)
Me O
O
H2N
NH2
(1 eq.)
(1 eq.)
18
19
17
O
Me
solvent-free 70–80 ⬚C, 6 h
O
HN
78%
O
20 O
CO2Et
2
NH2
OEt Cl
+
+
OEt
CO2Et
Cl
Br
N
ZnCl2
HC OEt
Me
NH
solvent-free, 2 h 71%
N
EtO2C Cl
OEt
21
Br Br
Me
O O O
O +
Me
H
N H
120–150 ⬚C
24
solvent-free 5–7 min 82%
NH2
H2 N
Cl
22
O +
23
NH
N H N H Cl
O
25
Copper has played a role in activating initiation sequences that led to substituted pyrimidines. An attractive ligand-free copper-catalyzed Ullmann N-arylation reaction afforded quinazoline 26 under mild conditions h10TL758i. A tandem Ullmann coupling/aerobic oxidation reaction was also employed to furnish 29 from 27 and 28 h10JOC7936i. Quinazoline derivative 30 prepared via copper-catalyzed alkynylation and cyclization was reported h10OL3963i. Desilyation was affected upon treatment of 30 with TBAF in THF–AcOH to provide 31 in 76% yield. Substituted quinazoline 33 was constructed via a Cu(OAc)2-catalyzed cascade reaction of benzylarylcarbodiimide 32 involving a CH activation/CN bonding event h10ASC2905i. A one-pot four-component reaction catalyzed by 1-methylimidazolium trifluoroacetate and Cu(OAc)2/sodium ascorbate afforded highly functionalized quinazoline derivative 34 h10JCO638i. The scope of this reaction was explored. NH2•HCl
I + CHO
10 mol% CuI Me
HN
O
MeO
NH2 Br
27
S
+ H N 2
28
N
Cs2CO3, MeOH 60 ⬚C, 18 h 94%
CuI, K2CO3 i-PrOH, air 110 ⬚C, 24–32 h 69%
Me N
26
MeO
N N
29
S
378
M.M. Miller and A.J. DelMonte
NH Ph
N H
+O2N
K2CO3 20 mol% CuBr Benzene 80 ⬚C, 1 h 62%
I O O
N
C
N
+
Ph
Me
N
30
Et Et
Toluene 100 ⬚C, 20 h 78%
32
CHO N3 O O Cl
Et N
N
31
Et
33
O N
87%
NH4OAc
Ph
N
Me
[Hmim]TFA, 30 ⬚C, 2 h Ph
N
N N N
Cu(OAc)2 Sodium ascorbate
+
N
TBAF PhTHF–AcOH (20:1) rt, 4.5 h 76%
N
Cu(OAc)2, O2
HN
Me
CH2TIPS
TIPS
34
Ph
N
NH2
Cl
Catalysis has been the topic of a variety of other transformations leading to pyrimidine motifs. A series of 4-allylquinazolines 35 were synthesized via an indium-mediated Barbier-type reaction and subsequent dehydrative cyclization and aromatization sequence h10TL2774i, while a series of quinazoline derivatives 37 were produced via base-catalyzed rearrangement of 2H-indazole-1-oxides 36 h10JOC4562i. 4-Aminoquinazoline 39 was synthesized in a one-pot three-component reaction mediated by catalytic Preyssler nanoparticles (H14[NaP5W30O110]) supported on silica h10SC861i. A mechanism was proposed and it was observed that 39 was not obtained without using the heteropolyacid. 2-Aminobenzonitrile 38 was also used in the generation of quinazoline-2,4-(1H,3H)-dione 40 via a solvent-free guanidine catalyzed CO2 fixation reaction h10T4063i. A mechanism has been proposed. Alternatively, quinazoline-2,4-dione 41 was synthesized via a selenium-catalyzed carbonylation reaction h10TL1500i. R3
R2 HN R1
O Br
In O CN
HN
2
R NH
R1
THF, reflux 60–76%
HN
R1
R3 O
O
R3
R2 N
36
N O- O
R1
N
35
R3
R3
O
R
N R
N
2
N N OH O
-H2O
R3
O 2
R DBU DMF, rt 1 R L
R2
R3
R3
2
OH R2 N
1
1
L
R
N
37
L
R TFA CH2Cl2
N R1
N
O
O 10–48%
H
379
Six-Membered Ring Systems: Diazines and Benzo Derivatives
NH2
O NH4OAc Me Cl H14[NaP5W30O110]/SiO2
Me
Me
N
N
NH
NH
N
NH
MeCN, reflux 95%
CN
Me
HN
N NH2
38
39
O
5 mol% NH
NH2
HN
HN ON
N(Me)2 (Me)2N CN + CO2 solvent-free 120 ⬚C, 4 h 89%
O C N OH
O O N-
O HN NH
N-
O
40
TMG H
NO2 50 mol% Se HN R1 Et3N + 3 CO THF O 170 ⬚C,11 h 89%
O C N HN R1
N HN R1 O -2 CO2
SeCO
O HN N R1 R1 = H
O
O
41
Microwave-assisted condensation and Dimroth rearrangement were utilized to access 4-anilino-6-nitroquinazoline 44 from aniline 43 with imine 42 h10T4495i. This synthetic approach was used for the synthesis of AzixaTM (45), the microtubule destabilizing agent currently undergoing phase II clinical studies.
CN
O2N
42
Me
43 PhNH2
O
N
R
R
HN N
Ph R
NH
HN Ph
AcOH, MW N 118 ⬚C, 3 min
N
N
Ph
N H
H2O
HN O2N
N N
O
44
88%
N Me
OMe Me CN NH2
N
OMe
Me
Me
OMe OMe MW 115 ⬚C, 2 min 90%
Me CN Me
Me
NMP, 200 ⬚C, 2 h N N Me 71% Me
OMe Me
N
N H AlCl3
N
NH Me N
N Me Me
Ph
N N
Me
45, Azixa
Newly prepared oxazolo[4,5-e]pyrimidine 46 was synthesized from 2-(acylamino-cyanomethylene)imidazolidines upon treatment with trifluoroacetic acid and then with triethyl orthoformate, thereby conveniently annelating the oxazole ring to the newly fused heterocyclic system h10CHE1116i. An X-ray structural investigation was performed to unambiguously confirm the product.
380
M.M. Miller and A.J. DelMonte
H N
Ph
CCl3
O
1. SOCl2 2. NaCN
OH
O
HN
Ph
Cl
NH2
CN
O
52%
NH
Ph
68%
CN
N H
1. CF3CO2H 2. NaHCO3
CF3CO2N
3
NH2
O
HN
H N
Ph
Et3N
NH HC(OEt)
N O
H2N
N NH
N
Cl
H N
Ph
N Ph
84%
H N CF3CO2H
N
N
N O
N
68%
Ph
N 46
O
2-Aryl quinazoline 50 was afforded upon condensation of 1,3-diamine 47 and aryl aldehyde 48 resulting in tetrahydroquinazoline 49 followed by a MnO2 oxidation h10JHC1240i. A similar oxidative approach was also reported using NaOCl as the oxidant in a one-pot protocol h10ASC341i. O NH2
47
NH
NH2
CH3Cl, 10 h 84%
48
N
MnO2
+
Ph CH3Cl, reflux, 12 h 70%
N
49 H
N
Ph
50
O NH2
NH
+ MeOH 5 h, rt
NH2
N H
Ph
N
NaOCl MeOH, 5 h, rt 98%
N
Ph
One brief report highlighted the uses of p-phenylenediamine (51), including the synthesis of 6-aminoquinazoline 52 h10SL987i, while another communicated a novel method for the synthesis of 6-methoxyquinazoline 53 and suggested a mechanism for this process h10CHE125i. NH2
THF
H2N
NHCO2Et
ClCO2Et
N 1. HMTA, TFA 2. KOH, aq. EtOH H N 2 K3Fe(CN)6
EtO2CHN
51 N
N
52
N N
HN
1. NaN3, PPA 60 ⬚C, 3 h MeO
2. 1,3,5-triazine 100 ⬚C, 4 h 54%
Ar
H N
N
N
O
P HO O
N H O N N Ar N P HO O
NH2
N
NH
N
MeO
53 MeO
A variety of quinazoline and quinazolinone derivatives were synthesized from benzoxazinone 54 upon treatment with nitrogen nucleophiles h10SC1516i.
381
Six-Membered Ring Systems: Diazines and Benzo Derivatives
X = O, S
X
N X
NH NHCOPhH2NNH
N
N
H N
Ph
NHCOPh
N
Fusion, oil-bath 160 ⬚C, 2 h OMe O
NHCOPh
N
54
Ar
O
Ph
N2H4–H2O
N
N
NH2
O
Ar
O
N
NH2
NaOAc/fusion
N
NH2
O
N
OMe
n-BuOH, D
OMe
N
NH2
Me D
NHCOPh
N
Ar
Ar
6.2.3.2 Reactions Several reports explored the functionalization of pyrimidines via cross-coupling in order to establish new carbon–carbon, carbon–nitrogen, or carbon–oxygen linkages. The nickel-catalyzed cross-coupling of organozinc reagents with N-heterocycles, including pyridines, quinazolines, triazines, benzothiazoles, and benzoxazoles, was reported h10JOC2131i. Specifically, it was demonstrated that treatment of thiomethyl-substituted pyrimidine 55 with Ni(acac)2/DPE-Phos at room temperature in the presence of organozinc reagent 56 affords the desired product 57 in good yields. Functional group compatibility was explored as well as the utility of several zinc reagents. The palladium-catalyzed Suzuki-Miyaura reaction was investigated on pyrrolo[2,3-d]pyrimidine 59, thereby allowing entry into densely substituted 4aryl-pyrrolo[2,3-d]pyrimides 58 and 60 h10CHE1122i. Another paper described the selective palladium-catalyzed cross-coupling reactions of 2,4,7-trichloroquinazoline 61 h10SL644i. Generation of a thioether selectively afforded one approach to controlling regioselectivity. Palladium was also used to catalyze amidations of a variety of heteroaromatic tosylates and afforded products with high structural diversity h10CEJ5437i. Pyrimidyl tosylate 62 was successfully amidated with b-lactam 63, and 64 was isolated in excellent yield on 20 mmol scale. ZnCl-LiCl
Me N N
+
THF, 25 ⬚C, 7 h
SMe
55
Ni(acac2) (2.5 mol%); DPE-Phos (5.0 mol%)
CN
Me
N
94%
56
But
CN
N
57 CHO B(OH)2
But NH2 N MeS
CO2Me N
58
N Me
B(OH)2
Pd(OAc)2, ligand K3PO4 Dioxane reflux, 5 h MeS 80%
Cl N N
59
N Pd(OAc)2, ligand K3PO4 N CO2Me CO2Me Dioxane N N N MeS reflux, 5 h Me Me 88% 60 NH2
382
M.M. Miller and A.J. DelMonte
R2 cross-coupling at C4 Cl Route A
Cl
N
N Cl
Me
Route B
61
H
63 N
Me
OTs Dioxane 100 ⬚C, 16 h 69%
N
N
R3
N
R1
cross-coupling at C4
R1
N
NH Ph
O [Pd(dba)2] (3 mol%) DPPF (3 mol%) K2CO3
62
N
Cl
R1
N
O
O
N
Cl
N
Cl
S
R2
at C7
N
Me
S cross-coupling Me at C2 N
deactivation at C4 Cl
Me
R2 cross-coupling
Cl
Me Cl
N
cross-coupling at C2
N
Me
Me O
N
Me
N
O N
64
N
Ph
Me
N
O O [Pd(dba)2] (0.1 mol%) Me DPPF (0.1 mol%) N K2CO3 OTs
O
Dioxane 100 ⬚C, 1 h 99%
Me
N
O N
O
Cycloadditions were carried out on pyrimidine derivatives to afford enhanced diversity and functionality. A BF3OEt2 catalyzed aza-Diels–Alder reaction was utilized to produce pyrido[3,2-d]pyrimidines h10SL2575i. Azapolycylic compound 67 was synthesized from the reaction of isoquinoline-1,3,4-trione 65 with pyrimidyl acetylene 66 via photoinduced tandem reactions h10JOC2989i. Regioselectivity of the [2 þ 2] cycloaddition and subsequent electrocyclization is debated. Quinazoline 68 was synthesized under basic conditions, and the subsequent appended alkyne was employed in a [3 þ 2] cycloaddition click reaction h10EJM78i. These novel compounds were evaluated for antimicrobial activity. Cl O
O
NH2
CHO +
Me N O
81%
Cl
N
O
O
N
O O
hn
+
MeCN, 24 h
Me
N
O
66
67
N
N
O
N Me
N
N
N
O
65
Me
Toluene, reflux, 4 h
N Me
N
O
10 mol% BF3·OEt2
O 69%
Me
+
N
O O N O 18%
Me
383
Six-Membered Ring Systems: Diazines and Benzo Derivatives
O
F3C(F2C)2 NH
N
O K2CO3, NaI
CF3
Acetone, reflux
+
N
Br
52%
O
CF3(CF2)5CH2CH2N3 CuI
N
THF CF3
N N
N
85%
N N CF3
68
In contrast to the means by which 68 was constructed, carbon–nitrogen bond construction was achieved via oxidative alkylamination on heteroaromatic compounds, including quinazoline 69 h10JOC5126i. Mechanistic understanding of the use of AgPy2MnO4 was sought and a comparison was made to other oxidant/additive combinations. A separate report employed CAN in aqueous AcOH to furnish quinazolin-4(3H)-one 70 followed by chlorination and subsequent condensation with a requisite aniline to achieve the desired substitution. This approach was used to make PD153035, Erlotinib, Gefitinib, and Vandetanib h10T962i. HN N +
H2N
Me
N
R2O
N
93%
O R1O N CAN AcOH 2 N rt, 5 min R O 86–90%
R1O
Me N
AgPy2MnO4
69 HN
Cl
R1O NH SOCl2 DMF 2 N reflux, 3 h R O 85–98% 70
R1O aniline N i-PrOH, MW 2 N 80 ⬚C, 15 min R O 88–92%
R3 N
N
Several papers described incorporation of pyrimidines into fused systems h10JHC477, 10RCB1403, 10T8214, 10JOC7233, 10T9912i. A method for the preparation of the highly functionalized 2-substituted [1,2,4]triazolo[1,5-c]pyrmidine 72 was described in which it is postulated that the Dimroth-type rearrangement of 71 involved temporary ring opening of the pyrimidine moiety followed by ring closure to 72 h10SL2179i. An Ugi-Smiles/Sonogashira cascade reaction was utilized to access pyrimidoalkynes 73. Subsequent base-catalyzed intramolecular cyclization afforded novel pyrrolo[2,3-d]pyrimidine scaffolds 74 h10JOC5343i. The chemistry was tolerant of a variety of functional groups, and the E/Z selectivity was controlled by the base selection. Spiro-fused pyrimidines have also been described h10TL6598, 10RCB1645i. Cl
Cl NH2NH2-H2O
N N
Cl
45 ⬚C, 2 h 88%
PhCHO N EtOH N rt, 30 min 73%
Ph
H N H
N
Br
1. Br2, AcOH Cl rt, 30–60 min 2. 0.5 N NaOH 30–60 min 83%
Br Cl
N N
N
71
N
N N Ph
N N
72
Ph
384
M.M. Miller and A.J. DelMonte
R5 R1NC R2NH2 R3CHO
Me I
N
+ HO
1. MeOH, 60 ⬚C
N
R4
2. R5CCH PdCl2(PPh3)2 CuI, DIPEA MeCN, 70 ⬚C
10 mol% DBU MeOH, reflux Me or
R2 N
O R1HN R3
N
73
N R4
O
R2 N
N
R1HN R3
10 mol% t-BuOK THF, reflux
R4
N
R5
Me
74
A pyrimidine-2-sulfonyl group is utilized as a new nitrogen protecting group to facilitate aziridine opening h10CEJ12474i. The utility of this functional group is demonstrated by a synthesis of selegiline, thereby highlighting the ease of incorporation and removal, as well as illustrating its synthetic effectiveness. N
Pymisyl chloride Me DMAP, pyr HO
NH2
N
CH2Cl2 -35 to 0 ⬚C 44%
Me
Me O NH S O O S O O N
Me
PhMgCl N K2CO3 CuBr·SMe2 O S O THF MeCN, CH2Cl2 N -78 ⬚C N N rt 91% 91%
NH O S O N
N
Me
Br K2CO3 DMF, rt
HSCH2CO2H LiOH·H2O, DMF N O S O N
N
Me N H
NaBH3CN, CH2O MeCN, 0 ⬚C to rt 86% 3 steps
Me N Me (R)-Seleginline
6.2.3.3 Applications Functionalized pyrimidines have been considered to be privileged structures and have been incorporated into a wide variety of pharmaceutical agents. In 2010, the reported biological activity which these pyrimidine-based scaffolds possessed spanned the gamut. Many pyrmidine derivatives were synthesized and evaluated as potential cancer treatments or preventatives. The pyridinyl-pyrimidine phthalazine 75 is a potent and selective Aurora kinase inhibitor h10JMC6368i. Several reports of cyclin-dependent protein kinase (CDK) inhibitors were disclosed h10BMC7639, 10CHB1111, 10JMC2171, 10TL6126i, including 76 h10JMC8508i. Additional potential anticancer agents include the B-Raf inhibitor 78 h10JMC7874i and PLK1 inhibitors h10BMCL4095, 10BMCL6489, 10JMC3532i. There were additional reports of inhibitors of H1F-1a h10BMCL6426i, VEGFR2 kinase h10BMC7260i, histone deacetylases (i.e., 79) h10BMCL6657i, and EGFR kinase h10JMC2104, 10JMC1862, 10JMC8546i, as well as microtubule-targeting agents h10JMC8116i. The pyrimidine analog 77 h10MCC355i and the furo[2,3-d] pyrimidine derivative 80 were active against cancer lines h10BMCL6188i. Other potential anticancer agents include protein lysine methyltransferase G9a inhibitors h10JMC5844i, anti-folate thymidylate synthase inhibitors h10EJM1560i, apoptosis inducers h10BMCL2330i, PI3K inhibitors h10BMCL6895i, and DNA-intercalating
385
Six-Membered Ring Systems: Diazines and Benzo Derivatives
agents h10JMC8089i. There were also several reports of pyrimidine derivatives which were evaluated as anticancer agents as well as for other unrelated activities such as antimicrobial or anti-inflammation agents h10EJM21, 10JMC8556, 10BMC2849i.
Me
H N
O
MeO
N
Me H N
N
N
N HO
MeO
N N
F
N
N N
MeO
O
N
F
N
77
NH
75
N
O
F N N
HN
N OH
N
N
NHBn
N N HO
N
H
Me
H
N
N
N NH
78 N
i-Pr
N NH
EtO2C F
76
79
OH
N Me
O
80
Many pyrimidine derivatives were synthesized and evaluated for antimicrobial activity. This list includes a variety of motifs such as a 6-substituted indolo[1,2-c]quinazoline h10EJM1200i, a pyrazole-pyrimidine-thiazolidin-4-one derivative 81 h10CPB1622i, a sulfur-linked di-pyrimidine 82 h10JHC1183i, a tetracyclic pyrimidinone 83 h10JHC1162i, a semi-carbazone quinazoline h10MCR283i, and a pyrrolo pyrimidine 84 h10EJM5243i. Pyrimidine scaffolds were evaluated for anti-plasmodial properties h10EJM616i, as well as antitubercular activity (85) h10JMC8421, 10EJM5056i, antiviral h10BMCL4004, 10EJM5251i, and antiparasitic activity h10BMC7302, 10JMC221i. N
S S
O Me
N N
N O
N
S
Me N N
Me
81
Cl
82
N
N
N
N
N N
O2N
NH2 N HN
O N N
N Ph
CN 83
N N
N N N H
O
O
N
N
S
N
O
84 F
F3CO
85
A series of pyrimidine derivatives were evaluated for anti-inflammatory or analgesic properties h10EJM2117, 10CHE96, 10EJM4947i. Quinazoline derivatives were synthesized and evaluated as potential immunosuppressants h10BMC6404i. A series of quinazoline sulfonamide derivatives were evaluated for their ability to interact with histamine H4 receptor h10JMC2390i. Pyrimidine derivatives were evaluated for potential treatment of diabetes including compound 86 which was found to be a selective DPP4 inhibitor h10BMCL6273i. A SGLT2 inhibitor
386
M.M. Miller and A.J. DelMonte
h10BMCL7046i, a GRP119 inhibitor h10BBR745i, and a GLP-1 agonist were also reported h10DIA3099i. Agents within the field of neuroscience were also described. The pyrimidine 4-carboxamide 87 was evaluated for activity against serotonin 5-HT2 receptors h10BMCL6439i, and the pyrazolo-pyrimidine 88 was evaluated as a CRF1 antagonist for potential treatment of depression, irritable bowel syndrome, anxiety, and irritability h10BMCL7259i. Lastly, pyrimidines were incorporated into compounds advanced for the treatment of osteoporosis h10BMCL6237i and pulmonary fibrosis h10JMC7715i. Me
OMe N
N
Me
N O
Me N
NH2 Cl
Me N
86
Cl
N
O
N
N
N H
Me
N H
N N
MeO
87
SMe
Me
Me N
Me
N
88
Me
Pyrimidines also played a role in a number of non-pharmaceutical applications. Pyrimidines were used as ligands with a variety of metals including ruthenium h10TMC801i, palladium h10OM4555i, zinc h10CPB875i, and copper h10JA9579i. One report utilizes a pyrimidine derivative as a fluorescence sensor for Cu2þ ions h10OL856i.
6.2.4. PYRAZINES AND BENZO DERIVATIVES 6.2.4.1 Syntheses Numerous syntheses of pyrazine and quinazoline derivatives were reported throughout the year. One strategy was the reaction between 1,2-diamines and 1,2-diketones or masked 1,2-diketones. This reaction has been catalyzed by a Bronsted acid ionic liquid h10SC1216i, NbCl5 h10JHC703i, Amberlyst-15 h10SC2047i, and a TiO2P25-SP42 catalyst h10JOMC2572i. A similar approach was employed to furnish bisindolylindenol[1,2-b]quinoxalines derivatives under montmorillonite K-10 catalyzed solvent-free microwave conditions h10T5196i. 13 mol% Me N + N
HSO−4 SO3H
H2O, rt, 10 min, 95% O
NH2
3 mol% NbCl5
N
+ NH2
O
EtOH, rt, 2 min, 95% Amberlyst-15 H2O, 99% cat. TiO2-P25-SO2− 4 EtOH, rt, 5 min, 98%
N
Six-Membered Ring Systems: Diazines and Benzo Derivatives
387
Catalysis continued to play a role in the construction of N-heteroaromatics. While several methods employed oxidation events of either substrate or intermediate, others did not. A novel aerobic oxidation of alcohol substrates in the presence of diamines was catalyzed by recyclable ruthenium on carbon and methylated cyclodextrin in water to afford quinoxalines with the same general structure as compound 89 in one pot h10SL2571i. Oxidation of alkynes by the recyclable catalytic system PdCl2/CuCl2 in PEG/H2O was also effective to provide 90 h10TL3623i. A DABCO-catalyzed cyclization/oxidation process between phenacyl bromides and 1,2-diamines was reported h10TL2580i. Implication to the applications of functionalized quinoxalines was described. An AlCl3-catalyzed reaction between bromomalonitrile 91 and o-phenylenediamine 92 was investigated h10SC739i. Yb(OTf)3 catalyzed formation of 3-methoxy-quinoxalin-2-one 94 from o-phenylenediamine 92 and methyl trimethoxyacetate 93 was reported h10TL337i. NH2
Ru/C Ra-Me-β-CD
HO +
NH2
O
N
H2O, O2, 16 h
N
96%
89
HO NH2
+ NH2
1. cat. PdCl2/CuCl2 PEG/H2O (8:2)
N
2. 1,2-diaminobenzene rt, 16 h
N
90
80%
OH
N Br
H2N
cat. DABCO
H2N
THF, rt 30 min
+ O
Br
N
N
N [O]
N H
O
N
90%
1. AlCl3, MeCN, rt, 2 h 2. NH2 MeCN NC 92 –20 ⬚C, 2 h NC CN + AlCl Br NH2 3 NC Br 3. O2, rt, 2 h
91
63%
NH2 +
92
NH2
MeO MeO
H N
CN
N
CN
N H
NH2
N
NH2
OMe O OMe
93
cat. Yb(OTf)3 Toluene, 100 ⬚C 52%
N
OMe
N H
O
94
388
M.M. Miller and A.J. DelMonte
Quinoxaline-2-carboxylate 96 from a-halo-b-ketoester 95 and 1,2-diamine 92 in ionic liquid was reported h10TL4313i. This catalyst-free one-pot synthesis provides an eco-friendly alternative, while providing other advantages such as increased yields, short reaction times, and mildness of reaction conditions. Me N
Cl Me
OEt O
N
H2N
BF4
+
95
N
EtO
rt, 60 min 90%
H2N
O
O Me
N
Me
92
96
Functionalized indolo[1,2-a]quinoxaline 97 was synthesized via a facile one-pot copper/sparteine catalyzed N-arylation and subsequent imine formation h10JOC992i. The scope of the regioselective construction and diversity of substitution were explored by varying the functionalization of both components. Annulation of 2-formylpyrazole, 2-formylindole, 2-formylimidazole, and 2-formylbenzimidazole was exemplified. In another paper, functionalized pyrrolo[1,2-a]pyrazines were reported to be prepared by a domino process from vinyl azide 99 and 1H-2-pyrrolecarbaldehyde 98 h10OL3863i. Mechanistically, it was suggested that an initial Michael addition yielded active intermediate 100 which subsequently partook in an intramolecular condensation to provide 101. F F
Me
I +
CHO
N H
10 mol% CuI 20 mol% sparteine
N
K3PO4, NMP 130 ⬚C, 24 h 83%
H 2N
N
Me
97
OH
O OHC NH
98
+
CO2Et CsCO3 N3 DMF, rt 62%
99
N N
100
CO2Et
N N H
CO2Et
EtO2C
N N
101
Six-Membered Ring Systems: Diazines and Benzo Derivatives
389
The chemistry to afford 2-phosphonylated quinoxaline 1,4-dioxide 102 was reported via a modified Beirut reaction h10TL5516i. While basic conditions failed to furnish the desired product, it was discovered that powdered molecular sieves were required in order to effectively provide phosphonylated quinoxaline dioxides in good yields. Access to these scaffolds should add to the medicinal chemists understanding of various biological processes. O O N + O Me N
O
OMe P OMe
MS 3A THF, 30 ⬚C, 3 days 70%
O Me N O N O
OMe P OMe O
O N N O
O N
Me O P OMe OMe O
102
N O
Me O OMe P OMe
6.2.4.2 Reactions In 2010, there were several reports describing the functionalization of pyrazine derivatives via carbon–nitrogen and/or carbon–carbon bond forming reactions. While one paper depicted the utility of palladium-catalyzed intermolecular amidation of pyrazine tosylates h10CEJ5437i, another report employed two catalysts (Pd- and Cu-) in a tandem amination procedure to provide pyrido[3’,2’-4,5]imidazo[1,2-a] quinoxaline 103 in excellent yield h10T6958i. Moreover, it was shown that solvent affected the outcome and product distribution between 104 and 105. Heck crosscoupling reactions afforded 2,3-disubstituted pyrazine 106 and quinoxaline 107 h10T1637i. Interestingly, under more stressing conditions, reduction of one or both of the vinyl groups was observed, and in some cases, mono-cross-coupling and des-chlorination were preferred. There have been a number of reports of using the nitrogens of pyrazine derivatives as directing groups. The palladium-catalyzed direct ortho-nitration of quinoxaline derivative 108 was reported h10CEJ13590i. The approach demonstrated functional group tolerability as well as mononitration selectivity and regioselectivity. The orthometalation of a series of aryl compounds (including quinoxaline 109) via Mg- and Zn-amide bases was reported h10OPRD339, 10JOMC775, 10AG(I)5451i. One example used the N,N,N’N’-tetramethyldiaminophosphorodiamidate directing group h10OL1984i.
390
M.M. Miller and A.J. DelMonte
H2N
Br
4 mol% Pd2dba3 8 mol% Xantphos
N
+ N
+ N
Cl
N
N
N
Cl
N
Toluene DME
103 N
H N
N
N
+
Cs2CO3, solvent reflux, 17 h
N
N
N N
4 mol% Pd(OAc)2 4.4 mol% Xantphos
N
H2 N
I
Cs2CO3, DME reflux, 17 h
N
Br
10% CuI 20% ligand reflux, 8 h
104
105
86% 0%
13% 82%
N
ButO2C EtO2C
CO2Et Cl N
Cl
2.5 mol% Pd(OAc)2 5 mol% Xphos, Et3N
N
DMF, 90 ⬚C 83%
CO2Et
Cl
CO2But
Cl
N N
N
N
2.5 mol% Pd(OAc)2 10 mol% Xphos, Et3N
107
N N
K2S2O8(2 eq.) DCE, 130 ⬚C, 48 h
108
N
75%
Pd(OAc)2 (10 mol%) AgNO3 (2 eq.)
N
N
DMF, 130 ⬚C, 24 h
106
N
CO2But
NO2
86%
Me Me
I
OMe
N Zn·2MgCl2·2LiCl N
OMe
2
Me
Me
0.5 mol% Pd(dba)2 1.0 mol% (o-Fur3)P
N
25 ⬚C, 2 h 82%
N
25 ⬚C, 2 h
N
109
N-Substituted pyrrolo[2,3-b]quinoxaline-2-carbaldehye 112 was formed from chloroquinoxaline-2-amine 110 and propargyl bromide 111 upon treatment with PdCl2(PPh3)2 and copper(I) iodide in wet morpholine h10S1599i. A mechanism involving a Sonogashira reaction, nucleophillic attack on a ketene, and air oxidation on work-up was proposed. Br N
111
Cl
N
O
PdCl2(PPh3)2, CuI N
110
N H
morpholine-H2O, 70 ⬚C 82%
N
Sonogoshira O N
N N
O NH R
N N
O C NH R
N heteroannulation
N
H
112
N N
N N R
-2H air oxidation N N
O N R
Six-Membered Ring Systems: Diazines and Benzo Derivatives
391
The asymmetric hydrogenation of pyrazine derivatives was reported. One set of reaction conditions involved catalysis by an iridium/diphosphine complex in the presence of piperidineTfOH h10TL3014i. An alternative methodology utilizing a Bronstead acid to facilitate a transfer hydrogenation with the Hantzch dihydropyridine was described, and the substrate scope explored h10CEJ2688i. N Me
N
EtO2C Me
CO2Et
anthracenyl H N
N H
Me
O O P O OH
N H
5 mol% Bronstead acid CHCl3, 50 ⬚C 98%
N
Me
N H 87% ee
TfOH·NC5H11, THF 700 psi H2 99%
2.4 eq. N
H N
2 mol% [Ir(COD)Cl]2 4.4 mol% (R)-SegPhos
anthracenyl 90% ee
There were several examples in which pyrazine derivatives were elaborated to build fused ring systems. The sodium azide mediated tandem cyclization of dialkynylpyrazine 113 into [1,2,3]triazolo[1’,5’:1,2]pyrido[3,4-b]pyrazine 114 was reported h10T146i. A series of fluorinated pyridopyrazine derivatives, exemplified by 115, were synthesized under basic conditions h10JFC1086i. The relative stability of Meisenheimer intermediates is proposed to explain the regioselectivity of the nucleophilic aromatic process. Quinoxaline-fused triazoline 116 was synthesized via an intramolecular 1,3-dipolar cycloaddition, and the products from photochemistry in the presence of dienes were subsequently investigated h10T176i.
N N
Cl Cl
Ph Pd(PPh3)2Cl2 CuI/Et3N
Ph N
DMF, rt, 4 h 69%
DMF, rt, 24 h 77% Ph
N
113
F
N
F
NaHCO3
+ F
N
F
N
F
NH2 MeCN, reflux F 79%
N N
N
NaN3
N
114
N
6 HNEt2
N
MeCN, reflux, 72 h 69%
115
CO2Et Me
EtO2C Me 1. NBS, dibenzoyl peroxide Me N
2. [(Me)2CNO2]–Na+ MeOH, rt, 6 h (86%) 3. CH2(CO2Et)2, piperidine AcOH, PhH, reflux (72%)
N
Ph
Et2N
N
N
F
N
N
CO2Et CO2Et
N
N
N N
N N N
1. NBS, dibenzoyl peroxide o-DCB, 40 ⬚C, 12 h (60%)
o-DCB, 60 ºC, 2.5 h (84%) N
Ph N
N
2. NaN3, EtOH, 12 h (91%)
116
hn multiple dieonophile products
392
M.M. Miller and A.J. DelMonte
Fused tetrazoles, including quinoxalinotetrazole 117, were used as azide surrogates in Cu-catalyzed click reaction to form 1,2,3-triazoles derivatives (118) h10OL2166i. A variety of tetrazoles and alkynes were explored to measure the reaction scope. N
N
N N
N +
N
Ph
10 mol% (CuOTf)2·C6H5 Toluene, 100 ⬚C 73%
117
N
N
118
Ph
N N
A practical platform for the direct CH arylation of boronic acid 119 and electron-deficient heterocycle 120 upon treatment with catalytic AgNO3 and K2S2O8 as a co-oxidant was reported h10JA13194i. While the pyrazine derivatives reported were the lowest yielding examples depicted in this study, the demonstrated functional group compatibility, substrate scope, scalability, and ease of execution are undoubtedly attractive features of this reaction protocol. A mechanism for this new transformation is discussed. Me
TFA (1.0 eq.) AgNO3 (0.2 eq.) K2S2O8 (3.0 eq.)
Me N
B(OH)2
119
Ar
N
N CH Cl :H O (1:1) 2 2 2 rt, 3–12 h
+
Me
Me
N
N
Ar H
N
H
H
Me
Me
Me Ar
N N
N N
H
50%
120
Lastly, one of the more intriguing reports in 2010 was the disclosure of a tungsten complex which is able to cleave a CC aromatic bond of quinoxaline 121 to form o-diisocyanobenzene compound 122 h10NAT523i. 121
PMe3 Me3P H Me3P
Me3P
PMe2
W
N N
CH2
H
-PMe3
PMe3 N W
H
N
Me3P
Me3P PMe3
PMe3
Me3P PMe3 H H Me3P
Me3P
N
W N PMe3
-H2
H H Me3P
Me3P
PMe3
N
PMe3
N PMe3
Me3P
PMe3 W
W N PMe3
N
W
Me3P
C N C
PMe3
N
122
6.2.4.3 Applications Pyrazines have found utility as part of metal complexes. The tetranuclear rutheniumbased pyrazine-linked metallarectangle 123 was synthesized and characterized h10HCA1313i. The ruthenium supramolecular photocatalyst 124 was studied to
393
Six-Membered Ring Systems: Diazines and Benzo Derivatives
gain knowledge about the catalytic efficiency during photoinduced water splitting h10AG(I)3981i. A dinuclear dysprosium complex [DY2(hfac)6(H2O)4pz]-2pz containing a pyrazine bridging ligand was constructed and characterized as a single-molecule magnet h10CC8264i. Coordination cages, whose cage height was determined by N-heterocyclic ligands, were synthesized and evaluated h10JA15553i. 4+ Me
Me Me Me
Me Me Me
Me
Me Ru O
N
N
Me Me
Ru
O
O
N
Me
O
N
2+
N
N
N
Ru
O
O
O
Ru
Me
N
Me
O
N
Ru
N
N
Cl
Me
Me
Me Me
Me
Me Me
Me
Me
N
N
Me
Cl Pd
N
123
124
Substituted pyrazines have been found as subunits of multiple synthetically constructed therapeutic agents, as well as several natural products. Pyrazine-based skeletons were incorporated into agents targeting a range of ailments. Many derivatives were synthesized and evaluated as potential cancer treatments. Compounds were found to be potent inhibitors of P38a MAP kinase (124) h10JMC1128i, the Wnt2/b-catenin pathway in non-small-cell lung cancer cell lines h10BMCL5900i, the folate cycle h10BMC7773i, Pim kinase h10EJM5520i, Aurora kinase (126) h10BMCL6739, 10BMCL5170, 10BMCL5988i, CHK1 h10BMCL4045i, and Nek2 (127) h10JMC7682i. The diaminopteridine-benzenesulfonamide 128 was evaluated as an inhibitor of carbonic anhydrases and dihydrofolate reductase h10BMC5081i, while the phenazine 130 was evaluated as an inhibitor of quinone reductases 1 and 2, and inducible nitric oxide synthase h10JMC8688i. A number of quinoxaline N-oxide derivatives, including 129, were found to be potent anticancer agents h10BMC3125, 10EJM2733, 10BMC4433i. Me O
F
127
Me N
126 N
HN
MeO
N
128
NH2 N
N
N
HN N
H2N
Me O
N
125
CO2H
Me
NH
N
N
N H
O N
O
N O
CF3
S
N
OMe
Me Me
N
Me
N
S Me
N
Cl
MeO
N
N
NH2
N
S
129
NH2 O
130
OMe N N
394
M.M. Miller and A.J. DelMonte
Many pyrazine derivatives were synthesized and evaluated for antimicrobial or antiviral activity h10BMCL406, 10EJM1237i. The pyrido[1,2,3-de]quinoxaline-6carboxamide 131 was evaluated for the ability to inhibit human cytomegalovirus polymerase h10BMCL1994i. Quinoxaline 1,4-di-N-oxide derivatives were synthesized and evaluated for antitubercular activity h10EJM4418, 10BMC2713, 10EJM4682i. The phenazine-1-carboxylic acid derivative 132 showed potent antifungal activity against rice sheath blight h10BMCL7369i. A pyrazine derivative 133 was evaluated as a HCV NS5B polymerase inhibitor h10AMCL466i. O
O N H
N OH Me
N
N Me
Cl
O
O
N
HN
NH
N
N
N O
N
N
131
132
133
Me Me
In addition to treatment for CNS diseases h10BMCL3844, 10BMCL5044, 10BMCL6773, 10EJM4479i and cardiovascular events h10JMC3296i, anti-inflammatory and analgesic properties were among the biological activity examined. The thiazolo[4,5-b]quinoxaline derivative 134 was synthesized and evaluated for antiinflammatory and analgesic activities h10EJM1976i. The pyrazine N-acyl hydrazone derivative 135 was active in a murine model of chronic inflammation h10BMC5007i. The pyrido[2,3-b]pyrazine 136 was evaluated as a TRPV1 antagonist h10BMCL4359i. CF3
134
135 O
N
N
N
N S
N
136 OMe
O
N N
OMe
CF3 N H
N
OMe H2NOC
HN
N
N N
N
N
Pyrazines and quinoxaline derivatives were also reported to be useful in a host of other miscellaneous applications. The dithieno[3,2-f:20 ,30 -h]quinoxaline 137 was used as a donor moiety in a copolymerization for potential development as photovoltaic cells h10AG(I)7992i. The power conversion efficiencies and photoresponses of a small band gap polymers 138 were reported h10OL4470, 10MM6270i, and a quinoxaline derivative was evaluated as a fluorescent anion sensor h10TL5402i. A number of pyrazine-based derivatives were used as dyes or fluorescent probes h10T8273, 10EJM5465i. The indolo[2,3-b]quinoxaline dye 139 was synthesized and investigated by optical, electrochemical, theoretical, and thermal studies h10JOC8100i.
Six-Membered Ring Systems: Diazines and Benzo Derivatives
C8H17O
OC8H17
137
138
R1
R1
N
N
N
139
N
N S
S N
S
395
S
N
N
n N
N
S
R1 = octyl
C8H17O
OC8H17 Me
REFERENCES B-10MI253 10AG(I)3981 10AG(I)5451 10AG(I)7992 10AMCL80 10AMCL466 10ASC341 10ASC2905 10BBR745 10BMC2537 10BMC2713 10BMC2849 10BMC3125 10BMC4433 10BMC5007
10BMC5081 10BMC6404 10BMC7260 10BMC7302
J.A. Joule, K. Mills, Heterocyclic Chemistry. 5th ed., p. 252. Blackwell Publishing Ltd, Chichester, UK, 2010. S. Tschierlei, Mi. Karnahl, M. Presselt, B. Dietzek, J. Guthmuller, L. Gonza´lez, M. Schmitt, S. Rau, J. Popp, Angew. Chem. Int. Ed. 2010, 49, 3981. M. Jaric, B.A. Haag, A. Unsinn, K. Karaghiosoff, P. Knochel, Angew. Chem. Int. Ed. 2010, 49, 5451. H. Zhou, L. Yang, S.C. Price, K.J. Knight, W. You, Angew. Chem. Int. Ed. 2010, 49, 7992. F. Zeng, D. Alagille, G.D. Tamagnan, B.J. Ciliax, A.I. Levey, M.M. Goodman, ACS Med. Chem. Lett. 2010, 1, 80. C.C. Cheng, X. Huang, G.W. Shipps, Jr., Y.-S. Wang, D.F. Wyss, K.A. Soucy, C.-K. Jiang, S. Agrawal, E. Ferrari, Z. He, H.-C. Huang, ACS Med. Chem. Lett. 2010, 1, 466. C.U. Maheswari, G.S. Kumar, M. Venkateshwar, R.A. Kumar, M.L. Kantam, K.R. Reddya, Adv. Synth. Catal. 2010, 352, 341. H.-F. He, Z.-J. Wang, W. Baoa, Adv. Synth. Catal. 2010, 352, 2905. S. Yoshida, H. Tanaka, H. Oshima, T. Yamazaki, Y. Yonetoku, T. Ohishi, T. Matsui, M. Shibasaki, Biochem. Biophys. Res. Commun. 2010, 400, 745. P. De, M. Baltas, D. Lamoral-Theys, C. Bruye`re, R. Kiss, F. Bedos-Belval, N. Saffon, Bioorg. Med. Chem. 2010, 18, 2537. S. Ancizu, E. Moreno, B. Solano, R. Villar, A. Burguete, E. Torres, S. Pe´rezSilanes, I. Aldana, A. Monge, Bioorg. Med. Chem. 2010, 18, 2713. F.A.M. Al-Omary, L.A. Abou-zeid, M.N. Nagi, E.-S.E. Habib, A.A.-M. AbdelAziz, A.S. El-Azab, S.G. Abdel-Hamide, M.A. Al-Omar, A.M. Al-Obaid, H.I. El-Subbagh, Bioorg. Med. Chem. 2010, 18, 2849. V. Junnotula, A. Rajapakse, L. Arbillaga, A.L. de Cera´in, B. Solano, R. Villar, A. Monge, K.S. Gates, Bioorg. Med. Chem. 2010, 18, 3125. M.L. Lavaggi, M. Cabrera, M. de los A´ngeles Aravena, C. Olea-Azar, A.L. de Cera´in, A. Monge, G. Pacho´n, M. Cascante, A.M. Bruno, L.I. Pietrasanta, M. Gonza´lez, H. Cerecetto, Bioorg. Med. Chem. 2010, 18, 4433. Y.K. Cupertino da Silva, C.V. Augusto, M.L. de Castro Barbosa, G.M. de Albuquerque Melo, A.C. de Queiroz, T. de Lima Matos Freire Dias, W. Bispo, Jr., E.J. Barreiro, L.M. Lima, M.S. Alexandre-Moreira, Bioorg. Med. Chem. 2010, 18, 5007. S.M. Marques, E.A. Enyedy, C.T. Supuran, N.I. Krupenko, S.A. Krupenko, M.A. Santos, Bioorg. Med. Chem. 2010, 18, 5081. I. Sagiv-Barfi, E. Weiss, A. Levitzki, Bioorg. Med. Chem. 2010, 18, 6404. Y. Oguro, N. Miyamoto, K. Okada, T. Takagi, H. Iwata, Y. Awazu, H. Miki, A. Hori, K. Kamiyama, S. Imamura, Bioorg. Med. Chem. 2010, 18, 7260. H. Cui, L.M. Ruiz-Pe´rez, D. Gonza´lez-Pacanowska, I.H. Gilbert, Bioorg. Med. Chem. 2010, 18, 7302.
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M.M. Miller and A.J. DelMonte
10BMC7639 10BMC7773 10BMC8374 10BMCL137 10BMCL406 10BMCL1994 10BMCL2330 10BMCL3844 10BMCL4004
10BMCL4045
10BMCL4095 10BMCL4359 10BMCL4607
10BMCL5044 10BMCL5170 10BMCL5900 10BMCL5988 10BMCL6188 10BMCL6237
10BMCL6273
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Six-Membered Ring Systems: Diazines and Benzo Derivatives
10OL1984 10OL2166 10OL3863 10OL3963 10OL4062 10OL4470 10OL4824 10OL5502 10OM4555 10OM5941 10OM6493 10OPRD339 10RCB1403 10RCB1645 10RJGC493 10S1097 10S1599 10S3943 10SC739 10SC861 10SC1216 10SC1516 10SC2047 10SL644 10SL987 10SL2179 10SL2311 10SL2407 10SL2571 10SL2575 10T146 10T176 10T962 10T1637 10T4063 10T4495 10T5196 10T6958 10T8214 10T8273
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CHAPTER
6.3
Triazines, Tetrazines, and Fused Ring Polyaza Systems Anton M. Prokhorov*, Dmitry N. Kozhevnikov** *Department of Organic Chemistry, Ural Federal University, Mira 19, 620002 Ekaterinburg, Russia
[email protected] **I. Postovsky Institute of Organic Synthesis, S. Kovalevskoy Str. 20, 620041 Ekaterinburg, Russia
[email protected]
6.3.1. INTRODUCTION Potential biological activity remains the most intriguing feature of polyaza heterocyclic systems. Significant activity against influenza A and B virus, of a novel antiviral agent of a triazolotriazine series, “triazavirine,” increased interest in this heterocyclic system. From this point of view, new methods for the synthesis and structural modification of condensed polycyclic azaheterocycles have a particular importance. At the same time, there has been a steady growth in the number of publications concerning applications of triazines and tetrazines as ligands for transition metals and building blocks for supramolecular systems. Materials with unique properties, for example, luminescence, are expected for such compounds. Extremely high reactivity of p-deficient triazines and tetrazines in reactions with nucleophiles and dienophiles is still one of the most attractive chemical properties of these systems. There is a noteworthy rise in the number of works utilizing the inverse electron demand Diels–Alder reaction of tetrazines as a linking mechanism in biomolecule labeling.
6.3.2. TRIAZINES 6.3.2.1 1,2,3-Triazines Research on the chemistry of 1,2,3-triazines is quite limited and usually gives rise only to a limited number of scientific reports. Generally, the research concerns development of some existing synthetic methodologies and characterization of new compounds, often related to the search for biologically active substances. In 2010, there were only a few communications in the literature. Except heterocyclic fused systems based on 1,2,3-triazines, which are reported in the corresponding part of this chapter, mention should be made of the preparation of 4-(4-methoxyanilino)-Nmethylbenzo[d][1,2,3]triazine 1, as an aza-analog of the corresponding quinazoline and a potent apoptosis inducer. Also, its activity toward human non-small cell lung cancer cell line H1299 and T47D in comparison with its quinazoline analogs was examined h10BML2330i.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00014-0
#
2011 Elsevier Ltd. All rights reserved.
403
404
A.M. Prokhorov and D.N. Kozhevnikov
OMe OH
Cl POCl3
N N
N N
N N
N
N
N
N
1
Apart from this, the synthesis of a new annelated heterocyclic system 6H-pyrrolo [20 ,30 ,40 :4,5]naphtho[1,8-de][1,2,3]triazines 2 via cyclization from 1H-naphtho[1,8de][1,2,3]triazine 3 was briefly reported h10CHE370i. HN
N
N
N
N
N
NH
NaN3
N
N
RCO3H
P2O5 HN
O
HN R
O
3
2
A series of 1,2,3-triazin-4-ones were screened for antidepressant activity by using tail suspension test (TST), the reserpine-induced hypothermia, and forced swim test (FST). The results indicate that the compounds possess antidepressant activity h10IFS143i.
6.3.2.2 1,2,4-Triazines Recent advances in the chemistry of 1,2,4-triazines have been reviewed h10AHC75i. 1,2,4-Triazines attract significant attention because of their reactivity, especially in cycloaddition reactions with formation of other heterocyclic systems, as multi-coordinating ligands, and as potential bioactive compounds and drug precursors. There have been no publications on new preparations of 1,2,4-triazines this year. All reported 1,2,4-triazine syntheses are based on well-known procedures. The major method is the cyclization of a-dicarbonyl compounds with hydrazine derivatives h10BML6024, 10BML742, 10JNM1892i. Some more novel methods for 1,2,4triazine functionalization are available this time. Cross-coupling reactions are not very common for 1,2,4-triazines, and therefore, they have received attention. An efficient palladium-catalyzed amination of the 5-aryl-3-methylthio-1,2,4-triazines 4 was reported as a Buchwald–Hartwig-type reaction with formation of 3-amino1,2,4-triazines 5 via methylsulfur displacement h10T4383i.
Triazines, Tetrazines, and Fused Ring Polyaza Systems
N
N
N
Ar
+ R1
S
H N
CuMeSal (2.0 eq.) Cs2CO3 (2.2 eq.) Pd(AcO)2, 10 mol%
N
toluene, 170 °C microwave irradiation
R2
Ar
N
N
R2
N R2
5
4
405
Another example of cross-coupling of a 1,2,4-triazine is the preparation of 6,60 bis(heteroaryl)-5,50 -bi-1,2,4-triazine 6 from 6,60 -bis-bromo-5,50 -bi-1,2,4-triazine 7 by Stille reaction h10JST186i.
Br
N(Me)2 N
N
X HetArSnBu3
N
N N
N
Pd(PPh3)4, dioxane
N
N N
Br
(Me)2N
N X
(Me)2N
7
N(Me)2 N
N
6
HetAr = 2 -Py, 2-Fur, 2-Thienyl
X = N, O, S
The 1,2,4-triazines 6 were prepared as potential extractants of nuclear waste, and their preferences to metal ion complexation were assessed using semiempirical AM1 and density functional theory (DFT) ab initio methods. The inverse electron demand Diels–Alder reaction (D–A) keeps the top position in 1,2,4-triazine functionalization and transformation into other heteroaromatics, mainly pyridines. As an electron-deficient diene, 1,2,4-triazine reacts easily with appropriate electron-rich dienophiles. In this way, an intramolecular D–A reaction starting from the 3-alkoxyalkynyl-1,2,4-triazines 8 or 9 leads to the series of new 2-(hydroxymethyl)-2,3-dihydrofuro[2,3-b]pyridines 10 and 3-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines 11 h10S1349i. R2 N R
R2
N
N
R2 TFA
chlorobenzene OTr
O
MW, 170 oC, 2 h
R
N
OTr
O
R
O
N
8
OH
9
n-C5H11 n-C5H11 N Ph
N
N
o
MW, 180 C, 2 h
O 10
OH
chlorobenzene
OH
Ph
N
O 11
Another example is the preparation of thiacrown ether macrocycles 12 containing a fused cyclopenteno[c]2,20 -bipyridine subunit. It was accomplished through first homocoupling of the 1,2,4-triazine bisulfides 13 tethered to poly(ethyleneglycol) chains in intramolecular hydrogen substitution reaction with potassium cyanide
406
A.M. Prokhorov and D.N. Kozhevnikov
and second D–A/retro-D–A reaction of the macrocycles 14 with 1-pyrrolidino-1cyclopentene h10EJO4868i.
N N
N
N
N N
N S
N O
S
KCN H2O
N
N
N N
S
N
N S
O
13
S
N S
O
14
12
Quite new is the synthesis of cyclopenta[b]pyrroles 15 from 3,5-disubstituted1,2,4-triazines 16 in D–A reaction with cyclobutanone in the presence of pyrrolidine. In contrast, 3,6-disubstituted 1,2,4-triazines 16 undergo a simple nucleophilic addition with cyclobutanone to give adducts 17 h10OL164i. R4 R1 N
R1 O H2NR4
N O
R1 N
R2 = H
R3
H
H
N
15
N
R3 R2 16
N R3
R1 N H
R3 = H
O
N H
NH N R2
17
In the field of biologically active compounds, the 5,6-diaryl-3-alkylthio-1,2,4triazines were evaluated as neuroprotective agents against oxidative stress exerted by hydrogen peroxide on a differentiated rat pheochromocytoma (PC12) cell line, and a consistent protection from H2O2-induced cell death, associated with a marked reduction in caspase-3 activation, was observed h10BMC4224i. 3,30 -Bis (methylthio)-5,50 -bi-1,2,4-triazines are potent antimalarial agents toxic to Plasmodium falciparum h10BML6024i. The 4-(4-(5,6-diphenyl-1,2,4-triazin-3-yl)-1H1,2,3-triazol-1-yl)piperidines, prepared by cyclization of diphenylglyoxal with 1,2,3-triazole-4-carbohydrazide, were evaluated for their in vitro antifungal activity, and structure–activity relationship (SAR) data for the series were developed h10BML742i. An initial evaluation and reproducibility in vivo of [O-methyl-11C] 2-(4-(4-(2-methoxyphenyl) piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5 (2H,4H)dione, a novel 5-HT1A agonist radiotracer, in Papio anubis, were published. The 1,2,4-derivative was shown to be suitable for the imaging of high-affinity 5HT1A binding in humans h10JNM1892i. The role of some 1,2,4-triazine derivatives
Triazines, Tetrazines, and Fused Ring Polyaza Systems
407
against cytotoxicity exerted by lipopolysaccharide (LPS) in differentiated rat pheochromocytoma (PC12) cell line was examined. The results indicated that LPSinduced cell death can be inhibited in the presence of such compounds h10NI958i. Polyaza-aromatic 1,2,4-triazines are widely explored as ligands for coordination of transition metals. Thus, the ruthenium(II) polypyridyl complexes 18 with a 1,2,4-triazine as highly p-deficient ligand were synthesized and characterized. The complexes display luminescence in ethanol/methanol (4/1) at 80 K, and all three complexes exhibit a temperature switch from single (150 K) to dual (80 K) emission behavior. There are two metal-to-ligand charge transfer (MLCT) excited states localized on different ligands with the short-wavelength component being essentially bipyridine-based, while the long-wavelength component is localized predominantly on the more conjugated 3,30 -bi-1,2,4-triazine derivatives ligand h10ICC1018i. R2
R2 N
N
N
N
R1
R1 N
N
2+ Ru
N
N N
N
18
Some new complexes with formula [M(SCN)2(L)2] where M ¼ Mn(II), Cu(II) were synthesized in simple reactions of metal chlorides with ammonium thiocyanate and 5,6-diphenyl-3-(2-pyridyl)-1,2,4-triazine (pytz) ligand and characterized by IR, UV–vis, EPR spectroscopy, and X-ray diffraction h10STC77i. Metal binding by 1,2,4-triazine finds a practical application in metal detections. In particular, 1,2,4-triazine-based chromogenic reagents are used for the detection of nonferrous metal traces left on contact with canvas and human skin in the criminal trace-metal-detection-test (TMDT) h10JFR747i. In addition to these traditional fields of the 1,2,4-triazine research, a rather unusual application of 1,2,4-triazine derivatives was reported: the preparation of liquid-crystalline materials with the 1,2,4-triazine cycle as a central core h10MCL127i.
6.3.2.3 1,3,5-Triazines 1,3,5-Triazines bearing additional chelating groups were used as ligands for transition metals. New specific tridentate iron(III) chelators of the 2,6-bis(hydroxyamino)-1,3,5triazine family for use in iron deprivation cancer therapy have been reported h10BML458i. Treatment of cyanuric chloride with N-methylhydroxylamine hydrochloride resulted in symmetrical tris-(hydroxyamino)triazine, which gave a mononuclear vanadium(V) complex h10DT9032i. 2,4,6-Tris(2-pyridyl)-1,3,5-triazine (tptz) remains widely used for coordination of various transition metals. Silver(I) complexes
408
A.M. Prokhorov and D.N. Kozhevnikov
of tptz were described as catalysts for oxidation of alcohols h10POL2837, 10JOM2201i. A trispyridyltriazine has been reported as a terdentate ligand to form luminescent samarium(III) and terbium(III) complexes of general composition [Ln(hfaa)3(tptz)] h10CC1253i. Excellent long-wavelength sensitized luminescent properties of a new europium(III) complex of 2-(N,N-diethylanilin-4-yl)-4,6-bis(pyrazol-1-yl)1,3,5-triazine have been reported h10PCP3195i. A new ruthenium(II) complex of 6-(pyrazin-2-yl)-1,3,5-triazine-2,4-diamine showed aggregation-induced emission (AIE) h10ICC1140i. A new trinuclear ruthenium(II) complex of 2,4,6-tri(1,10-phenanthroline-[5,6-d]imidazol-2-yl)-1,3,5-triazine has been synthesized, and its interaction with human telomeric DNA was explored h10CC1050i. The synthesis of a 1,3,5-triazine bearing three cobaltabis(dicarbollide) clusters has been reported h10OM5230i. Bionanoprobes with high dispersion stability in water were prepared by encapsulation of the europium(III) complex of 2-(N,N-diethylanilin-4-yl)-4,6-bis-(3,5dimethylpyrazol-1-yl)-1,3,5-triazine in water-dispersible polymeric nanospheres and modifying the nanosphere surfaces with a monoclonal antibody h10CEJ8647i. The C3 symmetry of the 1,3,5-triazine ring, simple methods for the synthesis, and easy introduction of different substituents via nucleophilic substitution make this heterocycle ideal for constructing various star-shaped triangular systems. Substitution of three chlorine atoms in cyanuric chloride 19 with 2,2’-dipicolylamine gives the 2,4,6-tris(di-2-pyridylamino)-1,3,5-triazine which forms trinuclear complexes 20 with rhodium(III) or iridium(III) h10JOM1932i. 3+
X
Cl M N CI
CI
N N
N N
CI
N
N M
X = Me5C5 or C6H6
N
N
CI 19
N
N
N
N
N N
X
M
X
M = Rh or Ir
CI
20
New donor-substituted 1,3,5-triazines have been prepared by nucleophilic substitution of cyanuric chloride 19 with carbazole, 3-methylcarbazole, phenol, and 3,5-dimethylphenol. These symmetrically substituted triazines were suggested as host materials for blue phosphorescent organic light-emitting diodes (OLEDs) h10CM2403i. Three phenothiazine moieties were incorporated on a 1,3,5-triazine in a reaction of cyanuric chloride 19 giving 21 which can be used as a host material of phosphorescent dyes h10MCL24i.
409
Triazines, Tetrazines, and Fused Ring Polyaza Systems
S Cl N
N N
Cl
N Cl
N
N
N N
N
S
S
19
21
A series of star-shaped donor–acceptor (D–A) molecules 22 based on electrondeficient 1,3,5-triazine have been described. The triazine core containing three bromofluorene moieties 24 was formed by the cyclization of cyanobromofluorene 23. The fluorene arms were capped by the electron-donating fragment of a diarylamine, for example, carbazole, via palladium-catalyzed amination of 24 to give 22. Donor–acceptor compounds 22 undergo electrochemical polymerization to form a conductive polymer film on the surface of the working electrode. Combination of the strong electron-withdrawing (triazine) and electron-donating (carbazole) parts means that compound 22 exhibits large solvatochromic effects with emissions ranging from deep blue to orange-red depending on the solvent polarity h10JA10944i.
N
Br
Br
CN
t
Pd(OAc)2, P Bu3
CF3SO3H
K2CO3, xylene N
N
N
23
N N
N
N
Br N
Br
24
22
A symmetric 2,4,6-tris[2-(10-butyl-10H-phenothiazin-2-yl)vinyl]-1,3,5-triazine bearing phenothiazine as the electron donor and triazine as the electron acceptor has been described as an orange-red emitter with high fluorescence quantum yield h10NJC1994i. Similar multibranched triarylamine derivatives based on the 1,3,5-triazine core have been reported to exhibit aggregation-induced emission and a large two-photon absorption cross section h10CC4689i. Computational studies were performed for pp-interactions of several electrondeficient p systems including 1,3,5-triazines and tetrazines to show that p-deficient heterocycles prefer face-to-face interactions in contrast to T-shape edge-to-face interactions of benzene or other electron-rich aromatics h10MI1931i.
410
A.M. Prokhorov and D.N. Kozhevnikov
DFT calculations on 2,4,6-triamino-1,3,5-triazines showed their strong affinity towards graphite, and the driving force for adsorption is a specific attractive interaction of the amino groups with the underlying surface h10CC2923i. Reactions of the acyl chloride derived from 1,3,5-triazine-2,4,6-tricarboxylic acid with various alcohols, thiols, and amines gave a series of novel 1,3,5-triazines with electron-withdrawing groups such as esters, thioesters, and amides. These compounds were suggested as azadienes for inverse electron demand Diels–Alder reactions h10SC361i. Exchange of functionalized iodo-1,3,5-triazine derivative 25 with Grignard reagents followed by transmetallation with ZnCl2 gave zincated 1,3,5-triazine 26. The cross-coupling of the latter with diodo-1,3,5-triazine 27 gave 1,3,5-triazine trimer 28 h10OL5398i. l COOEt
COOEt
l
N N
COOEt
COOEt
N Ph 27
1. RMgBr N
N
Ph
2. ZnCl2 l
N
N
N
N
Ph
N
Ph
N
N N
N N
ZnCl
N N
Ph
N Ph
25
26
28
Nucleophilic substitution of halogen remains the most used reaction for functionalization of 1,3,5-triazines. A large series of 2,4,6-trisubstituted-1,3,5-triazines were synthesized starting from cyanuric chloride 19 by consecutive substitution of all three chlorine atoms with tetrahydroquinoline (THQ), tetrahydroisoquinoline (THIQ), piperidine, or aniline. Fifteen compounds from this series exhibited good to moderate activity for the growth inhibition of Mycobacterium tuberculosis h10EJM3335i. Cl
Cl
N N Cl 19
N
R1H
R1
N N
Cl N
Cl
R2H
R1
N N
Cl N
R2
R 3H
R1
R3
N N
N R
2
R1H, R2H, R3H = THQ, THIQ, piperidine, aniline
A 5-amino-3-methylimidazolidine-2,4-dione moiety was incorporated in the 1,3,5-triazine ring via substitution of one chlorine atom in cyanuric chloride followed by substitution of the remaining two chlorine atoms with methoxyphenols or methoxyanilines yielding 29, analogs of the imidazole alkaloids naamidine A and G with a 1,3,5-triazine core h10S4312i.
411
Triazines, Tetrazines, and Fused Ring Polyaza Systems
OMe Cl N Cl
Cl N Cl
N
X
O
N
NH
N
O
MeO
N
O
Cl
N
NH O
N H
N H
N
X
19
N
X = O, NH
N H
N H
29
Substitution of two chlorines in cyanuric chloride with salicylic aldehyde and 4hydroxybenzoate gave corresponding 2-chloro-4,6-diaryloxy-1,3,5-triazines. Their crystal structures revealed strong N. . .Cl halogen bonding h10JST274i. A series of 2-fluorophenyl-4,6-disubstituted 1,3,5-triazines 30 were synthesized starting from cyanuric chloride via substitution of two chlorines with different amines followed by Suzuki coupling. New triazines 30 showed activity against gram-positive bacteria. The SAR demonstrated that the 3- or 4-fluorophenyl component attached directly to the triazine ring was essential for activity h10BML945i. HO
Cl N
HN
F
HN
1. R1NH2
N N
OH
R1
N
N
N
2. R2NH2 Cl
B
Cl
HN R
19
N
Cl
2
Pd(PPh3)4
HN
R1
N N F
R2 K2CO3
30
Cyclization of propargylamino-1,3,5-triazines 31 via intramolecular copper(I)catalyzed hydroamination gave dihydroimidazo[1,2-a][1,3,5]triazin-4(6H)-ones 32 with exclusive formation of E-isomers h10JOC8662i. NMe2 O
I
O Cu(I)
N R1 N
N N
N SO2Me
R2
31
R1 N
N+ I
N
N
O
H
I-
N
N SO2Me
R2
32
An efficient procedure for preparation of novel 2-(arylmethyl)amino-4-arylamino-6-alkyl-1,3,5-triazines 33, starting from dicyandiamide 34 and the corresponding arylamines 35, under microwave irradiation has been reported h10TL3174i.
412
A.M. Prokhorov and D.N. Kozhevnikov
NH2 HN
R2
NH2
2. R2COOEt/MW
NH
N
1. MW
NH2
N
R1
N HN
N
R1
34
35 33
A mercury(II) chloride promoted one-pot synthesis of trisubstituted 1,3,5-triazines by reaction of isothiocyanates, N,N-diethylamidines, and carbamidines has been reported h10TL1486i.
6.3.3. TETRAZINES 1,2,4,5-Tetrazines are still more reactive than 1,2,4-triazines, and their most exploited reactions are also inverse electron demand Diels–Alder reactions leading to other heterocyclic systems, followed by nucleophilic addition at the second position. Tetrazine chemistry has traditional applications in the preparation of high-energy materials, semiconducting polymers, and metal binding. Recently, a trend emerged in bioorthogonal chemistry, consisting in tagging biomolecules with tetrazine derivatives h10CC1589i. As for synthesis of new tetrazines, the preparation of the tetrazine fluoro derivatives 34 and 35 by cyclization of 1,1,1-trifluoro-2,4-pentadione with hydrazinotetrazine 36, followed by nucleophilic displacement of the pyrazole moiety, was reported h10CHE691i. F H2N
O
NH
N
N
N
N
HN
N
O
F3C
N
N
N
N N
NH2
F 3C
36
F
CF3
N
HN H2N
N
N
N
N
N N
F 3C
34
N 35
The tetrazine catalytic amination of the 3,6-di(methylthio)-1,2,4,5-tetrazine 37 is similar to that described above for 1,2,4-triazines and allows exclusive mono-substitution of the methylthio-group with formation of 3-amino-6-methylthio-1,2,4,5-tetrazines 38. The can in turn be converted into benzenesulfonamides 39 h10T4383i.
N
S N
N
37
N
+ R1–NH2 S
CuMeSal (2.0 eq.) Cs2CO3 (2.2 eq.) Pd(AcO)2, 10 mol% toluene, 170 °C microwave iradiation
S
N N
N
38
NaH PhSO2Cl
N N H
R2
DMF
S
N N
39
N
N R2 N SO2Ph
Triazines, Tetrazines, and Fused Ring Polyaza Systems
413
The reaction of 3,6-diaryl-1,2,4,5-tetrazines 40 and 2-aryl-substituted acetonitriles, under basic conditions, leads unexpectedly to 3,5-diaryl-1,2,4-triazoles 41 as a result of addition of the nucleophile, ring opening, and ring closure (ANRORC) mechanism h10TL1654i. Ar1 N
Ar2
N
N
N
CN Ar1
DBU, THF
N Ar1
N Ar2
N H 41
40
Two independent articles describing a total synthesis of lycogarubin C 42 starting from 1,2,4,5-tetrazine-3,6-dicarboxylate 43 appeared nearly at the same time. First, Fu and Gribble reported the efficient synthesis of lycogarubin C in seven steps in 30% overall yield via a D–A reaction between 43 and alkene 44 followed by a Kornfeld–Boger ring contraction to form the pyrrole ring h10TL537i. CO2Me N
N
N
N
H N
MeO2C
CO2Me
1. Toluene reflux
+ N
CO2Me
SO2Ph
43
2. Zn, AcOH
N H
N
N H
R
44
45, R = SO2Ph
Mg, NH4Cl MeOH
42, R = H
Then Oakdale and Bog described two complementary concise total syntheses of lycogarubin C 42 and lycogalic acid 46, which both include the D–A reaction between 43 and an alkyne h10OL1132i. MeO2C
N
N
CO2Me N N
CO2Me N N
N N CO2Me
MeO2C
toluene, 110 °C 65%
l
N CO2Me
CO2Me
MeO2C
CO2Me
Zn, AcOH N CO2Me
N CO2Me
43
Bu3Sn
H N
N CO2Me
LiOH
SnBu3 dioxane, 45 °C, 97% MeO2C Bu3Sn
N MeO2C
(PPh3)2PdCl2 CuCl2, LiCl
R
H N
R
N N CO2Me SnBu3
N H KOH
N H 42,R = CO2Me 46,R = CO2H
414
A.M. Prokhorov and D.N. Kozhevnikov
Due to their extremely high reactivity, the tetrazines recently emerged as prominent click-reagents in bioorthogonal chemistry. In 2010, quite a number of high-level publications were devoted to the application of tetrazine derivatives for biomolecule labeling. The bioorthogonal chemical reporter strategy consists of the following principle. A chemical reporter (e.g., an active alkene) linked to a substrate is introduced into a target biomolecule through cellular metabolism. In a second step, the reporter is covalently tagged with an exogenously delivered probe (e.g., a tetrazine bearing a luminophor unit). Both the chemical reporter and exogenous probe must be chosen so as to avoid side reactions with nontarget biomolecules h05NCB13i. For this strategy, the D–A reaction is an efficient tool for coupling of multifunctional molecules like active peptides, reformulated drugs, or small molecules, where the tetrazine derivative can be either a chemical reporter or a reactive partner h10IMS19i. Thus, a novel tumor pretargeting approach based on the Diels–Alder reaction between tetrazine-DOTA derivative 47 radiolabeled with 111In and trans-cyclooctene (TCO) 48 conjugated to the TAG72 antigen through the lysine residue was applied for noninvasive tumor imaging in live mice h10AGE3375i. O HO
N N
N
N N
H N
N N
O
H N
O
N O
O
O
10
OH N
N H
N 111ln
47
O
H N
OH O
O O
O
O
11
O
N
O O
48
A similar approach was applied for the conjugation of TCO-modified antibody with magneto-fluorescent nanoparticles connected to tetrazine h10NNT660i, and for imaging small molecules inside living cells, where fluorogenic tetrazine probes 49 react specifically and rapidly with strained dienophiles yielding highly fluorescent derivatives 50. In this case, the “click” reaction turns on fluorescence following cycloaddition h10AGE2869i.
N
B
HO
N
F F 49
O
N H
Weakly fluorescent
N N N N
OH N
B
N
F F 50
O
N H
Highly fluorescent
N N H
415
Triazines, Tetrazines, and Fused Ring Polyaza Systems
In addition to TCO derivatives, norbornene is also widely used in the cycloaddition reactions of tetrazines for bioorthogonal chemistry. For example, the reaction between norbornene acetamide derivative 51 and epidermal growth factor (EGF) modified with 3-(4-benzylamino)-1,2,4,5-tetrazine 52 was applied for live-cell imaging epidermal growth factor receptors (EGFR) with quantum dots (QD) on the surface of human skin cancer cells h10JA7838i. H N EGFR
H N EGF
QD
H N
+ O 51
N
N
N
N
H N
QD
N NH O
52
In the same way, norbornene-modified oligonucleotides 53 and tetrazine derivatives (e.g., derivative of biotin 54) were used for fluorescence labeling and affinity tagging in post-synthetic modification of DNA h10JA8846i. O
H N
S
H N
NH
O
HN
O
O
N N O
O
O
N
N
N
N
N
N
O 53
54
A radiolabeling method for bioconjugation based on the D–A reaction between 3,6-diaryl-1,2,4,5-tetrazines and an 18F-labeled TCO was also described. Attempts to prepare 18F-labeled tetrazines 55, by nucleophilic substitution in 56, were very low yielding. Fluorination of 57 gave 58 but only in 1% radiochemical yield h10CC8043i. 18
NO2
F
18
N
N
N
N
F-fluoride/ kryptofix
N
N
N
N
N
N
N
N
18
F-TBAF, MeCN
N
N
N
N
18
OMs R
56
R
55
57
F
58
416
A.M. Prokhorov and D.N. Kozhevnikov
In addition to the D–A reaction, the easy nucleophilic aromatic substitution in a tetrazine ring is also useful for labeling biomolecules. The 3,6-dichloro-1,2,4,5-tetrazine 59 can be readily incorporated within peptide oxytocin by disubstitution of chlorines with peptide thiols. The AcNH-1,6-S,S-Tet-oxytocin 60 was isolated. AcHN Cl
Cys
Tyr R
R
S N
N
Laserinduced
N
N
fragmentation
O N
N
N
N
oxytocin
Gly H2N
N
N
N
N
Leu
Cl 59
lle
R
S
Pro
Cys
Asn
N
N
N
N R
Gln
60
Such incorporation within a peptide allows the 1,2,4,5-tetrazine to act as a photochemical trigger due to easy photofragmentation of the tetrazine core with formation of inert products upon UV irradiation. Fast phototriggering can provide information on the dynamics of peptide and protein folding h10AGE3612i. Another developing application of tetrazine materials is in polymer solar cell technology. Modified polythiophenes containing electron-deficient units showed a reduced band gap and a low-lying HOMO (Highest Occupied Molecular Orbital), which can better cover the solar spectrum and offer the devices a higher voltage. It was reported for the first time that s-tetrazine is an effective electron-deficient unit for low-band gap semiconducting polymers. A new s-tetrazine polymer 61 was designed and synthesized, and then tested in a solar cell device h10JA13160i. A similar polymer, poly[2,6-(4,40-bis(2-ethylhexyl)dithieno[3,2-b:20,30-d]silole)-alt-5,50(3,6-bis[4-(2-ethylhexyl)thienyl-2-yl]-s-tetrazine)], PDTSTTz 62 was reported to show a low-band gap, strong absorption, and good thermal stability h10CC8668i. C6H13
*
C6H13
S
N
N
N
N
S
N
N
N
n C6H13
C6H13
S
* S
*
S
S
n Si
62
*
S
61
N
S
Triazines, Tetrazines, and Fused Ring Polyaza Systems
417
New tetrazine fluorophores 63 involve a borondipyrromethene (BODIPY) connected through a phenyl spacer and were synthesized via nucleophilic substitution of 64. It was shown that both chromophore units behave almost independently from the spectroscopic and electrochemical points of view h10EJO2525i. N N Cl
Cl N N
N
F
64
F
N
F B
B
2,4,6-collidine DCM
OH
N
F
N
N
N
N
O
N
Cl
63
The polyaza structure of 1,2,4,5-tetrazines stimulates their exploration as multicoordinating or bridging ligands. Complex formation in systems containing copper (II), cobalt(II) and nickel(II) ions and 3-(3,5-dimethylpyrazol-1-yl)-6-R-1,2,4,5-tetrazines (R ¼ 2-hydroxyethylamino, piperidino) was studied by voltammetry and spectrophotometry. Cu(II), Co(II), and Ni(II) were found to form complexes with derivatives of 1,2,4,5-tetrazine with the ratio of the components M:L ¼ 1:1 h10RJC1860i. The dinuclear copper(II) and cobalt(II) complexes 65 and 66 of 3-(pyrazol-1-yl)-1,2,4,5-tetrazines were prepared, and their magnetic properties were described. It was shown that the nature of the nonmonotonic changes in the effective magnetic moment is due to the effect of spin–orbital coupling h10RCB717i. NR2
Cl
N N
Cu
N
N
N
N
N
N
N
Cu Cl
65 NR2
N
N N
N N
Cl Co
N
N
N
N
Cl Co
Cl
Cl
66 NR2
A Zn(II) coordination of the 3,6-bis(2-pyridyl)-1,2-dihydro-1,2,4,5-tetrazine results in opening of the tetrazine ring and rearrangement to a 4-amino-1,2,4-triazole complex. The rearrangement is also accompanied by formation of a hydrazine derivative h10JCR3565i. Diruthenium(III,II) complexes with a 3,6-bis(2-pyridyl)1,2,4,5-tetrazine bridge and variable co-ligands were synthesized and characterized by spectroscopic and electrochemical techniques h10ICA163i. A two-dimensional Cu(I) complex of 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine whose structure contains single [CuSCN] ribbons as a characteristic motif was characterized using X-ray crystallography h10AXE217i. A 3,6-di-(4-pyridyl)-1,2,4,5-tetrazine was described as a bridging ligand for a self-assembled supramolecular structure comprising oligomeric porphyrins.
418
A.M. Prokhorov and D.N. Kozhevnikov
A reversible photoinduced charge transfer was found to be from the porphyrins to the electron-deficient tetrazine core with the remaining hole being delocalized on the oligomer and subsequent charge recombination in 0.19 ns h10CC547i. hv R N N
Zn N
R
N
R N
N N
Zn N
R
N
N N
R N
Zn
N N
R N
in 0.19 ns N N
N N
N N
N R N N R
Zn N
N
N N
ET
N R N N R
Zn N
N
N N
N N
N
R
N N
Zn
N N
R
In addition to this report on positron emission tomography (PET), an efficient fluorescence energy transfer (FET) system between CePO4:Tb3þ nanocrystals as donor and 6-mercapto-5-triazole[4,3-b]-s-tetrazine as acceptor was constructed. Based on this system, a simple and sensitive fluorescence method for the selective determination of formaldehyde was developed h10A2139i. A 3,6-di-4-pyridyl-1,2,4,5-tetrazine was also used as a bridging ligand in the preparation of a porous metal-organic framework. The material exhibited selective adsorption of CO2 over N2, O2, H2, and CH4. The gas adsorption properties can be modified by post-synthetic insertion/removal of the bridging ligand h10CEJ1162i. Some computational studies on tetrazine derivatives include highly accurate quantum chemical calculations to study “stacking interaction” and “spreading interaction” in several N-heteroaromatic dimers and trimers, including tetrazines. For the 1,2,4,5-tetrazine dimer, two geometries, parallel-offset and wedge-shaped, were the most stable. The complex was stabilized by weak CH N hydrogen bonding h10JPC9606i. The possible reaction pathways between methyllithium and disubstituted 1,2,4,5-tetrazines (bearing methyl, methylthio, phenyl, and 3,5-dimethylpyrazolyl groups) were investigated by means of the DFT B3LYP/6-31G* method. The coordination of the tetrazine molecule with methyllithium was found to play a crucial role in the process. These findings provide the first rationale for the experimentally observed unique reactivity of tetrazines toward polar organometallic reagents, suggesting the presence of a kinetically controlled process h10JOC6196i.
Triazines, Tetrazines, and Fused Ring Polyaza Systems
419
A significant part of the computational studies concerned the typical field of tetrazine application—high-energy and explosive materials. For example, DFT predictions and analysis of some properties of high-nitrogen compounds 3,6-diazido-1,2,4,5-tetrazine (DiAT) and N-oxides of 3,3-azo-bis(6-amino-1,2,4,5tetrazine) (DAATO) together with 3,6-di(hydrazino)-1,2,4,5-tetrazine (DHT) and 3,30 -azo-bis(6-amino-1,2,4,5-tetrazine) (DAAT) were carried out where experimental data are available h10JHM165i. There were also theoretical studies on the heats of formation, densities, and detonation properties of substituted s-tetrazine compounds h10JMM1021i and thermal behaviors, nonisothermal decomposition reaction kinetics, thermal safety, and burning rates of the 3,6-bis(1H-1,2,3,4-tetrazol-5-yl-amino)1,2,4,5-tetrazine h10JHM432i. Finally, a review on the chemistry and properties of 1,2,4,5-tetrazines as building blocks for new functional molecules and molecular materials was published in 2010 h10CRV3299i.
6.3.4. FUSED [6] þ [5] POLYAZA SYSTEMS 6.3.4.1 Triazino [6 þ 5] Fused Systems Antiviral activity, pharmacokinetics, and metabolism of a new perspective inhibitor of influenza A and B virus replication, 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c] [1,2,4]-triazine-7(4H)-one (“triazavirine”), have been published h10AAC2017i. O N MeS N
NO2
N N H
N
Triazavirine
High antiviral activity of the triazolotriazines encouraged studies on methods for the synthesis, modification, and structure elucidation of such heterocyclic systems. Thus, methods for selective 15N-labeling of tetrazolotriazines at the tetrazole ring were reported. A high excess of the 15N-isotope allowed detailed investigations of the azide–tetrazole isomerism of 67. New NMR spectroscopic approaches were suggested for unambiguous identification of (1) the ratio of isomers in different solvents and (2) the type of fusion between azole and azine rings. Analysis of chemical shifts and constants of spin–spin couplings in 15N and 13C NMR spectra revealed that triazines 67 exist in solution in the form of tetrazolo[1,5-b][1,2,4]-triazines 67T, while [5,1-c] type of fusion 67T0 was excluded. The equilibrium between the azide 67A and the tetrazole 67A depends on solvent: in DMSO 67 exist as tetrazolotriazines 67T, while in trifluoroacetic acid, the equilibrium partly shifts toward the azide form 67A h10JOC8487i.
420
A.M. Prokhorov and D.N. Kozhevnikov
R1
*N
R1 R
N
R2
N
N N
N
R1
2
N
N–
N
R2
N N
N
N
N
N+
N*
N
*N 67A
67T’
67T
Synthesis of novel nonnatural nucleosides of the triazolopyrimidine or triazolotriazine series has been reported. Alkylation of 1,2,4-triazolo[5,1-b]pyrimidin-7-ones 68 (Z ¼ CH) or 1,2,4-triazolo[5,1-c][1,2,4]-triazin-7-ones 68 (Z ¼ N) with appropriate alkylating agents proceeded at the azine ring to give 69. Cleavage of the protecting group gave nucleoside analogs 70 as new type of Herpes simplex virus inhibitors h10BOC265, 10H1149i. O R
Ph
N N N
N H
Y
O
O
X
AcO R
Z
Ph
N N N Y
AcO
68
N
MeONa
R N
Z
Y
HO
69
R = H, Me, MeS
Z = CH, N
X = Br, AcO
Ph
N N N
Z
70 Y = O, CH2
1,2,4-Triazolo[1,5-c]pyrimidines were suggested as receptor imaging agents for PET that target adenosine receptors h10BML5690i. ANRORC transformation of the pyrimidinium salt 71 on reaction with aminopyrazole 72 gave novel imidazopyridine 73 h10KG639i. Me N Me
H2N COOEt
+ N
Me
H N N
N
N
N
Ph
+
71
COOEt
N
Ph
Me 72
73
Thiazolo[3,2-a][1,3,5]triazine-4-thiones 74 were synthesized by the reaction of aroylisothiocyanates 75 with 2-aminothiazole 76 in the presence of tetrabutylammonium bromide as phase-transfer catalyst h10JHC908i. S N
O S Ar
C N
+
H2N
N S
75
N
S
76
N
74
Ar
Triazines, Tetrazines, and Fused Ring Polyaza Systems
421
6.3.4.2 Purines An efficient protocol for the synthesis of 7-substituted purines 77 has been described. The method included a reduction of the imidazole ring of N-9-tritylated 2,6-dihalopurines 78, then N-7-alkylation followed by N-9-trityl deprotection accompanied by spontaneous reoxidation to yield the 7-substituted purines 77 h10OL5724i. X N X
X N
N
DIBAL-H
N
N Tr
78
X H N
X
N
R-X
N Tr
R N
N
N Tr
N
X
X CF3COOH X
R N
N N
N
77
X = Cl, l
Ring-closing metathesis of 8,9-diallylpurines with the Grubbs catalyst gave fused dihydropyrido[e]purines h10TL6451i. Highly functionalized C6-aryl-substituted purine analogs 79 were synthesized through AlCl3-catalyzed direct arylation of 6-chloropurine 80 with various electron-rich aromatic compounds in a single step h10JOC6016i. Cl N X
N
Ar N
ArH
N R
AlCl3
80 OH
OMe
X
X = H, Cl OH
N
N
N R
N 79 OH
OH
H 2N ArH = OH HO
N R′
OH
Me
The scope and limitations of palladium-catalyzed cross-coupling reactions of diverse butyl metal species with 2-halopurines 81 have been analyzed. Tributylboranes reacted readily and regioselectively with both chloro and iodo derivatives 81; all the other alkyl metal species were much less reactive and gave very poor yields or/and selectivity of the desired butylpurines 82 h10JOC5398i. Y
Y N
N X
N
N
RM Pd
N
N Bu
N
Me 81
82
Y = NHBu, Cl X = Cl, l RM = Bu4Sn, BuLi, BuZnCl, Bu3B, BuBF3K
N Me
422
A.M. Prokhorov and D.N. Kozhevnikov
An unusual fused tricyclic purine derivative 83 was obtained via silver(I) catalyzed cyclization of 9-propargyladenine 84 h10CC3312i. NH2
NH2 N
N
N
N
N
N
AgNO3
N+
84
N
83
Replacing adenine with 2,6-diaminopurine (D) dramatically increased chargetransfer efficiency through DNA h10JA627i. Many examples of the synthesis of biologically active purine analogs have been reported. A few examples follow. The synthesis of new 4-amino-tetrahydroquinazolino[3,2-e]purine derivatives and their activity in cell-free enzymatic assays on Src have been reported h10EJM5678i. A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their antitumor activities h10BMC7639i. Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis h10BMC7274i.
6.3.5. FUSED [6] þ [6] POLYAZA SYSTEMS Multistep synthesis of polyfluorinated aminopyridotriazine 85 starting from aminodichloropyrimidine 86 has been described. Cl
Cl NH2
N N
N
Cl
86
N H
NH
H2N
87
EtOOC F
EtOOC
N
N
N O
F 89
N
N
88 CF3
N
F HN
N
F
F
N
F
OH
F HN
N F
O 90
N H
N
N N
F
F
N
N
N
85
The synthesis of 85 included pyrimidine ring cleavage in the reaction of pyrimidotriazine 87 with bromine, acylation of 88 with trifluorophenylacetyl chloride followed by cyclization of 89 to yield dihydroxypyrimidotriazine 90. Replacing the hydroxyls with fluorine atoms and then substitution of one fluoride with trifluoropropylamine gave 85, a fungicide against several phytopathogens h10TL2652i.
Triazines, Tetrazines, and Fused Ring Polyaza Systems
423
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CHAPTER
6.4
Six-Membered Ring Systems: With O and/or S Atoms John D. Hepworth*, B. Mark Heron** *University of Central Lancashire, Preston, Lancashire, United Kingdom
[email protected] **Department of Colour Science, School of Chemistry, University of Leeds, Leeds, United Kingdom
[email protected]
6.4.1. INTRODUCTION The large number of reviews published in 2010 on a wide structural range of O- and S-6-membered heterocycles reflects their significance in many aspects of chemistry. Reviews of marine natural products cover new compounds isolated h10NPR165i and synthesized h10NPR1186i. More specific publications relate to polyether toxins with spiroimine rings h10EJO5743, 10NPR1350i, ciguatoxin h10NPR1204i, gambierol h10BCJ1401, 10CEJ7586, 10H(81)2203i, and maitotoxin h10JA6855, 10JA9900i. The use of SmI2-induced cyclizations h10CSR1955i and epoxide-opening cascades h10JOC2681i in ladder polyether synthesis has been discussed. The isolation and synthesis of spiroketal natural products have been surveyed h10NPR1117, 10OBC29i, developments in berkelic acid h10CEJ12133, 10OBC1284i and spirostrellolide h10CC3967, 10S505, 10T6597i synthesis have been described, and various aspects of spirodioxynaphthalenes, fungal secondary metabolites, have been reviewed h10NPR1840i. Pigments produced by fungi h10NPR1531i, fungal natural products such as the pyrano-naphthoquinones h10OBC4793i, the cyclization of fungal and bacterial aromatic polyketides h10NPR839i, and strategies in the synthesis of fungal-derived benzopyran-containing indole alkaloids h10CSR591i have been discussed. A review of the engineered biosynthesis of plant polyketides has appeared h10TCC45i. The chemistry of black tea polyphenols h10NPR417i, colour aspects of anthocyanins h09THC1, B-09MI135i, and naturally occurring phloroglucinols have been discussed h10NPR393i. Reviews on specific O-heterocycles include those on tetrahydropyrans h10T413i, chromones h10JHC785i, flavones h10NPR1571i, naturally occurring caged xanthones h10CEJ9944i, trioxane antimalarials h10ACR1444i, and plants used for the treatment of malaria h10NPR961i. Interest continues in coumarin- and xanthene-based fluorescent sensors as indicated by reviews on the detection of Zn2þ h10CSR1996i and CN h10CSR127i, on chemodosimeters h10CR6280i, bioimaging h10CSR2048i, and oligonucleotide conjugation h10CSR2054i.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00015-2
#
2011 Elsevier Ltd. All rights reserved.
427
428
J.D. Hepworth and B.M. Heron
Discussions of specific reagents and reactions relevant to this chapter include those on Meldrum’s acid h10ACR440i, dimedone h09AHC1i, asymmetric organocatalytic h10T2089i, Pd-mediated h10H(81)517i, and carbonylative Pd-catalyzed h10H(80)697i synthesis of O-heterocycles, catalytic asymmetric CH insertion reactions h10T6681i, the Baylis–Hillman reaction h10CR5447i, the Heck reaction h10H(81)1979i, Pd-mediated O-bridged carbocycles h10H(81)1603i, and metal triflates as catalysts h10SL2973i.
6.4.2. HETEROCYCLES CONTAINING ONE OXYGEN ATOM 6.4.2.1 Pyrans In solvent-free conditions, the reaction of oxoalkyldithiocarbamates, isocyanides, and dimethyl acetylenedicarboxylate (DMAD) affords high yields of 2H-pyran-3,4-dicarboxylates 1 h10T8464i. Cyclohexanone-fused pyrans, for example, 2 also result from a Ph3P-catalyzed three-component reaction involving DMAD, dimedone, and carbonate derivatives h10HCA2218i. CO2Me
O R
1
2
S
NR
+
R
2
N C
CO2Me CO2Me
+ 70 ⬚C, 8 h
S
CO2Me
R1
NR2
O
1 10 examples, 83–94% O +
BnO
OH
O
CO2Me
O Cl
OBn
PPh3
+
CO2Me
rt O
CO2Me
90%
CO2Me
2
It is thought that a 4H-pyran is the initial product from the PPh3-catalyzed Michael addition of activated terminal alkynes to a,b-unsaturated ketones, but these normally rearrange under the reaction conditions to the 2H-pyran through a 1,3-proton shift (Scheme 1) h10T8095i. R1 EWG
O +
R1
Ph 20 mol% PPh3
EWG
R1 Bz
EWG
Bz
PhMe, rt R2
O
EWG = CN, CO2R
R2
O
R2
O
18 examples, 20–99%
Scheme 1
Heating a mixture of methylenecyclopropane aldehydes with 1,3-diketones in the presence of L-proline produces a 3-[(methylenecyclopropane)methylene]dione 3, electrocyclization of which leads to spiro(cyclopropyl-1,20 -2H-pyran) derivatives as a mixture of the cis- and trans-isomers in which the latter is dominant (Scheme 2) h10OL5120i.
429
Six-Membered Ring Systems: With O and/or S Atoms
CHO
O
O
O L-proline (10 mol%)
+
PhMe, 100 ⬚C
R
R
R
O
O
O
12 examples, 27–80%
3
Scheme 2
The 2H-pyran unit has been incorporated into polyene chains where it behaves as an efficient auxochrome, and the pyran carotenoids show a significant red shift. Protonation generates the aromatic pyrylium system and absorption moves into the near IR h10EJO435i. Ru complexes 4 catalyze the reaction between terminal propargyl alcohols and cyclic 1,3-diketones which leads to cyclalka[b]pyrans (Scheme 3). The nature of the products from internal alkynols is somewhat variable h10TL6630i.
O
HO + O
N
O
R1 Ru cat. 4 (2 mol%) TFA (2 mol%) R2 PhMe, 100 ⬚C
R1 R2
N
O 14 examples, 44–86%
Ph
Ph Ru O OC CO OC
4
Scheme 3
Highly functionalized 4H-pyrans result from the treatment of 2-(1-alkynyl)-2alken-1-ones 5 with a base. The generated carbanion initiates a Michael addition to unchanged enynone and a heterocyclization follows h10OBC5059i. R2 1
O
R
R
DBU (20 mol%) DMF 0 ⬚C
3
R 1
O
R2
R3
3
O
13 examples, 45–94%
R1
R2
5
The reaction of 2-(acetoxymethyl)buta-2,3-dienoates with acidic methylenes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and a base also forms highly substituted 4H-pyrans through a formal [3 þ 3] annulation (Scheme 4) h10CC7828i.
R1 •
OAc + CO2Bn
Scheme 4
DABCO (20 mol%) 1.3 eq. K2CO3
O R2
EWG
R1 BnO2C
EWG
DMF, rt, 2 h O R2 13 examples, 48–99%
430
J.D. Hepworth and B.M. Heron
A range of fused 4H-pyrans is obtained in a one-pot, three-component reaction between an aromatic aldehyde, malononitrile and cyclohexa-1,3-diones in an ionic liquid/water system h10JHC63i. Kojic acid, aldehydes and a 1,3-diketone afford pyrano[3,2-b]pyrans through an In-catalyzed domino Knoevenagel–heteroDiels–Alder (hDA) sequence (Scheme 5) h10TL5677i. O
O
O OH
+ ArCHO
+ HO
120 ⬚C
O
O
O
InCl3 (10 mol%) HO
O
Ar O 12 examples, 65–95%
Scheme 5
The reaction of pyrylium salts with alkynyl carbene complexes under basic conditions affords blue methylenepyran carbene complexes which gradually decompose to the spiropyrans 6 or the pyran ring-opened product, a substituted cyclopentenone (Scheme 6) h10TL605i. OMe MeO
W(CO)5 Et3N
+ R1
O BF4
THF
R1
W(CO)5
R2
R2 R1
R2
O +
O O
R2
R1 R1 R1 O 6 examples, 30–64%
R1 O 6 5 examples, 27–85%
O
R1
Scheme 6
The acid-catalyzed rearrangement of 7-methylene-6,8-dioxabicyclo[3.2.1] octanes provides diastereomerically pure 3,4-dihydropyrans. The bicyclooctanes are available from the reaction between ethyne and alkyl aryl ketones in a super base system, and their isolation can be by-passed making this a one-pot procedure (Scheme 7) h10EJO6727i. Me
Me R1
R2 + HC CH O
KOH DMSO
R2 R1
R2 O O
TFA (10 mol%) rt, 1–2 s
R1
R2
R2
R1 O
R1
O 7 examples, 86–93%
Scheme 7
A highly diastereoselective Prins reaction effected by BF3 etherate and involving allenic alcohols and aldehydes results in concomitant cyclization and fluorination providing trans-2,6-disubstituted 4-fluoro-3,6-dihydropyrans (Scheme 8)
Six-Membered Ring Systems: With O and/or S Atoms
431
h10TL1041i. 6-Trifluoromethyl-3,6-dihydropyrans are formed diastereoselectively from 2-benzylbuta-2,3-dienoates and trifluoromethyl ketones via initial addition of Ph3P to the allenoate (Scheme 9) h10OL4168i. 4-Aryl-3,6-dihydropyrans result from a one-pot reaction between but-3-yn-1-ols, aldehydes, and arenes catalyzed by BF3 which involves sequential Prins and Friedel–Crafts reactions (Scheme 10). Epoxides can successfully replace the aldehyde component h10SL1027i
R1O
F
R2CHO BF3.OEt2
TMS
O
•
CH2Cl2, 0 ⬚C
OH
TMS R1O2C R2 O 11 examples, 43–85%
Scheme 8
CO2Et • R1
R2R3CO EtO2C PPh3 (20 mol%) CH2Cl2, heat
R2 R3
O
R1
12 examples, 44–85%
Scheme 9 Ar OH
+
BF3.OEt2
RCHO
19 examples, 45–95%
ArH, rt -40 ⬚C O
R
Scheme 10
Annulated 3,6-dihydropyrans are formed as single diastereomers by an intermolecular Prins reaction when the anti-homoallyl alcohols 8 react with aldehydes in the presence of BF3OEt2. The alcohols 8 were obtained from the ()-myrtenol-derived vinyl carbamate 7 by a sequence of lithiation, titanation, and homoaldol reaction (Scheme 11) h10S329i.
OCb TMS 7 Cb = CON(i-Pr)2
(i) s-BuLi, TMEDA Et2O, -78 ⬚C (ii) R1CHO
H
R1 OH OCb TMS
R2CHO BF3.OEt2
H
R1 O
CH2Cl2
8 9 examples, 57–76%, dr > 94:6
R2 OCb 11 examples, 19–70%
Scheme 11
Diastereomerically pure 2-aminopent-4-yn-1-ols yield single diastereomers of 2-substituted 3-amino-3,4-dihydropyrans through a Ru-catalyzed cycloisomerization in which control appears to reside in O-capture of a vinylidene intermediate (Scheme 12) h10OL684i.
432
J.D. Hepworth and B.M. Heron
CpRu(PPh3)2Cl (5 mol%) NaHCO3, n-Bu4NPF6
R1HN Ar
R1HN
NIS, DMF, 80 ⬚C,
OH
Ar
7 examples, 75–89% O
Scheme 12
The stereoselective Au-catalyzed reaction of b-hydroxyallenes with NIS rapidly leads to 3-iodo-3,6-dihydropyrans; small amounts of the 3-iodo-2,5-dihydrofuran are sometimes produced. a-Hydroxyallenes derived from the dihydropyran via a Sonogashira coupling and epoxidation of the resulting alkyne undergo a further Au-catalyzed cycloisomerization to the furo[3,2-c]pyran (Scheme 13) h10EJO311i.
R2
•
R5
R3
R3 R4
I
(i)
R4
R2
R1 HO
R4 (iii), (iv)
(ii) R2
O
R6
R3
O
R1 = R2 = Me, R3 = R4 = H 13 examples, 24–95%
R1
R1
14 examples, 24–73%
OH •
R5
Me O Me 4 examples, 17–60% (v)
Reagents: (i) [Au] cat. (1–5 mol%), NIS, PhMe, rt; (ii) R5CCH, Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), Et3N, THF, rt; (iii) m-CPBA; (iv) R6MgCl, CuCN, P(OEt)3; (v) Ph3PAuCl/AgBF4 (5 mol%), PhMe, rt
R6
R5 4 examples, 76–96%, dr > 89:11 Me
O
H
O
Me
Scheme 13
Alkyne and allenylcyclopropanes tethered through a common O atom undergo a Rh(I)-catalyzed [5 þ 2] cycloaddition which produces cyclohepta[c]pyrans (Scheme 14) h10AGE2206i. High enantioselectivity is observed in the Rh-catalyzed cycloisomerization of similarly tethered 1,6-enynes which affords cyclopropa[c]pyrans (3-oxabicyclo[4.1.0]heptenes) (Scheme 15) h10AGE1638i. Similar products arise from the Au-catalyzed reaction between allylic acetates and internal propargyl alcohols which probably proceeds via the tethered 1,6-enyne h10OL3468i. O-Tethered dienynes afford 1,6,7,9a-tetrahydrocyclohepta[c]pyrans through a tandem Pt-catalyzed cycloisomerization and Cope rearrangement (Scheme 16) h10AGE415i and Ni(cod)2 catalyzes the reaction of related alkylidenecyclopropanes with activated alkenes which gives similar bicyclic products h10AGE9886i. SO2Ph • O
Scheme 14
SO2Ph
{RhCl(CO)dppp}2 (10 mol%) PhMe, rt, 24 h 60%
O
Six-Membered Ring Systems: With O and/or S Atoms
Ph
Ph RhCl(PPh3) cat. (5 mol%) NaBAr4 (10 mol%), 1,2-DCE, 20 ⬚C, 24 h 86%, ee 90%
Ph Ph
O
433
H Ph Ph
O
Scheme 15
O
Ph R5 R1 R4
R1 R2
PtCl (5 mol%), xylene 130 ⬚C
R2
O
R3
Ph R4
R3
R5
Scheme 16
Under Au(III) catalysis, cis-1-epoxy-1-alkynylcyclopropanes 9 rearrange in a highly diastereoselective manner to the cyclobuta[c]pyrans 10 in which expansion of the cyclopropane ring occurs simultaneously with 6-endo-dig oxacyclization. The trans-epoxides show much less selectivity. The oxyallylcation generated by protonation of 9 undergoes a [4 þ 2] cycloaddition with 2,3-dimethylbutadienes and enones producing tricyclic pyran derivatives (Scheme 17) h10CEJ2696i. H (i) AuCl3 (5 mol%), CH2Cl2, H2O, 1 h HO H R2
O
R1
10
AuCl3 (5 mol%)
H
O
(ii) PPh3AuCl/AgSbF6 O
H
R3
R1
CH2Cl2 H2O 83%
9
R2
R3
H
H R1
O
O
R2 10 examples, 71–91% H
(i) AuCl3 (5 mol%), CH2Cl2, H2O, 1 h
R4
(ii) PPh3AuCl/AgSbF6 R6
R5
R4
O
H R1 O
R6 R2 7 examples, 45–78%
R5
Scheme 17
The stereochemical integrity of the b-hydroxyaldehydes is retained in their conversion into 3,6-dihydropyrans by reaction with a vinyl phosphonium salt which involves an intramolecular Wittig reaction. Use of a vinyl sulfonium salt provides 4,5-epoxytetrahydropyrans as a diastereoisomeric mixture in which the anti-epoxide is predominant (Scheme 18) h10EJO183i. O
PPh3Br Ar Cs2CO3, DMSO, rt
6 examples, 34–56% S:R > 5:95
Scheme 18
O
OH Ar
SPh2OTf DBU, CH2Cl2, rt
O
O Ar
6 examples, 24–58% S:R > 97:3
434
J.D. Hepworth and B.M. Heron
An intramolecular Wacker cyclization of a range of 2-alkenyl-1,3-cyclohexanediones gives fused dihydropyrans 11 with moderate enantioselectivity in the presence of chiral bis-isoxazolines. The reaction is considered to proceed via isomerization of the 2H-pyran h10OL3480i. R1
O
2
R X
O O
diglyme, 25 ⬚C, 12 h
X
O
OH
N
R1
*
11 X = CH2, CHMe, CMe2, O, bond
i-Pr H
i-Pr
Pd(OCOCF3)2 (10 mol%) ligand 12 (12 mol%) p-benzoquinone
N
R2
O
8 examples, 38–80%, ee 51–81%
i-Pr
H i-Pr 12
The value of dihydropyrans in synthesis is exemplified by developments in the Nazarov cyclization h10AGE4463, 10CC1127i, the synthesis of phenanthrenes h10JOC951, 10S2092i and of condensed tetrahydropyridines h10S2348i. In the first example of a double intramolecular Michael addition featuring O- and C-centered nucleophiles, the ynones 13 were converted into complex 9-oxabicyclo [3.3.1]nonanes as single diastereomers on treatment with a polymer-bound Br nsted acid and under microwave irradiation. Furthermore, a retro-Michael reaction occurs when the bicyclononanes are treated with a base leading to cyclooctadienes h10CEJ9758i. Examples of oxabicyclononanes have been obtained from trans-pmenth-6-en-2,8-diol by reaction with aldehydes in the presence of BF3OEt2 which proceeds via a [3,5]-oxonium-ene cyclization h10OL1824i. R2
O
O PS-PTSA
OH
1,4-dioxane, 130 ⬚C, μW
R1 X 13
R1
O
R2
X 8 examples, 90–98%
HO
O
NaHDMS 1,4-dioxane, 100 ⬚C, μW
t-Bu 78%
Tetrahydropyran-2-carboxylates and their benzo[c]analogues are formed from o-hydroxy-a-diazo esters through a Cu-catalyzed enantioselective OH insertion h10JA16374i and a regioselective Heck reaction involving aryl bromides and hex5-en-1-ols affords 2-aryl-2-methyltetrahydropyrans h10OBC5614i. The Au-catalyzed cycloisomerization of allyl cyclopropenyl ethers 14 leads to 3-oxabicyclo [4.1.0]heptanes and is highly diastereoselective h10OL4144i. R1
R1 R2
AuCl (5 mol%)
R3
CH2Cl2, 0 °C, 15 min O 14
R4
R
2
H
14 examples, 72–99% dr > 87:13
R3 O
R4
Six-Membered Ring Systems: With O and/or S Atoms
435
(R)-Citronellal affords cyclohexa[b]tetrahydropyrans in a Sc(OTf)3-catalyzed Prins reaction with a wide range of aromatic aldehydes h10TL2963i, and a Prins cyclization–alkynylation sequence features in a one-pot synthesis of cis-2-aryl-4-phenacyltetrahydropyrans from homoallyl alcohol, an aldehyde, and phenylethyne h10TL1236i. Donor–acceptor cyclobutanes take part in Yb(OTf)3-catalyzed [4 þ 2] cycloaddition reactions with a wide variety of aldehydes to give simple and fused tetrahydropyrans as single diastereomers with exclusive cis-stereochemistry (Scheme 19) h10OL4736i. H O
H
CO2Et CO2Et + R1CHO
O
Yb(OTf)3 (10 mol%) CH2Cl2, 0 ⬚C
H
H
O
H
R1
CO2Et CO2Et
16 examples, 51–89%
Scheme 19
2-Methylene-6-vinyltetrahydropyrans undergo a Pd-catalyzed [1,3] O ! C rearrangement which produces trans-2,3-disubstituted cyclohexanones in high yield (Scheme 20) h10OL4832i. O
Pd(OAc)2 (10 mol%) P(n-Bu)3 (60 mol%) R1
O
R2
R2
MeCN, 55 °C, 24 h
6 examples, 66–87%, trans:cis > 95:5
R1
Scheme 20
6.4.2.2 [1]Benzopyrans and Dihydro[1]benzopyrans (Chromenes and Chromans) Developments in the synthesis of 2H-chromenes from salicylaldehydes include organocatalytic domino oxa-Michael–aldol reactions which lead to 3-substituted 2-phenylchromenes h10TL2567i and tetrahydroxanthenones h10CEJ801, 10SL128i. The Lewis acid-catalyzed cycloaddition of methylenecyclopropanes to o-quinonemethides generated in situ from the hydroxyaldehyde and CH(OEt)3 affords 3-(2ethoxyethyl)chromenes which are a source of highly substituted indenes (Scheme 21) h10OL2606i. Allylic alcohols 15 derived from salicylaldehydes and vinyl organometallic reagents undergo an Au(I)-catalyzed endo-cyclization to give chromenes (Scheme 22) h10CC6849i. Ph
R1
OEt
CH(OEt)3, Sc(OTf)3 CHO 1,2-DCE, rt OH
R2 then
Sc(OTf)3 R1
R2 R3 19 examples, 61–83% O
R3
1,2-DCE, 60 ⬚C 80%
(CH2)2OEt OH
R1 = H, R2 = R3 = Ph
Scheme 21
436
J.D. Hepworth and B.M. Heron
OH Au cat. 16, AgOTf (5 mol%) R1
R2
mol. sieves 4Å, THF, reflux
OH
R2
R1
t-Bu t-Bu P AuCl
O 7 examples, 53–91%
15
16
Scheme 22
3-Nitro-2H-chromenes have potential in synthesis. Thus, a Ni-catalyzed asymmetric Michael addition of dimethyl malonate offers high yields of 4-substituted chromans h10TL3972i, while a stereoselective hDA reaction of the 2-trihalomethyl derivatives with enol ethers affords a cyclic nitronate that can itself undergo a tandem [3 þ 2] dipolar cycloaddition (Scheme 23) h10T1404i.
O NO2
O
R1 O
40–60 ⬚C
CX3
O N
H R1 O
O
9 examples, 20–68%
CX3
Scheme 23
A pyrylium intermediate is postulated in the enantioselective reaction between 2ethoxychromene and boronates catalyzed by a chiral Br nsted acid and a lanthanide triflate which yields 2-vinylchromenes 17 h10AGE7096i. OH HO2C OEt R
1
+ O
OEt
EtO
B
R3 R
2
N(Bn)2 OH O (5 mol%) R1 Ce(OTf)4 EtOAc, 4 ⬚C
R3
O 2
R 17 7 examples, 40–85%, er > 86:14
The ring opening of naphtho[1,2-b]pyrans to the coloured photomerocyanine is well documented. The concomitant acid-catalyzed generation of a proximal cationic centre initiates a series of intramolecular cyclizations which culminates in the formation of the benzo[5,6]pentaleno[1,2-b]naphthalenones 18 h10CC8481i. The pyran ring of chromene 19 is opened on treatment with a thiol and reformed via a Hg2þ-promoted desulfurization and represents a molecular machine which behaves as an “ON-OFF-ON” chemosensor h10OL4756i.
Six-Membered Ring Systems: With O and/or S Atoms
437
MeO Ar1 Ar1
Ar1 = Ar2 = 4-MeOC6H4, R = OMe (76%) Ar1 = Me2NC6H4, Ar2 = 4-MeOC6H4, R = Me2 N (58%)
O
O
R
TsOH PhMe, warm
MeO OH
Ar2
Ar2 Ar 2
Ar2
18
O
HO2C
CO2H
HS
Cl
Ar1
S
O
Cl Hg2+
O 19
OH
An organocatalytic enantioselective oxa-Michael–aldol cascade sequence between salicylic acid esters and alkynals offers an attractive route to chiral 4H-chromenes involving the intermediacy of iminium and allenamine species (Scheme 24) h10OL4948i. A similar approach has been applied to 2-(2-nitrovinyl)phenols h10AGE1481i. Ph
O
H
O
+
N H CO2Et
R2
(15 mol%) Ph OTBDMS
PhMe, –15 to 10 ⬚C
EtO2C R2
OH
R1
OH CHO 20 examples, 69–99%, ee > 93% O R1
Scheme 24
Two equivalents of both simple and a,b-unsaturated ketones undergo a Au(III)catalyzed reaction with phenols and naphthols to yield 4H-chromenes 20 h10JOC1309i. R3
O R1
+ OH
R2
AuCl3 / 3AgOTf (3 mol%) R2
1,2-DCE, reflux R3
R3
R1 O 20
20 examples, 32–98%
R2
Dibenzo[b,d]pyrans result from the Pd-catalyzed annulation of arynes with 2-(2iodophenoxy)-1-arylethanones h10CC8183i. Highly functionalized dibenzopyrans are available from 2-aryl-3-nitro-2H-chromenes through a vinylogous Michael addition reaction with a,a-dicyanoalkenes h10T7590i. Although 7-methoxy-2-phenylchromene (7-methoxyflav-3-ene) undergoes an acid-catalyzed conversion into a benzopyrano[4,3-b]benzopyran, a similar dimerization of 5- and 6-methoxyflav-3-enes affords the corresponding [2,3-b] ring system. In situ isomerization of the flav-3-ene to a flav-2-ene is considered to be involved h10TL3636i.
438
J.D. Hepworth and B.M. Heron
4-Aryloxybut-1-enes readily undergo an In(OTf)3-catalyzed intramolecular hydroarylation to give 4-methylchromans h10TL4466i, and in a similar manner, phenols and allylic acetates yield chromans through a tandem allylation–cyclization sequence h10EJO6239i. Both salicylaldehydes and aldimines yield derivatives of 2-methylenechromans in phosphine-catalyzed reactions with allenic esters h10OL5664i and 2-allyloxybenzaldehydes undergo a diastereoselective Ni(0)-catalyzed cyanative alkene–aldehyde coupling to give cis-3-cyanomethylchroman-4-ols (Scheme 25) h10CC466i. OH
CHO
13 examples, 20–92%
R1
PhMe, 0 ⬚C to rt
R2
O
CN
Ni(cod)2, IPr, Et2AlCN
R1
O
R2
Scheme 25
2-Hydroxycinnamaldehydes afford chiral 4-substituted chroman-2-ols through an amine-catalyzed asymmetric 1,4-addition reaction with boronic acids (Scheme 26) h10TL5203i. By careful choice of amine catalyst, the regioselectivity of this addition can be adjusted such that the 1,2-adduct, a 2-substituted chromene, is the dominant product (Scheme 26) h10S3999i. O NMe HN N H (20 mol%)
Ph
B(OH)2 Ph Cl2CHCO2H (2 mol%) CHCl3, 0 ⬚C 8 examples, 66–99%, er > 80:20 dr > 3:1
R1 O
CHO R1 OH
(Bn)2NH (20 mol%) Cl3CO2H (100 mol%) B(OH)2 R2 mol. sieves 4Å, CH2Cl2, rt
7 examples, 42–80%
R1 O
R2
OH
Scheme 26
Chiral 4-nitromethylchromans are readily accessible through sequential Michael addition of acetone to 2-(2-nitrovinyl)phenols and acetalization in the presence of a 9-amino-9-deoxyepiquinine (ADEQ) catalyst (10 mol%) and Ph2CHCO2H (10 mol%) (Scheme 27). The products are versatile synthons partly as a consequence of the lactol ⇆ d-hydroxyketone equilibrium h10OBC4259i. Such nitrovinylphenols also undergo a Pt-catalyzed Michael addition and cyclization sequence with N-arylpiperidines to give chromano[2,3-b]piperidines 21 h10JOC2893i.
Six-Membered Ring Systems: With O and/or S Atoms
(i) Ph2CHCO2H ADEQ CH2Cl2, rt, 72 h
O2N
R1
(ii) TsOH, R2OH, rt, 2 h
O
1,4-dioxane, H2O, O2, 60 ⬚C
R1 OH
OR2 11 examples, 33–72 %
O2N
N Ar PtCl2 (10 mol%)
NO2
439
R1 O N 21 Ar 13 examples, 29–65%
Scheme 27
Electron-rich arenes undergo a stereoselective intramolecular Friedel–Crafts alkylation which yields trans-4-substituted chroman-3-ols when chiral 2-(aryloxymethyl)oxiranes are heated in hexafluoroisopropanol (Scheme 28) h10CC2653i. A regio- and stereoselective SN20 addition of an arylcyanocuprate to a protected epoxycyclohexanone features in an asymmetric synthesis of ()-D8-trans-tetrahydrocannabinol h10S1766i. R3
R2
R1
(CF3)2CHOH R3
O
reflux
OH R1
O
10 examples, 51–99%
R2
O
Scheme 28
3,4-Disubstituted chroman-4-ols are formed through an intramolecular carbonyl-alkene cyclization of 20 -(allyloxy)propiophenones initiated by a ketyl radical generated using a low valent Ti reagent (Scheme 29) h10SC2969i. O Et
R1
Et
TiCl4/Zn
OH Me
THF, reflux, 3 h
R1
3 examples, 45–62%
O
O
Scheme 29
3-Arylpropan-1-ols are cyclized to chromans, usually with concomitant 6-iodination, on treatment with 1,3-diiodo-5,5-dimethylhydantoin and irradiation; an O-centered radical is implicated (Scheme 30). 2-Phenylbenzoic acid gives benzo[c] coumarin under the same conditions h10SL2325i. O
R1 HO
R3 R2
+
I N O
N
X
I hν EtOAc, 40 ⬚C
R3 R2 X = H, 8 examples, 8–58% X = I, 8 examples, 1–64% R1
O
Scheme 30
A general approach to optically active isoflavans utilizes allylic picolinates as the chiral source and essentially involves a two-step procedure following chirality
440
J.D. Hepworth and B.M. Heron
transfer, namely oxidative cleavage of an alkene unit and cyclization of a derived phenol (Scheme 31) h10T197i. A stereoselective and general synthesis of an epi series of catechins (cis-flavanols) involves two key steps, namely an aromatic nucleophilic substitution of aryl fluorides and a sulfinyl–metal exchange prior to pyran ring formation (Scheme 32) h10OBC2693i. The interflavan bond in procyanidin B3 has been constructed with complete stereochemical control from catechin-derived reactants h10TL1193i and by using Yb(OTf)3 as the catalyst h10JOC4884i. MeO
Ar1
(i) MeO
Ar1
(ii) – (v)
OMe
HO
O Ar2 = 4-HOC6H4 Reagents: (i) 4-MeOC6H4MgBr, CuBr.Me2S; (ii) cat. OsO4, NMO, aq. Me2CO (75%); (iii) NaIO4, aq. MeOH; (iv) NaBH4 (82%); (iv) CBr4, PPh3 (90%); (v) BBr3, CH2Cl2 then K2CO3, Me2CO (74%) OMe
OCOPy
Scheme 31
O SPh R1
O
O SPh
(i)
+
R1
Br (ii), (iii) OTES
OH R1
O Ar Ar Reagents: (i) NaH, PhMe, DMPU, rt (39%); (ii) Li2NiBr4, THF, 0 ⬚C then TESOTf, 2,6-lutidine, CH2Cl2, 0 ⬚C (97%); PhLi, THF, rt then n-Bu4NF, THF, 0 ⬚C (99%) F
HO
Ar
O
Scheme 32
The Lewis acid-catalyzed C H bond functionalization of 2-alkoxybenzylidene malonates 22 that results in cyclization to 2,3,3-trisubstituted chromans is greatly facilitated by an ortho substituent adjacent to the alkoxy group. It is considered that a combination of buttressing and enforced rotational effects promotes the [1,5] hydride shift and pyran ring formation h10OL1732i. MeO2C
CO2Me
CO2Me CO2Me
cat. SnCl4 (5 mol%) 1,2-DCE, reflux OBn R1
O
7 examples, 5–99%
Ph
R1
22
A 2-benzopyrylium species is implicated in the conversion of 2-(6-hydroxyhex1-ynyl)-benzaldehydes into dihydronaphtho[2,3-b]pyrans or benzobicyclo[4.3.1] acetals dependent on the Au catalyst selected (Scheme 33) h10OL4640i, and ionic liquids facilitate the cyclization of primary and secondary halo- and alkoxy-propoxynaphthalenes to dihydronaphtho[2,1-b]pyrans h10TL54i.
441
Six-Membered Ring Systems: With O and/or S Atoms
R1
R1
O
R2 AuCl3 (5 mol%)
R1 R2
R2 Triazole-Au (5 mol%) CH2Cl2, rt, 1 h
CH2Cl2, rt, 1 h
O O
OH
O
4
8 examples, 36–82%
3 examples, 69–88%
Scheme 33
A hDA reaction features in a total synthesis of (þ)-cymbodiacetal from (R)-(þ)limonene oxide involving conversion to the allylic alcohol and oxidation to the exocyclic enone (Scheme 34) h10JOC8465i. Complex oxapolycyclic aromatic systems result from the reaction between phencyclone and pyrene quinones, providing the first example of a cyclopentadienone behaving as a dienophile in a hDA reaction h10T7933i. O O 80 ⬚C
(i) m-CPBA, CH2Cl2, 0 ⬚C
O
(ii) TsOH, aq. THF
O
OH
O OH 44%
Scheme 34
6.4.2.3 [2]Benzopyrans and Dihydro[2]benzopyrans (Isochromenes and Isochromans) Chromium complexes of ortho-alkynyl benzaldehydes undergo a stereoselective Au(I)catalyzed cyclization with added nucleophiles to give 1-substituted isochromene Cr complexes; nucleophilic addition to the aldehyde function precedes ring formation (Scheme 35) h10TL1166i. A similar but intramolecular asymmetric cyclization occurs with 1,3-dihydroxymethyl-2-alkynylbenzene Cr complexes h10OL4788i. Terminal alkynamides are converted into 1H-isochromenes through Pd-catalyzed cross-coupling reactions with 2-formylphenylboronic acids and treatment of the resulting 2-ethynylbenzaldehydes with MeOH (Scheme 36) h10JOC5635i.
OR2 O R1 Cr(CO)3 7 examples, 62–83%
Scheme 35
Nu
CHO Ph3PAuNTf2 (5 mol%) R2OH, CH2Cl2, rt
Nu, CH2Cl2 then Cr(CO)3
O
Ph3PAuNTf2 (5 mol%) CH2Cl2, rt R1 Cr(CO)3
R1
4 examples, 31–80%
442
J.D. Hepworth and B.M. Heron
O +
Ph N R1
OMe
Pd(OAc)2 (0.01 mol%) Ag2O, K2CO3
CHO
MeOH:MeCN (2:1) 70 ⬚C, 24 h
B(OH)2
O
Ph N 1 R
O R1 = Me 36%, R1 = n-Bu 42%
Scheme 36
The amide 23 with a 1,6-diyne tether cyclizes by a 6-endo-dig Au(I)-catalyzed process to give the isochromene-1-imidate 24 h10JOC4542i. The hydroxy amides 25, derived from protected 2-(hydroxymethyl)benzaldehyde by an Ugi reaction, cyclize on treatment with MsCl/Et3N to 3-amino-4-amido-1H-isochromenes which are readily ring-opened by O2 h10SL85i. CO2Me
CO2Me CO2Me
CO2Me Ph3PAuCl (5 mol%) AgNTf2, Et3N PhMe, 90 ⬚C 57%
O Et
O NEt
NH
23
24
O
OH NHR1 O 2
R3
N
R
25
NHR1
(ii) DMF, TBAI, Et3N/Et3NH+, 100 ⬚C
O
R2
air, rt
R3
N
NHR1
O
O
(i) MsCl, Et3N, CH2Cl2 –15 ⬚C to rt
O
O
R2
R3
N
6 examples, 25–75%
O
2-Alkynylbenzyl alcohols in which the alcoholic function is either primary or secondary afford 4-iodoisochromenes through a 6-endo-dig iodocyclization; tertiary alcohols yield dihydroisobenzofurans by a 5-exo-dig cyclization (Scheme 37) h10JOC897i. R2 R1
R3 OH
R2 I2, NaHCO3 MeCN, 25 ⬚C
R4
R1
R3 O
+ R4
I 15 examples, 41–92%
Scheme 37
R2
R3 O
R1
R4 4 examples, 35–82%
I
Six-Membered Ring Systems: With O and/or S Atoms
443
The formation of 1-substituted isochromans by the oxa-Pictet–Spengler (oPS) reaction between a b-arylethanol and a benzaldehyde is efficiently catalyzed by Bi(OTf)3 h10SC915i. The oPS reaction is a key feature of the enantioselective synthesis of a number of natural products h10EJO4306, 10EJO4442i. Pd-catalysis has been used to good effect in isochroman synthesis. Using C6F6 as solvent and in the presence of oxidants and a monoprotected amino acid ligand, 3-arylpropan-2-ols and related tertiary alcohols undergo a CH olefination with electrondeficient alkenes which is followed by an oxidative intramolecular cyclization to 3,3-disubstituted isochromans (Scheme 38). This hydroxyl-directed olefination can also be accomplished with primary and secondary alcohols, but yields are lower h10JA5916i. R2 R3 + OH
R1
R4
Pd(OAc)2 (10 mol%) ligand (20 mol%), Li2CO3
R2 R3 O 25 examples,
R1
AgOAc, C6F6, 89 ⬚C, 48 h ligand = (+)-menthyl(O2C)-Leu-OH
28–98% R4
Scheme 38
3-Benzyloxy-2-hydroxymethyldihydropyrans 26 undergo a regioselective acidcatalyzed intramolecular Friedel–Crafts alkylation which affords 3,4-disubstituted isochromans h10OL3222i.
R3 O R1
O
O
R3 cat. Sc(OTf)3, n-Bu4NPF6
R2
MeNO2
H
OH
H R2 R1
26
12 examples, 26–98%
High yields of isochromans result from a cycloaddition between o-(silylmethyl) benzyl carbonates and electron-deficient ketones. Two competing pathways are proposed to account for the regioselectivity of the reaction, which is sensitive to the structure of both reactants (Scheme 39) h10OL4332i.
O TMS + OC(O)OMe R1 R2
Pd(η3-C3H3)Cp, DPEphos DMF 120 ⬚C
R1 R2 O
11 examples, 41–93%
Scheme 39
Highly substituted phenols, obtained from 1,1-diacylcyclopropanes and 1,3-bis-(trimethylsilyloxy)buta-1,3-dienes through domino [3 þ 3] cycloaddition and cyclopropane ring-opening reactions, are a source of isochromans, chromans, and hexahydropyrano[3,4-f]benzopyrans h10JOC809i.
444
J.D. Hepworth and B.M. Heron
Bridged isochromans are accessible from aromatic 1-(2-acylphenyl)propynol derivatives 27 through a Au(I)-catalyzed reaction with vinyl ethers. The highly strained anti-Bredt products, 9-oxabicyclo[3.3.1]nona-4,7-dienes 28, are formed as a single diastereoisomer, and it is proposed that the reaction proceeds through a s-trans-vinyloxonium ⇆ a-carbonyl ylide species, which undergoes a [3 þ 2] cycloaddition and ring expansion sequence. Overall, a formal [4 þ 2] cycloaddition involving a s-trans-heterodiene is demonstrated h10JA12565i. Similarly, alkynyl acetates 30 derived from 2-bromoaryl alkyl ketones react with vinyl ethers in a stereocontrolled tandem oxacyclization–[4 þ 2] cycloaddition sequence which yields 1,4-bridged isochromans 31. A ketone-allene intermediate can be isolated, and the intermediacy of a 2-benzopyrylium species was invoked h10JA9298i. OR2
R1
t-Bu t-Bu P AuNTf2
OR2 +
OR3
Au cat. 29 (3 mol%) O
CH2Cl2, 25 ⬚C
R1
O
OR3
28
27
29
25 examples, 42–95%
OAc Au cat. 16 (3 mol%), AgNTf2 R2
R1
O
R3 OR4 CH2Cl2
R4O R3
R1
NaOMe
R4O R3
H R1
OAc R2
O
R2
30
O O
31 25 examples, 42–87%
6.4.2.4 Pyranones The rearrangement of 4-alkynyloxetan-2-ones, synthesized from acyl halides and propargyl aldehydes, to pyran-2-ones is catalyzed by Au(I) complexes (Scheme 40) h10OL5362i. The Michael addition of N-(diphenylmethylene)glycinate to alkynyl ketones and spontaneous ring closure provides good yields of 3-aminopyran-2-ones (Scheme 41) h10S211i. O R1
O Ph PAuOTf (5 mol%) 3 CH2Cl2, reflux R2
Scheme 40
R1 R2 O O 13 examples, 15–81%
Six-Membered Ring Systems: With O and/or S Atoms
445
O R2
R1 +
R2 CO2R3
Ph
NaOH
N
Et2O, 35 ⬚C R1
N Ph
Ph
Ph O O 14 examples, 62–94%
Scheme 41
3-Substituted pyran-2-ones are available through Suzuki coupling of the readily accessible electrophilic 3-trifloxypyranone with a wide range of boron reagents h10JOC7962i. Highly substituted pyran-4-ones arise from the Rh-catalyzed reaction between allylic alcohols and a fourfold excess of a,b-unsaturated aldehydes. It is proposed that three consecutive redox–aldol sequences occur with the final aldol reaction resulting in cyclization of a triketone (Scheme 42) h10CEJ8248i. OH
(i) n-BuLi, {RhCl(coe)2}2 (10 mol%) PPh3 (40 mol%), 1,4-dioxane, rt
O
R1
R3
+ R4
H
R2
(ii) TMSOTf, PhMe, 0 ⬚C – rt
O R4
R4 R1
R3 R2 14 examples, 44–80% O
Scheme 42
2,6-Dimethoxypyran-4-ones can be desymmetrized by reaction with 2-lithio1,3-dithiane, giving access to the 2-formyl and 2-methyl 6-methoxypyranones h10CEJ11229i. A comprehensive study indicates that the catalyzed hDA reaction between a,b-unsaturated acid chlorides and aldehydes involves the formation of enantiopure zwitterionic ammonium dienolates and leads to optically pure 5,6-dihydropyran-2-ones. Variation in the catalytic system chosen broadens the scope of the aldehyde component tolerated (Scheme 43) h10CEJ2503i. An enantioselective inverse electron demand DA reaction of chalcones with 2-oxazolin-5-ones catalyzed by a chiral bisguanidine produces 3-amino-3,4-dihydropyran-2-ones h10JA10650i. OMe O
catalyst 32 (10–30 mol%) Sn(OTf)2 (10–30 mol%)
O Cl
+ H
R1
CCl3
R1
TMSO N
i-Pr2NEt, PhMe, -15 ⬚C O O N Cl3C 12 examples, 43–78% ee > 54%
H 32
Scheme 43
A ring-opening–ring-closing sequence is involved in the conversion of pyran-2ones into 5,6-dihydropyran-2-ones by treatment with 1-hydroxypropanone h10TL961i.
446
J.D. Hepworth and B.M. Heron
The reaction of enals with 1,3-diketones catalyzed by N-heterocyclic carbenes under basic, oxidative conditions leads to highly substituted 3,4-dihydropyran-2ones 33 in a procedure that involves redox activation of the Michael acceptor h10AGE9266i.
R2 R1
N
I
O
N
H
N
O
(2 mol%)
3
R
O
t-Bu
R4
R3
R t-Bu
R5
O
R5
O
O
21 examples, 34–92%
O
33
O
t-Bu
R2
4
DBU (10 mol%)
+
R1
t-Bu
THF, rt
A wide range of 2, 3-dihydropyran-4-ones has been synthesized from 5-hydroxy1,3-diketones. InCl3 under dry conditions is an efficient catalyst for cyclization of the isolated hydroxydioneh10OBC698i, whereas an acidic work-up of the reaction between 1,3-diketone dianions with aldehydes affords the product in a one-pot procedure h10HCA1705i. Chiral 2,3-dihydropyran-4-ones are formed when cyclobutanones that incorporate a chiral auxiliary react with aldehydes (Scheme 44) h10OL4984i. O
O + O
R1CHO
CO2Et
TiCl4, SnCl2 CH2Cl2, 0 ⬚C O
R1
11 examples, 43–70 % ee > 75%
Scheme 44
6.4.2.5 Coumarins In a one-pot procedure involving sequential bromination, Wittig reaction, and cyclization, salicylaldehydes react with the ylide derived from methyl (triphenylphosphoranylidene)acetate and N-bromosuccinimide (NBS) to give 3-bromocoumarins (Scheme 45) h10EJO1046i. CO2Me
Ph3P
NBS, CHCl3 R1
Br
CHO
Ph2O
+ OH
Ph3P
CO2Me
80 ⬚C
R1
R1
Br OH
Br
CO2Me 200 ⬚C
O O 15 examples, 24–86%
Scheme 45
4-Arylcoumarins result from a microwave-assisted one-pot reaction between 2-hydroxybenzophenones and dialkyl malonates in DBU involving an initial Knoevenagel reaction h10EJO4130i. 4-hydroxycoumarins are readily obtained from
Six-Membered Ring Systems: With O and/or S Atoms
447
phenols and Meldrum’s acid through dehydration of the resulting monoaryl malonic acid ester h10SC732i. Both coumarins and dihydrocoumarins are available from the Pd-catalyzed reaction of arylboronic acids with 2-formylaryl but-2-ynoates; the counter anion of the Pd complex controls the nature of the product (Scheme 46). The use of a chiral catalyst confers excellent enantioselectivity to the 3-alkylidenedihydrocoumarins h10OL108i. OH
O
[Pd(S,S-bdpp)(H2O)2]2+(BF4-)2
R1
dioxane, rt O
Ar
R1
O O 14 examples, 65–99%, ee > 87%
O
+ ArB(OH)2
[Pd(dppp)(H2O)2]2+(TfO-)2
OH Ar
R1
aq. dioxane, rt O
O
12 examples, 56–89%
Scheme 46
Dihydrocoumarins are readily formed in good yields by the oxidative cyclization of 3-arylpropanoic acids with either phenyliodine(III) bis(trifluoroacetate) or oxone in the presence of BF3OEt2 h10TL192i. The reaction between an isocyanide, 2-formylbenzoic acid, and a primary aromatic amine leads to stable 3,4-diaminoisocoumarins, the primary adducts of an Ugi four-component condensation, although a rapid rearrangement to isoindolinones occurs in acidic conditions (Scheme 47) h10OL788i. The reaction is also facilitated by silica nanoparticles h10HCA2203i.
NHAr + CO2H
CONHR1
NHR1
CHO R1NC + ArNH2
H MeOH
O O 6 examples, 57–82%
NAr O 4 examples, > 99%
Scheme 47
The oxidative cyclization of 2-styrylbenzoic acids to isocoumarins is efficient using PhSeSePh and [bis(trifluoroacetoxy)iodo]benzene. The use of other electrophilic species such as disulfides and a very short reaction time allows the intermediate dihydroisocoumarins to be isolated (Scheme 48) h10EJO3465i.
448
J.D. Hepworth and B.M. Heron
Ar
PhSeSePh PhI(OCOCF3)2
SePh
O
MeCN, rt
CO2H
Ar
Ar +
O
7 examples, 88–99%
O
O PhSeSePh
Scheme 48
The enzymatic Baeyer-Villiger oxidation of racemic 2-alkylindanones offers a route to chiral 3-alkyl-3,4-dihydroisocoumarins h10JOC2073i and the TiCl4-promoted cyclization of 1,3-bis(silyloxy)buta-1,3-diene with 1-hydroxy-5-silyloxy-4en-3-ones leads to 6-(2-aryl-2-chloroethyl)salicylates which lactonize to 3-aryldihydroisocoumarins h10T1874i.
6.4.2.6 Chromones High yields of 3-cinnamoyl-2-styrylchromones are obtained from a facile, mild onepot Baker–Venkataraman rearrangement between 2,6-dihydroxyacetophenones and acryloyl chlorides. The presence of two OH groups is critical for success, and it appears that two Baker–Venkataraman reactions are involved h10EJO6417i. Chromones, chroman-4-ones, and xanthones have been synthesized by the reaction of carboxylic acids with the aryne precursors, o-(trimethylsilyl)aryl triflates. The initial product from aryne insertion into the carboxylic acid COH bond can undergo further reaction according to the structure of the acid with the above products arising from the use of ynoic, enoic, and 2-halobenzoic acids, respectively (Scheme 49) h10OL3117i. O Ph O
Ph
CO2H
CsF, THF, sealed vial, 125 ⬚C 56%
OTf TMS
CO2H Ph CsF, THF, sealed vial, 125 ⬚C 74%
O
O
Ph
Scheme 49
3-Aminochromones are available from the salicylaldehyde-derived nitrile 34 through a facile N-heterocyclic carbene-catalyzed intramolecular carbon–carbon bonding process h10OL352i, and 2-aminochromones result from the reaction between salicylic acid, N-substituted acetamides, and POCl3, which generates both a Vilsmeierlike species and an acid chloride (Scheme 50). Noteworthy are the syntheses of the [1,2b:4,5-b0 ] and [1,2-b:5,4-b0 ] benzodipyrandione systems, albeit in only moderate yields h10S849i. Reliable methods for the 3-nitration of flavones and for their reduction to the 3-amino compounds have been developed h10SL1381i.
449
Six-Membered Ring Systems: With O and/or S Atoms
N O
N
N Ph (10 mol%)
N
R1
O
O
NH2 30 examples, 80–95% R2
R1
DBU (10 mol%), CH2Cl2 R2
O
34 O OH
R1
OH
POCl3
O
1,2-DCE, rt
O N
R2
POCl3
1,2-DCE, 95 ⬚C then aq. NaOAc
10 examples, 44–84%
R1
NR2R3
O
1,2-DCE, rt
R3
Scheme 50
The Pd-catalyzed cyclocarbonylation of 2-iodophenols with terminal alkynes to yield 2-substituted chromones is efficiently conducted in a phosphonium salt ionic liquid without the need for either high pressure or ligand h10JOC948i, and the synthesis of a 3-iodoflavone from ynones using a modular flow reactor has been described h10CEJ89i. A general route to flavones involves the Pd-catalyzed oxidation of 2hydroxyaryl styryl ketones using t-BuO2H h10TL1095i, and several 2-(ferrocenyl) chromones have been obtained from the corresponding chalcones h10CC5145i. The photodimerization of chromone-2-carboxylates affords the anti-head-tohead [2 þ 2] dimer from the triplet state in solution but the head-to-tail isomer in the solid state where the crystal structure controls the process h10OL4435i. The DA adducts of chromones with cyclic dienes themselves undergo a [2 þ 2] photocyclization to produce a new diene (Scheme 51) which diastereoselectively cyclodimerizes. Further, the diene reacts with dienophiles, and these products can take part in sequential cycloaddition reactions h10TL3803i. X O
R1
X R1 heat
O
O +
X O
R1
hn
R1
heat O
O X
X = CH2, (CH2)2
O H
H O O
O 4 examples, 55–70%
3 examples, 70–100%
R1 3 examples, 24–80%
X
Scheme 51
The Rh-catalyzed asymmetric conjugate addition of tetraarylborates to chromones offers a general route to optically pure flavanones h10JA4552i, and a Sc-catalyzed rearrangement of 3-allyloxyflavones affords chiral chroman-3,4-diones h10JOC4584i. The direct Pd-catalyzed a-arylation of chroman-4-ones under aqueous basic conditions with aryl bromides leads to isoflavanones and can be adapted to produce the 3,3-diarylated derivative h10EJO1339i. Regioselective aromatic
450
J.D. Hepworth and B.M. Heron
hydroxylation of monohydroxylated flavones and flavanones and conversion of methoxyflavanones into flavones can be achieved with 2-iodoxybenzoic acid by careful choice of reaction conditions h10T6047i. Under basic conditions in a biphasic system, a photo-Fries rearrangement of aryl 3-methyl-but-2-enoates leads to enones which cyclize through an oxa-Michael addition to chroman-4-ones (Scheme 52) h10TL4387i. A Michael reaction also features in the diastereoselective formation of cyclopenta[b]chromanones from 2-cyclohexenylphenols h10OL3410i and in the synthesis of 2-substituted chroman-4-ones from 2-acylphenols and electron-deficient alkynes (Scheme 53) h10TL1748i. hν, C6H6
R1
O R1
aq. KOH O
O
O 7 examples, 79–100%
Scheme 52
O
O
R1
R1
COR2 OH
DABCO, KOt-Bu, DMF, rt
O COR2 13 examples, 38–76%
Scheme 53
6.4.2.7 Xanthenes and Xanthones Electron-rich arenes and heteroarenes react with 2-aryloxybenzaldehydes in the presence of Sc(OTf)3 to give 9-substituted xanthenes h10OBC1097i, and similar products arise from the microwave-assisted, FeCl3-catalyzed benzylation of phenols followed by a base-catalyzed cyclization h10OL100i. Michael addition of arynes to an a,b-unsaturated unit attached to a phenol is followed by spontaneous cyclization offering yet another approach to 9-substituted xanthenes (Scheme 54) h10JOC506i. The oxidative coupling of xanthene with various C-nucleophiles is achieved in MeSO3H h10AGE5004i, and reaction with vinylidenecyclopropanes and DDQ h10T7104i leads to further examples. EWG EWG R1
OTf +
OH
R2 TMS
CsF THF, 66 ⬚C
R1
R2
O 9 examples, 64–92%
Scheme 54
451
Six-Membered Ring Systems: With O and/or S Atoms
Microwave-assisted base-catalyzed cascade reactions of 3-(1-alkynyl)chromones are of value in the synthesis of xanthones (Scheme 55). Dimerization of the 2-methyl derivative and cross-coupling with the 2-unsubstituted chromone affords 3-(chromon3-yl)xanthones h10OL3086i. Desalicyloylation can accompany dimerization leading to 2-alkynylxanthones h10OBC1378i. Benzo[a]xanthones 35 are obtained from reaction with 3-a,b-unsaturated chromones h10OL3848i, and synthetically useful 3-aminoxanthones 36 result using a variety of acetonitriles h10JOC6304i. O
OH
O R2 O CO2Et O
O
OH R1 35 11 examples, 54–83%
DBU, DMSO R3 = H μW, 120 ⬚C
R3
R1
O R2
R1
O
DBU, DMSO
O
μW, 120 ⬚C O
R3
R2
R1 O
O
R2 ArCH2CN
13 examples, 14–90% O
DBU, DMF μW, 90 ⬚C
R3
R2
Ar NH2
O R1
36 12 examples, 60–95%
Scheme 55
Conversion of 3,6-bis(dimethylamino)xanthone and the S, Se, and Te analogues into their triflates 37 facilitates a Suzuki reaction with arylboroxins creating a route to novel rhodamine derivatives h10SL89i. The triflate 38 derived from fluorescein undergoes a Buchwald–Hartwig amination giving access to a variety of rhodols h10OL496i.
OTf TfO Me2N
X 37
NMe2
Ar
O B
Ar B O
O B
Ar Ar
PdCl2(PPh3)2 (10 mol%) Na2CO3, MeCN, 55 ⬚C then aq. HCl
TfO Me2N
X
NMe2
12 examples, 83–99%
The helical 1,13-dimethoxychromenoxanthenium species 39 has been synthesized from tris(2,6-dimethoxyphenyl)methylium and resolved. Its racemization (DG{ 27.7 kcal mol 1) is faster than its conversion into the planar trioxatriangulenium cation h10OL1748i. Anthracene-p-stacked oligomers 40 and a polymer
452
J.D. Hepworth and B.M. Heron
have been synthesized on a xanthene scaffold through a Sonogashira–Hagihara coupling of a diiodoxanthene with 9-(trimethylsilylethynyl)anthracene h10OL3188i. R
CO2H
O
O
R
O O Z= Z
O
O
OTf
Z
O
38
39
O
R
O
R
40
R
R
6.4.3. HETEROCYCLES CONTAINING ONE SULFUR ATOM 6.4.3.1 Thiopyrans and Analogues A hDA reaction between fluorinated thioamides and 2,3-dimethylbutadiene carried out under microwave irradiation affords 2-amino derivatives of 2-perfluoroalkyl3,6-dihydro-2H-thiopyrans h10TL990i, and the first examples of 2-perfluoroalkylthiopyrylium salts have been obtained through the oxidative aromatization of 2H-thiopyrans h10TL6406i. a-Diazosulfones undergo an asymmetric Cu-catalyzed CH insertion that affords 2-acyltetrahydrothiopyran 1,1-dioxides 41 in only moderate yields but with high enantioselectivity h10JA1184i. O
R2
O O S N2
O N
O Ph R1
N
R2 Ph
CuCl, CH2Cl2 heat
S COR1 O O 41
9 examples, 21–68%, ee > 70%
A two-step asymmetric synthesis of highly substituted cis-thiadecalins involves formation of enal 42 from a nitroalkene, a formylthioester, and an a,b-unsaturated aldehyde. An intramolecular thia-Michael addition completes the sequence in which six consecutive stereocenters are controlled (Scheme 56) h10S2271i.
Six-Membered Ring Systems: With O and/or S Atoms
O S + R2
O
Ph Ph N H OTMS (20 mol%)
O
R1
S O2N
O
PhMe, 0 ⬚C
O
K2CO3, MeOH
R2
+ R1
S
O 5 examples, 40–57%, dr > 85:25, ee > 99%
R2
R1
NO2
453
NO2 42
Scheme 56
A benzobisthioxanthene 43 that functions as a good emitter in organic light emitting diodes (OLEDs) is readily synthesized from 9,10-dibromoanthracene through a Suzuki coupling with 2-methylsulfanylbenzene-boronic acid and subsequent oxidation and demethylation h10CC8573i Enaminones 44, available from a-acyl-a-carbamoyl ketene S,S-acetals, are cyclized on heating with Na2S in DMF offering a good route to 4-oxo-4H-thiopyran-3-carboxamides h10AJC1267i. S O
O CONHAr
Na2S.9H2O
CONHAr
DMF, 75 ⬚C Me2N EtS
SEt
S
44
S
43
SEt
6 examples, 67–85%
A facile one-pot three-component synthesis of thiochromones carried out under microwave irradiation involves a Sonogashira coupling of o-haloaroyl chlorides with terminal alkynes followed by Michael addition of hydrosulfide ion and an intramolecular nucleophilic aromatic substitution (Scheme 57). This methodology is readily adaptable to the synthesis of other annulated thiopyran-4-ones h10OBC90i and tetrahydro-2H-thieno[3,2-c]thiopyrans result from a one-pot domino sequence during which three stereocenters are controlled h10JOC472i. (i) PdCl2(PPh3)2 (4 mol%), CuI (4 mol%), Et3N, THF, rt
O Cl + R1
R2 Hal
(ii) Na2S.9H2O, EtOH, μW, 90 ⬚C, 90 min.
O 15 examples, 35–77% R1
S
R2
Scheme 57
4-Hydroxydithiocoumarin reacts with a range of O-allylated, O-propargylated, and O-acrylated salicylaldehydes under aqueous conditions to give benzopyranannulated thiopyranothiochromen-5(4H)-ones through domino Knoevenagel–hDA reactions (Scheme 58) h10S4043, 10T8615, 10TL2297i. A similar reaction sequence involving 1-methylindoline-2-thione leads to indole-annulated thiopyranobenzopyrans h10TL147i.
454
J.D. Hepworth and B.M. Heron
OH O
R3
O
R2 R1
CHO R2 O
R1
S
S
CHO
H2O, reflux
H2O, reflux O
H
S
R2
S
H 5 examples, 65–84% R3
7 examples, 69–80% 1 R
R2 O
O
S
S
Scheme 58
3-Benzylidenechroman-4-ones and 2-mercaptobenzaldehydes undergo an enantioselective cyclization in the presence of a bifunctional amine-thiourea indane catalyst to produce spiro chromanone-thiochromans (Scheme 59). The reaction is successful with related thiochromanones and tetralones h10CC9232i. A spiro derivative 45 of thioxanthene 10,10-dioxide is formed when the dianion derived from diphenyl sulfone reacts with 2,3-dibromophthalazine-1,4-dione h10TL6605i.
R1
CHO
+
SH O
indane cat. (5 mol%) Ar
R2 X X = O, S, CH2
xylene, -30 ⬚C
O
HO O R2
O S
X Ar 25 examples, 93–98%, dr > 1.2:1, ee > 92%
S O
O 45
Scheme 59
6.4.4. HETEROCYCLES CONTAINING TWO OR MORE OXYGEN ATOMS 6.4.4.1 Dioxins and Dioxanes Endoperoxides can be isolated from the oxygenative photolysis of 1-methyl-9,10anthraquinones and subsequently produce 1-hydroxymethylanthraquinones on reduction h10JOC412i. Treatment of a carotenoid with FeCl3 in air affords a stable yellow cyclic hydroxy peroxide which undergoes a reversible change to the blue cationic polyene with water h10EJO4630i. The intramolecular insertion of a carbenoid into 3,6-dihydro-1,2-dioxines occurs preferentially into the peroxide linkage and leads to a mixture of bicyclic hemiacetals and tricyclic peroxides (Scheme 60) h10JOC450i.
Six-Membered Ring Systems: With O and/or S Atoms
O
O R1
O O
Rh2(OAc)4
O O N2
O
CH2Cl2
455
R1
+
O
O
1
R 1
1
1
1
R = Me 41%, R = Ph 62% R1 = H, 32%
R = Me 14%, R = Ph 11% R1 = H, 0%
Scheme 60
An acylketene is proposed as an intermediate in the Ag-promoted reaction between phenyl thioacetoacetate and ketones and offers a simple route to 1,3dioxin-4-ones h10JOC6054i. Their reaction with alcohols and amines offers a facile route to b-keto esters and b-keto amides h10S1053i. The Au-catalyzed cyclization of 1-alkynyl-1-cycloprop-1-yl t-butyl carbonates proceeds by a 6-endo-dig route in preference to the 5-exo-dig alternative and leads to spiro-cyclopropane 1,3-dioxin-2-ones (Scheme 61) h10T321i. R1 BocO
O
+
O
CH2Cl2, rt
O
R1
O
Ph3PAuCl, AgOTf
O O
R1
11 examples, combined yields 56–87%
Scheme 61
A urea-based catalyst 46 confers high enantioselectivity on the bromolactonization of conjugated cis-enynes 47 to allene-substituted 1,4-dioxanones h10JA3664i, and a Ru(VIII) species catalyzes the oxidation of diethylene glycol to the monoaldehyde which exists as the stable hemiacetal 2-hydroxy-1,4-dioxane h10S255i.
O O
OH
47
NBS, 1,2-DCE, rt R2
O
O
OMe
R1
O
R1 cat. 46 (20 mol%)
•
N
Br
R2 8 examples, 70–87% ee > 81%
S NH N
O
NHTs
46
A Cu(I)-BINOL-catalyzed intramolecular coupling cyclization features in a new route to benzo-1,4-dioxines from 2-(2-iodoaryloxy)alkanols and cycloalkanols (Scheme 62) h10S3509i. The reaction between phenols and 2-[(2-iodoaryloxy)methyl] oxiranes is also catalyzed by Cu(I) species and leads to 2-substituted benzodioxines h10OBC2700i. After reaction of 2-bromophenol with the epoxide 48, a Pd-catalyzed cyclization affords the 2-spiro-linked piperidine-benzodioxine system 49 h10TL4350i.
456
J.D. Hepworth and B.M. Heron
HO
O
BINOL-Cu salt (20 mol%)
R1 O
Cs2CO3, MeCN, 110 ⬚C
n
9 examples, 54–86%
R1 O
n
I
Scheme 62 Br
O
Br
K2CO3 NBn DMF 100 ⬚C
+ OH
OH O 78%
48
Pd(OAc)2 BINAP K2CO3, NBn PhMe, reflux
O O 60%
NBn
49
High enantioselectivities are observed when the [4 þ 2] cycloaddition of ketenes to 9,10-phenanthraquinone, which leads to benzo-1,4-dioxinones, is catalyzed by N-heterocyclic carbenes h10TL2316i.
6.4.4.2 Trioxanes and Tetraoxanes An account of the developments in artemisinin chemistry has appeared h10CSR435i, and a new eight-step stereoselective total synthesis of (þ)-artemisinin from (R)-(þ)citronellal with an overall yield of 13% has been described h10T2005i. A number of functionalized 1,2,4-trioxanes have been synthesized through the free radical sequential thiol-olefin co-oxygenation reaction of allylic alcohols with thiols and subsequent reaction of the resulting hydroperoxy species with ketones. Manipulation of the sulfide substituent enhances the value of this procedure (Scheme 63) h10OBC2068i.
(i) AIBN, ArSH, MeCN, O2, 0 ⬚C R1
OH
(ii) R2R3 CO, TsOH, CH2Cl2, rt
O
ArS R
1
O O
R2 3
R
15 examples, 25–80%
Scheme 63
Conditions for the catalytic hydrogenation of unsaturated bridged 1,2,4-trioxanes have been identified to allow for their selective conversion into saturated trioxanes or furan derivatives h10TL804i. 1,2,4,5-Tetraoxanes, accessible by the oxidation of 1,3-diketones, are readily oxidized to esters through a series of acid-catalyzed rearrangements h10S1145i.
6.4.5. HETEROCYCLES CONTAINING TWO OR MORE SULFUR ATOMS 6.4.5.1 Dithianes and Trithianes Dilithiation of 9,9-di-n-octylfluorene followed by reaction with S8 affords the fluorene[4,5-cde][1,2]dithiine 50 which is oxidized by NBS/SiO2 to the thiosulfonatebridged derivative 51 of potential as an end-capping reagent h10SL1333i.
457
Six-Membered Ring Systems: With O and/or S Atoms
S
R1
S
O O S
S
(i)
(ii)
60%
66%
R1 R1 R1
R1 R1
50
51
Reagents: (i) n-BuLi, TMEDA, S8, THF; (ii) NBS, SiO2, CH2Cl2, rt
2-(Trimethylsilyl)-1,3-dithiane 1-oxide forms a ketene acetal on reaction with carbonyl compounds and subsequent hydrolytic cleavage of the dithiane unit yields the homologous carboxylic acid h10S2616i. A Pummerer reaction of 2-(2,2,2-trifluoroethylidene)-1,3-dithiane 1-oxide with ketones offers a useful route to 2-trifluoromethyl-1,4-diketones and thence to 3-trifluoromethyl derivatives of 5-membered heteroarenes h10AGE2340i. 3-Nitrothiophenes result from the reaction of 1,4-dithian-2,5-diol with nitroalkenes and subsequent aromatization h10JOC2534i. A 1,4-dithiinyl moiety has been incorporated into a nucleoside through a Pummerer glycosidation of 2-hydroxymethyl-5,6-dihydro-1,4-dithiine 1-oxide h10TL6060i.
6.4.6. HETEROCYCLES CONTAINING BOTH OXYGEN AND SULFUR IN THE SAME RING 6.4.6.1 Oxathianes The o-thioquinone derived from the appropriately substituted o-hydroxy-Nthiophthalimide undergoes a hDA reaction with the phytone-derived pentadeca1,3-diene 52 to produce 4-thiatocopherol (Scheme 64) h10EJO2218i.
R1 3
RO R2
R1
R1 SNPht OH
(i)
3
RO
S
R2
O
R4
4 examples, 64–72%
(ii), (iii) HO
S
R2
O
4 examples, 56–70%
52 Reagents: (i) TEA, diene 52, CHCl3, 65 °C; (ii) H2, 10% Pd/C, PhMe, 60 °C; (iii) TBAF, THF, rt
Scheme 64
R5
458
J.D. Hepworth and B.M. Heron
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10OL108 10OL352 10OL496 10OL684 10OL788 10OL1732 10OL1748 10OL1824 10OL2606 10OL3086 10OL3117 10OL3188 10OL3222 10OL3410 10OL3468 10OL3480 10OL3848 10OL4144 10OL4168 10OL4332 10OL4435 10OL4640 10OL4736 10OL4756 10OL4788 10OL4832 10OL4948 10OL4984 10OL5120 10OL5362 10OL5664 10S211 10S255 10S329 10S505 10S849 10S1053 10S1145 10S1766 10S2092 10S2271 10S2348 10S2616 10S3509 10S3999 10S4043 10SC732
461
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10SC915 10SC2969 10SL85 10SL89 10SL128 10SL1027 10SL1333 10SL1381 10SL2325 10SL2973 10T197 10T321 10T413 10T1404 10T1874 10T2005 10T2089 10T6047 10T6597 10T6681 10T7104 10T7590 10T7933 10T8464 10T8095 10T8615 10TCC45 10TL54 10TL147 10TL192 10TL605 10TL804 10TL961 10TL990 10TL1041 10TL1095 10TL1166 10TL1193 10TL1236 10TL1748 10TL2297 10TL2316 10TL2567 10TL2963 10TL3636 10TL3803 10TL3972
B. Bouguerne, P. Hoffmann, C. Lherbet, Synth. Commun. 2010, 40, 915. S.K. Nayak, S. Bhatt, K. Roy, Synth. Commun. 2010, 40, 2969. L. Banfi, A. Basso, F. Casuscelli, G. Guanti, F. Naz, R. Riva, P. Zito, Synlett 2010, 85. B.D. Calitree, M.R. Detty, Synlett 2010, 89. S. Ay, E.M.C. Ge´rard, M. Shi, S. Bra¨se, Synlett 2010, 128. U.C. Reddy, A.K. Saikia, Synlett 2010, 1027. V.D.B. Bonifa´cio, J. Morgado, U. Scherf, Synlett 2010, 1333. D.T. Patoilo, A.M.S. Silva, J.A.S. Cavaleiro, Synlett 2010, 1381. S. Furuyama, H. Togo, Synlett 2010, 2325. S. Antoniotti, S. Poulain-Martini, E. Dun˜ach, Synlett 2010, 2973. Y. Takashima, Y. Kaneko, Y. Kobayashi, Tetrahedron 2010, 66, 197. Y.-X. Zhang, L. Guo, Y.-H. Wang, L.-L. Zhu, Z. Chen, Tetrahedron 2010, 66, 321. C. Olier, M. Kaafarani, S. Gastaldi, M.P. Bertrand, Tetrahedron 2010, 66, 413. V.Y. Korotaev, V.Y. Sosnovskikh, M.A. Barabanov, E.S. Yasnova, M.A. Ezhikova, M.I. Kodess, P.A. Slepukhin, Tetrahedron 2010, 66, 1404. I. Ullah, M. Sher, R.A. Khera, A. Ali, M.F. Ibad, A. Villinger, C. Fischer, P. Langer, Tetrahedron 2010, 66, 1874. J.S. Yadav, B. Thirupathaiah, P. Srihari, Tetrahedron 2010, 66, 2005. M.G. Nu´n˜ez, P. Garcı´a, R.F. Moro, D. Dı´ez, Tetrahedron 2010, 66, 2089. M. Barontini, R. Bernini, F. Crisante, G. Fabrizi, Tetrahedron 2010, 66, 6047. A.B. Smith, III, H. Smits, D.-S. Kim, Tetrahedron 2010, 66, 6597. C.N. Slattery, A. Ford, A.R. Maguire, Tetrahedron 2010, 66, 6681. W. Yuan, M. Shi, Tetrahedron 2010, 66, 7104. P. Li, L.-L. Luo, X.-S. Li, J.-W. Xie, Tetrahedron 2010, 66, 7590. Q. Qin, D.M. Ho, J.T. Mague, R.A. Pascal, Jr., Tetrahedron 2010, 66, 7933. M.A. Khalilzadeh, Z. Hossaini, M.M. Baradarani, A. Hasannia, Tetrahedron 2010, 66, 8464. Q. Zhang, T. Fang, X. Tong, Tetrahedron 2010, 66, 8095. F.M. Moghaddam, M. Kiamehr, M.R. Khodabakhshi, Z. Mirjafary, S. Fathi, H. Saeidian, Tetrahedron 2010, 66, 8615. I. Abe, Top. Curr. Chem. 2010, 297, 45. D.J. Hong, D.W. Kim, D.Y. Chi, Tetrahedron Lett. 2010, 51, 54. K.C. Majumdar, A. Taher, S. Ponra, Tetrahedron Lett. 2010, 51, 147. Y. Gu, K. Xue, Tetrahedron Lett. 2010, 51, 192. F. Ba, P. Le Poul, F.R. Le Guen, N. Cabon, B. Caro, Tetrahedron Lett. 2010, 51, 605. M.J. Riveira, A. La-Venia, M.P. Mischne, Tetrahedron Lett. 2010, 51, 804. A. Kumar, S.P. Singh, D. Verma, R. Kant, P.R. Maulik, A. Goel, Tetrahedron Lett. 2010, 51, 961. S.S. Mikhailichenko, J.-P. Bouillon, T. Besson, Y.G. Shermolovich, Tetrahedron Lett. 2010, 51, 990. H.-Q. Luo, X.-H. Hu, T.-P. Loh, Tetrahedron Lett. 2010, 51, 1041. M. Lorenz, M.S. Kabir, J.M. Cook, Tetrahedron Lett. 2010, 51, 1095. A. Kotera, J. Uenishi, M. Uemura, Tetrahedron Lett. 2010, 51, 1166. R.D. Alharthy, C.J. Hayes, Tetrahedron Lett. 2010, 51, 1193. J.S. Yadav, B.V.S. Reddy, Y.J. Reddy, B.P. Reddy, P.A. Reddy, Tetrahedron Lett. 2010, 51, 1236. L.-G. Meng, H.-F. Liu, J.-L. Wei, S.-N. Gong, S. Xue, Tetrahedron Lett. 2010, 51, 1748. K.C. Majumdar, A. Taher, S. Ponra, Tetrahedron Lett. 2010, 51, 2297. P.-L. Shao, X.-Y. Chen, L.-H. Sun, S. Ye, Tetrahedron Lett. 2010, 51, 2316. B.C. Das, S. Mohapatra, P.D. Campbell, S. Nayak, S.M. Mahalingam, T. Evans, Tetrahedron Lett. 2010, 51, 2567. J.S. Yadav, B.V.S. Reddy, A.V. Ganesh, G.G.K.S.N. Kumar, Tetrahedron Lett. 2010, 51, 2963. R. Devakaram, D. StC. Black, N. Kumar, Tetrahedron Lett. 2010, 51, 3636. R.A. Valiulin, A.G. Kutateladze, Tetrahedron Lett. 2010, 51, 3803. W.-Y. Chen, L. Ouyang, R.-Y. Chen, X.-S. Li, Tetrahedron Lett. 2010, 51, 3972.
Six-Membered Ring Systems: With O and/or S Atoms
10TL4350 10TL4387 10TL4466 10TL5203 10TL5677 10TL6060 10TL6406 10TL6605 10TL6630
463
K.A. Tony, S.K. Chittimalla, G.A. Rajkumar, A. Chakrabarti, Tetrahedron Lett. 2010, 51, 4350. C.S. Lo´pez, R. Erra-Balsells, S.M. Bonesi, Tetrahedron Lett. 2010, 51, 4387. K. Xie, S. Wang, P. Li, X. Li, Z. Yang, X. An, C.-C. Guo, Z. Tan, Tetrahedron Lett. 2010, 51, 4466. K.-S. Choi, S.-G. Kim, Tetrahedron Lett. 2010, 51, 5203. B.V.S. Reddy, M.R. Reddy, G. Narasimhulu, J.S. Yadav, Tetrahedron Lett. 2010, 51, 5677. C. Paolelle, D. D’Alonzo, A. Guaragna, F. Cermola, G. Palumbo, Tetrahedron Lett. 2010, 51, 6060. S.A. Siry, V.M. Timoshenko, Tetrahedron Lett. 2010, 51, 6406. K. Dahms, A.S. Batsanov, M.R. Bryce, Tetrahedron Lett. 2010, 51, 6605. S. Berger, E. Haak, Tetrahedron Lett. 2010, 51, 6630.
CHAPTER
7
Seven-Membered Rings John H. Ryan*, Jarrod L. Green**, Christopher Hyland**,{, Jason A. Smith**, Charlotte C. Williams* *CSIRO Division of Materials Science and Engineering, Clayton, Victoria 3168, Australia
[email protected];
[email protected] **School of Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
[email protected];
[email protected];
[email protected] { Department of Chemistry and Biochemistry, California State University Fullerton, Fullerton, CA 92831, USA
[email protected]
7.1. INTRODUCTION This chapter summarizes the chemistry of seven-membered heterocycles as published in 2010 and puts particular emphasis on new synthetic methods and novel heterocyclic structures. There continues to be strong interest in molecules with one, two, and three heteroatoms, particularly those systems fused with aromatic or heteroaromatic rings. There is continuing strong interest in new transition metal-catalyzed processes for the preparation of aryl- or heteroaryl-fused seven-membered heterocycles. Cascade, multicomponent, telescoped, and flow processes are emerging. While application of seven-membered heterocycles in medicinal chemistry continues to thrive, there is also an expanding interest in materials science applications.
7.2. SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM 7.2.1 Azepines and Derivatives A number of transition metal-catalyzed synthetic methods have been developed for the preparation of azepines. The copper(I)-catalyzed tandem hydroamination/alkynylation reaction of tethered alkynylamines 1 afforded 2-alkynyl hexahydroazepine 2 h10JA916i, while the iron(III)-catalyzed cyclization of tethered alkynyl-acetal 3 gave 4-acyltetrahydroazepine 4 h10CEJ9264i. Ph
H N
(i)
Bn
1
N Bn
Ph
Ts N
3
2
Reagents: (i) Phenylacetylene, CuBr 5 mol%, dioxane, 100 °C, microwave, 0.5 h, 90%
(i)
OEt
Ts N
O
4
OEt
Ph
Reagents: (i) FeCl3·6H2O 20 mol%, Cl(CH2)2Cl, dioxane, 80 °C, 51%
The [5 þ 2] two-step annulation of secondary amines involves alkylation of dibenzylamine with pent-4-yn-1-yl tosylate affording alkyne 5 followed by
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00016-4
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2011 Elsevier Ltd. All rights reserved.
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J.H. Ryan et al.
N-oxidation and gold(I)-catalyzed cyclization with alkyne oxidation to yield azepan-4-one 6 h10CC3351i. Metal-free intramolecular aminohydroxylation of N-hexenylsulfonamide 7 occurs with 7-endo selectivity yielding the 3-hydroxyhexahydroazepine 8 h10JA1249i. O (i) Ph
N
N
Ph
Ph
Ns Ph
5
OH
(i)
H N
N Ns
7
6
8
Reagents: (i) PhI(OAc)2, TFA, CH2Cl2, rt, 24 h, 81%
Reagents: (i) m-CPBA, 4 MS, CH2Cl2, 1 h then (2-biphenyl)Cy2PAuNTf2, 0 °C, 87%
The reaction of nucleophiles with 2-chloromethylpiperidine 9 gave a mixture of the ring-expanded hexahydroazepine 10 and the direct substitution product 11 emanating from the ring opening of a bicyclic aziridinium salt h10JOC7734i. Ar N
Ar
Ar N
N
Cl
+
OAc Ph
CN
OAc
(i) Ph
9
CN
Ph
10
CN
11
Reagents: (i) NaOAc, EtOH, rt, 2 h, 96–97% [10:11 = 1:2]
The photochemical-induced ring contraction of N-chlorolactams was shown to give carbamates. The rearrangement was shown to be stereospecific as the cis-dimethylpiperidine (43%) was produced from the cis-dimethylazepinone and the isomeric trans-dimethylpiperidine 13 was produced from the corresponding trans-dimethylazepinone 12 h10JOC2610i. O
CO2Me
Cl N
N
(i)
12
13
Reagents: (i) hn, 254 nm, CH2Cl2, –78 °C then MeOH, K2CO3, rt, 18 h, 51%
The bicyclic compound 16, formed from the Diels–Alder reaction of diene 14 and azirine 15, undergoes silica gel-promoted ring expansion to yield the dihydroazepin-4-one 17 h10TL5325i. CH3 +
CH3
(i) N
15 OCH3 14
O
OTMS
EtO2C
TMSO
H3CO
N
CH3
(ii)
CO2Et
16 Reagents: (i) reflux, CH2Cl2; (ii) silica gel, 41%
CO2Et N H
17
Seven-Membered Rings
467
Polyhydroxylated azepines, of interest as imino sugar analogues, were prepared by a number of different methods, including the intramolecular ring opening of epoxides h10AJC821i, the reductive amination of nitroalkanol intermediates generated by the reaction of 1-bromo-1-nitroalkanes with aldehydes h10EJO5190i and from an amino furanose derivative h10T8522i. Finally, an asymmetric synthesis of the natural product ()-balanol was described involving a double alkylation of benzylamine with an appropriately substituted hexane-1,6-diol h10TL467i.
7.2.2 Fused Azepines and Derivatives Reports of preparations of fused azepines and their derivatives were much less numerous than that of the benzoazepines and their derivatives (see Section 7.2.3). Nonetheless, pyrimidoazepines have been generated by both ring-closing metathesis (RCM) h10S1176i and Dieckmann cyclization h10S2017i. In addition, the reductive ring expansion of fused cyclic ketoximes with diisobutylaluminium hydride yielded the corresponding fused azepines. The reaction was exemplified through production of a range of bicyclic and tricyclic fused azepines, and the reaction mechanism was elucidated h10JOC627i.
7.2.3 Benzoazepines and Derivatives In addition to being the target of synthesis, chiral benzoazepines have been applied to chiral phase-transfer catalysis h10AGE2772i and to the asymmetric aminoxylation of aldehydes h10AGE6638i. Simple unsubstituted benzoazepines were prepared by the reductive ring expansion of tetralone ketoximes h10JOC627i. A particularly common method for the formation of benzoazepines is via reaction of iminium-type species with aromatic rings. For example, water accelerated Pictet–Spengler reaction allowed formation of indolobenzoazepines 19 from 18 h10EJO5108i, while condensation of hydrazides with chloromethyl methyl ether yielded benzoazepine hydrazides 20 h10ARK195i.
H3CO
NH NH2
R (i)
N H
18
N
H3CO N H 19
Reagents: (i) RCHO, TFA 10 mol%, H2O, 80 °C, 30 min, 83–95%
OCH3
OCH3 N
20
New syntheses of benzoazepines and their derivatives have been developed using transition metal-catalyzed ring-closing reactions. In this respect, the deployment of ruthenium-catalyzed RCM resulted in the N-heterocyclic carbene precursor 22 from 21 h10OM3765i. Recent examples of palladium-catalyzed reactions include an intramolecular Heck reaction h10JOC5134i, the ring-closing reactions of o-(20 bromophenyl)anilide enolates to afford dibenzoazepinones h10JOC6445i, and intramolecular reductive arylations of propargylamines 23 to give benzoazepinylidenes 24 h10EJO4861i.
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MeO N
MeO NR
(i)
N
N
N
MeO
Br
C6F5
C6F5
21
Pr Ph
R = PMB
23
Reagents: (i) Ru catalyst, CH2Cl2, 77%
MeO
Pr
Ph
22
NR
(i)
24
Reagents: (i) Pd(PPh3)4 3 mol%, HCOONa, DMF/H2O 3:1, 110 °C, mW, 0.25 h , 91%
The propargylamine substrates used in the above reaction were prepared by a copper(I)-catalyzed coupling of an aldehyde, alkyne, and amine, otherwise known as an A3 coupling h10EJO4861i. Elsewhere, microwave-assisted intramolecular A3 coupling was used as the ring-forming step in the preparation of dibenzoazepines h10OL2774i. As a further example of palladium catalysis, the syntheses of the natural products ()-aurantioclavine 28 (R ¼ H) and clavicipitic acid 28 (R ¼ CO2H) involved one-pot Heck/N-alkylation reactions of 25 and 26 to form the indoloazepine intermediate 27 h10JOC7626i. ()-Aurantioclavine 28 (R ¼ H) was also synthesized by intramolecular reaction of a sulfinamide with an alkyl tosylate h10OL2004i. Boc
CO2Me I NHBoc N Boc
OH
25
CO2Me
H N
N
R
(i)
N Boc
26
27
N H
28 R = H, CO H 2
Reagents: (i) Pd(OAc)2, Ag2CO3, PhH, 90 °C, 1 h, then CH3CN, Mg(ClO4)2, 90 °C, 3 h, 94%
The iridium(I)-catalyzed tandem allylic vinylation–amination reaction of 2-allyl and 2-vinylanilines with an allylic dimethyl dicarbonate is a further example of transition metal catalysis directed toward benzoazepines h10AGE1496i. Gallium(III)-catalyzed tandem cyclization/Friedel–Crafts insertion reactions of nitrogen-tethered aryl alkynes 29 favored the 6-exo product 30 over the 7-endo dihydrobenzoazepine product 31 h10JOC8435i. OMe TsN
TsN
TsN
(i)
29
+
30
31
Reagents: (i) GaCl3 10 mol%, anisole, CH2Cl2, rt, 10 h, 97% (ratio of 30:31, 77:23)
Similarly, the tin(IV)-catalyzed cyclization and rearrangement of 1-aryl-g-hydroxylactams 32 proceeded via an intermediate iminium ion to afford the pyrroloquinolines 33 in preference to the pyrrolobenzoazepines 34 h10OL1696i.
469
Seven-Membered Rings
Cl MeO
Cl
H MeO
MeO
OH
(i)
+
H
N
N
32
O
O
N
33
H
34
O
Reagents: (i) SnCl4, CH2Cl2, rt, 2 h, 85% (ratio of 33:34, 80:20)
In other circumstances, product selectivity between quinolines and benzoazepines can be achieved with choice of catalyst. For example, the cyclization and rearrangement of yne-enones such as 35 can be directed toward benzoazepines 36 using a carbophilic Lewis acid or toward quinolones using an oxophilic Lewis acid h10CC6593i.
O O (i) O
N N O
35
36
Reagents: (i) i-PrAuOTf 5 mol%, CH3CN, rt, 3 h, 85%
In addition to transition metal-catalyzed routes to benzoazepines, molecular rearrangements are also of great utility. For example, the Stevens rearrangement can be exploited to generate benzoazepines from tetrahydroisoquinolinium salts h10EJO4393i. Further, reaction of cyclohexadienone 37 with a thiosilane and triflic acid resulted in benzoquinonobenzodiazepine 38 via a dienone-phenol-type rearrangement h10CC797i. The benzannulated aza-enediynes 39 underwent a polar cycloaromatization to yield naphthalenoazepines 40 h10JOC5953i. O
SMe
N H
(i)
37
Ts N (i)
NH O
Ts N
O
O
O
OH
38
Reagents: (i) TMSSMe, TfOH 10 mol%, CH2Cl2, reflux, 120 h, 86%
39
OH
OH
40
Reagents: (i) TsOH, THF/H2O 2:1, 60 ⬚C, 48 h, 46%
An interesting route to naphthalenoazepines 42, which exploits the tert-amino effect, involves thermal rearrangement of 1-(dialkylamino)-8-vinylnaphthalenes such as 41. A deuterium-labeling experiment suggested that the rearrangement proceeds via a hydride shift from an N-methyl group to the vinyl carbon to give a dipolar intermediate that then ring closes h10SL2109i. A 1,7-electrocyclization reaction of azomethine ylide intermediates, prepared by treatment of (dihydro)naphthalene-2-carbaldehydes
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43 with an amino acid such as sarcosine, results in an efficient synthesis of (dihydro) naphthaleno-fused azepines 44 h10SL2411i. OMe
CN
CN
MeO
NC
NC
NMe2
NMe O
(i)
41
MeO
42
Reagents: (i) DMSO, 100 °C, 2.5 h, 81%
NMe
(i)
43
44
MeO
Reagents: (i) sarcosine, xylene, reflux, 80%
A further approach to benzoazepine preparation involves the utilization of Friedel–Crafts chemistry. Treatment of N-(2-arylethyl)-N-(2,2-dimethoxyethyl) amines 45 with trifluoroacetic anhydride effects amine protection and enables intramolecular Friedel–Crafts cyclization and methanol elimination in a single pot to afford dihydrobenzoazepine 46. Catalytic hydrogenation of 46 led to the corresponding tetrahydrobenzoazepine 47 h10OPD380i. The acid-catalyzed intramolecular Friedel–Crafts alkylations of substituted 2-allyl-N-benzylanilines 48 led to dibenzoazepines 49 h10S1291i. An interesting acid-promoted rearrangement and Friedel–Crafts alkylation of tetrahydroisoquinolines 50 produced tetracyclic benzoazepines 51 in high yields h10OL1649i. Benzoazepine ring formation can also be achieved via intramolecular pyrrole alkylation wherein annulation results from treatment of an N-(2-hydroxyethylindane)pyrrole with Dess–Martin periodinane h10OL4560i. OMe
OMe
OMe O
(i)
Br
45
N H
46
Br
OMe
O
(ii)
N
OMe
N
CF3
CF3 Br
47
Reagents: (i) TFAA, –15 °C, TFA, 40 °C, 18 h; (ii) H2, 10% Pd/C, EtOH/EtOAc 1:1, rt, 48 h, 61%
MeO (i) N H
48
MeO N
MeO N H
49
Reagents: (i) 95% H2SO4, 70–75 °C, 0.5 h, 75%
O
O
N
(i)
O
MeO
50
51
Reagents: (i) HCO2H, reflux, 6 h, 92%
Finally, cycloaddition chemistry was a commonly used method for producing benzoazepines. When 2-(2-(2-chloroethyl)-4,5-dimethoxyphenyl)cyclohex-2-enone was treated with sodium azide, a tandem regioselective [3 þ 2] cycloaddition/1,2migration resulted in a cyclohexenonyl-fused dihydrobenzoazepine as the major product h10JOC5289i. Alternatively, oxidation of substituted N,2-diallylanilines with hydrogen peroxide yielded a nitrone intermediate that underwent intramolecular 1,3-dipolar cycloaddition to generate a substituted 1,4-epoxybenzoazepine h10T8392i.
471
Seven-Membered Rings
7.2.4 Oxepines and Fused Derivatives Several new benzoxepine-containing natural products were reported in 2010, including dibenzoxepinediones from Mangrove Endophytic Fungus h10MRC496, 10HCA1369i and four new polyketide derived oxepinochromenones, conioxepinols A–D, isolated from the Endolichenic Fungus Coniochaeta sp. h10JNP920i. In the context of a study of p38 MAP kinase inhibitors, dibenzoxepinones 52 were prepared by intramolecular Friedel–Crafts acylation reactions of the corresponding acid chloride generated in situ h10BML3074i. In a separate report, dibenzoxepinones 52 were oxidized with selenium dioxide to afford diketones that could be condensed with ammonium acetate to give the imidazolodibenzoxepines, e.g. 53 h10JHC640i. The condensation of dimedone with furaldehyde to yield dipyrimidino-fused oxepines was also reported h10CJC478i. CO2H
N
O
O
NH
(iii), (iv)
(i), (ii) O
Cl
Cl
O
Cl
52
53
Reagents: (i) (COCl)2, CH2Cl2; (ii) AlCl3, CH2Cl2, rt, 83–91%; (iii) SeO2, AcOH, 100 °C, 74%; (iv) (CH2O)n, AcOH, NH4OAc, reflux, 84%
Bromination of dialkyl-2-(2-methylbenzylidene)malonates 54 followed by thermolytic extrusion of methyl bromide led to the formation of benzoxepin-3-one-4carboxylates 55 h10RJO216i. CO2Me CO2Me
(i), (ii) O
CO2Me CH3
O
54
55
Reagents: (i) NBS, AIBN, CCl4, reflux; (ii) 190–200 °C, 66%
A silver(I)-promoted ring expansion of D-glucose-derived gem-dihalocyclopropane 56 produced 2-bromooxepine 57, a new member of the septanoside family of carbohydrate mimetics h10JOC955i. A desymmetrizing asymmetric ring expansion of dihydro-2H-pyran-4(3H)-one 58 with N-a-diazoacetyl camphorsultam 59 yielded oxepin-4-one-5-carboxylate 60 with high diastereoselectivity h10CC6810i. OBn O BnO
H Br H
OBn
Br
56
(i)
O
BnO BnO
BnO α:β 4.3:1
OAc
O + N2
Br
57
Reagents: (i) NaOAc, AgOAc, toluene, reflux, 65%
O
O
O
H
58
(i) N O2S
59
H COXc
O
60
dr = >20:1
Reagents: (i) BF3.OEt2, toluene, 110 °C, 75%
A range of interesting new transition metal-catalyzed methods were developed for the preparation of oxepines and derivatives. The syntheses of the
472
J.H. Ryan et al.
oxepinochromone ptaeroxylin and related natural products ptaeroxylinol and eranthin involved RCM as the key step to form the oxepine ring h10JOC353i. RCM was also employed in the synthesis of the oxepine B ring of brevenal h10OL2614i. A glyceraldehyde-derived allene 61 underwent an interesting palladium(II)-catalyzed cyclization to afford tetrahydrooxepine 62. It was proposed that the reaction proceeds via palladium(II)-activation of the allene followed by insertion of allyl bromide and b-bromide elimination to regenerate the catalyst h10CEJ13243i. Palladium-catalyzed oligocyclizations were applied to the preparation of fused tricyclic oxepines h10EJO4687i. OBn
OBn HO
HO OCOPMP
OCOPMP
(i) O
HO
61
62
Reagents: (i) allyl bromide, PdCl2 5 mol%, DMF, rt, 59%
A benzoxepine 64 has been constructed via a palladium-catalyzed CH insertion of tethered aryl iodide 63 containing an auxiliary 8-aminoquinoline carboxamide directing group h10OL3414i.
H N
I O
N
N
H N
(i) O
O
O
63
64
Reagents: (i) Pd(OAc)2 10 mol%, Ag2CO3, o-PBA, t-BuOH, 110 °C, 48%
A highly functionalized bicyclic oxepine 66 was synthesized by a novel cascade process involving PtCl2-catalyzed 1,2-acyloxy migration of a propargylic ester 65 to give a carbonyl ylide intermediate which then underwent an intramolecular [3 þ 2] cycloaddition reaction with the pendant double bond h10JA1788i. H O Ph
OH
(i) O
O O
65
Ph
O
O 66
Reagents: (i) PtCl2 10 mol%, CO 1 atm, 60 °C
A copper(II)-catalyzed intramolecular OH insertion reaction of diazoketone 67 was employed to synthesize enantiomerically pure oxepine-2-carboxylate 68, albeit in low yield h10JA16374i. Copper catalysis has also been used to synthesize chlorinated bicyclic C-fused oxepino[3,2-c]azetidin-2-ones via radial chlorine transfer h10JOC7408i.
Seven-Membered Rings
O
OH O
(i)
OBn
N
ligand =
N2
N
O
OBn O
473
67
96% ee
tBu tBu
O
68
Reagents: (i) Cu(OTf)2 5 mol%, ligand 6 mol%, NaBAr F 6 mol%, CH2Cl2, 25 °C, 14%
An indium(III)-catalyzed tandem Nazarov cyclization/intramolecular Coniaene-type reaction of alkynyl dienones, including 69, has been used to prepare a range of fused polycyclic systems, including pentacyclic oxepine 70. These reactions displayed exo selectivity with only the cis system being obtained h10CEJ11813i. O
O E
CO2Me
O
O
(i) O
E = CO2Me
O
O
O
H
69
70
Reagents: (i) ln(OTf)3, toluene, 110 °C, 61%
With the construction of the dibenzo[b,f]oxepine ring system of bauhinoxepin J in mind, a DDQ-promoted oxidative dearomatization–cyclization of 2-phenethylsubstituted tetramethoxybenzene 71 was deployed to construct tricyclic quinone monoacetal 72 h10H(80)623i. OMe OMe
OH
OMe OMe O
(i) O
MeO OMe
MeO
71
72
Reagents: (i) DDQ, dioxane, rt, 81%
An impressive increase in molecular complexity was realized during the synthesis of ent-abudinol B by way of a Lewis acid biomimetic cyclization of polyepoxide 73 which afforded the intermediate 74 containing the oxepine ring of the natural product h10JA5300i. H O Me
H O (i)
O Me H
TBSO
73
HO O H
Reagents: (i) TMSOTf, DTBMP, CH2Cl2, –78 °C, 50%
74
J.H. Ryan et al.
474
An iodolactonization and an iodine-mediated cyclization were used to construct oxidized fatty acids and benzoxepine derivatives, respectively h10H(80)689, 10SL1407i. A synthesis of anti-microtubule benzoxepines using a Suzuki–Miyaura coupling, a Grignard addition, and a cyclodehydration as key steps has been developed h10TL3127i. Treatment of 75, derived from conjugate addition reaction of an indole and a nitroalkene, with di-t-butyl dicarbonate generated a nitrile oxide in situ which then underwent intramolecular [3 þ 2] cycloaddition with the pendant alkyne to afford isoxazolobenzoxepines 76 in high to very high yields h10TL3006i. RN
NR R
R R
(i)
N R
NO2 O R
O R1
O
75
R
R1
76
Reagents: (i) (Boc)2O, DMAP, toluene, 90 °C, 72–96%
7.2.5 Thiepines and Fused Derivatives The majority of new syntheses of thiepine derivatives involve the reaction of sulfides with alkyl- and aryl- bis-electrophiles. A chemoselective heterocyclization reaction of enantiopure C2-symmetric bis-epoxide 77 with sodium sulfide nonahydrate was shown to lead to the chiral polyhydroxylated thiepane 78 h10T7487i. Using the same sulfide reagent with dichlorostilbene 79, an SNAr-isomerization-SNAr sequence led to dibenzo[b,f]thiepine 80 h10TL5277i. O
O
S
Cl
(i)
OBn
BnO
77
(i)
OH
HO BnO
78
OBn
Cl
Reagents: (i) Na2S.9H2O, MeCN:H2O, reflux, 94%
S
79
80
Reagents: (i) Na2S.9H2O, NMP, 180 °C, 44%
The radical addition-transfer of S-(2-fluoro phenacyl)xanthates 81 with alkenes was used to construct xanthates 82, which, following aminolysis to the corresponding thiol and addition of base, underwent intramolecular nucleophilic aromatic substitution of the ortho-fluorine to give benzothiepines 83, generally isolated in high yields h10TA1649i. O
O R
SCSOEt
(i)
(ii)
+ F
F
81
O
F
F
82
R F SCSOEt
S
83
Reagents: (i) lauroyl peroxide 5 mol%, cyclohexane or EtOAc, reflux, 94%; (ii) ethylenediamine, Et2O:EtOH, rt then DBU, THF, reflux, 18–97%
R
475
Seven-Membered Rings
Swager and coworkers have synthesized thermally stable thiepines 85 that are electropolymerizable, giving thiepine-containing electroactive polymers. These thiepines were prepared in high yields by a direct electrophilic aromatic substitution reaction of 1,2-dithienylbenzene derivative 84 with sulfur dichloride h10JOC999i. MeO
OMe
MeO
OMe
(i)
S 84
S
S
S
S
85
Reagents: (i) SCl2, CH2Cl2, –40 °C, 80%
7.3. SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETEROATOMS 7.3.1 Diazepines and Derivatives Aimed at the construction of RNA-directed ligand libraries, cyanamide-induced rearrangement of epoxy-d-lactam 86 produced the ring-expanded tetrahydro-1,3diazepine carboxylic acid 88. It was proposed that the rearrangement proceeds via cyanamide ring-opening of the epoxide, followed by silyl migration and proton transfer to give lactam 87. Under the reaction conditions, a complex mechanism follows involving ring-closure of the lactam nitrogen onto the pendant nitrile moiety of 87 producing 88 in low yield h10OL360i. O
O
(i)
HN
O
NHCN
HN
O– OR
86
O
O NHCN
HN
– N
NHCN
O–
OR
OR
HN
OR
OR
CO2H
N
(ii) H2N
OH 87
88
OH
Reagents: (i) NaNHCN, DMSO; (ii) MeOH, H2O, HCl, 15% (2 steps, R = TBDMS)
The ring expansion reaction of 4-chloromethyltetrahydropyrimidin-2-ones 89 with nucleophiles such as PhSNa, NaCN, or NaCH(CO2Et) is favored over direct substitution reactions to give tetrahydro-1,3-diazepin-2-ones 90 h10TL5056i. CO2Et
CO2Et Nu•• –
Cl NH
HN O
89
CO2Et
CO2Et Nu
Cl N
HN O
•– •
•– •
–Cl
N
HN O
HN
NH O
90
Carbon dioxide can be used as a carbonylating agent in the synthesis of cyclic ureas. N,N-Dibenzyl-1,4-diaminobutane 91 reacts with carbon dioxide, 1,1,3,3-tetramethyl-2-phenylguanidine (PhTMG) and diphenylphosphoryl azide (DPPA) to
J.H. Ryan et al.
476
give an activated carbamoyl species 92 which then undergoes ring-closure to afford the 1,3-diazepan-2-one 93 h10JOC3037i. Bn
Bn N H H N Bn
N O
O
H N
P
O OPh
N
OPh
Bn
91
Bn
O
N
(i)
Bn
92
93
Reagents: (i) CO2, PhTMG, DPPA, CH3CN, 73%
Reductive amination of the Garner aldehyde 94 with amino ester hydrochlorides 95 followed by divergent functional group manipulation produced azide 96 and alcohol 97. Intramolecular alkylation reactions of the amine derived from azide 96 or the alcohol 97 resulted in chiral perhydro-1,4-diazepines 98 or perhydro-1,4-oxazepines 99, respectively h10TL1483i. N3 TsO O
R
H3CO2C +
N Boc
H N
(i)
BocHN
R
NTs 96
R NTs 98
BocHN
CIH.H2N
CHO 94
OTs
95
O
(ii)
HO
R
R BocHN
BocHN
NTs 97
NTs
99
Reagents: (i) H2, Pd/C, MeOH then K2CO3, rt, 66–72%; (ii) K2CO3, MeOH, rt, 90–93%
Multicomponent reactions of 1,3-diamine 100, carbonyl compounds 101 (ketones and aldehydes), and isocyanides 102 resulted in 2-amino-tetrahydro-1,4diazepines 103 h10EJO1525i. Intramolecular aza-Wittig reaction of chiral aminophosphorane 104 produced chiral tetrahydro-1,4-azepin-2-ones 105 h10RJO480i. R′
+ NH2 100
H N
R
O NH2
(i) 101
N 103
CN R′′ 102
CH3
R R′
F3C
R′′
Ar
O N PPh3
HN
(i)
Ar
N
HN
O 105
O 104
Reagents: (i) TMSCl, CH3CN, MeOH, 40–50 °C, 20–24 h, 43–91%
CH3
F3C
Reagents: (i) toluene, reflux, 64 h, 52–60%
Reaction of substituted 1,2-diaminoethanes 106 with skipped diyne 107 afforded perhydro-1,4-diazepine derivatives 108 with good stereoselectivity through consecutive aza-Michael additions, the latter involving a 7-exo-dig cyclization h10CEJ3276i. R
BzO
NH2
BzO
Ph (i)
+ R′
NH2 106
CO2Me HN
MeO2C
107
Ph
MeO2C
CO2Me
Reagents: (i) CH2Cl2, rt, overnight, 54–74%
R
NH R′
108
477
Seven-Membered Rings
A continuous flow process was developed for tandem SNAr reaction of 1methyl-homopiperazine with the 2-fluoronitrobenzene 109 and hydrogenation to afford aniline 110, an intermediate in the flow processing of the potent 5HT1B antagonist 111. In-line purification was achieved by flowing product solutions through glass columns consisting of Quadrapure-benzylamine (QP-BZA) to scavenge hydrofluoric acid from the SNAr reaction and Quadrapure thiourea (QP-TU) to scavenge leached palladium from the hydrogenation reaction h10SL505i. O
MeO
MeO
MeO (i)
NH2 N
NO2 F 109
N
NMe 110
N H
NMe
O
N O
111
Reagents: (i) 1-methylhomopiperazine, EtOH, 135 °C, 10 min, R4 convection heater; QP-BZA, glass column; H2, 10% Pd/C, H-Cube® hydrogenator reactor; QP-TU, glass column, ‘quantitative’ yield
Desymmetrization of homopiperazine 113 with La Rosa’s lactone 112 afforded amide 114 in high purity, as part of the 100 g scale synthesis of the histamine H3 receptor antagonist 115 h10JOC4463i. 1,4-Diazepane derivatives such as 115 and 116 show promise as potential candidates for treatment of various conditions including ADHD, narcolepsy, and Alzheimer’s disease h10BML2755, 10BML4210i. The 1,4-diazepanyl ring conformation plays a critical role in the activity of a dual orexin receptor antagonist MK-4305 117 in phase III clinical trials for treatment of insomnia h10JME5320i. Novel chelating agents have been prepared based on the 1,4-diazepane core. Derivatives of 6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid 118 have been prepared for complexation of gadolinium(III) and europium(III) in search for new magenetic resonance imaging contrast agents h10OBC4569, 10ICC663, 10DT9897i. 1,4-Diazepane derivatives have been prepared for selective complexation of heavy lanthanide(III) cations and for complexing iron(III) to provide models for intradiol-cleaving protocatechuate dioxygenases h10IC616, 10DT9611i.
O N Ac
NH +
(i)
HO
N
O N
HN
N
N
O 112
F
H N
113
Ac
O 114
Reagents: (i) t-amyl alcohol, 90 °C, 15 h, 72%
N Ac
O 115
J.H. Ryan et al.
478
F N
O N O
O
N O
N
Cl
HO2C
N
N
N
N
N
Me
HO2C
N
HO2C
N
CO2H
N
Me
116
118
117
7.3.2 Fused Diazepines and Derivatives The condensation of diamines with dielectrophiles continues to be a useful method for preparation of novel fused diazepines. Thus, hexahydropyrano-1,2-diazepin-3ones 119 were prepared by condensation of pyranose keto-esters with hydrazines and were reported to inhibit proliferation of a number of cancer cell lines h10EJM4615i. Condensation of cyclopropanated diamines with imidate esters followed by deprotection resulted in the formation of novel 3,5-diazabicyclo[5.1.0] octanes 120, which acted as selective competitive glycosidase inhibitors h10T5566i. Condensation of 1,4-diaminobutane with dihydropyrans gave novel octahydropyrido-1,3-diazepines 121 h10S2348i. MeO
O
O
Ph HO
NH
O
F3C
R
N N R H
N
N
119
120
121
N H
A novel radical synthesis of bicyclic guanidines was reported. Slow addition of Bu3SnH and AIBN to a solution of azide-substituted N-acyl cyanamide 122 in benzene at reflux initiated a radical domino process that led to the formation of the novel diazepino-fused system 123 h10AGE2178i. O N N3
O (i)
O
N
N
N •
•
NH
N
O
N
N H
N
122
N H
N
123
Reagents: (i) Bu3SnH 2 equiv, AIBN 1.5 equiv, benzene, reflux, 1 h, 24%
The application of 1,3-diazepine ketene aminals to the construction of novel annulated heterocycles continues to be utilized. Cyclocondensation of the ketene aminal 124 with 1,4-benzoquinones delivered tetrahydro-1,3-diazepinoindole derivatives 125 h10S3536i. Three-component condensation of ketene aminal 124 with triethoxymethane and ethyl 4,4,4-trifluoro-3-oxo-butanoate afforded hexahydropyrido-1,3-diazepine derivatives 126 h10GC2043i.
Seven-Membered Rings
O
479
O
NH
Ar (i)
N
NH
Ar
NH
O (ii)
Ar
N NH 125
OH
F3C
124
OH CO2Et
126
Reagents: (i) benzoquinone, acetic acid 10 mol%, dioxane, reflux, 6–8 h, 76–86%; (ii) triethoxymethane, ethyl 4,4,4-trifluoro-3-oxo-butanoate, reflux, 40–59 min, 78–88%
Unusual fused 1,3-diazepines continue to be of significant biological interest, with the tetrahydroimidazolono-1,3-diazepine 127 exhibiting good potency as gsecretase modulators, excellent pharmacokinetics in rats and lowering of Ab42 levels in animal models in vivo h10BML5380i. The imidazo-1,3-diazepine 128 showed in vitro antitumor activity against a range of cancer cell lines h10BML4386i. F NH2 O
N
N
N
N
N
N
N
H3C(H2C)17HN
N
NH2
N Et
127
128
Laccase-mediated oxidative CN bond formation followed by cyclization of dihydroxybenzoic acid derivatives such as 129 with 2-aminobenzamide and heteroaromatic analogues such as 130 produced novel fused 1,4-benzodiazepine derivatives such as 131. Optimal yields were generally obtained with the solubility enhancing N-(2-hydroxyethyl)amide side-chain was incorporated h10GC879i. O OH
O
H2N NH(CH2)2OH
OH
H2N
N H O
129
NH(CH2)2OH
N (i)
+
130
O
HO HN O
NH N N H
131
Reagents: laccase (Pycnoporus cinnabarinus), air, NaOAc buffer, pH 5, rt, 71%
The chiral aldehyde 132 underwent iminium cyclization with anilines in the presence of TFA to afford a mixture of pyridodiazepine diastereoisomers 133. Both diastereoisomers undergo Smiles rearrangement to afford a single chiral pyrrolo-pteridine product 134 with implications for the mechanism h10JOC8147i. The TFApromoted iminium cyclization of 2-amino-3-enaminopyrimidines with aldehydes resulted in tetrahydrobenzopyrimido-1,4-diazepines 135 h10JHC990i.
J.H. Ryan et al.
480
Cl
Cl
Cl N
N
(i)
N
N N
N
Cl N
N
NHAr
O N
(ii)
N
N
N
N
H N
N
Ar
132
133
134
H N N H
O R
135
Reagents: (i) ArNH2, TFA, Cl(CH2)2Cl, rt; (ii) TFA, Cl(CH2)2Cl, 60 °C
Novel 1,4-diazepanyl-fused quinazolinones 137 and 139 were generated via reductive amination of pendant aldehydes 136 and 138, respectively. A derivative of 139 was identified as a potent and highly selective 5-HT2C agonist that caused weight loss in a rat model upon oral dosing, a result relevant to the development of anti-obesity agents h10BML1128i. O
R3
Boc HN (i)
N
R1
R3
N NH
R1
O
NHBoc
N
R2
NH
R2
O
NH
O
NH
NH Cl
Cl
O
137
136
NH N
(i)
O
139
138
Reagents: (i) TFA, Et3SiH, CH2Cl2
There continue to be numerous reports of isocyanide-based multicomponent reactions for the preparation of fused 1,4-diazepines. Ugi reaction of isonitriles 140 (derived from the Baylis-Hillman adducts of acrylates), trimethylsilyl azide, aliphatic amines, and aldehydes or ketones afforded tetrazoles 141. Ester hydrolysis followed by peptide coupling yielded the novel tetrazolo-1,4-diazepinones 142 h10TL510i. In alternative format, Ugi reaction of 2-aminonicotinic acid derivatives, amines, aldehydes, and the convertible isocyanate, 2-isocyanophenyl benzoate, gave a product which cyclized in the presence of potassium t-butoxide to afford pyridodiazepines h10EJO5397i. Starting with 2-amino-thiophene-3-carboxylic acids, other variations of the Ugi–deprotection–cyclization reactions afforded thieno-1,4-diazepine-2,5-diones h10CBD116, 10CBD130i. Ar CN CO2R + 140 R3-NH2
O R1
Ar R2
TMSN3
(i)
N
N N CO2R N R1 2 NH3 R R 141
Ar (ii), (iii) N
N N N R1
Reagents: (i) MeOH, rt,10 h, 60–86%; (ii) LiOH 5 equiv, THF-H2O 1:1 v/v, rt, 8 h, 70–86%; (iii) EDC 1.1 equiv, NMM 1.1 equiv, CH2Cl2, –10 to 0 °C, 1 h, 68–84%
O N 3 R2 R 142
481
Seven-Membered Rings
The reactions of bifunctional starting materials and/or reagents have been applied to make novel fused diazepines. Tandem alkylation-intramolecular lactamization of pyrimidine derivatives 143 with amines resulted in pyrimido-1,4-diazepinones 144 h10JCO503i. Glycine methyl ester acts as a nucelophile and an electrophile in the reaction with pyrazolopyridine 145 to afford novel tricyclic scaffold 146 h10T2843i. Cl
Cl
Cl R2
N N
(i)
R3
N
CO2Et N R1 143
N N
N N
N
NH2
O N
N R1
R2
144
Ph
N
Cl
NH
(i)
O Ph
N
145
N H
146
Reagents: (i) H2NCH2CO2Me.HCl, Et3N, nBuOH, 160 °C, mW, 30 min.
Reagents: (i) R3NH2, Et3N, CH3CN
During the development of high-load nitric oxide donors, the “click” reactions of di- and tetra-azides were explored. Thus, 1,3-dipolar cycloaddition reactions of the bis-azide 147 with alkynes 148 afforded a mixture of the expected bis-triazoles 149 and bis-tetrazolo-1,4-diazepines 150. Using copper(II) sulfate-sodium ascorbate, the bis-triazoles 149 predominated; however, with copper(I) iodide-diisopropylethylamine, the coupled products 150 predominated, the latter resulting from copper(I)catalyzed oxidative coupling h10OL4256i. N3 N3
O Ph + O 147
(i) or (ii)
R
O
R
N N N
R
O N N N 150
O
Ph +
R 148
N N N
R
O
N N N
149
Reagents: (i) CuSO4.5H2O 40 mol%, Na-ascorbate 80 mol%, THF/H2O 3:1, rt, 3: 60%; 4: 12%; (ii) Cul 2 equiv, DIPEA 2 equiv, CH3CN, rt, 3: trace; 4: 74%
R
=
Ph
H3CO N + –N N O
O N O
There is significant interest in bis(pyridinylidene) derivatives and their oxidized diquaternary counterparts as neutral organic donors and nonlinear optical chromophores, respectively. Treatment of 1,3-dipyridinium salts 151 with base resulted in elimination of two mole equivalents of hydrogen iodide and formation of the bis (pyridinylidene)derivatives 152. These species were converted into the more air stable bis(pyridinium) salts 153 for cyclic voltammetry studies. Changes in the substituents at the 4- and 40 -positions of the pyridines led to only slight changes in the redox potential. The seven-membered central ring analogues were more powerful electron donors than the analogous six-membered ring systems, and it is thought that the flexibility of the seven-membered ring plays a role in such differences h10BJO73i. A series of similar derivatives were prepared with variation in the amine electron donor substitutents, p-conjugated bridge and alkyl quaternizing tether. The compounds acted as highly active, two-dimensional nonlinear optical chromophores with reversible electrochemistry h10JA10498, 10JPC12028i.
482
J.H. Ryan et al.
2l
R
–
R
+
N
–
+
N
base
2l
R N
l2
N R= N
[–2Hl]
+
N R
151
N
+
N R
or N
N
152
R
153
When the chlorodiazepinedione 154 was treated with sodium cyanide at elevated temperatures, the unexpected cyclobutene fused tetrahydrodiazepinedione 157 was obtained. The transformation was rationalized as occurring via substitution product 155, which undergoes a-elimination of hydrogen cyanide to give carbene intermediate 156 which in turn rearranges to the cyclobutene derivative 157 h10EJO3665i.
NH
Cl O
R N
O
154
NH
NC O
R N
O
155
O
NH
:
R N
O
156
H N
O
NH O 157
Reagents: (i) NaCN, DMSO, 100–140 °C, 6 h, 45% (R = n-C5H11), 38% (R = CH2CH2Ph)
7.3.3 Benzodiazepines and Derivatives Among the various methods for synthesis of benzodiazepine derivatives, there is much current interest in isocyanide-based multicomponent reactions. A novel azide-Ugi five-center four-component reaction of 2-carboxymethyl phenylisocyanide 158 with ketones, ammonium chloride, and sodium azide afforded amino ester intermediates 159 which spontaneously lactamized to give tetrazolo-1,4-benzodiazepines 160 h10OL3894i. Many other Ugi–deprotection–cyclization strategies have been developed. The Ugi five-component carbon dioxide-mediated condensation of ortho-N-Boc-amino benzylamines, phenylglyoxaldehydes, isocyanides, and a saturated solution of carbon dioxide in methanol, led to a Boc-protected amine intermediate that was deprotected with TFA promoting cyclization to afford novel fused hydantoin-benzodiazepine derivatives 161 h10TL4689i. Similar Ugi reactions with aniline or amine Boc-protected 2-aminobenzylamines, aldehydes, isocyanides, and N-Boc anthranilic acids followed by deprotection and ring closure afforded quinazoline–benzodiazepine derivatives 162 or 163 h10TL3951i. Four-component Ugi–deprotection–lactamization reactions of N-Boc-1,2-phenylenediamines (or 2Boc-aminobenzylamines), glyoxalates, isocyanides, and N-Boc-anthranilic acid afforded fused quinoxaline-benzodiazepines 164 (or bis-benzodiazepines 165) h10TL4566i. Further variations of these multicomponent reactions have been applied to the synthesis of libraries of benzo-1,4-diazepine-2,5-diones 166 and benzo-1,5-diazepin-2-ones h10JCO206, 10JCO186, 10JCO497i.
483
Seven-Membered Rings
R2
O
O
OMe
R1
R3 NH4Cl
+
(i)
OMe H2N R2
R1
N N
NC NaN3
158
O
O
N
NH R1 N N
R3
N
159
R2 R3
N N 160
Reagents: (i) MeOH/H2O, 32–81%, 19 examples
O R3
N
N
N
R1
O
N H
N
N N H
R2 161
N H
162
O
R2 N N H
N H
164
R1
NH
R1
O O
R2 N
N
NH
R1
163
O
R2
O
O
O
O
O
Ar N H
165
O 166
Pictet–Spengler-type reactions provide ready access to benzodiazepine derivatives. For example, the reaction of indoline 167 and formalin produced tricyclic benzodiazepine intermediate 168 a key step in the synthesis of the glycogen synthase kinase-3 (GSK-3) inhibitor bisarylmaleimide 169 h10OL3700i. A condensation reaction of a soluble PEG polymer supported indolinylquinoxalinone with ketones and trifluoroacetic acid in chloroform heated at reflux, produced fused indolodiazepinoquinoxalinones 170 h10OL2174i. Similar reactions of 3-aminoquinazolines afforded benzodiazepinoquinazolines 171 h10CHE592i. A related iminium cyclization reaction involves the interaction of trimethylsilyl chloride with aromatic compounds tethered with N,O-acetals and led to 1,4-benzodiazepines 172, an example of a benzo[f][1,4]oxazepine 173, and 1,4-diazepinoindoles 174 h10T8837i. H N
O
O F
F N AcOH.H2N
N N N H
167
168
N N
Reagents: (i) CH2O/H2O 1 equiv, cat. H2SO4, AcOH, 70 °C
O
2 H R R3 N
H N
O N
R1
N
F (i)
N
N
170
H N
R1
X
N
R1 NR2
N
171
169
O
R2
R3 172 X = NR
173 X = O
NMe R 174
484
J.H. Ryan et al.
There is significant continued interest in intramolecular 1,3-dipolar cycloaddition reactions for the construction of novel fused benzodiazepine derivatives. Intramolecular cycloaddition reactions of azides with terminal alkynes led to 1,2,3-triazolo-fused 1,4-benzodiazepines 175, 1,2,5-benzothiadiazepines 176, pyrrolobenzodiazepines (PBDs) 177 and pyrrolobenzothiadiazepines 178, the latter being tetracyclic analogues of the antitumor antibiotics PBDs h10TL4859i. A similar approach with aryl-substituted alkynes afforded aryl-substituted triazolo-1,4-benzodiazepines h10OBC4971i. Reversing the amide and switching the position of the acetylene and azide led to isomeric triazolobenzodiazepines 179 h10S858i. Intramolecular cycloaddition reactions of nitrilimines and alkenes led to pyrazolobenzodiazepines 180 h10EJO1694i. CO2Et
Me X NH
X N
N
N
R N
N N
175 X = CO 176 X = SO2
1
R
N N
Ph H Me N
N
R
N
N
O
N
N
177 X = CO 178 X = SO2
N
Ph
O
O
R2 180
179
Some interesting examples of palladium- and copper-catalyzed N-arylation reactions have emerged for diazepine synthesis. Intramolecular palladium-catalyzed amidation of chloroamide 181 afforded pyridopyrrolo-1,4-diazepinone 182. Intramolecular N-arylation of prolinamides was successfully developed for the preparation of isomeric pyridopyrrolodiazepinone cores 183–185 with the latter two examples requiring palladium catalysis for efficient cyclization. Also noteworthy is the requirement for N-methylation of the amide linker to favor the E-rotamer, as without the methyl group, cyclizations were not observed h10TL4053i. Construction of the dibenzodiazepine skeleton of the retinoid X receptor synergist 186 involved intramolecular palladium-catalyzed arylation of an aniline h10H (81)2465i. Copper-catalyzed amination of aryl iodides followed by intramolecular lactamization afforded pyrrolo-1,4-benzodiazepinediones h10T5714i. An efficient synthesis of the quinazolinobenzodiazepine natural products ()-circumdatins H and J 188 was achieved via copper(I)-catalyzed intramolecular N-arylation of quinazolinone 187 h10OL3716i. N
Cl H
CONH2
(i)
H N
N
N
O H
Y Z
N
181
X
N
H O N Me
182
183 X = N, Y = CH, Z = CH 184 X = CH, Y = N, Z = CH 185 X = CH, Y = CH, Z = N
Reagents: (i) Pd(OAc)2 8 mol%, K2CO3 2 equiv, BINAP 2 equiv, dioxane, 120 °C, 24 h, 90%
R
R
H N
O
O Br NH
MeO N
186
N
187 CO2H
(i) N
O
MeO
N N
O N
188 R = H, OMe
Reagents: (i) Cul, L-proline, NaH, DMF, 120 °C, 89–90%
Seven-Membered Rings
485
The quinazolinobenzodiazepine natural products circumdatins E, H and J, asperlicin C, benzomalvin A and schlerotigenin, and analogues have been the target of much synthetic endeavour h10OBC1287, 10S643, 10ARK282, 10M1249, 10JCO125i. A noteworthy example is the total syntheses of asperlicin C, circumdatin F and schlerotigenin, and other fused quinazolines 190 by scandium(III) triflate and microwave-promoted double-cyclization of anthranilate-containing tripeptides 189 h10OBC419i. O O
N H
(i)
CO2H
NH
N
O
R
189
R
O NH
N
NH2
190
Reagents: (i) Sc(OTf)3, DMF, mW, 140 °C, 10–15 min
New approaches to PBDs have been reported. Furan ring opening-intramolecular pyrrole ring closure of N-(furfuryl)anthranilamides resulted in pyrrolo-1,4-benzodiazepines such as 191. This procedure was applied to the preparation of the heteroaryl-fused system, pyrazolo[3,4-f]pyrrolo[1,2-a][1,4]diazepine, as well as the parent core system, pyrrolo[1,2-a][1,4]diazepine h10OBC3316i. Me
Me MeO
NH2
O
(i)
H N
MeO
N
MeO MeO
NH
O O
191
Reagents: (i) HCl, AcOH, 24 h, 78%
The PIFA-mediated ring closure of N-(3-aminopropyl)alkynamides 192 gave functionalized 5-aryl-2-pyrrolidinones, which underwent ring closure to afford the corresponding perhydropyrrolodiazepines 193. The method was then readily adapted to the preparation of isomeric PBDs 194 and 195 h10T5811i. R R
R
R CBzNH
HN
O
HN
HN
(i), (ii)
HN
PMP PMP
192
N
PMP
Ar
N
N
O
O
O
193
194
195
Reagents: (i) PIFA, TFE, rt; (ii) H2, Pd/C, MeOH/HCl, 34–38% (two steps)
Ar = Ph, PMP, 4-ClC6H4 PMP = 4-methoxyphenyl
486
J.H. Ryan et al.
A novel approach to the tetrahydro-2H-1,3-benzodiazepin-2-one core involved base-promoted ring closure of diurethanes, which in turn were produced by Curtius rearrangement of bis-azides in the presence of alcohols h10S1365i. Benzo-1,3-diazepin-2-ones and pyrimido-1,3-diazepin-2-ones were prepared by reaction of precursor diamines with triphosgene in THF h10BML3897i. Intramolecular N-alkylation, cyclocondensations of amines and aldehydes (or ketones), and lactamization continue to be useful methods for the preparation of new benzodiazepine derivatives. Cyclodehydration of aminobenzhydrols leading to 5-arylpyrrolo[2,1-c][1,4]benzodiazepines was achieved under mild conditions by N-methylation of the amide link connecting the nucleophile to the electrophile, which favored the more reactive E-rotamer and the exit of the leaving group h10T2718i. Condensation of dialdehydes with phenylenediamines afforded novel spiro-fused benzodiazepines h10PS1484i. Amino-1,5-benzooxazepines and hydroxy-1,5-benzodiazepines, some exhibiting anti-inflammatory activity, were prepared in a one-pot condensation of 2,3-diaminophenol and ketones h10JME8409i. Lactamization of a solid-supported ester resulted in traceless synthesis of novel pyrazinediazepinedione derivatives h10T2514i. Some interesting benzodiazepine derivatives have been prepared. Two total syntheses of fuligocandins A and B were reported. The first approach involved chemoselective sulfurization of a pyrrolobenzodiazepinedione derivative followed by Eschenmoser episulfide contraction h10TL238i. The second approach involved selective nucleophilic addition to the same pyrrolobenzodiazepinedione derivative followed by Meyer-Schuster rearrangement and aldol condensation h10SL2498i. An enantioselective synthesis of benzodiazepinones was achieved via catalytic hydrogenation using a Hantzsch ester in the presence of chiral N-triflyl phosphoramide derivatives, which also contain a seven-membered dibenzodioxaphosphepine scaffold h10ASC2629i. The chemistry of seven-membered N-heterocyclic carbenes continues to be of considerable interest as the larger NCN angle compared to smaller ring systems, leads to increased nucleophilicity. The first seven-membered N,N0 -diamidocarbene (DAC) was reported in 2010. Condensation of N,N0 -dimesitylformamidine with phthaloyl chloride afforded the carbene precursor 196 which was dehydrochlorinated with strong base to afford the DAC 197, isolated as a bright yellow powder. The carbene 197 was characterized by complexation reactions with rhodium(I), iridium(I), and gold(I) and by a coupling reaction with an aryl isocyanide to give the N, N0 -diamidoketenimine 198 h10OM4569i. Mild heating of the seven-membered carbene 199 resulted in unexpected intramolecular insertion of the carbene into an ortho-methyl C H bond to afford an indolodiazepine 200 h10TL557i. The structurally complex seven-membered amidine salts 201 were prepared via a stereoselective Diels–Alder reaction of olefinic cyclic amidine salts with cyclopentadiene. The amidines were converted into the corresponding rhodium(I) carbene complexes h10EJI1604i.
487
Seven-Membered Rings
O N
O N
N
H
Cl
Mes
Mes
O
O
196
O N
N
C
Mes Me
Mes
:
Mes
(ii)
(i)
O
N Mes
C
197
N
Reagents: (i) NaHMDS, C6H6, 25 °C, 30 min, 85%; (ii) CN-2,6-(Me)2-C6H3, toluene, 25 °C, 4 h, 92%
Me 198 Mes = 2,4,6-(Me)3-C6H2
N
N
(i)
N
Mes
:
Mes
H
N
H –
H N
N
Mes
199
+
BF4
Mes
201
200 Reagents: (i) C6H6, 70 °C, 24 h, 99%
Benzodiazepine derivatives continue to be of significant interest in medicinal chemistry. Triazolobenzodiazepinenone 202 was shown to be an orally active, gutselective cholecystokinin 1 receptor agonist and was recently evaluated in phase IIA clinical trials for treatment of obesity and management of glycemic control h10BML6797i. An intramolecular Buchwald–Hartwig coupling reaction was used to prepare the benzodiazepine core of 203, a coactivator peptide mimetic that inhibits the interaction of vitamin D receptor with coactivators. Suppression of vitamin D receptor-mediated transcription is being explored for development of therapies for treatment of Paget’s disease h10BML1712i. N
H N
O
O
N
N
O H 2N
N
N H
N N
203
202
7.3.4 Dioxepines, Dithiepines, and Derivatives There has been a significant amount of research endeavor on dioxepine chemistry but little on dithiepine chemistry. In search of simpler analogues to the stolonoxides, marine tunicate metabolites, cyclic peroxide 205 was prepared by intramolecular Michael addition of a secondary hydroperoxide group to an a,b-unsaturated ester 204 h10T157i.
488
J.H. Ryan et al.
MeO2C
(i) O
H O
MeO2C
O
O O
204
O
205
Reagents: (i) CsOH, CF3CH2OH/MeOH 7:3, 15%
For the synthesis of benzodioxepinones, new methods have been developed including enantioselective bromolactonization of tethered conjugated Z-enynes 206, in the presence of novel cinchonidine sulfonyl urea-derived catalyst 207, which afforded high enantioselectivity in the allenyl-substituted benzodioxepinones 208 h10JA3664i. H O
Br
O
(i)
R OH
OMe N
R O
O O
206
NH
208
N
O 207
NHTs
Reagents: (i) NBS 1.2 equiv, catalyst 207 20 mol%, CICH2CH2Cl, rt, 0.5–10 h, 68–88%, 94–99% ee, 8 examples
The carbene-catalyzed oxidative lactonization of hydroxy-tethered benzaldehydes 209 led to high yields of the corresponding benzodioxepinones 210. An optimization study of a range of heteroazolium-derived carbene precursors identified the thiazolium precatalyst 211 as the optimal catalyst precursor. Additionally, using ferric chloride, the by-product diphenylhydrazine was readily recycled back to the oxidant azobenzene h10OL4552i. 2 O R 1
R
O OH
(i)
R2
R1 O
O 209
O 210
ClO4– Mes
+
N
S
211
Reagents: (i) PhN = NPh 1 equiv, 211 5 mol%, Et3N 8 mol%, THF, 80 °C, 74–95%, 10 examples
The 1,3-dioxepine ring is useful for bridging 1,10 -biaryl compounds as the bridge induces a smaller dihedral angle between the adjacent aromatic rings, which in turn can lead to interesting and enhanced properties of the derivatives. Axially chiral 1,10 binaphthyls, -quarternaphthyls, and -octinaphthalene rings 212, bridged with 1,3dioxepine rings, were synthesized. The dihedral angles for the adjacent naphthalene rings were calculated to be approximately 49 for the bridged systems compared with 75–90 for the open-form oligonaphthalenes. The small dihedral angles resulted in extensive conjugation of the bridged oligonaphthalenes as evidenced by red shift of the absorption and fluorescence as the number of naphthalene rings was increased h10OL1832i. Thermally reversible photochromic axially chiral spirooxazines were prepared, including an example 213, containing a 1,3-dioxepine ring bridging the binaphthalene unit. The bridged system exhibited greater helical twisting power than
Seven-Membered Rings
489
the corresponding unbridged analogues, with this effect thought again to be due to the smaller dihedral angle between the naphthalene rings of the bridged analogues h10OL3552i. New asymmetric ligands containing the dibenzo[d,f][1,3]dioxepine ring system were prepared h10ICC153i. O BnO
O
O
O O
O
O
OBn
N
N
O R
S
R O N
n
212
N O
R-213
There is a tremendous amount of research into applications of the 3,4-dihydro-2Hthieno[3,4-b][1,4]dioxepine (3,4-propylenedioxythiophene or ProDOT) heterocyclic scaffold in the field of organic electroactive materials. Various applications of ProDOT homopolymers were reported including poly(2,2-dimethylProDOT) as polymeric electrodes in type 1 electrochemical supercapacitors h10AMI3586i, and poly(2,2diethylProDOT) as an electrochromic material with long term stability h10AMI351i. Alternative ProDOT polymerization reactions have been developed including Grubbs’ ring-opening metathesis polymerization of norbornene substituted ProDOTs and copolymerization of ProDOT derivatives with dimethylsilane and tetramethyldisoloxane h10PLM378i. The side chains of ProDOT homopolymers have been functionalized as carboxylic acid salts resulting in highly water soluble and spray processible materials. Films of the poly(ProDOT) salt 214 were readily neutralized with p-toluenesulfonic acid in methanol to provide an insoluble film of the poly(ProDOT) acid h10AM5383i. New donor–acceptor copolymers of ProDOT derivatives, thiophenes and benzothiadiazole, that is, 215, were found to be black to transmissive switching electrochromic materials, desirable and rare properties in the field h10AM4949i, whereas copolymers of ProDOT derivatives with benzothiadiazole gave spray-processable blue-to-highly transmissive switching electrochromes h10AM724i. Other new copolymers include that of ProDOTs with benzothiadiazoles, benzoselenadiazoles, or benzotriazoles, with the latter being a blue-to-colorless electrochrome, of ProDOTs with isoindigo which gave a blue-green hue, of ProDOTs with diketopyrroles, and of ProDOTs with other thiophene-based monomers h10CM4034, 10MM8348, 10SM2422, 10PSA286, 10PIN517, 10SM2265, 10MM7577i. CO2K
KO2C
RO
OR S
O
O
S
n
O N
O
214
S
m
N
S
n p 215
490
J.H. Ryan et al.
Methods for incorporation of ProDOT or the analogous 3,4-propylenedioxypyrrole moiety into small molecules have been developed. ProDOT derivatives were introduced into triphenylamine-based dyes to give 216 which exhibited enhanced light capture, suppressed dye aggregation, and retarded charge combination in dyesensitized solar cells h10OL1204i. To date, the preparation of polymeric dioxypyrroles has been restricted to homopolymers, in part due to the difficulty in applying organometallic coupling chemistry to the unstable 2,5-dihalo-3,4-dioxypyrroles. To address this limitation, a palladium-catalyzed decarboxylative coupling was developed, exemplified by the coupling of pyrrole carboxylic acid salt with diaryl bromides to afford 3,4-propylenedioxypyrrole-based conjugated oligomers 217 h10OL1328i. Pr
Pr O
O
O
S CO2H
S N O
216
Pr
O
C12H25 O
EtO
O
Pr
NC
N
O
Ar
N
OEt
C12H25 O
O
217
In search of new perfumes, novel propenyl-substituted benzo[b][1,4]diazepin-3ones were prepared and exhibited intense marine and/or spicy-vanillic odor at extremely low thresholds h10S3029i. Dioxepines have been utilized as key synthetic intermediates, for example, a dioxepine intermediate that underwent Wessely oxidative dearomization of a phenol and subsequent intramolecular Diels–Alder reaction to give the highly strained core of maoecrystal V h10JA16745i. A 1,3-dioxepin-2ylidene intermediate, prepared by methylenation of a 1,3-dioxepin-3-one or thermal elimination of a 2-(selenoxymethyl)-1,3-dioxepine, underwent spontaneous Claisen rearrangement to give a chiral nine-membered lactone, an advanced precursor to simplified eleutherobin analogues h10AJC529i.
7.3.5 Miscellaneous Derivatives with Two Heteroatoms A convenient route for the synthesis of enantiopure 1,2-oxazepine derivatives has been developed from readily available 3,6-dihydro-2H-1,2-oxazines. Dibromocarbene addition to 1,2-oxazines provides a dibromocyclopropane intermediate 218 which undergoes ring expansion and methanolysis to give 5-bromo-1,2-oxazepine derivatives 219 in reasonable yields h10S304i. Fused bicyclic furo[3,4-d][1,2]oxazepines (e.g., 220) have been prepared with good diastereoselectivity and in good yields by a gold(I)-catalyzed [4 þ 3] cycloaddition reaction of nitrones to 1-(1-alkynyl)cyclopropyl ketones h10CEJ6146i. Thermal ring opening of aziridinodibenzoxazepines led to dibenzoxazepinium ylides which underwent stereoselective cycloaddition to fullerene C60 to give dibenzopyrrolooxazepine fused C60 h10JOC5211i.
491
Seven-Membered Rings
_
Br Br
O
OR
MeO OR Br
O
O O
Ph
N
Bn
O
218
Ph
O
R N R′
Me
Me
219
Reagents: (i) K2CO3, MeOH, reflux, 20 h, 53%
R
(i)
O
N Bn
+
N
R′
(i) O
O
Ph
O
Ph
220 Reagents: (i) Ph3PAuOTf 2 mol%, CH2Cl2, rt, 10 min, 62–96%
New methods have been developed for the preparation of tetrahydrobenzo[f][1,2]thiazepine 1,1-dioxides. N-Allylic sulfonamides undergo intramolecular Friedel–Crafts-type reactions in the presence of the superacid HF/SbF5 to afford benzothiazepine dioxides 221 h10OL868i. Radical cyclization reactions, that ensue when bromoaryl N-allylic sulfonamides are treated with azobis(isobutyronitrile) and tributyltin hydride, also provide access to scaffold 221 h10TL2681i. O
O R1
O
R3 (i) or (ii)
S R4
N
O
R2
S N R1
R2
221
R3
Reagents: (i) HF/SbF5 4:2, –20 °C, 10 min, 73% (R1, R2, R3 = Me; R4 = H) Reagents: (i) AIBN, Bu3SnH, toluene, 110 °C, 3 h, 64–74% (R1, R3 = H; R2 = Ar; R4 = Br)
The copper(I)-catalyzed intramolecular aziridination of sulfonamide 222 afforded aziridinobenzothiazepine 1,1-dioxide 223 which underwent regioselective ring opening with amines to give 224, which showed potent in vitro calcimimetic activity toward the extracellular calcium-sensing receptor h10BML7483i. O
O S
O
O
S N
(i)
NH2
O
O S NH
(ii)
HN
222
223
224
Reagents: (i) Cu(CH3CN)4PF6, PhlO, CH3CN, MS, rt, 31%; (ii) (R)-naphthylethylamine, THF, 50 °C, 68%
A process for carbon dioxide fixation was described involving the nanoparticulated ceria-catalyzed condensation reaction of bidentate o-aminoalcohols 225, via a carbamic acid intermediate, to form 1,3-oxazepin-2-ones 226 h10CC4181i. NHR
HO
(i)
HO HO
225
O NR
O O
NR
226
Reagents: (i) CO2 7 bar, np-CeO2, EtOH, 160 °C, 6 h, 20%
492
J.H. Ryan et al.
A stannous chloride-trimethylsilyl chloride-promoted cyclization of the allylsilane and vinyl ether groups of 4-vinyloxy-azetidinones 227 produced bicyclic 1,3oxazepine 228 as a single isomer with both bridgehead protons syn-located h10T3904i. New benzo-1,3-oxazepinedione derivatives (e.g., 230) have been synthesized by the cyclocondensation reaction of imines e.g. 229 with various anhydrides. All compounds prepared possess relatively high phase-transition temperatures with only 230 exhibiting texture characteristics of the nematic phase, which demonstrates this compound possesses remarkable phase stability h10JST33i. A copper(I)catalyzed tandem intramolecular cyclization–addition reaction of N-(o-alkynylphenyl)imines provides an efficient route to 1,3-oxazepino-fused indoles under mild conditions h10AOM499i. O
H
H
O
(i)
N
O
N
O
TMS
227
O
O
(i)
N
N
228
Reagents: (i) CH2Cl2, SnCl2/TMSCI, 0 °C-rt, 88%
OC14H29 229
230 OC14H29
Reagents: (i) phthalic anhydride, benzene, reflux, 60%
The Boc-protected amine 231 (produced via Baylis-Hillman chemistry) was reacted with TFA and carbon disulfide to give a dithiocarbamic acid intermediate that on treatment with base underwent intramolecular conjugate displacement to yield the unusual bicyclic 2-thioxo-1,3-thiazepine derivatives 232 h10JOC7014i. Intermolecular photocyclization reactions between N-o-hydroxyalkyl-4,5,6,7-tetrachlorophthalimide 233 and alkenes have been reported to lead to the regio- and diastereoselective synthesis of polycyclic heterocycles and are especially efficient in constructing oxazepines 234 h10CEJ2873i. MeO2C
OAc
H
(i)
MeO2C N Boc
231
Cl Cl
OH
N
S S
N Cl
232
Reagents: (i) TFA, CH2Cl2, CS2, i-PrNEt2, CH3CN, 65%
Cl
Ph Cl HO
O
O 233
(i)
O
Cl N Cl Cl
O 234
Reagents: (i) hn 500 W, styrene, benzene, 28 h, 66%
A novel approach to alkyl- and aryl-substituted benzomorpholines has been realized by means of a palladium-catalyzed domino CC/CN bond coupling using a norbornene template. This one-pot ortho-arylation/aromatic amination synthesis yielded novel 1-aryldihydrodibenzoxazepines 235 h10JOC3495i. A series of substituted dibenzo[1,4] oxazepinones 236 was prepared by intramolecular cyclocarbonylation reactions of substituted 2-(2-iodophenoxy)anilines, efficiently catalyzed by palladium iodide and 1,3,5,7tetramethyl-6-phenyl-2,4,8-trioxa-6-phospha-adamantane (Cytop 292) affording good yields under mild reaction conditions h10JOC6297i.
493
Seven-Membered Rings
NH2
O
Br
O l
R′
O
(i)
NH
+
R R
N H
R
235
O
236
Reagents: (i) Pd(OAc)2 10 mol%, P(m-ClC6H4)3, norbornene K2CO3, CH3CN, 135 °C, 18 h, 17–50%
Several triazolo[4,3-d]benzo[f][1,4]oxazepine derivatives have shown potent anticonvulsant activity, in particular 237 showed better anticonvulsant activity and higher safety than marketed drugs h10EJM3080i. The isocyanide-based multicomponent reaction between isocyanides, Meldrum’s acid, and 2-aminophenols leads to the synthesis of tetrahydrobenzo[b]-[1,4]oxazepinediones 238 h10JCO630i. R′ O
NH2
O OH
O C7H15O
R′
O
237
O O
(i)
N N
H N
NH
O O
N
O
238
R
Reagents: (i) R-NC, CH2Cl2, rt, 12 h, 75–87%
An efficient domino strategy was reported for the synthesis of 1,4-benzothiazepin-5ones based on a one-pot palladium-catalyzed tandem aziridine ring-opening-intramolecular carboxamidation reaction of N-tosylaziridines and o-iodothiophenols. By using (2-biphenyl)di-t-butylphosphine (Johnphos) as the ligand in these reactions, the products, for example, 239, were obtained in high yields h10OL5567i. Similarly, 1,4-benzo- or pyrido-oxazepinones were obtained by one-pot sequential phase-transfer-catalyzed ring opening/carboxamidation reactions of N-tosylaziridines with halophenols or halopyridinols, respectively h10OL192i. The reaction of alkylidene monothiosuccinic anhydride with 2-mercaptoethylamine led to the preparation of a series of substituted 1,4-thiazepin5-ones, for example, 240 h10T6383i. Interestingly, only the 1,4-thiazepin-5-one regioisomer was isolated, arising from ring closure of the amine onto the proximal carbonyl group following conjugate addition. A series of benzo[1,4]thiazepines were prepared by reaction of nitro-enones with o-aminobenzenethiol to produce 2-aryl-4-methyl-3-nitro-2,3-dihydro-1,5-benzothiazepines rapidly and under mild conditions h10RJO1590i. N–Ts
l SH
O
Ts
O
S
N (i) S 239
Reagents: (i) Pd(OAc)2 4 mol%, Johnphos 4 mol%, base, 100 °C, 17 h, CO 500 psi, 93%
Ph
O
O Ar S N O (i)
H N S
OO N
Ph
240
Reagents: (i) H2N(CH2)2SH, DMF, 0 °C, o/n; Cs2CO3, DMF, 2 5 °C, 1 h, 65%
494
J.H. Ryan et al.
A facile solid-phase synthesis gave novel 2-amino-6-arylmethyl-7-carboxamido7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones 241, with a wide range of substituents, in good yields h10TL4486i. A series of short oligomers were prepared, and their cellular uptake and subcellular localization studied. Fluorescein-labeled oligo(DBT) [DBT ¼ (3-S)[amino]-5-(carboxymethyl)-2,3-dihydro-1,5-benzothiazepin-4 (5H)-one] noncationic dipeptide mimic oligomers 242 were synthesized on Rink-amide resin and labeled at their N-terminus with fluorescein isothiocyanate. Oligo-(DBT)s are described as b-turn mimics, and these potential new vectors for intracellular delivery were shown to be highly internalised by cells and, importantly, exhibited no significant detrimental effect on cell viability h10BCC1850, 10AGE8240i. R2 O R
O
Fluorescein
N
1
O
H N
NH2 N
N H N
S
O S
N
241
2–4
R3
242
The first total synthesis of isokidamycin, a member of the pluramycin class of C-aryl glycoside antibiotics, has been reported. The synthesis features a seven-membered silicon tether as a disposable linker to control the regiochemistry in an intramolecular Diels–Alder reaction of substituted naphthyne and a glycosyl furan followed by a subsequent O ! C-glycoside rearrangement h10JA15528i.
7.4. SEVEN-MEMBERED SYSTEMS CONTAINING THREE OR MORE HETEROATOMS 7.4.1 Systems with N, S, and/or O As in previous years, there are numerous interesting reports of systems containing three heteroatoms nitrogen, oxygen, and/or sulfur; however, very few noteworthy examples of systems with four or five heteroatoms. The use of Br nsted acids as organocatalysts in asymmetric reactions is an expanding area of research. New ligands are often reported for improved catalysis of individual reactions, such as an L-proline-substituted binaphthyl sulfonimide for the enantioselective Michael addition of ketones to nitroalkenes h10EJO5160i. An interesting general approach for the synthesis of optically pure 3,30 -diaryl chiral disulfonimides from racemic BINOL (via the sulfonyl chloride derivative ()-243) has been developed that provides an enantiopure 3,30 -dihalide (R)-()-244 which could serve as common precursor for a range of aryl-substituted chiral disulfonimides h10EJO4181i.
Seven-Membered Rings
Ph SO2Cl
O S
H2N (i)
X O O S
O Ph N
(ii), (iii), (iv)
NH S O O X
S O O
SO2Cl
495
(R)-(–)-244
(±)-243
Reagents: (i) Et3N, DMAP, CH2Cl2, 88%; separate diastereoisomers; (ii) Pd/C, H2, MeOH, EtOAc, 97%; (iii) n-BuLi, THF, –40 °C; (iv) Br2, 56%, X = Br; l2, 61%, (X = l)
Rhodium-catalyzed oxidative rearrangement of allene-sulfamate esters (e.g., 245) gives substituted oxathiazabicyclo[5.1.0]octane dioxides (e.g., 247) h10CC2835i. The intramolecular amination proceeds via a cyclopropylimine intermediate 246 which can also be intercepted with a range of Grignard reagents which undergo rearrangement and generate the desired sulfamates h10JA2108i. OSO2NH2 (i)
O O S O NH
O O S O HN
O O S O N RO
CH3
246
245
247
HN
248 Reagents: (i) Rh catalyst 5 mol%, Phl(O2CR)2, t-BuCO2H, C6H5CF3, 45 °C, 2 h, 73%
The biologically active benzylsulfamate 248 was prepared by rhodium-catalyzed intramolecular aziridination of an olefinic arenesulfonamide, followed by nucleophilic ring opening of the aziridine by reaction with (R)-naphthylethylamine. The seven-membered sulfamate 248 showed excellent calcimimetic activity, compared to a known potent allosteric modulator of the extracellular calcium-sensing receptor h10BML7483i. A new efficient synthetic route to prepare pyrido[1,2-b][1,2,4]triazepine derivatives has been reported for the development of new antimicrobial agents, by reaction of 1,6-diaminopyridone with 1,3-dielectrophilic reagents or ketene N,S-acetal derivatives h10JBS1007i. Fused quinolino[1,2,4]triazepine derivatives 250 displaying significant antioxidant activity was prepared regioselectively by condensation of 4hydroxy-3-acetylquinolin-2-one 249 with thiosemicarbazide followed by acid-catalyzed cyclization h10BML7147i. H2N OH
O (i)
N H
249
S
HN OH N
S
(ii)
HN
NH N
O N H
O
N H
O
250
Reagents: (i) thiosemicarbazide, NaOAc, EtOH, reflux, 80%; (ii) conc. H2SO4, 82%
496
J.H. Ryan et al.
Fused 1,2,4-benzotriazepine derivatives can be prepared by a facile and efficient method via palladium-catalyzed cyclization of a wide variety of aryl hydrazones and aryl isocyanates under microwave irradiation h10OBC4827i. The microwaveenhanced reactions showed shorter reaction times and improved yields and selectivity when compared to conventional reaction conditions. Saccharin can be converted into 2-chlorosulfonyl benzoyl chloride 251 in two steps, and this intermediate undergoes cyclocondensation reactions with urea or thiourea to give 1,2,4-benzothiadiazepinone dioxide derivatives 252 in reasonable yields h10IJS71i. Novel fused triazolo[1,2,4]thiadiazepine derivatives 253 have been prepared as potential antibacterial and antifungal agents, by cyclocondensation of a dinucleophilic substituted triazole with an appropriately functionalized (E)-propenone h10CPB1081i. N N
O COCl
NH X
(i) or (ii)
N
S NH O O
SO2Cl
251
S
N
N
HN
NO2
N
252
Reagents: (i) urea, MeOH, 1.2 h, 77% (X = O); (ii) thiourea, MeOH, 1.6 h, 53% (X = S)
O
R
253
Nucleophilic attack of substituted hydrazides on chlorinated quinones (254 or 255) leads to an interesting multistep process to give naphthalenooxadiazepine 256 or benzoxadiazepine 257, respectively, in good yields h10JHC118i. O O
Cl
R
R (i)
Cl
Cl
O
O 254
O
256
Cl
Cl
N O
NH N O
R
O Cl
O
N H
NH2
O
O
255
Cl
Cl (ii)
NH
Cl
OH
257
Reagents: (i) DMF, rt, 72 h, 79–88%; (ii) DMF, rt, 48 h, 66–74%
Synthesis of new fused 1,2,5-triazepine-3,6-diones 258 and 1,2,5-triazepine-3,7diones 259 proceeded via a multicomponent Petasis condensation reaction. A variety of substituted hydrazines were condensed with glyoxylic acid, and a variety of boronic acids, coupling of the intermediate with L-proline-CO2Me, followed by deprotection and cyclization then yielded the fused triazepinediones h10JCO75i. Intramolecular condensation of a carbonitrile intermediate 260 with hydrazine hydrate gave the interesting spiro(cyclohexane)benzotriazepine 261 h10PS1301i.
497
Seven-Membered Rings
O N NH
R2
H
S
N
NH
R2
N
O
O
O
H
R1
R1
O
258
NH N
(i) HN
O CN
HN
N
CH3
NH2
259
260
261
Reagents: (i) NH2NH2, dioxane, reflux, 7 h, 50%
Saturated 1,2,5-triazepane and 1,2,5-oxadiazepane analogues of the oxazolidinone antibacterial agent linezolid have been prepared from differentially protected triazepane and oxadiazepane cores 262. The analogues 263 and 264 showed excellent in vitro antibacterial activity, and the triazepane 263 also exhibited good in vivo efficacy in an animal model of systemic infection h10CPB1001i. O
F Boc
(i)
NH
Boc
N X
X
N Cbz
X N
HO
N F
O
262 X = NCbz, O
X = NHCbz, OH
N
O H N
263 ( X = NH) 264 ( X = O)
OMe S
Reagents: (i) NaH, bis(2-chloroethyl)carbamic acid benzyl ester, DMF, 60 °C
The sulfonamido-aniline 265 underwent cyclization with 1,2-dibromoethane to give benzothiadiazepine dioxide 266. An alternative synthesis of the benzothiadiazepine scaffold involved an interesting microwave-assisted copper(I)-catalyzed, intramolecular N-arylation of N-tethered mono-brominated bis-arylsulfonamides, providing the corresponding sultam 267 in good yield h10OBC2198i. F F O F 3C
O S
N H NH
(i)
O S NH
O
N
S N
O S O
O F3 C
O
N
265 Reagents: (i) (CH2Br)2, Cs2CO3, DMF, 60 °C, 87%
266
267
Chiral benzoxathiazepine 1,1-dioxides 269 have been prepared by an interesting microwave-assisted multigram flow synthesis protocol involving an intramolecular SNAr reaction of 2-fluorobenzenesulfonamide 268 h10CEJ10959i. The benzoxathiazepine 1,1-dioxides 269 were also prepared by a one-pot multicomponent reaction of 2-fluorosulfonyl chlorides, amines, and epoxides h10TL1079i. Similarly, intramolecular SNAr reaction of chiral 2-nitrosulfonamides 270 resulted in the corresponding chiral benzothiaoxazepine derivative 271 in good yield h10OL2822i.
498
J.H. Ryan et al.
S
R1
O
O
2 O R
O
N H
OH
F
O S
R2 O
R1
268
O O S N
OH
O
S NH
R3 (i)
(ii)
N
O
O2N
R3
269
270
Reagents: (i) Cs2CO3, DMF, 140 °C, MW, 83–95%
271
Reagents: (ii) NaH, THF, –10 °C, 75%
Cascade protocols for the synthesis of oxathiazepine-1,10 -dioxides (e.g., 272) and benzothiaoxazepine 1,10 -dioxides (e.g., 273) from vinyl- or aryl-sulfonamides respectively have been described. The protocols combine epoxide ring opening by the sulfonamide nitrogen followed by either intramolecular oxa-Michael addition or SNAr cyclization reactions h10JCO850, 10OL1216i. O O O S N R1 H
R2
(i)
O
O O R S N 1 O
R3
272 R2
R4 O O R S N 1 H F
(i)
R4 O O R 1 S N
R2 R3
O R2
273
Reagents: (i) Cs2CO3, BnEt3NCl, dioxane/THF/DMF, MW, 110 °C, 20 min, 53–65% (272); 65–78% (273)
Native chemical ligation is reported by the reaction of a peptide featuring a unique seven-membered bis(2-sulfanylethyl)amino group at its C-terminus 274 with a cysteinyl peptide h10OL5238i. The intermediate bis(2-sulfanylethyl)amine is prepared on a solid support and the disulfide reduced in situ with tris(2-carboxyethyl)phosphine (TCEP) prior to ligation. O peptide-1
N S
+
SH peptide-2
peptide-1
H 2N
N H
O
S
274
O
(i)
SH peptide-2 O
Reagents: (i) TCEP, 4-mercaptophenylacetic acid, pH 7, 37 °C, 32–77%
Condensation of the 1,5-dinucleophile 4-amino-3-hydrazinyl-6-methyl-1,2,4triazin-5(4H)-one with 1,2-bis-electrophiles such as 3-chloropentane-2,4-dione led to triazinotetraazepines such as 275 h10CCL1419i. PEGylated benzopentathiepin 276, a structural analogue of the natural product varacin, has been synthesized and observed to have improved water solubility and improved antiproliferative activity against a range of human tumor cell lines h10JOC5549i. O CH3
H3C HN N HN
O O
NH N
O
O
O
276 N
CH3 275
N H
S S S S S
Seven-Membered Rings
499
7.5. FUTURE DIRECTIONS Seven-membered heterocycles will continue to be of interest in biological applications, and there appears to be much opportunity for these ring systems in materials science applications. Innovative applications of existing synthetic methods combined with the development of new synthetic methods will continue to drive innovation in the discovery of novel heterocyclic scaffolds.
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10BML1712 10BML2755
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10BML4386 10BML5380
10BML6797
10BML7147 10BML7483 10CBD116 10CBD130 10CC797 10CC2835 10CC3351 10CC4181 10CC6593 10CC6810 10CCL1419 10CEJ2873 10CEJ3276 10CEJ6146 10CEJ9264 10CEJ10959 10CEJ11813 10CEJ13243 10CHE592 10CJC478 10CM4034 10CPB1001 10CPB1081 10DT9611 10DT9897 10EJI1604 10EJM3080 10EJM4615 10EJO1525 10EJO1694 10EJO3665 10EJO4181 10EJO4393
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Seven-Membered Rings
10EJO4687 10EJO4861 10EJO5108 10EJO5160 10EJO5190 10EJO5397 10GC879 10GC2043 10H(80)623 10H(80)689 10H(81)2465 10HCA1369 10IC616 10ICC153 10ICC663 10IJS71 10JA916 10JA1249 10JA1788 10JA2108 10JA3664 10JA5300 10JA10498 10JA15528 10JA16374 10JA16745 10JBS1007 10JCO75 10JCO125 10JCO186 10JCO206 10JCO497 10JCO503 10JCO630 10JCO850 10JHC118 10JHC640 10JHC990
501
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CHAPTER
8
Eight-Membered and Larger Rings George R. Newkome The University of Akron, Akron, OH, USA
[email protected]
8.1. INTRODUCTION Numerous reviews as well as perspectives, feature articles, tutorials, and minireviews have appeared throughout 2010 that are of particular interest to the macroheterocyclic enthusiast and those delving into supramolecular chemistry at the macromolecular level, as well as those studying nanoconstructs: macrocycles and cavitands possessing phosphorus h10JIPMC3i; calixarene metal complexes h10JIPMC15i; thienyl-appended porphyrins h10CCR77i; meso-patterned porphyrins h10ACR300i; components in functional devices h10CEJ4224i; supramolecular architectures of porphyrins on surfaces h10CCR2342i; topology-controlled expanded porphyrins h10CSR2751, 10ACIE1359i; water-soluble phthalocyanines h10CCR2792i; porous porphyrin nanostructures h10EJIC3715i; porphyrins, as molecular electronic metallophthalocyanine, as catalysts h10CCR2755i; poly(arylene-ethynylene)s containing dithia[3.3]metaphanes h09CRC332i; supramolecular gels h10CR1960i; supramolecular oligotriazoles and polytriazoles h10CC3437i; metal-coordination-driven, dynamic, heteroleptic assemblies h10CSR1555i; mechanically bonded macromolecules h10CSR17, 09OBC415, 10CC54i; molecular machines h11MI1i; thermodynamic self-assembly of metallosupramolecular complexes h10CC6209i; three-dimensional molecules and supramolecular aggregates via coordination with metals h10ACIE5042i; dynamic selection in hybrid organic–inorganic constitutional networks h10CC7466i; rotaxanes h10CSR70, 10CCR2267i; molecular shuttles to [3]rotaxanes h10CCR1748i; copper-complexed catenanes and rotaxanes h10DT10557i; polyammonium macrocyclic and cryptand receptors h10CCR1726i; metal ion chemistry of dibenzo-substituted mixed-donor macrocycles h10CCR1713i; linked azamacrocycles and complexes h10CCR1661i; azacyclam complexes h10CCR1628i; tetraalkylcyclams h10CCR1607i; biomedical applications of macrocyclic ligand complexes h10CCR1686i; macrocycles with embedded carbohydrates h10EJOC4959i; functionalized cyclophanes for optical bimolecular recognition h10CSR4158i; cryptand-like anion receptors h10CSR3980i; crown etherbased cryptands h10CC8131i; anion binding in covalent and self-assembled molecular capsules h10CSR3810i; ion-pair receptors h10CSR3784i; highlights of anion receptor chemistry h10CSR3746i; metal-containing nanofibers via coordination chemistry h10CCR2363i; cyclic polymers h10JPSA251i; macroheterocycles via the Prins cyclizations h10T413i; interlocking macrocycles functionalized with fullerenes h10CC9089i; macromolecular chemistry of fullerenes h10AM4220i; and solar fuel cells h10DT10021i.
Progress in Heterocyclic Chemistry, Volume 23 ISSN 0959-6380, DOI: 10.1016/B978-0-08-096805-6.00017-6
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2011 Elsevier Ltd. All rights reserved.
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G.R. Newkome
An interesting presentation of approach to molecular creation/assembly has been shown in a tutorial entitled “Heuristic thinking makes a smart chemist” h10CSR1503i. As always, because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings have been reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated, where appropriate. I apologize in advance that it is impossible to do justice, to this topic and the numerous researchers that have elegantly contributed to the field, in the allotted 20 pages.
8.2. CARBON–OXYGEN RINGS A three-step procedure to 1,5-dinaphtho[38]crown-10 has recently appeared, and the methodology can be applied to other crown ethers possessing a 1,5-dinaphtho moiety h10TL983i; use of this dinaphthocrown ether in polycatenation reactions under thermodynamic control has been reported h10ACIE3151i. The bis(m-phenylene)-26-crown-8-based lariat ether possessing 2,20 -(OCH2Ph) moieties has been synthesized and demonstrated (1) to bind paraquat more strongly than the unsubstituted bis(m-phenylene)-26-crown-8 in solution h10EJOC5543i, (2) to be a convenient precursor for pseudorotaxanes and catenanes h10EJOC6798i, and (3) to be an integral part of bis(1,2,3-phenylene) cryptands h10EJOC6804i. Related internal functionalization at the 2,20 -positions of these O-macrocycles enhanced their “selfsorting” abilities with diamine compounds depending on the “induced fit” rule via a folding phenomena h10CEJ13850i. As bis(m-phenylene)[32]crown-10-based cryptands form strong complexes with paraquat derivatives, the cryptand and paraquat components were incorporated into a single monomer via Click chemistry and then shown to effectively form a supramolecular polymer h10AGIE1090i also see h10CEJ6088i. Substitution at the 5,50 -positions of the bis(m-phenylene)-26-crown8 by initial ester reduction, treatment (84%) with propargyl bromide, followed by CuII-mediated Eglinton coupling afforded (97%) a cyclic diacetylene, that was reduced (93%) to the desired cryptand h10EJOC1904i. A novel pair of crown ethers with in-bedded triphenylene moieties, specifically bistriphenyleno-18crown-6 and tristriphenyleno-27-crown-9, have been prepared and shown to form new discotic motifs supporting the meso-phase formation h10OL472i and also see h10CEJ6326i. A novel triptycene-derived bisparaphenylene-34-crown-10 has been synthesized and shown to form 1:1 stable complexes with paraquat h10JOC1767i. A related triptycene-based macrotricyclic host (1) possessing two dibenzo-30-crown-10 units has been synthesized and shown to form a stable complex with a (9-anthracenylmethyl)benzylammonium salt in a 1:2 ratio, where two anthracenyl moieties are nested within the cavity h10JOC5092i. The macrotricycle 1 has been shown to form a novel bifunctional [3]rotaxane h10CC5536i and to be a powerful host for
Eight-Membered and Larger Rings
507
bispyridinium dications h10OL1888i. Expansion of this macrotricycle to a bismacrotricycle 2 has been accomplished and shown to complex with 4 equiv. of a dibenzylammonium salt or, interestingly, 2 equiv. of a bis-secondary ammonium salt (3) to form a “handcuff-like” superstructure h10EJIC5056i.
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
+ N H2
O
PF6-
O O
O
O
O
O
O
O
O
O
O
O
O
O N
O
O O
O
O
O
O N O
O O
O
1
O
O
O
O
O
O
O
O
O
O
O
O
O
O
-
O
H2 +N
PF6
O
3
O
2
2–1 thru 3
An effective free-radical approach for the activation of an otherwise unreactive a-CH bond in a series of structurally diverse mono- or poly-ethers and -sulfides enabled the direct covalent functionalization of fullerene C60 with crown ethers h10ACIE5891i. A metal-free phthalocyanine was prepared from 4,5-bis(1,4,7,10tetraoxacyclododecan-2-ylmethoxy)phthalonitrile in the presence of a strong base in n-pentanol h10JOMC1729i. The appendage of a metal center onto a crown ether gave rise to either [PhI2SnCH2([16]crown-5)] or [I3SnCH2([16]crown-5)], which with silver perchlorate generated the organotin(IV)-substituted crown ether complexes [PhSnCH2([16]crown-5)][ClO4]2 and [HOSnCH2([16]crown-5)][ClO4]2, respectively h10CEJ8140i.
508
G.R. Newkome
The functionalization of the known 25,27-bis(hydroxycarbonylmethoxy)calix[4]crown-5 with 1-aminomethylpyrene (for detecting TNT) h10CEJ5895i and 4-aminomethylphenyl-60 -phenyl-2,200 -bipyridine (for detecting ZnII in MeCN) has been reported h10TL3719i. The related bis(2-propyloxy)calix[4]crown-6 has been created for the removal of CsI from an aqueous environment, as needed for the removal of radioactive 137Cs from nuclear waste h10DT3897i. An approach to chiral biscalix[4] arenes by the covalent assembly of a 1,3-alternate calix[4]arene possessing two triethylene glycol units with 25,26-dibenzyloxy-27,28-dihydroxy-p-tert-butylcalix[4]arene, followed by deprotection, has been accomplished h10JOC464i. The related (1,3)-calix[5]arene-crown-3, bearing either n-butylureido or 1-naphthylureido
OEt
O
O
O
OH
OEt
OEt
EtO
OH
O
HO
O
HO
O
HO
O
O
OH
NH2
4
O
O
5
CO2H
HO2C
O
O
CO2H
O
O
6
2–4 thru 6
attachments on the lower rim, has been synthesized and shown to accommodate both the ion pair (heteroditopic host) h10T4987i. Although previously prepared, the aminocalix[6]arene 4 has been transformed to the corresponding isocyanate and has been proposed to be a calixarene dendron h10CC1044i. The synthesis and resolution cryptophanol 5 from cryptophane A were accomplished in three steps; 5 is water-soluble and possesses a > 99% ee h10CEJ4507i. The reaction of cyclotricatechylene with methyl 3,5-bis(bromomethyl)-benzoate in DMF with
Eight-Membered and Larger Rings
Bu
Bu O
EtO2C
donor
CO2Et O
O
509
7
acceptor
O
8 Br
Br
I
I O
I O
O
O I
I
9
I
10 2-7,8,9,10
Cs2CO3, as base, gave after saponification and protonation the desired 6, which with Co(OAc)2 generated a metallocryptophane with a central Co7 cluster h11CC176i. Two phenanthrene-fused furan-containing cyclophenes (7 and 8) have been prepared and shown to exhibit charge transfer bands in the absorption spectra and unusually large Stokes shifts in the emission spectra h10JOC4591i. The tetrahalogenated oxacyclophanes 9 and 10 have been prepared, derivatized, and shown to afford access to parallel and orthogonal monomers for directed, stacked polymers h10CC5136i. The synthesis of configurationally fixed chiral perylenebisimide, bridged with a small crown ether linkage, was reported; the isolation of the novel atropo-enantiomers have thus been realized h10CEJ7380i.
510
G.R. Newkome
OR
RO
N N
N
N
N H
N H
N
N N
N
n
N
OR N
11
N
N N
N
N
N
H N
H N
N N
12
N O
O
N
N N
N
13
(n = 1−3)
8.3. CARBON–NITROGEN RINGS Coupling reactions of 2,6-diiodopyridine and cis-3,6-diethynyl-3,6-dimethoxycyclohexa-1,4-diene or the related 9,10-dihydroanthracene gave a macrocyclic hexameric intermediate, which with a tin-mediated reductive aromatization under mild conditions generated the desired C3-symmetric 2,6-diethynylpyridine-based cyclotrimer 11 h10JOC3537i. A cyclic, free-base porphyrin dimer bearing 4-pyridinyl groups was generated (20%) from the corresponding zinc porphyrin monomer possessing two terminal alkyne moieties by a Glaser coupling, catalyzed by CuI in the air; these cyclic dimers form novel nanotubes in the crystalline state and can encapsulate C60 within their cavity h10CEJ11611i. Click chemistry was utilized to generate (20%), after deprotection, the 1,3-bis(pyrro-2-yl)(1,4)-1,2,3-triazolobenzene, which was condensed with acetone to generate (10%) the calix[2]1,3-bis(pyrro-2yl)(1,4)-1,2,3-triazolophane (12) h10JA14058i. Treatment of 2,6-bis(bromomethyl)pyridine with 5-tert-butyltetrahydro-1,3,5-triazin-2(1H)-one with either NaH or LiH gave (1–30%) a series of macrocycles 13 depending on the base counter ion h10JOC5453i. The treatment of tetra-tert-butyl-N,N000 -triethylenetetraamine N,N0 , N00 ,N000 -tetraacetate with either 2,6-bis(bromomethyl)pyridine or 6,600 -bis(bromomethyl)-2,20 :60 ,200 -terpyridine in MeCN with Na2CO3 gave (ca. 50%), after a nearly quantitative hydrolysis, the desired macrocycles 14 h10T8594i. The reaction of 2-(aminomethyl)-1,4,7,10-tetraazacyclododecane with 9-formylanthracene formed 15, then after a nearly quantitative reduction, the ring-opened product possessing a ring-CH2NHCH2R side-chain was characterized h10EJOC1688i. Although lactams are not generally included, the treatment of tris(aminoethyl)amine (TREN) with tris (2-pyridyl)methanol with Pd(PPh3)4 in CO and Et3N gave (41%) 16.
Eight-Membered and Larger Rings
511
OH n N HO2C
N
N N
N O
NH
O
CO2H
14
N
HN
N
HO2C
N
CO2H
N
HN
O
(n = 0,1,2)
16
N Ts
n
N Ts
NH HN
N N
NH
N
N
N
N Ts N
R N H
15
Ts
N
N
N
N
Ts
(n = 0, R = anthracenyl)
N Ts
17
A new 1,9(4,7)-diphenanthrolino-3,7,11,15-tetraazacyclohexadecaphane with outward-directed phenanthroline moieties was synthesized from a 1:1 mixture of 1,10-phenanthroline-4,7-dialdehyde with 1,3-diaminopropane, followed by NaBH4 reduction h10DT10128i. The condensation of 1,3,5-tris(aminomethyl)mesitylene with 4-substituted 2,6-formylpyridine gave (95–99%) the initial trisimine cage, which was subsequently reduced to afford 17 h10TL6521i. Similarly, in quest of a rational design of a hexamine macrocycle, N-methyl-2,20 -diaminodiethylamine was reacted with terephthaldehyde under high-dilution conditions, followed by hydride reduction and lastly treatment with dansyl chloride h10TL1329i. The uncatalyzed preparation of symmetrical and unsymmetrical tetraaza[1.1.1.1]m,p,m,p-cyclophanes by the treatment of 1,5-difluoro-2,4-dinitrobenzene with substituted 1,2(4)-diaminobenzenes has been H
N H
N H
N H
R
R N H
N NH
N HN
H N NH
HN HN
18
R
19
reported h10T4377, 10OL2722, 10OL4300i. Similarly, treatment of 4,6-dichloropyrimidine with 4,6-di(methylamino)pyrimidine was shown to generate the azacalix[4]pyrimidine in variable yields h10JOC741i.
512
G.R. Newkome
Treatment of 1,3-bis[10 -(pyrrol-2-yl)-10 ,10 -(dimethyl)methyl]benzene with triethyl orthoformate, catalyzed by TFA, formed 1,3-bis[10 -(pyrrol-2-carboxaldehyde-5-yl)-10 ,10 -(dimethyl)methyl]benzene, which with its starting material generated the in/out calixpyrrole 18 in 15% yield h10JOC6263i. Azatri(or tetra)pyrrolic macrocycles (19) were prepared in a single step by a Mannich reaction of pyrrole in the presence of primary amine hydrochloride h10OL3212i; their ability to act as receptors for selected anions was also demonstrated h10OL3910i. X
M2
Me2N
Ar
Ar
NMe2
N N N
M
N N
NMe2
Me2N X-M
N
M2-X
M N
Ar
Ar
N 1
2
N
23
Ar
M NMe2
Me2N
OR
RO N
N Ni
N
N OR
RO
20
Me2N
2
M
NMe2 Ar
X Ar
21
Ar OR
RO N
N
N
N
N
N
Zn N
Zn N
RO
OR
22
Ar
Ar
R = n -C8H17 or 2,4,6-trimethylphenyl
Porphyrins and chlorins were readily prepared in minutes via dehydrogenation of the respective porphyrinogen and bacteriochlorin using activated manganese dioxide under microwave conditions h10ICC395i. A novel porphyrin system with a fused dihydropyran ring has been prepared from commercially available 4-oxotetrahydropyran h10T4413i. Cyclo[8]pyrrole was obtained when 3,30 ,4,40 -tetraethylbipyrrole underwent bulk electrolysis in the presence of tetra-n-butylammonium hydrogensulfate h10CSR6810i. When bis(methoxymethyl)-4-bromobenzaldehyde was reacted with pyrrole under Alder-type condensation conditions, the desired meso-tetrakis[3,5-bis(methoxymethyl)-4-bromophenyl]porphyrin was generated in 20% yield; this was subsequently transformed into the desired meso-tetrakis[3,5-bis(dimethylaminomethyl)-4bromophenyl]porphyrin precursor for its transformation to the metallo pincers 20 h10JOC1534i. The novel synthesis of fused bis-anthracene porphyrin (monomer 21 and dimer 22) was accomplished by the oxidative ring-closure using FeCl3 and Sc (OTf)3/DDQ, respectively h10OL2124i. A different type dimer was reported by the use of a porphyrin annulated to an N,N0 -dimethylimidazolium salt, which was
Eight-Membered and Larger Rings
513
subsequently transformed to the related carbene 23 h10EJOC1912i. Tetrameric porphyrin construction of 2-hydroxymethylpyrrole fused with porphyrins via a bicyclo[2.2.2]octadiene moiety gave bicyclo[2.2.2]octadiene-fused porphyrin pentamers, which under thermolysis (ca. 200 C) conditions, gave in quantitative yield the cruciform porphyrins 24 fused with benzene units h10CEJ4063i. A porphyrin “Lego block” strategy has been reported affording ready access to multiple meso-b-linked porphyrin rings, for example, a combination of a b,b0 -diborylporphyrin being coupled with 5,15-dibromoporphyrin by a Suzuki–Miyaura reaction ([Pd2(dba3)], PPh3, Cs2CO3, and CsF) provided the meso-tob directly linked tetrameric porphyrin ring 25 in 21% yield h10ACIE3617i. The use of b,b0 -diborylporphyrin with N-bromophenyl ZnII diporphyrin gave the porphyrin pentamer 26 in 15% yield h10OL1820i. Synthesis of pyrrole-bridged porphyrin rings via a Suzuki–Miyaura cross-coupling of 5,10-diaryl-15,20-dibromoporphyrin and 2,5-diborylpyrrole has been demonstrated h10CEJ13320i. Kim and Osuka et al. reported a bisphosphorus complex of [30]hexaphyrin as the first example of a stable [4n þ 2]p Mo¨bius antiaromatic macromolecule in which two phosphoramide moieties gave a highly reduced stable [30]hexaphyrin h10ACIE4950i. A singly N-fused [28]hexaphyrin was isolated and metalated with Pd(OAc)2 to give a conformationally twisted Pd(II) complex that displayed distinct Mo¨bius aromatic properties h10JOC7958i, also see h10ACIE6619i. An unprecedented rearrangement of hexaphyrin(1.1.1.1.1.1) to hexaphyrin(2.1.1.0.1.1) was found upon BIII complexation h10ACIE4297i. nBu
nBu
R
Me
R N
R
Me
R N
N M
N
N
N
Ar
Ar
N
N
N M1
1
N
N
Ar
N
Zn nBu
nBu
N
Ar
N
Ar N
Ar
N
Me
Me N
N
NH
M2 N
N N
N N
N
HN
Me
Me
N
nBu
nBu N
M
M N
N
N
R
N
N
N
26
R Ar
24
Ar N N
N
Ar
N M
N
N
N
N Ar
M
Ar
Ar
Ar
Ar
N
N
R
nBu
nBu
Zn N
N
Ar
1
N
Ar
Ar
Zn
Me
Me
Ar
N
N
N
N 1
R
Ar
Zn
M N
N N
Ar N
N M
N
N Ar
Ar
25
Ar
M = 2H or Zn
A novel porphyrin-cored dendrimer derived from the octabutoxycarbonyltetracyclohexenoporphyrin was dendronized, then surface coated with PEG moieties affording a macromolecular porphyrin-based pH-sensitive dye suitable for measurements in microcompartmentalized systems h10IC9909i.
514
G.R. Newkome
8.4. CARBON–SULFUR RINGS The convenient conversion of ethylenedithioglycol into reasonable quantities of the scarce as well as expensive di-, tri-, and tetrathiaethylenethioglycol along with oligothiaethylenethioglycols has been demonstrated h10CEJ6365i; their procedure was simple, without expensive or toxic catalysts, and used water as the solvent. The [6.6](9,10)anthracenophane (27) was prepared by the macrocyclization of disodium-(Z)-1,2-dicyanoethene-1,2-dithiolate with 9,10-bis(chloromethyl)anthracene under high-dilution reaction conditions h10CC2034i; this anthracenophane is being developed as an optical sensor for PdCl2 via enhanced selective fluorescence when in its presence. The novel in-ketocyclophane (28) was prepared (13%) from 2,20 -bis(bromomethyl)benzophenone with commercial 1,4-bis(mercapto)benzene under high-dilution conditions, followed by oxidation (89%) with Oxone h10OL928i. The related 3,7-dithia-1(2,5)thiopheno-5(1,4)benzenacyclooctaphane was formed (18%) from 1,4-bis(mercaptomethyl)benzene and freshly prepared 2,5-bis(bromomethyl)thiophene in benzene in the presence of KOH and NaBH4 in EtOH h10CEJ7456i. A novel synthesis of calix[4]thiophenes was shown by reaction of 1-(2-thienyl)cyclooctene with N-iodosuccinimide in CH2Cl2 at 25 C to give (61%) the desired tetraspirocyclooctylcalix[4]thiophene (29) h10CC5009i. The alkylation of thiacalix[4]arene with propyl iodide under phase transfer conditions gave (48%) the 1,3-alternate-dipropoxy derivative, subsequent alkylation with PrI in NaH/DMF led to (68%) the tetrapropoxy product, as a mixture of cone and partial cone conformers h10JOC407i. A series of new p-tert-butylthiacalix[4]arenes with o-, m-, and p-(amidomethyl)pyridine substituents on the lower rim in cone, partial cone, and 1,3-alternate conformations were prepared h10T359i. NC
CN
S
S
S
S
NC
CN
O2S
27
O
28
SO2
S
S
S
S
29
Me2Si
SiMe2 SiMe2 Me2Si
30
Eight-Membered and Larger Rings
515
8.5. CARBON–SILICON RINGS The one-step conversion of 1,8-diiodoanthracene to 1,8-dilithioanthracene was accomplished by lithium–halogen exchange, followed by treatment with 1,2dichlorotetramethyldisilane affording (50%) the desired disilanyl double-pillared bis-anthracene (30), which can be used in light-emitting diode devices h10ACIE7239i.
8.6. CARBON–OXYGEN/CARBON–NITROGEN–OXYGEN RINGS Historically, there have been interesting examples of this family of poly C,N/C,N, O-macrocycles. The recent threading of a trisdialkylammonium strand 31 through the cavities of a rigid triptycene host 32, which comprises three [24]crown-8 moieties, followed by a olefin metathesis to form the macrocyclic encapsulated ring and lastly an alkene reduction generated the novel [2](3)catenane 33 h10CEJ14285i. + N H2
O O O 3PF6−
O O
O O O
+ NH2
H2N O O O
O
O
O
O O
O
31 O + O N H O 2 O O O
O O
NH O + O2 O
O O
O
3PF6−
O
O
O
O HN O 2 + O O O
33
O O O
32 O O
O O
O
O
516
G.R. Newkome
8.7. CARBON–NITROGEN–OXYGEN RINGS Because of the aza-center(s) in azacrown ethers, N-alkylation has been an ideal location to append diverse substituents: 4-(1,4,7-trioxa-10-azacyclododecan-10-ylmethyl)acridin-9(10H)-one h10T350i; 4,5-bis(1,4,7-trioxa-10-azacyclododecan-10-ylmethyl)acridin-9(10H)-one h10T2953i; 2-[(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)methyl]4-(phenyldiazenyl)naphthylen-1-ol h10T4292i; N,N0 -bis[(8-hydroxy-7-quinolinyl) methyl]-1,10-diaza-18-crown-6 h10JOC6275i; (4,5-dimethyloxy-2-nitro-phenyl) [4-(1,4,7,10,13-pentaoxa-16-azacyclooctadec-16-yl)phenyl]methanol h10EJIC5069i; N,N0 -bis[(6-carboxy-2-pyridyl)methyl]-1,10-diaza-15-crown-5 h10EJIC2495i; as well as 7-[4-(4,5-di(furan-2-yl)-1H-imidazol-2-yl)phenyl]-, 7-[4-(4,5-diphenyl-1Himidazol-2-yl)phenyl]-, and 7-[4-(4,5-di(thien-2-yl)-1H-imidazol-2-yl)] phenyl1,4,7,13-tetraoxa-7-azacyclopentadecane h10IC10847i. A series of 15 homodimeric and 5 heterodimeric macrocyclic bisintercalators was created by either one- or two-step condensation procedures from aromatic dialdehydes with aliphatic diamines; then binding studies to DNA duplexes containing a mispaired thymine residue as well as to the fully paired control were conducted h10CEJ878i. Functionalized dialkoxy-substituted tetraoxacalix[2]arene[2]triazine macrocycles have been easily prepared by coupling methyl 3,5-dihydroxy-4-alkoxybenzoates with cyanuric chloride under mild conditions h10JOC3786, 10CEJ7265i. An ion-pair receptor comprising a calix[4]pyrrole and calix[4]arene pseudodimer has been synthesized and shown to possess a strong anion-recognition site h10JA5827i. Macrocyclization using 2,7-dihydroxytriptycene and 2,7-dichloro-1,8-naphthyridine gave 34 in 37% yield, but the cyclization was highly dependent on the reaction conditions h10CC4199i. A family of 27- to 39-membered pyridino-macrocycles has been synthesized by either a Williamson ether synthesis or ring-closing metathesis h10EJOC4932i. The macrocyclization of 2,5-bis(o-phenolyl)tetrazole with a,o-dibromoalkanes was accomplished in high overall conversion h10CEJ13325i. A new class of [2]catenanes that contain a zincII-porphyrin and [60]fullerene, as attached moieties, has been reported h10JA3847i. The transformation an appropriate tris-benzaldehyde precursor h10JOC2099i with tris(2-aminoethyl)amine, followed by added NaBH4, gave hemicryptophane 35 in a 97% overall yield h10IC7220i. The conversion of a sugar-diaza-crown h09CR1020i with propargyl bromide under alkylation conditions generated the intermediate bis-dialkyne, which with 9,10-bis(azidomethyl)anthracene using Click conditions gave the desired cavitand 36 in 35% yield h10TL109i.
Eight-Membered and Larger Rings
O
N
N
O N N
N N N
N N
N O
O O
N
N
517
O
O
34
O
36
O
O
OMe O P
N
O
N
OMe OMe
Ph HN
NH
N
H N
N
Ph
Ph
O
35
37
8.8. CARBON–NITROGEN–PHOSPHORUS RINGS Although C,N,P-ring-systems have been prepared and reported previously, there have appeared new routes to this basic core macroring (37) h10JOC375, 10OL1112, 10PAC583, 10SRE1098i, as noted h10CEJ14486i.
8.9. CARBON–NITROGEN–SULFUR RINGS Treatment of the bis-tosylate of 1,2-di(o-aminophenylthio)ethane with 1,2-dicyano4,5-bis[(2-iodoethyl)sulfanyl]benzene gave 18,19-dicyano-13,24-bis(tosyl)6,7,14,15,23,24-hexahydro-13H,22H-tribenzo[b,h,n][1,4,10,13,7,16]tetrathiadiazacyclooctadecine in 54% yield h10JOMC1210i. The thirty-p-electron-expanded hemiporphyrazines (38) has been prepared by a cross-over condensation between 2,5diamino-1,3,4-thiadiazole and either the corresponding phthalonitrile or diiminoisoindoline derivatives h10JA12991i. The treatment of a fused bithiophenediol with pyrrole using modified Lindsey’s conditions gave ( 15%) the expanded porphyrin 39 containing dithienothiophene moieties h10CC5915i. The condensation of 5-(p-tolyl)10,15,17-trihydro-16-thiatripyrrane with 2,5-[hydroxy(p-tolyl)methyl]thiophene under mild acidic conditions generated a single product 40 in reasonable yields h10EJOC1544i.
518
G.R. Newkome
R R
R S
N
S R
N
N
R Ar
HN
N
R
N NH N
N
N
S
N
HN N
38
R
N S
Ar R
Ar
S
N
S
N
R R
S
N
CH3
S
Ar
S
R
39
R
N
S
S
N
H3C
H
40 CH3
8.10. CARBON–SULFUR–OXYGEN RINGS New calix[4]arene-dithiacrown ionophores in the cone and 1,3-alternate conformations have been prepared; responses to different metal ions were described, notably they found a high potentiometric selectivity for Hg2þ over Naþ, as well as diverse transition and heavy metals h10T447i. In an attempt to make a bis-terminal thiol, hydrolysis of a bis-thioester with carbonate gave the disulfide macrocycle 41, which was isolated in 80% along with 8% of its dimer h10OL4078i. A series of spiroacetals thiocrown ethers derived from monensin, a spiroacetal-containing ionophore, has been demonstrated to show an affinity for heavy metals h10TL1072i. A polyfunctional tripod was subjected to a macrocyclization procedure giving rise to the macrotricycle 42 in ca. 5% yield (R ¼ Br or MeS) h10EJOC2701i. The six-step sequence, starting from 3-bromothiophene, gave the desired monomer 43, which was transformed (22%) to a polymeric chirality-sensing binaphthocrown etherealpolythiophene conjugate h10CEJ7859i. N-(4-Amino-2-methoxyphenyl)-4,7,10,13-tetrathia-1-aza-15-crown-5 was prepared and coupled with 6-acyl-2-[N-methyl-N(carboxymethyl)amino]naphthalene by a dicyclohexylcarbodiimide (DCC) coupling to produce the two-photon fluorescent probe AHg1 that was excited by 780 nm
Eight-Membered and Larger Rings
519
femtosecond pulses demonstrating high photostability, negligible toxicity, and can visualize the site of Hg2þ accumulation h10CC2388i.
S O
O
O
S
O
O
O
S
O
O O R
41
S S
R O R
42 O S
O
O
O
O
S
(R = Br or CH3S) E
S O
O
O
O O
43
S
44
E 3 (E = As, Sb, Bi)
8.11. CARBON–SULFUR–PHOSPHORUS/ARSENIC/ANTIMONY/ BISMUTH RINGS The rigid dithiol ligand, 1,4-bis(mercaptomethyl)naphthalene with pnictogen trichloride (ECl3, where E ¼ As, Sb, Bi, P), gave 44 via a self-assembly processor or by a transmetallation reaction from the Sb cryptand; their solid-state structures were determined h10ACIE1248, 10IC9985i.
8.12. CARBON–NITROGEN–SULFUR–OXYGEN RINGS A simple three-step route to 4,7-dioxa-1,10-dithia[13](6,60 )-2,20 -bis(cyclopenta[c]pyridine-2-yl)cyclophane (45) was accomplished through a novel homocoupling of 1,2,4-triazine bisulfide tethered to poly(ethylene glycol) chains with KCN, followed by a Diels–Alder/retro-Diels–Alder reaction of the intermediate thiamacrocycle with 1-pyrrolidino-1-cyclopentene h10EJOC4868i. The bis-thiamacrocycle 46 was mono-oxidized in moderate yield using Davis oxaziridine to give 47. The macrocyclic ethereal sulfone diimides 48 and 49 were prepared by the direct [1 þ 1] cycloimidization of the corresponding diamine with either 1,4,5,8-naphthalenetetracarboxylic dianhydride or pyromellitic dianhydride, respectively; their uses in supramolecular encapsulation have been described h10CEJ907, 10OL3756i.
520
G.R. Newkome
N
N
N
N N
N
N
O
S
S 2
O
N S O
O
S
S
2
2
45
O
N
N O
S
46
O
O
S
S
O
O
N
N
O
47
O
O
O
O
O
S
S
O
O
48
O
O
N
O
O
N
O
O
49
8.13. CARBON–SELENIUM–IRON RINGS Reduction of NCSe(CH2)3SeCN with NaBH4 gave [¯Se(CH2)3Se¯], which was treated with 1,10 -bis(3-bromopropylseleno)ferrocene to generate the desired 1,5,9,13-tetraselena-[13]ferrocenophane in 58% yield without the use of a template h10DT8812i.
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G.R. Newkome
10OL1888 10OL2124 10OL2722 10OL3212 10OL3756 10OL3910 10OL4078 10OL4300 10PAC583 10SRE1098 10T350 10T359 10T413 10T447 10T2953 10T4292 10T4377 10T4413 10T4987 10T8594 10TL109 10TL983 10TL1072 10TL1329 10TL3719 10TL6521 11CC176 11MI1
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INDEX A Acid catalyzed halogen dance (ACHD), 163. See also halogen scrambling Acinetobacter baumannii, 109 Aggregation-induced emission (AIE), 408 Alstonia pneumatophora (Apocynaceae), 311 Arbuzov reaction, 161 2-Arylacetaldehydes, 37 a-Arylation, 66 2-Arylpyrroles, 167 Aspergillus fumigatus, 34 Aspidofractinine, 4–5 Aspidophytine, 14–21. See also Haplophytine lactonization, 16 Sonogashira coupling, 15 TBAF-mediated hydrolysis, 16 Aspidospermidine, 2–3 Aspidospermine, 2–3 racemic synthesis, 3 Aurora kinase inhibitor, 384 Aza-rings (S)-N-Acetylindoline-2-carboxylate, 30 3-Anilino-pyrazinones, 45 annulation of medium size, 56–60 N-acetylbenzazepine, 56 benzazepines syntheses, 56 7-benzolactams, preparation, 56 1-benzyl-tetrahydro-1-benzazepines, 57 Buchwald–Hartwig reactions, 59 Heck condensation, 57 b-hydride elimination, 57 oxazepine synthesis, 58 pyrido[2,3-e] pyrrolo [1,2-a][1,4] diazepin-10-ones, synthesis 58 vitamin D receptor (VDR)-mediated transcription, 57 annulation of 5-memberd, 28–45 annulation of 6-member, 45–56 amino-ester, preparation, 47 3-amino-indol-2-ones, 51 androgen receptor modulators, 52 2-arylacetaldehyde derivatives, 49 Baylis–Hillman acetate, 49 benzo-oxa(thia)zines, 51–54
cyclic enamine ring, 55 1,2-cyclic sulfamidates, 52 1,4-dihydroquinolines, 55 [1,2]-fusion of azoles, 54–56 keay ligand, 47 (3S)–3-methyl-1,4-benzoxazine, 52 palladium-catalyzed synthesis, 52 phenazines, 51–54 quinazolines, 50 quinolines, 45–50 quinoxalines, 51–54 synthesis of bis(imidazole)-annulated terphenyls, 55 dihydrodipyridopyrazines, 53 N-methylsulfonyl tetrahydroquinolines, 48 tetrahydroquinolines, 46 2,3,7,8-tetrachlorodibenzo-p-dioxin, 53 toad poison dehydrobufotenine, preparation, 48 tricyclic aldehyde, 49 Ugi four-component reaction, 51 Bischler–Napieralski reaction, 37 bromo-olefins, 39 Buchwald–Hartwig cyclization, 39 clausenamine-A, 35 copper-catalyzed process, 44 dihydroisoquinoline, 37 5,7-dinitroindoline, 32 fused imidazoles, 43–45 Heck reaction, 30, 38 Horner–Emmons reaction, 38 imidazoindolone moiety, 34 indazoles, 41–43 2-aryl indazoles, 41 palladium-catalyzed indazole synthesis, 41 preparation 1-aryl-1H-indazoles, 41 fused indazole, 42 3-substituted indazole, 42 N,N-substituted hydrazines, 41
525
526
Index
Aza-rings (Continued )
synthesis indazolone derivative, 43 tricyclic indolo, 42 indolines, 28 iodobenzaldehydes, 40 iodoquinoline, 36 b-lactam antibiotics, 39 methyl ester, 30 o-bromo benzylamide, 30 oxazoles, 43–45 palladium-catalyzed cyclization, 29–28, 33, 44 solid-phase synthesis, 38 Stille coupling, 36 syntheses 2-aminobenzimidazoles, 43 marine alkaloids damirone, 33 imidazoindolone motif, 34 N13-protected precursor, 35 thiazoles, 43–45 (Z)-isomers, formation of, 38 Azepines, 465–467 Azetidines, 101–104 2-acetoxyazetidine, preparation, 102 chiral building, 107 enantiopure polyhydroxylated, 101 heterocyclic synthesis, 101 homoallylic amines, selenocyclization, 102 hydroacylation, 104 stereoselective synthesis, 102 Azetines, 101–104 Aziridines, 85–96 preparation, 85–89 alkenyl sulfonyliminoiodanes, 86 1,2-amino leaving group motif, 87 aza-Darzens or Darzens- approach, 87 aza-MIRC (Michael-Initiated Ring Closure), 86 catalytic aziridination, 85 chiral and achiral aziridination, 88 Jacobsen’s diimine catalyst, 86 Shioiri acylation of trimethylsilyldiazomethane, 88 reactions, 89–96 g-amino acids, 91 b’-amino-a,b-unsaturated ketones, 92 aziridine ring-opening, 90 carbanion nucleophiles, 91
Dess–Martin periodinane (DMP), 95 dihydrobenzisoxazoles, synthesis of, 95 gold-catalyzed ring expansion, 93 meso-aziridines desymmetrization, 89 metalated aziridines, 94 nitrogen-based nucleophiles, 91 p-nucleophiles, 91 nucleophilic ring-opening, 89 SNV-mode ring opening, 94 Suzuki–Miyaura reactions, 94 (–)-swainsonine, synthesis, 90 torquoselectivity, 93
B Baylis–Hillman reaction, 428 Benzene ring, Functionalization of the, 183 Benzo analog. See Pyrroles Benzoazepines, 467–470 A3 coupling, 468 1,7-electrocyclization reaction, 469 Friedel–Crafts chemistry utilization, 470 Heck/N-alkylation, 468 Heck reaction, 467 palladium-catalyzed reactions, 467 Pictet–Spengler reaction, 467 ring-closing reactions, 467 tandem cyclization, 468 vinylation–amination reaction, 468 Benzo[b]furans, synthesis, 216–222 Benzo[c]furans, synthesis, 222–223 Benzodiazepines, 482–487 Buchwald–Hartwig coupling, 487 coupling reaction, 486 Diels–Alder reaction, 486 intramolecular cycloaddition, 484 Pictet–Spengler reactions, 483 Ugi–deprotection–lactamization, 482 [1]Benzopyran, 435–441 ADEQ catalyst, 438 4-aryloxybut-1-enes, 438 3-arylpropan-1-ols, 439 chiral 4-nitromethylchromans, 438 3,4-disubstituted chroman-4-ols, 439 Friedel–Crafts alkylation, 439 hDA reaction, 436, 441 2-hydroxycinnamaldehydes, 438 7-methoxy-2-phenylchromene, 437 Michael–aldol cascade, 435, 437 3-nitro-2H-chromenes, 436
Index
[2]Benzopyran, 441–444 2-alkynylbenzyl alcohols, 442 bridged isochromans, 444 cross-coupling reactions, 441 oPS reaction, 443 Pd-catalysis, 443 1-substituted isochromans, 443 Ugi reaction, 442 Benzothienoazepinone synthesis, 66 7-Benzyloxyindole, 18 Birch reduction, 4 Black tea polyphenols, 427 Boronic ester, 21 Buchwald–Hartwig amination, 45, 47, 70 Buchwald condition, 43
C Camphorsulfonic acid (CSA), 45 (2R)-Camphorsultam dichlorophthalic (CSDP) acid, 285 b-Carbon elimination, 104 Carbon–nitrogen–oxygen ring, 516 Carbon–nitrogen–phosphorus ring, 517 Carbon–nitrogen rings, 510–513 Alder-type condensation, 512 click chemistry, 510 2,6-diiodopyridine, coupling reactions 510 Glaser coupling, 510 Mannich reaction, 512 meso-b-linked porphyrin rings, 513 Mo¨bius aromatic properties, 513 porphyrin-cored dendrimer, 513 Suzuki–Miyaura reaction, 513 Carbon–nitrogen–sulfur–oxygen rings, 519 Carbon–nitrogen–sulfur rings, 517 Carbon–oxygen rings, 506–510 absorption spectra, 509 Eglinton coupling, 506 “handcuff-like” superstructure, 507 metal-free phthalocyanine, 507 stokes shifts in emission spectra, 509 Carbon–selenium–iron rings, 520 Carbon–silicon rings, 515 Carbon–sulfur–oxygen rings, 518 Carbon–sulfur rings, 514 1,10-Carbonyldiimidazole (CDI), 272 Carboxamidation reaction, 493 Cascade protocols, 498
527
Cascades, 63–70 C–N arylation, 65 Heck/Buchwald–Hartwig, 68 inter-/intramolecular double amination, 64 intramolecular amidation, 65 palladium-catalyzed step, 67 Suzuki cyclization, 67 Catalytic system optimization, 56 Catalyzed benzodiazepinedione synthesis, 70 Catch and release purification, 43 C2–C3 Annulation, 180 Chelating, 347 Chelation, 60 C-heteroatom, 27 Chromones, 448–450 3-aminochromones, 448 Baker–Venkataraman reactions, 448 Michael reaction, 450 Pd-catalyzed a-arylation, 449 Pd-catalyzed cyclocarbonylation, 449 photo-Fries rearrangement, 450 sequential cycloaddition, 449 “Click” chemistry, 248–249 Click cycloaddition chemistry, 304 Click end-capping reactions, 305 Click polymerization, 305 “Click” reaction, 414 C–N intramolecular coupling, 66 Concerted metallation-deprotonation (CMD), 181 Conophyllidine, 21–23 Conophylline, 21–23 Coumarins, 446–448 Baeyer-Villiger oxidation, 448 Knoevenagel reaction, 446 N-bromosuccinimide (NBS), 446 one-pot reaction, 446 2-styrylbenzoic acids, cyclization 447 “Cream of the crop”. See 1,2,3-Triazoles C-ring double, 16 Cyclin-dependent protein kinase (CDK), 384 Cyclization aryl benzyl, 50 polysubstituted pyrroles, 168 Cycloaddition cascade, 13 Cyclocarbonylation reactions, 492 Cyclocondensation reaction, 492, 496
528
Index
D Density functional theory (DFT), 113, 405 (þ)–4-Desacetoxy-5-desethylvindoline, 13 Detoxification treatment, 35 Di- and Tetrahydrofurans, 201–204 Synthesis, 210–216 [3þ2] photocycloaddition reaction, 211 aldol condensation, 214 Baylis–Hillman adducts, 216 3-carbonyl-2,5-dihydrofuran, 216 cycloisomerization reaction, 213 eurylene, synthesis 210 Marson-type cyclization, 212 8-oxabicyclo octane, preparation 212 oxygen-bridged ring system, 213 Pauson–Khand carbonylation, 214 Prins cyclization, 212 substituted dihydrofurans, 216 tetrahydrofuran, 211, 214 tetrahydrofuran ring-containing natural products, 210 trilobacin, 210 Diazepines, 475–478 aza-Wittig reaction, 476 4-chloromethyltetrahydropyrimidin-2ones, ring expansion reaction, 475 1,3-diazepan-2-one, 476 intradiol-cleaving protocatechuate dioxygenases, 477 intramolecular alkylation, 476 SNAr reaction, 477 Diazo compound, 16 Dicarbonyl compounds (Paal–Knorr), 159 2-(Dicyclohexylphosphino)-biphenyl (DCPB), 53 Dihydro[1]benzopyrans. See [1]Benzopyrans Dihydro[2]benzopyrans. See [2]Benzopyrans Dihydrocoumarin, 447 Diketene, 115 1,2-Dimethylindole, 180 2,4-Dinitrobenzenesulfonyl (DNs), 22 Dioxepines, 487–490 Dioxetanes. See b-Lactones Dioxetanones. See b-Lactones Dioxins and Dioxanes, 454–456 1,2-Dioxolanes, 299 1,3-Dioxoles and dioxolanes, 293–295 Dipolar cycloaddition, 161
Dithianes and trithianes, 456 Dithiepines, 487–490 1,2-Dithioles, 299–300 1,3-Dithioles and dithiolanes, 295–298
E Electron-withdrawing groups (EWG), 174 Epidermal growth factor receptors (EGFR), 415 Epoxides, 75–85 preparation, 75–80 a-branched a,b-unsaturated aldehydes, 77 chiral sulfonium salt usage, 79 conversion of one epoxide, 80 darzens reaction, 78 dioxiranes, 76 epoxidation reactions, 75 Fe-based catalysts, use 76 hafnium catalyst, 77 methyltrioxorhenium (MTO), 75 sulfur ylides usage, 79 two-step process, 76 a,b-unsaturated ketones, 78 reactions, 80–85 acid-catalyzed 6-endo cyclization, 82 acid-catalyzed Meinwald rearrangement, 84–85 amino acid-derived epoxides, 81 dipolar cycloaddition of azides, 82 Horner–Wadsworth–Emmons reagent, 84 nucleophilic ring opening, 80 Reaction with a Zn-enolate, 83 SNAr reaction, 82 stilbene oxide with aniline, 81 Zn-enolate with a vinyl epoxide, 83 p-nucleophiles with epoxides, 84 E-ring carbonyl, 16 Escherichia coli, 103
F Fischer indole, 19, 175 Five-membered ring. See Thiophenes Flash vacuum pyrolysis (FVP), 220 Fluorescence energy transfer (FET), 418 Forced swim test (FST), 404 Friedel–Crafts acylations, 164
Index
Friedel–Crafts alkylation, 165 Furans, 196–201 aziridination, 200 cycloisomerization, 198 Diels–Alder reaction, 197–198 gold-catalyzed transannular [þ3] cycloadditions, 196 oxidative cleavage of ring, 199 synthesis, 203–210 3-alkyne-1,2-diols, 204 Cu-catalyzed reactions, 209 2,3-disubstituted furan, 205 fluorine-containing polysubstituted furans, 204 ketal-functionalized nitroalkanes, 206 Knoevenagel condensation–cyclization, 204 7-methyl-1,5,7-triazabicyclo[4.4.0] dec-5-ene (MTBD, 206 phenanthrene-tethered, 203 polysubstituted furans, 209 Pt-catalyzed reaction, 207 tandem rearrangement–nucleophilic substitution, 207 trisubstituted furans, 203, 207 Wittig reaction, 209 g-hydroxyketones, 204 zwitterionic oxazolidinone, 196 Fused and Bridged Rings, 132–135 3-alkylthiophenes, cyclization of, 132 benzothieno[3,2-b]benzophenes (BTBT), 133 coupling-addition-SNAr (CASNAR), 134 [3,4-b]diheteropentalenes, synthesis, 135 dipropargylic disulfides, preparation, 133 fused thiophene ring systems, 134 palladium-catalyzed cyclocoupling, 133 Fused [6]þ[5] polyaza system, 419–422 purines, 421–422 triazino [6þ5], 419–420 Fused [6]þ[6] polyaza system, 422 Fused azepines, 467 Fused diazepines, 478–482 anti-obesity agents, 480 “click” reactions, 481 1,3-dipolar cycloaddition reactions, 481 laccase-mediated oxidative C–N bond, 479 Ugi reaction, 480
529
G
a-Gem-vinylpyrrole, 167 Gewald reaction, 146 Gold-catalyzed cycloisomerization, 156 Grignard reagents, 88 Grubbs–Hoveyda second-generation catalyst (G-H-II), 159
H Halogen scrambling, 163 Haplophytine, 14–21 Haplophytine, HBr-mediated rearrangement, 17 Heteroatoms, 300 Huisgen reaction, 161
I Imidazoles, 237–243 acid-catalyzed rearrangement, 239 addition–cyclization–isomerization, 237 1-alkyl-2-aryl-5-nitrobenzimidazoles, 238 3-alkyl-4-hydroxybenzimidazoles, synthesis 239 Boulton–Katritzky rearrangement, 237 2-bromoanilines, 240 cascade reaction of sulfonyl azides, 240 C–H arylations, 240 copper-catalyzed reactions, 240 cyclocondensation of benzil, 238 dehydrative cyclization, 238 4,5-disubstituted-2-aminoimidazoles, 237 6p-electrocyclization/dehydrogenation reactios, 240 2-fluoro-5-nitroaniline, 238 GABA derivatives, 242 imidazole-catalyzed protocol, 242 imidazole-fused ring, 243 N-heterocyclic carbene (NHC), 242 2-nitroanilines, 238 palladium-catalyzed reaction, 240 2-substituted benzimidazoles, preparation 239 transition metal-catalyzed methods, 239 Indole acetic acid derivative, 16 Indole ring construction, 171 Indoles, 28–40 Indole side-chains, elaborations, 184 Indolines, 28–40 Intramolecular cyclizations, 173
530
Index
Isoquinolines preparation, 358–361 azide-based cyclization, 359 Bischler–Napieralski reaction, 360 6-endo-dig cyclization, 358–359 Larock isoquinoline synthesis, 358 N-tosyl stabilized N-amino ylide, 359 reactions, 361–364 Buchwald amination, 362 isoquinoline-based ylides, 363 isoquinoline-1,3,4-triones, 363 metal-directing/activating methodologies, 364 Isothiazoles, 280 pharmaceutical usage, 285 reactions of, 281–282 reagents in organic syntheses, 283 synthesis of, 280–281 Isoxazoles, 303–306 alkylidenepyrrolidine reactions, 304 Beckmann rearrangement, 307 1,2-benzisoxazoles, synthesis 303 boronic acid catalysis (BAC), 305 Cinchona alkaloids, 307 5-endotrig cyclization, 309 5-hydroxy-2-isoxazolines, 307 SN2-type O-alkylation, 308 thermal bioconjugation reaction, 309 valdecoxib, synthesis, 306 Isoxazolidines, 310–313 cocaine analogues, synthesis, 310 a-diazo ester, cycloaddition of, 312 perhydrohistrionicotoxin, synthesis, 310 tetrahydronaphthalene isoxazolidines, 312 Isoxazolines, 307–308
K Knoevenagel–hDA reactions, 453
L
b-Lactams, 105–108 b-hydroxy oximes, 107 Cope rearrangement, 107 fused and spirocyclic, 109–111 bisfunctionalization–cyclization, 111 dichloro-b-lactam ring, 111 enzymatic deacetylation, 110 Lewis acid-catalyzed intramolecular substitution, 110
Staudinger reaction, 110 Grubbs’ carbene, 107 preparation of, 105 solid-phase synthesis, 105 Staudinger reactions, 105–106 synthesis of, 106 cis-b-lactams, 106 a-fluorinated amino acid derivatives, 105 macrocycle, 108 TFA-mediated release, 108 b-Lactones, 112–116 chiral phosphine-catalyzed homodimerization, 115 chiral Schiff ligand, 115 esterase inhibitors, synthesis, 114 indanedioneketene, dimerization of, 115 b-keto tertiary amide, 114 paclitaxel (PTX)-Phe-PheArg-chloromethyl ketone, 112 Paterno`–Bu¨chi reaction, 113 ring-opening polymerization, 112 Larock type indole synthesis, 175 Lawesson reagent, 134 Lewis-acid catalyst, 164 Lewis-acid catalyzed alkylation, 179 Lipopolysaccharide (LPS), 407 a-Lithiation, 102 Lymphocyte-specific kinase (Lck) inhibitors, 59
M Macrocycles, 60–63 application, treatment of Alzheimer’s, 60 BACE-1 inhibitors, 60 Buchwald–Hartwig C–N coupling, 61 2,6-dibromopyridine, 62 fragment-coupling, 62 preparation oligonuclear metal complexes, 63 pyridine-containing macrocycles, 61 synthesis benzoaza crown ethers, 60 N-(p-Tol)azacalix[n](2,6)pyridines, 63 Mannich reaction, 47 Meloscine, 9–10 enantioselective synthesis, 10 racemic synthesis, 10 wittig olefination, 9 metal-to-ligand charge transfer (MLCT), 407 Mitsunobu reaction, 15
Index
531
N
P
Nazarov photocyclization, 181
PCC oxidation, 18 Pd-mediated O-bridged carbocycles, 428 Pd-promoted cyclization, 182 Pericyclic transformations, 176–177 Petasis condensation, 496 Phenothiazine, 53 Photochemical ring closure, 172 Photocyclization reactions, 492 Photolysis, 96 Phthalocyanines, 505 Pictet-Spengler cyclization, 107 Polarizable continuum model, 113 Polonovski–Potier reaction, 22–23 Porphyrins, 512–513 Positron emission tomography (PET), 418 ProDOT polymerization reactions, 489 Pseudo-domino process, 68 Pseudolabrus japonicus, 34 Pummerer glycosidation, 457 Pyranones, 444–446 aldol reaction, 445 2,6-dimethoxypyran-4-ones, 445 hDA reaction, 445 3-substituted pyran-2-ones, 445 Pyrans, 428–435 2-alkenyl-1,3-cyclohexanediones, 434 2-aminopent-4-yn-1-ols yield, 431 dimethyl acetylenedicarboxylate (DMAD), 428 Friedel–Crafts reactions, 431 b-hydroxyaldehydes, 433 Knoevenagel–hetero-Diels–Alder (hDA) sequence, 430 Nazarov cyclization, 434 Prins reaction, 430–431, 435 retro-Michael reaction, 434 Tetrahydropyran-2-carboxylates, 434 Wittig reaction, 433 a,b-unsaturated ketones, 428 Pyrazines, 386 applications, 392–395 murine model of chronic inflammation, 394 ruthenium supramolecular photocatalyst, 392 reactions, 389–392 hydrogenation of pyrazine, 391
O Oceanobacillus iheyensis, 109 O-macrocycle, 506 Oppolzer sultams, 285 Organic light emitting diodes (OLEDs), 453 (Ortho-nitrophenyl)phenyliodonium fluoride (NPIF), 6 Oxacyclophanes, 509 Oxadiazoles, 324 p-conjugated systems, 324 1,3,4-oxadiazoles, 324 Ugi-4CR/aza-Wittig method, 324 Oxathianes, 457 1,3-Oxathiole, 298–299 1,2-Oxathioles, 300 Oxazoles, 313–316 a-chloroglycinates, 314 Grignard reagents, 314 palladium-catalyzed methods, 315 2-phenylsulfonyloxazole, 315 oxazole-4-carboxylates, syntheses 314 structural determination, 316 Oxazolidines, 320–324 5-aryl-2-oxazolidinones, synthesis, 322 atropisomeric benzoylformamides, 322 2-Butenyloxazolidine, 323 Diels–Alder reactions of 1,2-dihydropyridines, 322 oxidative amidation reactions, 323 preparation chiral oxazolopiperidine, 321 cyclic carbonates, 322 Oxazolines, 316–320 bis(oxazoline) (Box) ligands, 319 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), 317 Fre´chet-type dendrimers, 319 Friedel–Crafts alkylation reactions, 319 Nazarov reactions, 319 2-oxazolines, synthesis, 316 trichloroacetimidates, 317 Oxepines, 471–474 Oxetanes. See b-Lactones 2-Oxetanones. See b-Lactones 3-Oxidopyrylium ion, cyclodimerization of, 197
532
Index
Pyrazines (Continued )
Sonogashira reaction, 390 tandem amination procedure, 389 syntheses, 386–389 aerobic oxidation of alcohol, 387 Beirut reaction, 389 DABCO-catalyzed cyclization/ oxidation, 387 3-methoxy-quinoxalin-2-one, 387 quinoxaline-2-carboxylate, 388 Pyrazole-fused ring, 237 Pyrazoles, 231–237 3-aminoindazoles, synthesis 234 C–H arylation reactions, 235 diethylaminosulfur trifluoride (DAST), 231 1,3-dipolar cycloaddition reaction, 232 N-alkylation of 3-iodoindazole, 236 Sonogashira coupling, 234 Suzuki–Miyaura cross-coupling, 231, 235 syndones, 232 1,3,4,5-tetrasubstituted pyrazoles, synthesis 233 2-thio-3-chloroacrylamides, 232 Z-tosylhydrazones, cyclization of 234 Pyridazine ring, 162 Pyridazines, 372 applications, 375–376 reactions, 373–375 copper-catalyzed coupling reaction, 374 Diels–Alder reactions, 373 Negishi cross-coupling, 373 pyridazine-derived hydrazone, 374 pyrrolo[2,1-a]phthalazines, 374 syntheses, 372–373 Pyridine N-Oxides, 345–349 p-acidic copper, 345 metalation-deprotonation mechanism, 346 metal-catalyzed cross-couplings, 347 tosyl azole reagents, 345 3-spiroindolizine oxindole, synthesis 348 a,b-unsaturated oximes, 345 Pyridines preparation of, 330–335 Aza-Diels–Alder approaches, 333 Bohlmann–Rahtz synthesis, 331 chiral cobalt catalyst, 334 Curtius rearrangement, 332 cyclocondensation, 330
Defluorination sequence, 331 1,5-dialdehyde, 332 Hantzsch synthesis, 331 reactions of, 335–345 azide–alkyne click chemistry, 344 C–H functionalization, 341 functionalization, 336 gold-catalyzed cycloisomerization, 342 Hartwig–Miyaura boronylation, 341 Knochel conditions, 340 lithiation, 337 metalation with zinc and magnesium, 339 Negishi coupling, 339 nucleophilicity, 336 palladium-catalyzed methods, 340 SNAr-type mechanism, 336 Suzuki–Miyaura reaction, 340 Pyridinium salts. See Pyridine N-Oxides Pyrimidines, 376 applications, 384–386 diabetes treatment, 385 neuroscience, 386 non-pharmaceutical applications, 386 reactions, 381–384 [3þ2] cycloaddition click reaction, 382 aza-Diels–Alder reaction, 382 cycloadditions, 382 spiro-fused pyrimidines, 383 Suzuki-Miyaura reaction, 381 Ugi-Smiles/Sonogashira reaction, 383 syntheses, 376–381 4-allylquinazolines, 378 2-aryl quinazoline, 380 Biginelli reaction, 376 desilyation, 377 dihydropyrimidinones, 376 Dimroth rearrangement, 379 Preyssler nanoparticles, 378 selenium-catalyzed carbonylation reaction, 378 Pyrrole cyclocondensation (Paal–Knorr variant), 159 Pyrrole-fused alkaloids, 157 Pyrroles, 155 azaindoles, 186–188 carbazoles, 186 carboline analogs, 186–188 oxindoles and spirooxindoles, 185 reactions, 162–170
Index
functionalization of side-chain substituents, 169–170 substitutions at pyrrole carbon, 163–169 substitutions at pyrrole nitrogen, 162–163 synthesis of, 155–157 intermolecular approaches, 157–162 intramolecular approaches, 155–157 reactions of indoles, 176–184
Q Quantum dots (QD), 415 Quenching, 140 Quinolines, 349–358 preparation, 349–355 alkyne-based method, 351 2-aminobenzaldehydes, 351 6p-electrocyclization, 354 elimination–oxidation aromatization, 354 Friedel–Crafts reaction, 353 Friedla¨nder synthesis, 349–350 Houben–Hoesch ring, 354 lactamization, 350 Povarov reaction, 354 proline-based catalyst, 349 Skraup methods, 353 Ullmann coupling, 351 Wittig olefination, 350 reactions of, 355–358 azine moiety, 355 cinchona alkaloids, 358 quinoline-based sensor, 357 silylated dialkyl phosphite, 356 Suzuki–Miyaura cross-coupling, 356 tetrahydroquinolines, 356 4-thioalkyl quinolines, 355
R Radical cyclization, 3 Radical cyclization, 491 Radiolabeling method, 415 Regioisomers, 305 Rhodium-catalyzed cyclization, 158 Rhodium-catalyzed insertion reactions, 157 Rh-stabilized vinylcarbenoids, 180 Ring annulation, 168–169 Ring-closing metathesis (RCM), 107 Ring-expansion/Kornblum oxidation, 13 Rotaxanes, 505
533
S Saegusa reaction, 15 Schmidt reaction, 3 Schotten-Baumann acylation, 43 Selenazoles, 289 Selenodiazoles. See Thiadiazoles Se/Te derivatives. See Thiophenes Silica-bonded S-sulfonic acid (SBSSA), 236 Silica gel chromatography, 317 Silicon and phosphorus heterocycles, 117–119 11 B NMR spectra, 119 cyclic polyphosphines, 118 cycloaddition reaction, 118 diphosphines, 118 1,4-disilabenzene, 117 Heck coupling, 118 metal-catalyzed silylene transfer, 117 nickel-catalyzed ring expansion, 117 Woollins’ reagent, 118 Spirocyclization, 178 Streptomyces staurosporeu, 35 Structure–activity relationship (SAR), 406 Subincanadines, 7–8 Dieckmann condensation, 7–8 Heck cyclization, 8 Michael addition, 7 Nozaki–Hiyama–Kishi reaction, 7 Pictet–Spengler cyclization, 7 racemic synthesis, 8 Supramolecular, 519
T Tabersonine, 5–7 gram-scale synthesis, 5 indole synthesis, 6 wittig olefination, 5 Tail suspension test (TST), 404 Tandem sequences, 63–70 Buchwald–Hartwig amination, 63, 68 C–N/Suzuki coupling, 67 cyclization–coupling process, 67 TaxolÒ, 112 TaxotereÒ, 112 Tetrahydro-b-carboline, 18, 20 Tetrazines, 412–419 ANRORC mechanism, 413 borondipyrromethene (BODIPY), 417
534
Index
Tetrazines (Continued )
HOMO (Highest Occupied Molecular Orbital), 416 Kornfeld–Boger ring contraction, 413 lycogarubin C, syntheses, 413 tetrazine fluoro derivatives, preparation, 412 Tetrazoles, 254–257 Diels–Alder reactions, 255 fused rings, 257 montmorillonite K-10, 255 nitriles treatment, 254 preparation of, 254 Ugi five-center four-component reaction (U-5C-4CR), 257 Thiadiazoles, 285–289 Gould-Jacobs reaction, 288 pharmaceutical usage, 289 reactions, 287–288 syntheses, 285–287 2-amino-1,3,4-thiadiazoles, 286 2,5-disubstituted 1,3,4-thiadiazoles, 285 N-(Cbz-aminoacyl)thiosemicarbazides, 285 1,2,4-thiadiazoles, 286 Thiazoles, 267 pharmaceutical importance, 279 reactions of, 273–277 synthesis of, 267–272 thiazole-containing natural products, 277–278 Thiepines, 474–475 Thietanes, 116–117 Mitsunobu reaction, 116 synthesis of isonucleosides, 116 b-Thiolactams, 104 Thiol-olefin co-oxygenation reaction, 456 Thiophenes, 127–150 elaboration, 135–140 alkynylation of thiophenes, 137 3-aminobenzothiophene, 137 Anderson catalyst, 139 cross-coupling reactions, 135 Diels–Alder intramolecular cyclization, 139 electrochemical cathodic hydroxylation, 139 Evans–Tishchenko coupling, 140 oxidation of, 139
perfluoro alkyl groups, 137 stoichiometric organometallics, 135 Suzuki–Miyaura reaction, 137 Ugi reaction, 139 medicinal chemistry, 144–147 bioactive thiophenes, 147 catechol-O-methyltransferase (COMT), 147 conformational modeling, 147 4,7-dichlorobenzothien-2ylsulfonylaminomethyl boronic acid (DSABA), 147 Friedel–Crafts acylation, 144 Michael addition acceptors, 147 novel Schiff, 145 novel thienopyridine derivatives, 146 pharmacophore model, 147 PTP1B inhibitors, 146 Rho kinase inhibitors, 145 SGLT inhibitors, 144 space limitation, 145 selenophenes and tellurophenes, 147–150 3-alkynyldihydroselenophene, 148 copper-catalyzed synthetic method, 148 cyclopenta[c]selenophenes, 149 2,3-dihydroselenophene, 147 electrophilic cyclization, 147 o-ethynylbenzyl phenyl selenides, 148 novel 2,5-diarylselenophenes, 149 poly(3-hexylselenophene-block-3hexylthiophene, 149 synthesis, 141–144 azole-functionalized oligo, 141 BODIPY-oligothiophene donor, 143 cyclic voltammetry, 141 1,3-disubstituted benzo[c]thiophenes, 141 l-leucine, preparation of, 142 McMurray coupling, 144 poly(3-dodedyl-2,5-thienylenevinylene)s, 141 l-leucine, preparation of 142 Stille cross-coupling, 142 UV–vis spectroscopy, 141 Thiophene rings, 128–131 Buchwald–Hartwig (C–N) coupling, 132 diarylalkynes, 128 1,3-dihydrobenzo[c]thiophenes, preparation, 130 electrophilic cyclization, 128
Index
ferrocenylacetylenes, reactions, 128 five-cascade sequential reaction, 129 Gewald reactions, 130 sulfur-assisted synthesis, 129 Sonagashira coupling, 128 synthesis 2-amino derivatives, 131 EDOT, 129 phenylbenzo[b]thiophenes, 131 2-trifluoromethylbenzothiophenes, 131 Thiopyrans and Analogues, 452–453 Thorpe–Ziegler reaction, 157 Topoisomerase inhibitor, 54 Transmetallation reaction, 519 Triazines, 403–412 1,2,3-Triazines, 403–404 1,2,4-Triazines, 404–407 1,3,5-Triazines, 407–412 1,2,3-Triazoles, 244–251 a-azidohydrazones, 247 Beckmann rearrangement, 248 1,2,5-benzothiadiazepines, 250 1,3-dipolar regioselective cycloaddition, 245 1,1’-disubstituted-4,4’-bis-1H-1,2,3triazoles, 245 fused-1,2,3-triazole, 250 substituted propargyl alcohols, 248 triazolofused-1,4-benzodiazepines, 250 1,4,5-trisubstituted triazoles, 245 1,5,7-triazabicyclo dec-5-ene(TBD), 246 1,2,4-Triazoles, 251–254 3,6-diaryl-1,2,4,5-tetrazines, reaction of 252 four-component palladium-catalyzed reaction, 251
535
Michael addition of a,b-unsaturated ketone, 252 palladium-catalyzed coupling of aldehydederived hydrazones, 253 s-triazolo[3,4-b][1,3,4] thiadiazines, 254 synthesis of, 252, 254 use, 253 Tricyclic ketone, 18 b-Trifluoromethylpyrrole, formation, 160 Trioxanes and Tetraoxanes, 456 tris(2-carboxyethyl) phosphine (TCEP), 498
U Ugi four-component condensation (4CC), 104
V Vinblastine, 11–14 Vincristine, 11–14 Vindoline, 11–12 Vinyl iodide, 21
W Wittig olefination, 172 Wolff–Kishner reduction, 2, 164 Woollins reagent, 149
X Xanthenes and Xanthones, 450–452 Xantphos, 56, 66 Xantphos ligand, 44 Xylene induced ear edema model, 375
