x
Foreword
This is the nineteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2006 on most of the important heterocyclic ring systems.
References are
incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews. The first, by Xuechuan Hong and Michael Harmata, covers 'Recent progress in the chemistry of 2,1benzothiazines'. The second, by Ana Silva and Jose Cavaleiro, discusses 'Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions'. The remaining chapters examine the 2006 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. In the previous volume, Vol. 18, it was not possible to include a chapter on 'Six-membered ring systems: diazines and benzo derivatives' so this volume has two chapters on this topic: chapter 5.4 (2005) covers the literature of 2005 and chapter 5.4 (2006) covers the publications of 2006. Due to unforeseen and unfortunate circum stances, 'Six-m embered ring system s: with 0 and/or S atom s' does not appear in this volume; Volume 20 will include a double chapter on this topic, covering the literature of 2006 and 2007. The Index is not fully comprehensive - it includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever 'pyrido[3,4-b]indoles' are mentioned an indexed entry under that name will be found; similarly 'aceanthryleno[ I,2-e][ I,2,4]triazines', 'azirines', '2H-pyran-2-ones', 'I ,2,4-triazoles', etc., etc. are listed. But, subjects like '4-ethyl-5-methylpyrrole', '5-acylazirines', '6-alkyl-2H-pyran-2-ones', '3alkylamino-I,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. However, again this year, the Contents pages list all the subheadings of the chapters which we hope will considerably improve accessibility for readers. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Joan Anuels of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.
Gordon W. Gribble John A. Joule
xi
436
Chapter 6.4Editorial Advisory Board Members
Progress in Heterocyclic Chemistry Six-membered ring systems" with 0 and/or S atoms 2006 - 2007 PROFESSOR M. BRIMBLE (CHAIRMAN) University of Auckland, New Zealand Unfortunately, due to unforeseen and unfortunate circumstances, the regular chapter on 'Six-membered ring systems: with O and/or S atoms' does not appear in this volume. We apologise for this anticipate that PHC 20 will include double chapter on this PROFESSOR D. omission. ST CLAIRWeBLACK PROFESSOR H. aHIEMSTRA area, covering the literature of 2006 and 2007.
University of New South Wales Australia
University of Amsterdam The Netherlands
PROFESSOR M.A. CIUFOLINI University of British Columbia Canada
PROFESSOR D.W.C. MAcMILLAN California Institute of Technology USA
PROFESSOR 1. FUKUYAMA University of Tokyo Japan
PROFESSOR M. SHIBASAKI University of Tokyo Japan
PROFESSOR A. FORSTNER Max Planck Institut Germany
PROFESSOR L. TIETZE University of Gottingen, Germany
PROFESSOR R. GRIGG University of Leeds UK
PROFESSOR P. WIPF University of Pittsburgh USA
Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb.uni-graz.aU-kappeco/ISHC/index.html
Chapter Chapter 1 Recent progress progress in the chemistry of of 2,1-benzothiazines 2,1-benzothiazines
Xuechuan Hong and Michael Hannata Harmata** Missouri 65211, Department ofChemistry, of Chem•try, University University ofMissouri-Columbia, of Missouri-Columbia, Columbia, Columbia, Missouri 65211, USA USA
[email protected] [email protected]
1.1 INTRODUCTION INTRODUCTION
<65JOC3163; The study of of the chemistry of 2,1-benzothiazines 1 started in the 1960s <65JOC3163; 81JHC73>. Subsequently, their preparation and intensive biological and physiological studies 8IJHC73>. have been reported <66MIl; <66MI1; 66MI2; 66MB; 66MI3; 67MIl; 67MI1; 67MI2; 67MB; 67MI3; 67MI4; 68MIl; 68MI1; 69MIl; 69MI1; 71MIl; 71MI1; 77MIl; 77MI1; 84MIl; 84MI1; 89MIl; 89MI1; 92MIl>. 92MI1>. In recent years, 2,I-benzothiazines 2,1-benzothiazines I, 1, have been of of enonnous enormous interest to synthetic chemists. The current review is intended to present the progress of synthetic procedures and applications of of 2,1-benzothiazines 2,1-benzothiazines 1 and related compounds. 5
4
6CO~ 6 ~ ~ N ~ S 33 /./ N/SZ 2
7 7
8
1 (1 (1))
I-benzothiazines 1 Figure 1. General structure of 2, 2,1-benzothiazines SYNTHESIS OF 2,1-BENZOTHIAZINES COMPOUNDS 1.2 THE SYNTHESIS 2,I-BENZOTHIAZINES AND RELATED RELATED COMPOUNDS 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide 2,2-dioxide Derivatives 1.2.1 Synthesis of 3,4-Dihydro-2,I-benzothiazine
3,4-Dihydro-2,I-benzothiazine 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives 2, a type of benzosultam, possess very strong biological activities and have been used as drugs for treating heart diseases and 92MI1; 94MIl; 94MI1; 98MIl; 98MI1; 02MIl; 02MI1; 02MI2; 04MIl> (Figure as lipoxygenase inhibitors <89MI1; <89MIl; 92MIl; 2). These remarkable biological activities have made the synthesis of the 3,4-dihydro-2,1benzothiazine 2,2-dioxide skeleton of interest. Several different methods of synthesis of 3,4dihydro-2, I-benzothiazine 2,2-dioxide derivatives are already established. dihydro-2,1-benzothiazine
*' University) on 70thth birthday birthday **This This review review is is dedicated dedicatedto Professor Professor Albert Albert Padwa Padwa (Emory (EmoryUniversity) on the occasion occasionof his 70
2
x. Hong and M M. Harmata X
R2
R3~
V
R3"~N~SO2 J0
N II
R R1 1
R R1 = H, H, PhCH PhCH2 2 1= 2
= =
R R2= H, alkoxyl, alkoxyl, hydroxyl hydroxyl 2 H, R R3= H, piperazinyl piperazinyl 3 H,
(2) (2) Figure 2. 3,4-Dihydro-2, 1-benzothiazine 2,2-dioxide derivatives. 3,4-Dihydro-2,1-benzothiazine
1965, the first first 2,1-benzothiazine 2,2-dioxide was synthesized by Leov's group In 1965, <65JOC3163; 67MI1> through cyc1ization cyclization of 2-(ortho-aminopheny1)ethanesulfonic 2-(ortho-aminophenyl)ethanesulfonic acid or chloride. They also demonstrated its sodium salt with phosphorus pentachloride and acetyl chloride. that 4-phenyl-3,4-dihydro-2,1-benzothiazine-2,2 4-phenyl-3,4-dihydro-2,1-benzothiazine-2,2 dioxide (6) can be smoothly obtained by treatment of styrenesulfonanilide 5 with polyphosphoric acid (PPA) <67MI1>. Sianesi Sianesi and co-workers <71 CB 1880> <71CB 1880> developed an alternative approach to prepare 4 in 73% yield by pyrolysis of the corresponding aminosulfonamide hydrochloride 7 (Scheme 1).
oc:
H
H
:::,...1 ~ S O 3 XSOY<
PCl PCls5,, AcCl AcCI
-40%
..
H H
{~ < cr?~ 5
v
aye' 6
CX::: :::,...1
H H
PPA PPA
Ph Ph
v
C1
02
4
3: 3: X= X= Na, Na, H H
N.s02
00 ~;02
Ph
H H
200 DC ~
.. _ w
73% SO2NH2 73% S02NH2
7
00
02 02
4 4
Scheme 1 Scheme
1969, Hromatka et al. <69M928> found found that the cyclization cyc1ization of 5-chloro-2-(NIn 1969, methyl-iodomethanesulfonamido)-benzophenone methyl-iodomethanesulfonamido)-benzophenone 8 with ammonia or alcoholic ammonia gave 6-chloro-4-hydroxy1-methyl-4-phenyl-3,4-dihydro-2,1-benzothiazine 6-chloro-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-2, I-benzothiazine 2,2-dioxide 9 and 6chloro-4-hydroxy-3-iodo-l-methyl-4-phenyl-3,4-dihydro-2, chloro-4-hydroxy-3-iodo1-methyl-4-phenyl-3,4-dihydro-2,1I-benzothiazine -benzothiazine 2,2-dioxide 10 in 30% and 33% yields, respectively (Scheme 2).
3
Recent progress in the chemistry chemistry of of 2,l-benzothiazines 2, I-benzothiazines
(~H3 N-SO2CH21 NH NH3, CHCI3= 3, CHCI 3 ..
~
Ci/-,m/-x~O>'-~ >'- Ph
30%
30%
(~H3 " ;02 Cl
)H Ph
8
9
-SO2CH21 NH3, EtOH= CI/'~~O
~
2
33%
I OH I Ph
Ph 8
10
Scheme Scheme 2
Abramovitch and co-workers <75JA676> also synthesized 3,4-dihydro-2,1benzothiazine 2,2-dioxide 4 by flash vacuum pyrolysis of ~-arylethanesulfonyl [3-arylethanesulfonyl azides 11. The 3,4-dihydro-2,I-benzothiazine 3,4-dihydro-2,1-benzothiazine 2,2-dioxide 4 was obtained in 13% yield at 300°C 300 ~ along with some side products, such as dihydropyrindine, indoline, indole, and styrene. Although the reaction yield was low, this new approach appeared very promising for the synthesis of 2,I-benzothiazenes 2,1-benzothiazenes (Scheme 3). After an extension of this work reported by the same group, <78H(lI)377; 8lJA1525; <78H(11)377; 81JA1525; 84JOC5124; 84MI1; 85JOC2066> the thermolysis of compound 11 (R (R]r = H; R R2, R33 = OMe) at 400°C 400 ~ in Freon 113 as solvent gave compound 12 in 46-62% 2, R yield. Rz
Rz H ,", H
~ ~OZN3 _1':.__ ;YN~~Oz R 3 ~ R3" " ~ "]/ R~ R~ R R11
R 11
4: 4 : R 1R 1= = H, R R2, R3= z, R 3 =H 12: R 1= 12:R1 = H, Rz 2,, R R3= OMe 3 =OMe
11
Scheme Scheme 3
5-Hydroxy-3,4-dihydro-2,I-benzothiazine 5-Hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 can be synthesized in a convenient manner <94TL2911>. Blondet and co-workers used a cyclization of an ortho(chloromethyl or carboxaldehyde) N-protected sulfonanilide 13 or 16 with sodium hydride in DMF to give the benzothiazine dioxide 14 or 17 in 35% and 47% yields, respectively (Scheme 4). Finally, removal of the methoxy group and hydrogenation led to the formation of 5-hydroxy-3,4-dihydro-2,I-benzothiazine 5-hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 in good yield over two steps.
xx. Hong and and M M. Harmata
4
ac> OCH 3
~ _CH3 N
~
CI Nail, DMF DMF •.~ NaH, SO2CH3 60 60 DC, ~ 35% 35% N- 802CH lL
13 13
Ph Ph
ceo 16 16
1. BBr3' BBr3, CH CH2CI2, 77% • 1. 2CI 2, 77% y /80 2 2. H , Pd(OHh, 85% 02 2. H2, Pd(OH)2, 85% 2 N
~
14 14
OCH33 OCH
~I
&
OH OH
OCH3
L
lph Ph
NaH NailCDMF •=_ 25 DC, 47%
N~SO2CH3 25 80 CH
W
2
3
,47 Yo
CO
Lph
lph
~
02 N/ 802 H .
~
15 15
OCH3
CliO
60 OH OH
BBr3, CH CH2CI 650/0 • 1. BBr3' 2CI 22,, 65% /80 022 2. H2, H2, Pd(OH)2, Pd(OH)2, 82% =
N 17 17 lLph Ph
60 ~
02 N/ 802
15 15 H H
Scheme Scheme 4 An improved synthesis of 3,4-dihydro-2,I-benzothiazine 3,4-dihydro-2,1-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions <00JOC8391; 00JOC926>. Treatment of N-alkyI2-(aryl)ethanesulfonamides N-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 DC ~ afforded 2,I-benzothiazines 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant's substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyc1ized cyclized products, since their a-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product.
Table 1. Formation of l-benzothiazine 2,2-dioxides with N-alkyl 2of 3,4-dihydro-2, 3,4-dihydro-2,1-benzothiazine (aryl)ethanesulfonamides
~
SO2NHR Phl(OAc)2 Phl(OAc)2 (1.6 (1.6 eq.) ~802NHR 1 (1.0 eq), 12 (1.0 eq), 20-30 DC ~ 2 1.--:;:; R' X' X' W-hag, W-h'o, 2 h
ira,
X' X'
JC(l .--:;:;
R'
1
N/ 8022 + X'' + X
XXX
N/ 8022
.--:;:;
I
I
R
18
R'
R
20 20
19 19
Entry
Solvent
R R
R'
X'
Yield % of19 of 19
Yield %0f20 % of 20
1
THF
CH33 CH
H
H
0
0
2
EtOH
CH3 CH 3
H
H
0
0
3
AcOEt
CH3 CH3
H
H
81
10
4
CICH 2CH 2CI C1CH2CH2C1
CH 3 CH3
H
H
6
89
5
C1CHeCH2C1 CICH 2CH2CI
Et
H
H
0
89
6
CICH 2CH 2CI C1CH2CH2C1
CH 3 CH3
CH 3 CH3
H
0
97
7
C1CH2CH2C1 CICH 2CH 2CI
CH3 CH 3
H
CH 3 CH3
0
94
8
CICH 2CH 2CI C1CH2CH2C1
CH 3 CH3
H
CI C1
34
49
5
Recent progress in the chemistry of of 2,l-benzothiazines 2,1-benzothiazines
Table 2. Cyclization of N-methoxyl 2-(aryl)ethanesulfonamides
~I~
~S02NHOCH3 R" R
J:X) ~
SO2NHOCH3Arl(OH)OTs ArI(OH)OTs(1.1 (1.1eq.) eq.) ~ S O 2 o0 °C_ 20 min. ~ rt. rt. 20 min.
~
N/ S02
• R R
[I
OCH OCH 3 3
22 22
21
Entry
R
Solvent
~ E
Temp./°C Temp./o C
Time/min
Yield % of 22
1
H
CHC13 CHCh
4.7
20
18
2
H
AcOEt
6.0
20
29
3
H
ClCH C1CHzCHzC1 2CH 2 Cl
20
73
4
H
CH CH3CN 3CN
37.5
o0 °c ~ to rt o0 °c ~ to rt. o0 °c ~ to rt o0 °c ~ to rt
20
86
5
H
CH CH3CN 3CN
37.5
60-65
5
65
6
H
CH CH3CN 3CN
37.5
0
20
65
7
H
CH CH3CN 3CN
37.5
10-15
20
84
8
CH33 CH
CH CH3CN 3CN
37.5
20
85
9
C1 Cl
CH CH3CN 3CN
37.5
20
52
10
F
CH3CN
37.5
o0 °c ~ to rt o0 °c ~ to rt o0 °c ~ to rt
20
44
lOA 10.4
2,1-benzothiazines via Togo's group also reported the preparation of the 2,I-benzothiazines via an ionic pathway with hypervalent iodine compounds <030BC1342>. <03OBC1342>. Using this method, it was found to be far easier to synthesize five- or seven-membered benzosultams and avoid the difficult deprotection of the N-alkyl group in the six-membered benzosultams to give the free NH group. The reaction of N-methoxy 2-(aryl)ethanesulfonamides 21 with various hypervalent iodine reagents produced the cyclization products in various yields, which were dependent on the dielectric constant (£) I-benzothiazines 22 (e) of solvents. The best yield of 2, 2,1-benzothiazines was 85% by treatment of N-methoxy 2-(aryl)ethanesulfonamides 21 with [hydroxy(tosyloxy)iodo] benzene in CH3CN CH3CN solvent from 0 °c ~ to room temperature for 20 [hydroxy(tosyloxy)iodo] minutes (Table 2). An electron-withdrawing group on the ppara a r a position of the aromatic ring in 21 (e.g., Cl, C1, F) reduced the yields of the cyclization reaction. In 2003, Togo and co-workers described a radical cyclization and ionic cyclization onto the aromatic rings of 2-(aryl)ethanesulfonamides 21 to produce 3,4-dihydro-2,1benzothiazine 2,2-dioxides with polymer-supported hypervalent iodine reagents in good yields <03ARK11 >. <03ARKll>. 1.2.2 Synthesis Derivatives Synthesis of of Dibenzo[c,elIl,2]thiazine Dibenzo[c,e] [1,2]thiazine 5,5-dioxide 5,5-dioxide Derivatives
Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives 23 are phannacologically Dibenzo[c,e][1,2]thiazine pharmacologically interesting <91JMC2477; 93JMC2242; 99BMCL673>. Various methods for the construction of these <9IJMC2477; biarylthiazines have been reported (Figure 3) <00SL475; 01 T5915>.
6
X y. Hong Hong and M M. Harmata Harmata
RI= H,alkyl I
R1 23
Figure 3. Dibenzo[c,e][1,2]thiazine Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives
-0
Pd(OAch, Na2C03 Pd(OAc)2' Na2CO3ide ~N~SO2 PhO2S.~N- ~~- Ii --:-:--------:,-----c-==--,-,...=----=-_. N, N-dimethylacetam N,N-dimethyiacetamide PhO2S reflux, reflux,56% 56% H
PhO 2 S , N Ph0 S/ 2
24 24
25
Scheme 5 Ames and Opalko have developed a palladium-catalysed cyclization of compound 24 to afford compound 25 in 56% yield (Scheme 5) <84Tl9l9>. <84T1919>. Glover and co-workers published a study involving the synthesis and photolysis of N-halogenobiphenyl-2-sulfonamides (26a or 26b) <86JCS(P2)645>. <86JCS(P2)645>. The photolysis of compound 26a or compound 26b in benzene formed an intermediate N-methylbiphenyl-2-sulfonamidyl N-methylbiphenyl-2-sulfonamidyl radical, which resulted in 21% compound 27a or 27b in 21 % or 50% yield, respectively. In this procedure, the reaction only afforded the six-membered six-membered ring product 27(Scheme 27(Scheme 6).
(;Ha
=
26a: 26a: R R = iI
27a: 221% 1% 27a:
26b: R 26b: R = = Sr Br
27b: 50% 27b: 50%
Scheme 6
reductive, intramolecular, intramolecular, free free radical arylation using tributyltin hydride/AIBN was A reductive, introduced CC877; 97TL 137>. The reaction of 28 under radical introduced by the Motherwell Motherwell group <91 <91CC877; 97TL137>. of28 conditions conditions produced the direct addition product 29 and ipso-substitution ipso-substitution product 30 in ortho and para para substituents. Electron-withdrawing various yields, which depended on the ortho of compound 29, while the ortho ortho carbomethoxy group, and groups favored the formation of even the CH3 CH 3 group led to greatly improved yields of the ipso substitution product 30 (Scheme 7).
7
Recent progress in the chemistry chemistry of 2, 2,1-benzothiazines l-benzothiazines
02 ~I
O2 R1 i H 3 C "I N " S ' ~ I R2
(n-BuhSnH, (n-Bu)3SnH, AIBN, AIBNk benzene, benzene, reflux reflux •
~,~ ~
~I
R1 NHM
v
-R2 R
[
/-/
'-":::
2
'-"::: "~
R2 R 2
/-/
28
29
= =
= =
=
=
28a: R RI= R2= 1 H, R 2 CH 33
30
29a: 39% 29b: 10% 2ge: 29c: 44% 29d: 19% 2ge: 29e: 0%
28b: R R11 = H, R R2= 2 OCH 33 28e: 28c: R R11= H, R R2= 2 F
R COOMe, R R11= = COOMe, R2= 2=H 28e: R RI= R2= 1=Me, R 2 =H 28d:
30a: 34% 30b: 33% 30e: 30c: 29% 30d: 65% 30e: 57%
Scheme 7
1.2.3 Synthesis of 1H-2,1-Benzothiazine IH-2,1-Benzothiazine 2,2-dioxide (sulfostyril) Derivatives The synthesis of 1H-2,1-benzothiazine IH-2,I-benzothiazine 2,2-dioxide was pioneered by Loer and coworkers <66JOC3531> and also Rossi group <66AC(R)728; 66AC(R)74 I>, The also by the Rossi 66AC(R)741>. general class of compounds is represented in Figure 4.
R R3 3
~R2
U
N
/$02
II
R R11= H, H, CH CH33 R = H, ester, acid, R2= H, ester, acid, ketone, ketone, arene arene 2 R R3= H, CH CH3, Phenyl 3=H, 3 , Phenyl
R1 R1 (31)
Figure 4. 1H-2,I-Benzothiazine 1H-2,1-Benzothiazine 2,2-dioxide derivatives Compound 34 can be synthesized by a Bamford-Stevens procedure from compound 33. Loer explored the cyclization of 32 with polyphosphoric acid (PPA), (PPA), followed by decomposition of the tosylhydrazone to form the desired IH-2,I-benzothiazine 1H-2,1-benzothiazine 2,2-dioxide 34 in good overall yield (Scheme 8) <66JOC353 1>. <66JOC3531>. H
O~o,
N'.SO2 /O OH OH
32
H
PPA PPA
cy~
" 02
"
0O 33
Scheme 8
1)TosNHNH~ 1)TosNHNH~ 2) Base Base
H
i~/-~--.~N.so2
CO /-/
/-/
34
O2
8
X. X Hong and M. M Harmata
An improved synthesis IH-2,I-benzothiazine 4(3H)-one 2,2-dioxide 33 that results in synthesis of 1H-2,1-benzothiazine a relatively high overall yield was developed by Lombardino's group <710PP33; <71OPP33; 72JHC315>. This This general method offered an easier entry into into the 2,I-benzothiazine 2,1-benzothiazine 2,2dioxide heterocyclic system <67JHC403>. Treatment of methyl N-benzyl-Nmethylsulfonylanthranilate l-benzyl-4-oxo-IH-2,1methylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-lH-2,1benzothiazine-4(3H)-one 2,2-dioxide 36 in 68% yield. Reduction of36 of 36 gave 4-oxo-1H-2,14-oxo-lH-2,1Bn
Bn
~ v
i
H
Ii
N"sO2CH3 CO2Me
O?~
Nail D. ~ NaH 68%
O2
36 36
35
Pd/H2 Pd/H z •= 68%
0
33
O
Scheme Scheme 9 benzothiazine-4(3H)-one 2,2-dioxide 33 in 68% yield (Scheme 9). Lombardino also benzothiazine-4(3H)-one also reported IH-2,I-benzothiazinethe reaction of 37 with isocyanates in dimethyl sulfoxide to yield the 1H-2,1-benzothiazine3-carboxanilide 2,2-dioxide 38 in high yield (Scheme 10) <72JHC315>.
yH CH33
CH33 yH
~"RNCO ~"~/N'-SO 2
+ RNCO
N •= NN,~Oz Et3N fi..-'~/N-.SO 2 E13 DMSO
oO
~I ~ ~ N H R ~NHR OH ON 0O
37 37
38 R= alkenyl. alkenyl, arene arene
Scheme 10 I0 Scheme
Rossi and co-workers <66AC(R)741> independently reported the synthesis of 33 using the same same method. method. Reduction of 33 with sodium sodium borohydride, followed by dehydration afforded 34 in 80% yield. Compounds Compounds 40a and 40b were prepared from 39a and 39b with >. II) <66AC(R)741 <66AC(R)741>. phosphorus oxychloride in 92% and 65% yields, respectively (Scheme 11) H [
H H
i
I
R N.so Pocl3L_. RnN,?OZ R RV~O' _P_O_C_1
~
Ph Ph
39a: 39a: R R = = CH 33 39b: 39b: R = = OCH 33
Ph Ph
40a: 40a: R = = CH CH3, 3 , 92% 40b: R = OCH 3, 3• 65%
Scheme 11 II Scheme
methanesulfanilides Rossi and co-workers <66AC(R)728> also also showed that ortho-acyl ortho-acyl methanesulfanilides 41 carrying an electron-withdrawing electron-withdrawing group at the a~ position of the sulfonyl group can readily
99
of2,1-benzothiazines 2,l-benzothiazines Recent progress in the chemistry of
convert under under basic basic conditions conditions to 3,4-disubstituted 3,4-disubstituted 1H-2,1-benzothiazine lH-2,1-benzothiazine 2,2-dioxides 2,2-dioxides 42 in convert good to excellent excellent yields (Scheme (Scheme 12). Similar Similar work work was also reported reported by Sianesi Sianesi and cogood <67AC(R)1426>. workers <67AC(R) 1426>.
~4 ~4 ~N'S02CH2R1
"SO2CH2RNaOEt> 1N • 3 ~
R3 R3-
v
NaOEt
COR2 -COR2
~4
42
2
3
CI R 1 R33 ==H, Cl R4 ==H, H, CH 3 R4 3
R
41
CO2Et
R 1 =ArCO, C02Et R1 = ArCO, R R2 = =CH CH 3,, Ph Ph
N "S,O2 R2
Scheme 12 Scheme
of Azathiabenzenes Azathiabenzenes and Azathiaphenanthrenes Azathiaphenanthrenes Synthesis of 1.2.4 Synthesis
Cyclic sulfilimines are considered useful reagents in organic synthesis <00JOC8086;
. 03JOC9574>. The chemistry of of cyclic sulfilimines has been studied extensively since the 1970s. of azathianaphthalene Hori and co-workers accomplished the first synthesis of azathianaphthalene and azathiaphenanthrene azathiaphenanthrene in 1979 <79TL3969>. Their approach began with the formation of of an ortho-nitrobenzaldehyde 43, via a Wittig reaction with an ylide and a subsequent olefin from ortho-nitrobenzaldehyde ortho-aminostyryl methyl sulfide 45. The cisreduction with zinc to afford cis and trans ortho-aminostyryl olefin was then treated with NCS, AgC104 AgCI04 and KOH to yield 2-methyl-l-aza-2thianaphthalene 47 in 41% yield. 9-Methyl-IO-aza-9-thiaphenanthrene 9-Methyl- 10-aza-9-thiaphenanthrene 48a and 9-ethyl-lO9-ethyl- 10aza-9-thiaphenanthrene aza-9-thiaphenanthrene 48b were obtained in a similar fashion in almost quantitative yields, whereas 6-benzyl-6H-dibenzo[c,e][1,2]thiazines 6-benzyl-6H-dibenzo[c,e][1,2]thiazines 50 were isolated in moderate yields via a l,2-rearrangement 1,2-rearrangement (Scheme 13) <90TL702l>. <90TL7021>. CliO ~ N O
+ [~CH:CHSCH3 Ph3P-CHSCH3
2
89%
w:
43
1.NCS • [ ~ ~ N ~ S 2.AgCI0 ~ 2.AgCIO44~ 41%
I
~
o
~
-
NO2
+ ,S,+
1. NCS NCS 1.
2•2. KOH KOH H2R " CH2R
N
48a: =H, 100% 4 8 a : RR= H 100% '
48b: 48b: R R = = Me, Me, 90% 90%
~]~CH:CHSCH3
80%
NH2
44
+ CH 33 "CH H H CICI 46 46 I
Zn-CaCl2 >
45
KOH > ~ 57%
S
+ "CH3
47
~ I ~ _ . ~ ,,jSCH2R NH2
1. NCS
.~
1. NCS • 2. 2. n-BuLi n-BuLi
49 49
Scheme 13
~D 0.1 0
~,S
CH CH2Ar 2Ar 5 0 a RR = P= h Ph, 50% 50% 50a: '
50b: R R = = pTal, pTol, 57% 57%
10
X Hong and M. M Harmata x.
Moody and co-workers independently reported the synthesis of of azathiabenzenes by thermolysis <86JCS(Pl)483>. <86JCS(P1)483>. Azides 51a and 51b were decomposed in boiling toluene to give the corresponding cyclic sulfimides 52a and 52b in 52% and 13% yields, respectively (Scheme 14). m
N3SR [ C():
f::,. roN';-R -_. I
N3sR
h
h
. f.rN
COzE! CO2Et
::::... h COzE!t ~[~~'L'~CO2E R= = Ph, Ph, 52% 52% 52a: R 52b: 52b: R R = Me, Me, 13% 13%
R= = Ph 51a: R 51b: R R = Me Me
Scheme 14
1.2.5 Synthesis of 1,2-Thiazine 1,2-Thiazine S-oxide by Cycloaddition Cycloaddition of N-Sulfinylaniline N-Sulfinylaniline
The reaction of aryl sulfinylamines as heterodienes has been well documented in the <64JOCI688; 67JOC506; 67CB2151; 84JCS(Pl)2429; literature <64JOC1688; 84JCS(P1)2429; 72JCS(P2)1134; 67CB2164; 86H(24)2739>. The first cycloaddition of N-sulfinylanilines, ArN-S=O ArN=S=O 53, to an alkene was reported by Collins in 1964 and afforded the 1,2-thiazine S-oxide 54 in 82% yield <64JOCI688>. (Scheme 15) <64JOC 1688>.
' b__ 6 N~'s"O N
•
toluene, reflux, reflux, 82% 82% toluene,
"
, ,~s:'~H df H U " S
II
H"
54 54
53
Scheme 15
Several years later, Macaluso and Hamer extended the research to bicycloalkenes <67JOC506>. They also pointed out that this type of of reaction occurred only when bridged bicyclic alkenes were used. However, Beecken <67CB2151> reported some cycloaddition reactions of heterocyclic sulfinylamino compounds to ethoxyacetylene. Hanson and Stone <84JCS(Pl)2429> demonstrated that cycloadditions of compound 53 and substituted <84JCS(P1)2429> derivatives with certain hetero-bridged bicyclic alkenes, particularly with I,4-epoxy-l ,41,4-epoxy-l,4dihydronaphthalene 55 are pericyclic reactions (Scheme 16) <83JCS(P2) 1719>. <83JCS(P2)1719>.
N<-s>O S-;.O
6
00 [ ~ ~
55 55_-.
_H
. ~NH ~ S H H I
[~
oO
56 56
53
Scheme 16
11 11
I-benzothiazines Recent progress in the chemistry of 2, 2,1-benzothiazines
In order to explore the regioselectivity of aryl sulfinylamines as heterodienes, a variety of of unsymmetrical (N-sulfinylamino)azines, such as (N-sulfinylamino)pyridines (57, 60, 63), <90JCS(PI)2089>. In refluxing toluene, I,4-epoxy-I,4were studied by Hanson <90JCS(P1)2089>. 1,4-epoxy-l,4dihydronaphthalene 55 prefers to react at the C-2 position of3-(N-sulfinylamino)pyridine of 3-(N-sulfinylamino)pyridine 60. On the other hand, 2-(N-sulfinylamino)pyridine 63 reacted at the ring nitrogen with 1,4epoxy-I,4-dihydronaphthalene epoxy-l,4-dihydronaphthalene 55 to give only a single trans-exo-adduct 64 in 64% yield (Scheme 17). Hogeveen and co-workers <82JOC1909; <82JOCI909; 83JOC4275> also reported the synthesis of tricyclic sulfinamides by the reaction of cyclobutadiene aluminum halide ocr complexes (65 or 66) with 53 at low temperature. Treatment of 65 or 66 with 53 at a t --60°C 6 0 ~ resulted in the formation of67 of 67 or 68 in 52% and 55% yields, respectively (Scheme 18).
s.,::-o N~S ~O
I
~ 00 6 N~
55%
N
57 N~
H~N~
H o
H oA
58
sO S.,::-O
6 ~
H~N~
00
N N
5:1 5:1
H W" ~
I
NY
~ ~ I
~
- S,NH -NH ~ S H H ~"
" ~' ~ _ _
60
59
7' ~ _ _
0O
61 61
62 62
75% 75%
0O
5.5% 5.5%
00 ~n -----ons~(
N~s~O [ ~ ~ N
,NH . s.NH ~ S H H •"
- ~1~
,.
64% 64%
H S'N H ~ O o
63 63
64
Scheme 17 Scheme H H3C't:dH3C. H
e AAIAI2Br6 Br,Q 2
H H3C OH3 3C"~~" CH 3
65
6
e
H H 3C C ~H 3
O )tAIAI2Br6 2 Br;
H H
OH33 CH 66 66
Figure 5. Cyclobutadiene aluminum halide cr Figure o complexes.
x Hong and M. M Harmata x.
12 S-:;.O
N~'S~.O
N~
65
H
}(5?
65
6
CH 3 '~ CH3~
'I ~ 52% = H H3 C~ ~ s ~ N H cy~...-NH 3C 0O
52%
53
67
S-:;.O N~S :'O
CH C H33 ~
}f9
N~
66
6
=
55% 55%
~ It
Ii
H3 C/ cy~...-NH (~S ~NH H 3C 0O
53
68 Scheme 18
of Harmata-type Harmata-type Benzothiazines Benzothiazines 1.2.6 Synthesis of Recently, the Harmata Hannata group developed several novel ways to synthesize 2,1benzothiazines represented by the general structures 69 and 70 (Figure 6) <87TL5997; 91JOC5059; 98JOC6845; 99AG(E)2419; 03JA5754; 04TL5233>. 9IJOC5059; R1 R3-~-
Ar 69
R1
o
R3
Ar
o
70
Figure 6. Harmata-type Hannata-type benzothiazines.
2,1-Benzothiazenes 1.2.6.1 Lewis Acid-mediated Synthesis of 2,I-Benzothiazenes In 1987, the Hannata Harmata group reported a general and novel procedure for the synthesis of benzothiazenes during an attempt to synthesize alkynyl sulfoximines <87TL5997>. They of the N-aryl demonstrated the Lewis acid-mediated electrophilic addition reaction of substituted sulfonimidoyl chlorides to alkynes. Intermediate Intennediate vinyl carbocations may fonned formed in the reaction, and converted into benzothiazenes by a Friedel-Crafts electrophilic substitution reaction. As an example, the reaction of N-phenylsulfonimidoyl chloride 71 with 1-trimethylsilyl-1-propyne and aluminum chloride in dichloromethane at at-78 ~ generated 72 I-trimethylsilyl-l-propyne -78°C in 75% yield (Scheme 19). 19). This and other reactions took place with high Markownikov regioselectivity (Table 3). Whether the fonnation formation of the cr tJ complexes 74 could be a concerted "cyc1oaddition" "cycloaddition" between the iminosulfonium "heterodiene" 73 and the alkyne dienophile or more likely a stepwise process, does not appear to have been established (Scheme 20) <9IJOC5059>. <91JOC5059>.
13
2,I-benzothiazines Recent progress in the chemistry chemistry of of 2,1-benzothiazines
P~
CI I N=S=O + RIC-CR 2
R2 ~F~
AlCl3, CH2Cl2,-78 ~
I
:~I
75%
pTol
O pTol
=
71
=
72: R1 = TMS, R22 = Me 72:R1
Scheme Scheme 19
CI II N=S=O N=S=O / I ph/ Ph pTal pTol
R1C-CR 2 AICI3
74
73
71
R2
=~
~R10 pTol 75
Scheme Scheme 20 Table Table 3. N-Phenylsulfonimidoyl chlorides with alkynes in the presence of Lewis acids CI1 N=S=O + R RiG-OR /N=r=O + 1C=CR22 I Ph/ pTol Ph pTal
9
ro""~R10
" ~I
----
.&
R R2 2
1
R
N'/r:::O pTal pTol
Entry
R1 R1
Rz R2
Yield%
1 1
H
Ph
90
2
H
n-Bu
60
3
TMS
Me
75
<91JOC5059; 98JOC6845> An extension of this work was also reported by this group, <9lJOC5059; in which the reaction was applied with success to alkenes, as shown in Scheme 21. The reaction not only proceeded with high Markownikov regioselectivity, but sometimes was very diastereoselective as well (Table 4).
14
X Hong and M. M Harmata x.
ro I-I Et H,.Et
(~1 H N=,~= 0 + Ph/ pTol Et
Et H
H t "'Et
Et. H Et ,.H Et
CX1
AICI3,CH2CI2,- ~I '-H + ~ I '-':::E H', o"H '::: E .& ',8:::: .& -:-8::::0 78 ~ 74%, ~.~.~-k..N.,S~ 0 + ~~...N.. iSmO N I N t 0 1211 pTol pTolI pTal pTa 76a
76b
Scheme 21
ro ro
Table 4. Reaction of N-phenylsulfonimidoyl chlorides with alkenes R3 R2
CI
3
R):R /N=.=O Ph pTol R( ~ R4 R I
I '-':::
i N=8=0 + / I Ph pTal
R
iR 4 o"~4
/""~'~ N~'~~O .& N-:-Y::::O pTol pTal
1
76a
Entry
R1 R1
R R22
1
H
H
2
H
3
R3 R3
R4 ~
R2 R3
R
o"R,R' 1
I '-':::
1
/""~'~ N~"~~O .& N-:-Y::::O pTol pTal 76b
Yield %
Ratio (76a : 76b)
CH 2k -(CH2)4-(
91
25:1
H
-(CH -(CH2)32)3-
81
5:1
H
H
-(CH -(CH2)52 )s-
70
2.4:1
4
H
H
-(CH -(CH2)62)6-
76
2.1 :1 2.1:1
5
H
Et
H
Et
85
122:1
6
H
H
Et
Et
85
2.3:1
7
H
Me
H
Me
62
45:1
8
H
H
Me
Me
78
2.3:1
9
H
Bu
H
H
77
1.6:1
10
H
Et
H
H
90
1.5: 1.5:11
11 11
H
n-Pr
H
H
66
1.6:1
12
H
i-Pr
H
H
78
2.4:1
13
H
Ph
H
H
62
1.4: 1.4:11
14
H
I-Bu t-Bu
H
H
65
4.1 :1 4.1:1
15
H
TMS
H
H
35
10:1
1.2.6.2 Synthesis of Enantiomerically Pure 2,1-Benzothiazines 2,I-Benzothiazines The Harmata group has also developed a route to enantiomerically pure 2,1benzothiazines. The process involves the N-arylation of of sulfoximines using the BuchwaldBuchwaldHartwig reaction conditions, <02MI3; 99JOM(576)125> 99JOM(576)125> a reaction first reported by Bolm
15
progress in the chemistry I-benzothiazines Recent progress chemistry of 2, 2,1-benzothiazines
<98TL5731 >. The Bolm group has already made use of this reaction in the preparation of a <98TL5731>. variety of of chiralligands chiral ligands and unique cyclic sulfoximines <030L427; <03OL427; OISLl878; 01SL1878; 02SL832>. Critical to the development of this reaction in the preparation of enantiomerically pure 2.1benzothiazines is the ready availability of enantiomerically pure sulfoximines 77a or 77b <97TA909>. NH -t-tl +" -o/~"'Ar _ o--S"/Ar Me Me
NH
-t-tl
Me/S',/Ar O_ (R)-77a, Ar = = pTol (R)-77b, Ar = Ph
(S)-77a, Ar = pTol (S)-77b, Ar = Ph
Figure 7. Enantiomerically pure sulfoximines. The Harmata group's initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731; OOJOC169> Buchwald'Hartwig 00JOC169> for sulfoximine Northo-bromobenzaldehyde 78 with enantiomerically arylation. For example, treatment of ortho-bromobenzaldehyde pure N-H suIfoximine sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. pTol _pTol
.CHO CHO
et
+ ,N=S=o N=S=O + H' . H I~e Me
78
(R)-77a (R)-77a
I
v
..&
BBr r
Pd(OAc)2, 7.5%-15% 5-10% Pd(OAch,
. ~'(O_
BINAP, 1,8 1.8 eq, eq. CS Cs2CO toluene, 2C0 33,, toluene, 110 DC, ~ 40 h, 78%
~
_
I~~N'..
~, ,O pTol
(R)-79 (R)-79
Scheme 22 Scheme ortho-bromobenzoate ester 80 or orthoExamples of coupling reactions of ortho-bromobenzoate 23a!b). In these bromobenzonitrile 87 with sulfoximine (R)-77a were also reported (Scheme 23a/b). cases only coupling occurred. However, the products could be converted into the 2,1benzothiazines 82 and 85 by treatment with a strong base.
I [~ et ..&
C02Me CO2M e + +
Br Br
80
pTol
o2Me +
5% Pd(OAch, Pd(OAc)2, 7.5% BINAP, 1,4 1.4 eq.. eq~
N=S=O CS ,,N=,S--O 0s2003, ~ 40 h 2 C03 , toluene, 115 DC, H' ~e 84% H !r 84% (R)-77a (R)-77a
OH
Me _ 1,8 1.8 eq. KH, THF /
N=S', 'O
o0 DC ~ to rt, rt, 73% 73%
' ,O
pTol
pTol
(R)-81
(R)-82 (R)-82
Scheme Scheme 23a
16
x. X Hong and M. M Harmata
[~ o~Br
CN CN
+
Br
pTol N=S=O H' ~ H Me I~le
Pd(OAc)2, 7.5% 7.5% BINAP, BINAP, 1.4 eq. eq,; 5% Pd(OAch, , CS C0 toluene, 115°C, 40 h • 0S2003, toluene, 115 ~ 2 3
N=~=O
83
94%
(R)-77a
":: C(
CN CN
[ ~
~
~ ~N~S L NH2
Me
+ +Me _[ ~ N~.S, ,O N"/~"O pTol
2.0 eq. n-BuLi, 2.0eq. n_BuLi, THF THF
,"
~ to rt, rt, 68% o0 °C
•
,OUN:~'' [0pTol
(R)-84
(R)-85 (R)-85 Scheme 23b Scheme 23b
Enantiomerically pure bis-benzothiazines 87 and 89, are potentially useful templates for asymmetric catalysis. The Harmata group reported their syntheses from the corresponding dibromodialdehydes 86 and 88 under the reaction conditions used for the production of (R)79 (Scheme 24) <99AG(E)2419>. <99AG(E)24 19>. OHC~/~CHO OHCnCHO Br" Br
[~ v
pTol _pTol
+ +
Br Br
Me
86
Br
Tol epTol
CHO
OHC OHC
v0 88
~
S ~ Pd = -0.-O"S-l:. I 48% .:- 'N 48% N Tolp Tolp Pd
(R)-77a
Br::n:::cCHO 1
N=S=O ,N=S=O H H" I~le
Br Br
+ +
,N=S=O ,N=$= O H :
Me Me
~
-
~ S·,,0 '0-
N~ ~
r~
pTol
(R, R)-87
-
Pd
41% 41%
pTol ,,N~ N ~ pTol~
=
(R)-77a
_O\·~ ~
0
-
'~S"O
N
~
"O
pTol pTol
(R, (R, R}-89 R)-89
Scheme Scheme 24 In 2003, the Harmata group reported a stereoselective, intramolecular Michael addition of sulfoximine carbanions to a,~-unsaturated a,13-unsaturated esters as exemplified in Scheme 25 <03JA5754>. Preparation of sulfoximine 90 was conducted via via the methodology introduced by Bolm as used in the initial studies of catalyzed benzothiazine synthesis <98TL5731 <98TL5731;; 00JOC169; 99AG(E)24l9>. 99AG(E)2419>. The sulfoximine 91 was transformed via via treatment with LDA into 92. Importantly, 92 was formed as a single stereoisomer. This appears to be a general phenomenon for these types of reactions. Two procedures were reported for this cyclization. The first involved adding a THF solution of 2.0 equivalents of base in THF to the sulfoximine at -78°C, -78 ~ but addition of the sulfoximine to base worked as well, and was occasionally absolutely necessary.
17
I-benzothiazines Recent progress in the chemistry of 2, 2,1-benzothiazines
cO2Me
5% 5% Pd(OAch, Pd(OAc)2,7.5% 7.5% BINAP BINAP
1.4 1.4 eq. eq. GS Cs2CO 1.2 eq. eq. (R)-77b (R)-77b 2 G0 33,, 1.2
toluene, reflux, reflux, 44 h toluene, 91% 90
CO2Me
s ;o
/CO2Me
2.0 eq. eq. LDA,THF LDA,THF
~ to -20 -20 °G, ~ 11 h -78 °G 92% 92%
" ~N~S~,
91
OPh
92
Scheme 25 Scheme 25
Two substrates could not be cyclized under normal addition conditions. An N-thienyl sulfoximine afforded benzothiazine 98 in good yield, but the corresponding the furanyl sulfoximine appeared to polymerize when base was added in the normal way. This problem was circumvented simply by adding the furan to a solution in base. The best reaction conditions involved adding a THF solution of the N-furanyl sulfoximine to 2.0 equivalents of at-50 ~ at a very slow rate. Stirring the solution for an additional 3 hours LiHMDS in THF at -50°C gave the benzothiazine 99 as a single stereoisomer in 85% yield. Similarly, the N-pyridyl sulfoximine also gave either decomposition or side products when treated with base. This problem was solved by addition of the sulfoximine to base coupled with degassing, and the desired benzothiazine 100 was obtained in 77% yield. The rationalization for the outcome of these cyclization reactions was based on minimizing steric interactions in the transition state leading to benzothiazine formation. For example, at least two possible transition states 101 and 102 could give rise to product 92 (or a diastereomer). Transition state 102 has gauche steric interactions that appear to be absent in the staggered transition state 101. This favors the latter and leads to the observed products 92 (Figure 8).
O-
H~ MeO2C H 101
H
OH CO2Me-r 102
Figure 8. Possible transition state structures of the intramolecular Michael reaction of Figure of sulfoximine 91.
x Hong and M. M Harmata X.
18
cl I
Entry Entry
co cO2Me ,,",
+1Me S,I 0N'" 'Ph
o /C02Me
LDAor or LiHMDS LiHMDS(2.0 (2.0eq.) eq.) LDA THF, -78°C THF,-78 ~
• "
'M'
[ ~S"O~N~S~,ON 'Ph Ph
Product Product
Yield(%) Yield(%)
Entry Entry
BnO ..~ ~ w s n o ~ I ;S"Ph N •0-
c6
Product Product
Yield(%) Yield(%)
o /CO2Me
/C02Me .....-C0 2 Me _
1
a5
Table Table 5. Reaction of sulfoximines with an amide base
91 91
5
5
'M'
S~ ~ N ~;S"OS ~O-
S ~
N
93
93
'Ph Ph
97 97
93
/CO2Me .....-C0 2 Me
/C02Me .....-C0 2 Me _
_
_
_ _
2
3 3
,Ph ~"Ph Me 0Me N •094 94 C02Me ,",w~M' M es ~. ~ ~~
~
[
+~ ,0-
;S"ON ~Ph 'Ph "N
83
6 6
S s o. _h 98 98
/CO2Me .....-C0 2 Me _ _
87 87
7
85 ro"Ph N C-
"~ OMe OMe
99 99
95 95
/C02Me .....-C0 2 Me
/C02Me
4
o~O'M' ~O~ ~ I ;s~,O-
N
96 96
91
{D"Ph N/ •0-
Ph Ph
_
88
88
~S~
,Ph ffi,'Ph N No;. C-
77 77
O-
100 100
The Harmata group demonstrated that benzothiazine formation via the intramolecular Michael addition is stereospecific, at least in one case. When sulfoximine Z-103 was treated with 2.0 equivalents LDA the 2,I-benzothiazine 2,1-benzothiazine 104 was obtained in 89% yield (Scheme 26) as the only product. Rationalizing this outcome was not straightforward. Transition state 106 suffers from gauche interactions and should be disfavored. However, the interaction of of the ester group with a neighboring hydrogen (highlighted) in 105 was argued to be more severe. As it stands, these rationalizations are at best hypotheses that need to be investigated further.
19
Recent progress in the chemistry of of 2,l-benzothiazines
=/CO2Me
M•
2.0 +Me 2.0 eq. eq. LDA,THF LDA,THF ~ ~ q . --7-8--'--C-t-o--2-0--C"'" V~r;S' ,0N4S' 'O-~ph -78 ~ to-20 ~ "
o
o
Scheme Scheme 26
.-kHH ~ N MeO'rC2~ H S p h O-
H O_ H~-
Ph
14HI'CO2Me
HH
105
106
Figure 9. Putative transition states structures for the Michael reaction of sulfoximine 103.
The Harmata group also found that certain ortho-bromocinnamates underwent a Michael addition during the course ofthe of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (R)-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. a 107. This presumably favored conformation that placed the methyl group of its suifoximine sulfoximine functionality near the p-carbon ~-carbon of the a,p-unsaturated o~,~-unsaturated ester, thus favoring cyc1ization. cyclization.
~
/C02Me C0 2Me
CO Me
Me
~ ScO2Me
~Br tQC OMe ":
[
.&
Br
2
0,OAc, 7.5% , NAP 5% Pd(OAch, BINAP 1.4 eq. eq. CS 0S2003, 1.2 eq. eq. (R)-77b (R)-77b ~ Me 1.4 2C0 3 , 1.2
-----,--"----'-,,------,-........
toluene, reflux, reflux, 44 44 hh toluene,
~ -:/
I
~
107
-
N"/S~ ,0 -
OMe OMe
OMe
Ph
108: 53%
C02Me C0 2Me
~
Me
+I
W
Me -:/ ~
I
OMe OMe
+
0-
. ,ON"/S~' -N" ~Ph Ph
95: 36%
Scheme 27 Scheme
Two other substrates, 109 and 111, exhibited this behavior. Most interesting was that the reaction of both 109 and 111 with (S)-77b under standard reaction conditions gave only benzothiazines 110 and 112, respectively, with no sign of the corresponding sulfoximine (Scheme 28). While using the argument of a buttressing effect may be useful, the Harmata group also reported that the reaction of bromocinnamate 113 with (S)-77b gave not only the sulfoximine 114, but the benzothiazine 96 as well (Scheme 28). There is no buttressing effect possible in this case and it is likely that other factors (e.g., electronic effects) can also favor direct benzothiazine formation.
20
X Hong and and M. M Harmata x.
/CO2Me
IV
/CO2Me
(S)-77b
5% Pd(OAc)2, Pd(OAch, 7.5% 7.5% BINAP BINAP 5% CSZC03, 1.4 eq. Cs2CO 3, 1.2 eq. (S).77~ toluene, reflux, reflux, 44 h, 61% 61% toluene,
_
109 109
110 110 COzMe CO2Me
(B'Br O)-E
""'" ~ ~ IN ~
5% 5% Pd(OAc)2, Pd(OAc)z, 7.5% 7.5% BINAP BINAP
/CO2Me
1"4eq'Cs2CO3'1"2eq'(~N S)'77b=-~S~,
1.4 eq. CSZC0 3, 1.2 eq. (S)-77b reflux, 44 h, 82% toluene, reflux,
Ph
•
\
CH 3 ~H3
H3C
112
111
d °
0
<
COzMe ~j ~'cO2Me
I ":: ~
Br
5% Pd(OAc)=,7.5% 7.5% BINAP BnNAP I/c~ / 5% Pd(OAc)z, 1.4 eq. eq. CS Cs2CO3, 1.2 eq. eq. (R)-77b ,Me 1.4 (R).77~ / O ~ ZC0 3 , 1.2 (N ..L~ ~ -t-~,~Otoluene, toluene, reflux, reflux,44 44 hh O~~-.~./.--...N~.bPh
113
114: 60%
t:06:' O
°
~
cO2Me
N
'Ph
96: 25%
Scheme 28
1.2.7 Heterocyclic Ring-fused Thiazines and Ring-fused 2,I-Benzothiazine 2,l-Benzothiazine Derivatives The first synthesis of pyrazolo[5,I-c]-1,2,4-thiadiazines pyrazolo[5,1-c]-l,2,4-thiadiazines 116 ll6 and pyrazolo[3,4-c]-1,2pyrazolo[3,4-c]-l,2thiazines 118 was reported by Aiello and co-workers <76JHC615>. Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. 116. However, compound 117 gave compound 118 when treated with triethylamine. Similar ring systems were prepared <97JHCI693> <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-IH-pyrazole-4-carboxylates 5-[methyl(methylsulfonyl)amino]-lH-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4c][1,2]thiazin-4(3H)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield I-methyl-7-(trifluoromethyl)-IH-pyrido[2,3-c][1,2]thiazin-4(3H)-one 1-methyl-7-(trifluoromethyl)-lH-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>.
21
I-benzothiazines Recent progress in the chemistry chemistry of of 2, 2,1-benzothiazines
R R1
=
R2 N~
N-
N'N')/" NHSO2CH2COPh H
R1 116a: 116a: R R11 = = Ph, Ph, R R2z= = CH OH33 116b: 116b: R, R, Rz2 = (CH (CH2) Z)44 "NH 116c: 116c: R R11 = = (CHzh, (CH2)3,R R2z = = (CHzh (CH2)3
Ph~1.S02
115
R al1
R Ph R11 Ph ,' I Et3N 3 Et N N , ~ ~ ----. N I
b6,-,:::
~
t-(.)(
~ NHSOzCHzCOPh 'N~NHSO2CH2COPh I
I
Ph
118a' 118a:R R1 = CH CH3
.
1
02 118b: 118b: R R11 = Ph Ph WSOz
'N Ph Ph
3
H
117
Scheme 29
ff~CO2Et N'N')/"NSO2CH3 i i R1 CH3
O,N~N~S
NaH/DMF " N i R1
02 I
CH3
120: R1 = 120:R1 = Ar, Ar, CH CH33,, 27-72% 27-72%
119 119
Scheme 30
.,~~
cO2cH3
F3C" "N" "NSO2CH 3 j OH3
O~S
.
NaH/DMF NaH/DMF = 79% 79%
02
F3C
I
CH3 121 121
122 122
Scheme 31
The first synthesis of of substituted 2,2-dioxo-1H-thieno[3,4-c][1,2]thiazines 2,2-dioxo-lH-thieno[3,4-c][1,2]thiazines 124a and 124b was achieved by Fanghanel and co-workers <98JHC1449>. Reaction of of the thiazinecarboxaldehydes 123a and 123b with Et3N Et3N in DMF at room temperature gave compounds 124a and 124b in 59% and 49% yields, respectively (Scheme 32). The methyl group of 125a,b is easily deprotonated by a base, such as NaOEt. The corresponding intermediate attacks the nitrile group to yield the benzo[c]thiazines benzo[c]thiazines 126a and 126b in 53% and 72% yields, respectively. This method is a very convenient way to prepare substituted 2,2-dioxo-benzo[c]1,2-thiazines 2,2-dioxo-benzo[c] 1,2-thiazines (Scheme 33) <99JPR403>.
22
x. X Hong and M. M Harmata
CHO
S
H 3 C ~, CH33 sulfur, sulfur, triethylamine triethylamine. H3C - ~c t i/// H3CO"CH -'--_ _ H 3
1~~N'Ph
X/~,,.S.. N, ph X
I
dimethylformamide dimethylformamide •
X,~s.,N,ph X S/N'Ph
°° O0
O,'i0~,', 61\0 124a: X= X= SCH SCH3, 3 , 59% 124b: X= CI, 49%
123a, b 123a,b
Scheme 32
. R2 H3C~CH3
~NH2 NaOEt, EtOH
= H3C""~~ X/14...S...N-.ph
MeS-""~/S~,~"N" ph O0
6,,b
126a: R R11 = = C0 CO2Et, R22 = = CN, 53% 2 Et, R
125a, b 125a,b
=
=
126b: R R11 = CN, R22 = CN, 72%
Scheme 33
Moody and co-workers independently independently prepared the fused 1A4,2-thiazines 1X4,2-thiazines by mild 4,2]thiazines were successfully thermolysis <86JCS(P I)483; 1)483; 81 81CC927>, CC927>. The thieno[3,2-c][ 1X4,2]thiazines thieno[3,2-c] [1A synthesized from the azides 127a-g in boiling toluene with varying yields (Scheme 34), which were generally good. good. Thermolysis of 127g gave a very poor yield of the corresponding corresponding sulfimide 128g, 128g, since product 128g 128g lacks a stabilizing substituent, and thereby is unstable in 4 1A4,2]thiazine-3-carboxy1ate 130 has been refluxing toluene. Ethyl 2-phenyfuro[3,2-c][ 2-phenyfuro[3,2-c][1X,2]thiazine-3-carboxylate prepared by a similar procedure from 129 (Scheme 35). N3 \N3
~
m
N..~R
~N'$~R
\S~Z
I
S
RS
Z
127a-g 127a-g
128a: R = = Ph, Z = = C0 CO2Et, 2 Et, 90%
=
=
128b: R = Me, Z = C0 CO2Et, 2 Et, 85% 128c: R = = Et, Z = = C0 CO2Et, 2 Et, 30% 128d: R = = Ph, Z = = COMe, COMe, 90% = Ph, Z = = CHO, 75% 128e: R =
128f: R = Ph, Z = CN, 90%
=
=
H, 4% 128g: R = Me, Z = H,
Scheme 34
23
Recent progress progress in 2,l-benzothiazines Recent in the the chemistry chemistry of 2,1-benzothiazines
a~:_l
N3 N3
m
,~
N..5~,,Ph
70%
70%
COzEt CO2Et
PhS
129 129
130 130
Scheme 35 Chiacchio and co-workers <97T13855> <97Tl3855> reported a stereoselective synthesis of 133 via an intramolecular 1,3-dipolar cycloaddition. Intermediate 132 was generated in situ by the onamide 131 with Nreaction of trans-N-(2-formylphenyl)-N-methyl-2-phenylethene-l-sulf trans-N-(2-formylphenyl)-N-methyl-2-phenylethene-l-sulfonamide I% yield (Scheme 36). methylhydroxylamine and afforded a tricyclic benzothiazine 133 in 551%
" c(
MeNHO~
O~N ~ -(/ J J "O- F 0 H r Ph MeNHOHIF~ - 'Me'~! H //--Ph .--:::- N-SOz.!l --SO2 51% -" 51% I
CH 3
131
L-
]/ Ph
I 132 132
~ MH"N~Q =
H
Ph
Me 133 133
I ~-~ s-::
~
(~/~._Ph NIO ~ ~~/~Ph <ell"" tol"",., , , THF, PPh 3 ~ . . ? \S "Ar PPh3, THF,25 ~ ~" I'~ \S "Ar reflux,toluene, Ph 25°C • ~ II 5h ~'~N 3 S ~ ' ~ N NII 06 5h L~_.,.~N,S_Ar PPh PPh3 3 136a: 136a: Ar = = pTal, pTol, 50% 50% 135a: 135a: Ar = = pTal, pTol, 91% 91% 134a: Ar = = pTal pTol 134a: 136b: Ar = Ph, 48% 136b: Ar Ph, 48% 135b: Ar Ph, 95% 95% 135b: Ar =Ph, 134b:Ar Ar =Ph Ph 134b: Scheme 36 Isoxazolo[ 4,3-c]-2, I-benzothiazine, a new heterocyclic system, was synthesized by an Isoxazolo[4,3-c]-2,1-benzothiazine, intramolecular aza-Wittig type ring closure process <04SLlOI>. <04SL 101 >. This was the first example of of the construction of a cyclic sulfimide using aza-Wittig chemistry. Treatment of 3-(0azidophenyl)-4-sulfoxyaryl-isoxazoles 134 with triphenylphosphine under Staudinger reaction conditions gave the corresponding aryliminophosphoranyl 4-sulfoxyaryl-isoxazoles 91% aza-Wittig 135a and 135b in the yields of 91 % and 95%, respectively. A subsequent azaWittig type cyclization of 135a and 135b in refluxing toluene produced isoxazolo[4,3-c]-2,1benzothiazines 136a and 136b in the yields of 50% and 48%, respectively (Scheme 36). In order to study heterocyclic steroid analogues, such as the 7, II-dithiaazasteroid 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems: tri- and I-methyltetracyclic 2,I-benzothiazines 2,1-benzothiazines <82JHCI045>. <82JHC1045>. Intermediate 137 was prepared from 1-methyl4-oxo-lH-2,1-benzothiazine-4(3H)-one 2,2-dioxide 37 and thioglycolic acid and could be 4-oxo-1H-2,I-benzothiazine-4(3H)-one converted into 6-methyl-4-oxo-3,4-dihydro2H,6H-thiopyrano[3,2-c] [2, 1]benzothiazine 5,56-methyl-4-oxo-3,4-dihydro-2H,6H-thiopyrano[3,2-c][2,1]benzothiazine dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl
24
X Hong and M. M Harmata x.
oxalate afforded the glyoxylate 139 in 60% yield. Condensation of the glyoxylate 139 in acetic acid with hydrazine hydrate and hydroxylamine hydrochloride respectively, furnished 5-methyl-I-carbomethoxyl-5H, 5-methyl- 1-carbomethoxyl-5H, IIH-isoxazole[4,5-c]thiopyrano[3,2-c][2, 11H-isoxazole[4,5-c]thiopyrano[3,2-c][2,1I]benzothiazine ]benzothiazine 4,4dioxide 140a and 5-methyl-I-carbomethoxyl-5,II-dihydro-3H-pyrazolo[4,35-methyl- 1-carbomethoxyl-5,11-dihydro-3H-pyrazolo[4,3c]thiopyrano[3,2-c][2,1]benzothiazine 4,4-dioxide 140b in the yields of 62% and 39%, c]thiopyrano[3,2-c][2,I]benzothiazine respectively. Decarbonylation of 139 gave the p-keto ~3-keto ester 141 in 69% yield. Reduction of 141 afforded 5-methyl-I-hydroxy-5, II-dihydro-3H-pyrazolo[4,3-c]thiopyrano[3,25-methyl- 1-hydroxy-5,11-dihydro-3H-pyrazolo[4,3-c]thiopyrano[3,2c][2,I]benzothiazine c][2,1 ]benzothiazine 4, 4-dioxide 142 in 40% yield (Scheme 37). O o-"[L- R
OH
O 144a: 144a R = 2-chloro-4-(methylsulfonyl), 68% 144b: R = 2-(2,4-Dichloro-phenyl)-vinyl, 17%
I
144c R = 2-(2,6-Dichloro-phenyl)-vinyl, 40% 144c:
I
CH3
~,
CH3
143
Ph
oO o
64%
~
%~,N.SO~
o~
[
j
CH 3
CH3
137
00""
o YPh O
~
o
I "" "" ~
I
,
I
CH3
CH33 CH 139 139
138
~
OH OH
~..~N.SO~
0
N?SOZ
I "" "" ~
0
N?SOZ
CH CH33
146a: 146a: R = = H, 31%
COCOZCH3
ce5:
c6: I
II
145a,b: 44-64% 44-64%
ooo2cH
K~,-,~ N,.S02 I
N
-
N?SOZ 02
CH CH33
37
57%
R
R
R
146b: R R= = Me, 27% 27%
coeN
""
~ , .~ ~ , ~ N?SOZ N,.S02 It
CH CH33
69% 69%
S
COZCH 3
""
0
140a: X= X= 0, O, 62% 140b: XX= NH, 39%
40%
""
~ N?SOZ %-~N "s~ I
I CH3
CH 33
142
141
Scheme 37 Recently, Coppo and Fawzi <98JHC983> reported the synthesis of tricyclic 2,1benzothiazines starting starting from compound 37 (Scheme 37). They discovered that the O-benzoyl compound 143 can rearrange to the C-benzoyl compounds 144a-c in the presence of acetone and triethylamine in fair to good yields. However, a rearrangement of 145a-b under similar 2,I-benzothiazines 146a and reaction conditions resulted in the formation of novel tricyclic 2,1-benzothiazines 146b in the yields of31% of 31% and 27%, respectively.
25
progress in the chemistry chemistry of of 2,1-benzothiazines 2,l-benzothiazines Recent progress
CHEMISTRY OF OF 2,1-BENZOTHIAZINES 1.3 CHEMISTRY Reactions of of 2,1-Benzothiazine 2,1-Benzothiazine 2,2-dioxide 2,2-dioxide 1.3.1 Reactions
IH-2,I-benzothiazine 2,2-dioxide (34, R == H) R) can be As mentioned previously, 1H-2,1-benzothiazine 3,4-dihydro-2,I-benzothiazine 2,2-dioxide 4 by hydrogenation hydrogenation <66JOC3531 <66JOC353 I>. converted into 3,4-dihydro-2,1-benzothiazine >. of 4 occurred on the sulfonamide nitrogen to give compound 152 in Alkylation and arylation of Alkylation 71CB1880; 66JOC3531>. A similar reaction was further reported high yield <65JOC3163; 71CB 1880; 66JOC3531>. 2,I-benzothiazine 150 was formed from acrylonitrile and 34 via via by the Loev group in which 2,1-benzothiazine <67MB>. Electrophilic aromatic a Michael addition reaction, followed by a reduction <67MI3>. studied by Loev and Kormendy <65JOC3163> and by substitution reactions have been studied of 152 only afforded a 6<71CBI880> Sianesi <71CB 1880> and co-workers. Bromination and nitration of mono-brominated product product 153, 153, whereas bromination and nitration of 4 gave a mixture of mono-brominated 151, where the yields are dependent upon the reaction mono- and disubstituted products 151, 67MIl>. Another interesting reaction has been reported by Rossi conditions <65JOC3163; 67MI1>. and Pagani <66AC(R)728>. Indole Indole 148 and N-methylaniline 149 were isolated from 2,I-benzothiazine 147 with copper powder at around 300 300°C treatment of 2,1-benzothiazine ~ (Scheme 38) <8URC73>. <81JHC73>.
R' s
153: R =CH 3 R1 = Br, NO 2
H2
02
I R
A
CH 3
NBS or l
Me
HNO3
149
A CH3
H3~I
Cu
~~N~
S 02
02 ,
CH 3
I 148
152
l
l
R1 = CH3
Me2SO4
-
02
02 RI= H
H
33
Base, RX
H2 . ~
~ 02
R
147
H
H
4
34: R 1= H or CH 3
I NBS or R1 = H
1. CH2=CHCN 2. H2
HNO3
~~N~SO2
I
(CH3)3NH2
150 Scheme 38
- --SO2 R2
151:R1, R2 = Br, NO 2
26
X Hong and and M. M Harmata y.
Reactions of of Azathiabenzenes Azathiabenzenes and Azathiaphenanthrenes Azathiaphenanthrenes 1.3.2 Reactions
of azathiabenzenes azathiabenzenes and azathiaphenanthrenes azathiaphenanthrenes was reported by the Hori A further study of <84CPB4360; 87CC385> 87CC385> and the Moody group <81CC927; 86JCS(P1)497; 86JCS(Pl)497; group <84CPB4360; 86JCS(Pl)501>. An interesting reaction of of azathiabenzenes azathiabenzenes with electrophiles 86JCS(P1)501>. <9IJCS(Pl)1733; 94JCS(P1)1709> 94JCS(PI)1709> was observed as their compounds possess an ylidic <91JCS(P1)1733; <94JCS(Pl)1709>. This structure was confirmed by spectral and some chemical structure <94JCS(P1)1709>. <9lJCS(Pl)1733>. For example, treatment of of 52a with dimethyl evidence <91JCS(P1)1733>. acetylenedicarboxylate (DMAD) 154 in an aprotic solvent, such as dry benzene, at room temperature gave the adduct 157 in 47% yield. The proposed mechanism involves a fourcentered intermediate 156, which can arise from the first intermediate 155, which was formed of the ylide anion to DMAD (Scheme 39). When the solvent was by a nucleophilic addition of changed to a protic solvent (e.g., methanol or ethanol), no thiazocine was observed, but adduct 160 (2:1) was isolated in 65% yield. The structure was determined by X-ray crystallography. It is possible that intermediate 155 was protonated by the protic solvent to give a relatively stable species 158. The next step requires intermediate 158 to be attacked by another molecule of of 52a to result in the formation of intermediate 159, which afforded the final product 160 after deprotonation (Scheme 39) <84CPB4360; 82CC1060>. 82CC 1060>.
~ ?
~
~
O2Et C02Et
I + ~/k.N.S.p h ",::;
~CO2Et
PhH ~
" ~-P~N-S-ph
N/S'Ph
CO2Et
. ~N~S-Ph
52a ( f'I
MeO2C-CCO2Me Me02C==CC02Me 154
~
EtOH
155
156
CO2Et ~ C O 2 E t
~J'~ N~S+ph
CO2Et
~N.S+~ph
~N~CO2Me
CO2Me
CO2Me
158 158
CO2Et CO2Me "~SPh
CO2Et
~ ~N
157: 47%
S'ph
~
MeO2C .~.,~ N'~~/ ?+--k. MeO2C Pfi CO2Et
mhs
CO2Et
159
160: 65% 2:1
Scheme 39
27
Recent progress progress in in the the chemistry of of 2,1-benzothiazines
Azathiaphenanthrenes can be oxidized by KMn04 KMnO4 or m-chloroperbenzoic acid to the corresponding sulfoximines 163 in good yields. Azathiaphenanthrene 48a underwent a thermal ring expansion to afford 7H-dibenzo[dJ][1,3]thiazepine 7H-dibenzo[d,J][1,3]thiazepine 163 in 26% yield by a Stevens-type rearrangment <79TL3969; 84CPB4360; 9lJCS(Pl)1733> 91JCS(P 1) 1733> while compound 48c furnish compound 165 by cycloelimination via 164 (Scheme 40). underwent dealkylation to furnish
"':::
, .0
~I -/s~ ~
+
CHzR H2R
N
r ~ l>.
xylene
H-
H,~__~
= =
48a R R=HH 48a: 48c R R = alkyl alkyl 48c:
KMnO4 KMoO,
~O C(~\S
-
N H H
=
H, 26% 162: R = H,26%
161
j Xy~ xy
ca ]- ce9 '-'::
r
+
H2R
0
163 163
'.0
~yHz2
~
N~
1
S
H
H Hq Ha-HC R' R' 164 164
165. R= R= alkyl, alkyl, -40% -40% 165.
Scheme 40 Scheme
+
+ .0 ~ ~ N~S'CHzR S +CH2R 48c 48c
i
=
RI(( R R = Me, Me, Et, et et al.) RI
--- r LDA
- S N~
48a 48a
+ 'CH 3
LOA
:-:; ·1~ TMSCl
CH z
N
+ +
166
Li
H
TMS 167
1RCO2Et RCOzEt
9-~
S
R
WOH
168
Scheme 41
28
x. X Hong and M. M Harmata
The methyl hydrogen of 9-methyl-IO-aza-9-thiaphenanthrene 9-methyl-10-aza-9-thiaphenanthrene 48a is acidic. It can be readily deprotonated by LDA in THF <91TL4359>. <91TL4359>. The corresponding anion can be quenched by alkyl iodides to give various 9-alkyl-1O-aza-9-thiaphenanthrenes 9-alkyl-10-aza-9-thiaphenanthrenes 48c in fair yields (Scheme 41). However, none of the expected products were found when the anion was quenched by TMSCI TMSC1 or esters. Ring expansion product 167 was obtained via sulfonium ylide intermediate intermediate 170 derived from the expected product 169 by a 1,2-shift (Scheme 42) . The novel spiro compound 168, 168, the structure of which was confirmed by X-ray analysis, was generated by Sommelet-Hauser rearrangement (Scheme 43) <91JCS(P1)1733; <9lJCS(PI)1733; 9ITL4359>. 91TL4359>.
Y"I ~ ~
Y"I
LDA
LDA
~
+ N,S'CH
. ~ ~ 8 +/ Ic TMSC/
TMSCI
~
~ ~ . 8 + +c ~
~
+
3
48a 48a
]
+
H2
a2ta
N,S'CH 2 + + 166 Li
N::CH 2TMS
169
Y" I ~
+
~
]
-
NHS~HTMS HTMS - ~
170 170
TMS
H
-~
171
167
Scheme 42 Scheme
Y"J ~ ~
. [I
1. LOA 2. RC02 Et
+ N,S'CH 3 48a 48a
& ~ } ~
~
Y"I
1.LDA 2. RCO2Et,. ~ ~ , S +S ++C N/ 'CH H2COR 2COR 172 172
~
S S R R
'Hi)'
174 174
-
~
~
~
I~OR] OR
H
173 173
~ ~~ " S}
S
~ ~
--N N
R OH OH
168 168
Scheme Scheme 43 Recently, Shimizu reported a novel polar cycloaddition of a 1,2-thiazinylium 1,2-thiazinylium salt <99TL95>. Compound 175 was generated in situ situ from the reaction of compound 165 with trifluoroacetic trifluoroacetic anhydride and lithium tetrafluoroborate. tetrafluoroborate. It can undergo a cyclization reaction
29
I-benzothiazines Recent progress in the chemistry of of 2, 2,1-benzothiazines
with 1,3-butadienes in 1,2-dichloroethane to afford the corresponding cyc10adducts cycloadducts 176 in good yields (Scheme 44).
2
R/~
(0F300)20 (CF 3 CO hO..
LiBF4 LiBF 4
H
9
BFZ
165 165
F4
~'L'R2 RI
175 175
176 176
Scheme 44 Scheme
Fused l~4-2-thiazines lA4-2-thiazines prepared by Moody and co-workers <81CC927; 86JCS(Pl)497; 86JCS(P1)497; 86JCS(Pl)50l> 86JCS(P1)501> were expected to be photo-labile and indeed the sulfur-nitrogen bond was cleaved to give pyrrole products in good yields under irradiation in acetonitrile at 300 or 350 nm (Scheme 45 and Table 6) <81CC927; 86JCS(PI)497; 86JCS(P1)497; 86JCS(P1)501>.
-
C(iR I~ N.,
%R
~X Z
Z
H H
hu hu
OQ-z
,_ x ~ ~ Z
MeCN MeCN
SR
SR 178a-f 178a-f
177a-f 177a-f Scheme Scheme 45
Table 6. Photochemical rearrangement of fused IA 1~4,4, 2-thiazines Table Entry
X
R
Z
Yieki (%) (%) Yield
1
S
Me
COzEt C02Et
50
2
S
Ph
CO2Et C02Et
83
3
S
Ph
COMe
77
4
S
Ph
CHO
75
5
0O
Ph
CO2Et C0 2Et
32
6
CH=CH
Ph
C0 CO2Et 2Et
75
1~4, 4, 2-thiazines, 177a-f were the The initial intermediates in the photolysis of the fused 1A nitrenes 179. Then electrocyclic ring closure of the resulting nitrenes 179 led to the non-SR and hydrogen to aromatic fused 2H-pyrrole 180, followed by [1,5] [1,5] sigmatropic shifts of of-SR !78a-f. It is very interesting that the observed products arose from give the pyrrole products 178a-f. the exclusive migration of the sulfur substituent in 180 in the presence of ester, ketone and aldehyde groups (Scheme 46) <86JCS(Pl)497; <86JCS(P 1)497; 86JCS(P1)50l>. 86JCS(P 1)501>.
30
X Hong and M. M Harmata X.
A'yN-s+-R
.. N
0"·NI N$
hu
.SR
\~z x9 - - - ~ % ~ . . . z
\x ~~J'~ z 177a-f
179 179
~
[1,5]shift ~ N \...-l,J'z
SR [1,5) shift ~NVSR
OQ:
of -SR ~f x~x ~ z, ' \ z X
H/ SR SR
H
180
181
shift ~1 ,5]Z shift
"•1,5]z
2X[1,5]H 12X[1 ,5)H shift
H H
W
~SR X ~ Z
z
182 182 H H
178a-f 178a-f SR
Scheme 46 Scheme 46
On the other hand, thermal thennal rearrangement of sulfimides gave completely different products, resulting from [1,4] )483; 86JCS(PI )491; 82CC884>. Usually, [1,4] shift <86JCS(PI <86JCS(PI)483; 86JCS(P1)491; fused 1A thennal stable up to 120°C, 1~44,, 2-thiazines are thermal 120 ~ but they were gradually consumed when they were heated in boiling xylene. They were found to rearrange to the 4aH-isomers 4all-isomers 183a-g in good to excellent yield, with the exception of the benzo compound, which was thermally stable (Scheme 47 and Table 7). thennally
w
R
f:::"
'.&-
X I":""~"~Z "X Z
..
<0
" ~X Z .&R R
177a-g 177a-9
Z
183a-g 183a-9
Scheme 47 47 Scheme
Table 7. Thennal IJ-,4, Thermal rearrangement of of fused 1~ 4, 2-thiazines Entry
X
R
Z
Yield (%)
1
S
Me
C0 CO2Et 2Et
40
2
S
Ph
CO2Et C0 2Et
94
3
S
Ph
COMe
80
4
S
Ph
CHO
54
5
0O
Ph
C0 CO2Et 2Et
98
6
CH=CH
Ph
C0 COzEt 2Et
7
S
Ph
CN
88
31
Recent progress in J-benzothiazines in the the chemistry of of 2, 2,1-benzothiazines
1.3.3 Functionalization of Harmata-type Benzothiazines via a Sulfoximine-Stablized Vinyl Carbanion
Lithiation of to form 184 was reported by the Harmata group to be the first example of a sulfoximine-stabilized vinyl carbanion. The resulting organolithium species 184 reacted with various electrophiles to supply structurally diverse benzothiazines <88TL5229>. However, the diastereoselectivity of the reactions with aldehydes was low (Scheme 48). CH CH33
TMS ~TMS
89% 89%
CH31 %
(~H3 ~)H EtCHO E t 83%, 1.9:1
~N~
CH3 CH3
I
TMSCI TMSCI
pTol
~
c6:
~N..S=O ~~I~~=O N I pTel To,
CH3 .-~CH3
;=O
pTel
Br CI C2Br2ClJ C2 / 4
3
c6:
N'/S=O
•
73%
I
pTel
t-BuCHO t-BuCHO
l PhCHO PhCHO 84%, 1.2:1 1.21 84%,
j
/ //
CH CH3 3
~
I /-
~N'~
~
CO C H CO2C3H5 2 3 S
S-O '/-
N \ =O
pTol pTel
cCC,-,::: I /
3 OH CH CH3 OH ~ t - B u t-Bu
~ N//' ~
CH3 OH CH 3 OH
~ ~ cCC
c6:
~ % , 2.4-2.8:1 2.4-2.8:1 ~o,
Ph
pTol
N'/1=0
CIC0 73% 2C3Hs,.
184 184
CH3 OH
/-
Li
I
/-
pTol Ph2CO, / 65% /
~
1CH CH3 98% 98%/ ~
Br
~
,S=O N/ =O bTel pTol
Ph
,S=O N/ I
pTal pTol
Scheme Scheme 48 Synthesis 1.3.4 Indole Synthesis
<9IT8855>, discovered that the adducts from from Lewis-acid mediated Harmata and Herron <91 T8855>, discovered 2, I-benzothiazines could have use in the synthesis of the other heterocyclic synthesis of 2,1-benzothiazines
cC90H H
~ r
H _1_._n_-B_u_L_i•• 1. n-BuLi = ~ ' ~ ~ 22. MoOPH MaOPH l ; l N N I 3. KOH H 185 pTol H 185 pTal 3. KOH
186: 55% 55% 186:
Scheme 49 Scheme
32
x. X Hong and M. M Harmata
systems. For example, benzothiazine 185 was reacted with n-BuLi followed by oxidation of the corresponding carbanion with MoOPH. A hydrolytic work-up gave tetrahydrocarbazole tetrahydrocarbazole 186 in 55% yield (Scheme 49). 1.3.5 Aniline Synthesis
Harmata and co-workers introduced a procedure for the reductive desulfurization of selected 2,1-benzothiazines 2,1-benzothiazines with sodium sodium amalgam, leading to the formation of the 2alkylanilines in high yields <94S142>. <94S142>. This This method is regioselective and general. general. As an example, alkylation of 187 followed by treatment with Na/Hg resulted in the formation of the aniline 188 in 68% overall yield (Scheme 50). n-Buki 1. n-BuLi TMS
cO~o
~I 2. Na/Hg
~O 2. Na/Hg 68% 68%
pTol pTol
187
ct( I~
I
[ ~ NH2 NH z 188
Scheme Scheme 50
Harmata and co-workers also also discovered that 2,1-benzothiazines 2,1-benzothiazines could be conveniently conveniently converted into into 2-alkenylanilines by treatment with KDMSO in DMSO <91JOC5059; <9lJOC5059; 91T8855>. 91 T8855>. For example, the reaction of benzothiazine 185 with KDMSO for 20 minutes at 70 DC ~ resulted in the formation of the 2-alkenyl sulfinamide 189 in 90% yield (Scheme 51).
ci2
H N-~Y::OO
1"<:::
~
2.0 KDMSO. 2.0 eq. eq. 90% KDMSO,. 90%
pTol 185 185
[~~.~.'~
05?aPTOI
NHSOpTol
189 189
Scheme Scheme 51
The 2-alkenyl sulfinamides sulfinamides appeared to be slightly unstable. unstable. They could, could, however, be quickly converted into into anilines anilines by base-catalyzed hydrolysis in good yields (Scheme 52) <9lJOC5059; T8855>. This <91JOC5059; 91 91T8855>. This general route to 2-alkenyl anilines is regioselective, but not stereoselective.
R2
R2 1. KOH (2.0 eq.) 2. H+ • pTol
190
1 191: 191: RR1, R2, R33 = = H, H, alkyl, alkyl, cycloalkyl cycloalkyl 1, R z. R 67-92% 67-92%
Scheme Scheme 52
33
Recent progress in the chemistry of of 2,l-benzothiazines 2,I-benzothiazines
The Hannata Harmata group <95TL4769> also used the reductive desulfurization of 2,1benzothiazines to produce 2-alkenylanilines 192 in good yields (Scheme 53). 53). This method is quite general, regioselective and stereoselective in some cases.
R1
R R~1 + ~ R 2 +~R2
R~
~H
Na/Hg Na/Hg,. ~ 2 - 1 _
U~IU~ NH
llANH2~2
0
pTol
2
(Z)-192 (Z)-192 (major) (major)
(E)-192(minor) (minor) (E)-192
R R11,, R R22 = = H, H, alkyl, alkyl, TMS, TMS, phenyl phenyl 57%-92% 57%-92%
Scheme 53
A general route to allylanilines, reported by Hannata Harmata and co-workers <95TL4769> could BuLi be of value in organic synthesis. Deprotonation of 2,I-benzothiazines 2,1-benzothiazines 193 with nn-BuLi followed by alkylation with iodomethyltrimethylsilane, and subsequent desilylation with fluoride followed by hydrolysis led to allyl aniline 194 in good yields (Scheme 54).
R1 ~R2
R1. ~a2
1. 1. n-BuLi n-BuLi 2. TMSCH21 "
3. TBAF 4.KOH
=
193 193
194: 194: R R1, R2 H, alkyl alkyl 1, R 2 = H,
Scheme 54 In 1998, Hannata and co-workers <98T9995> published a new synthesis of 2-alkenyl 1998, Harmata 2,1-benzothiazines 187 could be deprotonated by n-BuLi and alkylated anilines. The silylated 2,I-benzothiazines by different electrophiles. electrophiles. The corresponding products could be desilylated by fluoride with concomitant cleavage of of the carbon-sulfur bond to give 2-alkenylsulfinanilides that can then be hydrolyzed by base to the anilines 195 in good yields (Scheme 55). TMS TMS
m~o 187 187
N
~O pTol pTol t
1. n-BuLi n-BuLi 1. 2. RX 3. 3. TBAF TBAF 4. 4. KOH KOH
Scheme 55
195
y. X Hong Hong and M. M Harmata Harmata
34
1.3.6 Chiral Ligands in Asymmetric Asymmetric AIIyIic Allylic Alkylation The development of sulfoximines as ligands for transition metal-catalyzed asymmetric organic reactions is only currently being realized . Recently, Harmata and Ghosh <00S l>. <01 OL3321 > reported the preparation of both enantiomers of ligand 197 using the procedure <0 I0L3321> mentioned earlier <99AG(E)2419> <99AG(E)24I 9> starting with the dialdehyde 196, as shown in Scheme 56.
~
~
CHO Br
Ph +
Br
+
Pd(dbah, Pd(dba)2, rac-BINAP, rac-BINAP, CS 0s2003, 2C0 3 , toluene, 110°C, 110 ~ 2 days, days, 68%
,N=,S=O H I~le
o:?
~[
N
~+~.'Ph
CHO 196
p
~~Ph
(R)-77b
O_ Q
(R, R)-197 R)-197
Scheme 56 OAc OAe 2(C0 2Meh p h ~ . ~ - . . Ip h ++ CH CH2(CO2Me)2
Ph~Ph 198
2.5 mole% mole% Pd, Pd, (R, (R, R)-197, R)-197, (10 mol%)
solvent, BSA (3 eq.), eq.), KOAe KOAc (cat.) solvent,
199
M:XC02Me Ph "::: Ph (S)-200 (s)-2oo
Scheme 57 Table 8. Reacemic 1,3-diphenylallyl acetate with dimethyl malonate under various conditions Entry
Ligand
Pd source
Sovent
Time (h)
Yield (%)
Ee (%)
1
(R,R)-197
[Pd(allyl)C1]2 [Pd(allyl)Clh
THF
5
80
80
2
(S,S)- 197
[Pd(allyl)C1]2 [Pd(allyl)Clh
THF
3.5
90
80
3
(R,R)- 197
[Pd(allyl)Clh [Pd(allyl)C1]2 benzene
3
90
82
4
(S,S)- 197
[Pd(allyl)Clh [Pd(allyl)C1]2 benzene
3
85
82
5
(R,R)- 197
[Pd(allyl)C1]2 toluene [Pd(allyl)Clh
3.5
85
78
6
(S,S)- 197
[Pd(allyl)Clh [Pd(allyl)C1]2 toluene
3.5
70
78
7
(R,R)- 197
[Pd(allyl)Clh [Pd(allyl)C1]2 CH CH2C12 2Ch
4
30
8
(R,R)- 197
[Pd(allyl)Clh [Pd(allyl)C1]2 CH CH3CN 3CN
5
45
o0 o0
9
(R,R)-197 (R,R)- 197
Pd2(dba)3 Pd2(dba)3
THF
3.5
75
86
10
(S,S)- 197
Pd2(dba)3 Pd 2(dba)3
THF
3.5
69
86
11 11
(S,S)- 197
Pd(OAc)2 Pd(OAch
THF
7.5
67
73
12
(R,R)- 197
Pd(OAc)2
THF
7.5
68
73
13
(S,S)- 197
Ph(PPh Ph(PPh3)4 3)4
THF
5
90
16
14
(R,R)- 197
Ph(PPh Ph(PPh3)4 3)4
THF
5
79
6
Recent progress progress in the chemistry of of2,1-benzothiazines Recent 2,1-benzothiazines
35
bis-benzothiazine (R,R)-197 (R,R)-197 was an effective They demonstrated that the C2-symmetric bis-benzothiazine ligand in the asymmetric allylic alkylation reaction. reaction. The best result in this case was the of 198 and 199 in the presence of of BSA, Pd2(dba)3 Pd 2(dba)3 and (R,R)-197, which gave the reaction of product product (S)-200 in 75% yield and 86% ee. More experimental data revealed that solvent important in this reaction (Scheme 57). Relatively nonpolar solvents solvents resulted effects are very important in good yields and enantiomeric enantiomeric excesses while reaction in CH3CN CH3CN and CH2C12 CH 2CIz gave only products in moderate yields (Table 8). racemic products
_o,.S:N\
N=S.,_ -
ph4:.
201 201 C4
C
~
S
1
C8 ,5 ~ '
C18
o19~,
023
C.~
;3D ' C28
C29
Figure Figure 10. X-ray structure of201, of 201, a chiral, copper(I) complex of styrene
Although the basis for the stereochemical outcome of asymmetric allylic alkylation reaction by bis-benzothiazine is not very clear , <01OL3321>, bis-sulfoximines, the closely related bis-benzothiazines, and other ligands stereogenic at sulfur are important and potentially practical ligands for the future <030L427; <03OL427; OISLl878; 01SL1878; OOSI; 00S1; 010L3321; 01OL3321; OIJA3830; 01JA3830; 03MIl>. 03MII>. In order to expand the scope of the chemistry associated with 197, 197, the Harmata group has examined asymmetric cyclopropanation reactions using ligand (R,R)-197 <03JSMC349>. As a part of this research, the crystal structure of a chiral, copper(I) complex of styrene 201 was obtained, which suggested that edge-face interactions interactions as well as stacking may be important in the recognition of enantiofaces of alkenes by chiral copper(I) complexes of 197 <03JSMC349>.
36
X Hong and M. M Harmata x.
1.3.7 New Chiral Benzothiazine Ligand for Catalysis and Molecular Recognition A new chiral benzothiazine ligand 205 was synthesized by Harrnata Harmata and co-workers <06JOC3650>. It could be converted into a chiral molecular receptor 207 in a simple way. This chiral species 207 could be used as a new class of of chiral molecular tweezers. The synthesis of of 205 commenced with the protection of the commercially available compound 202, which was then coupled with (R)-sulfoximine (R)-sulfoximine 77b using the one-pot, one-operation procedure <99AG(E)2419> affording enantiomerically pure benzothiazine 204. This was followed by deprotection to produce benzothiazine 205 in good yield.
[~ 9C ~I
CHO
~ C H O CHO
eq. TEA, 0.5 ego eq. _-5.0 ego aBr
Nal, 2.0 eq. MOMCI,
OH
rt, 2 h THF, rt,
202 202
93%
(Yj.\O••'1• s~,oYN~\h "]I -N- Ph
9C ~
I
"]I
Pd(OAc)2, 7.5% 7.5% BINAP 5% Pd(OAc)2' Cs2CO3, 1.2 eq. (R)-77b 1.6 eq. C~C03'
Br Br
~
toluene, reflux, 48 h
OMOM OMO M
89%
203 203
/-PrOH, THF, H HzO, h i-PrOH, 2 0, rt, 3 h. 100%
N- Ph
OMOM
OH
204
20,
A CI I J .. C
CI-
~CICI
, ~+ H H
2.3 2.3 eq. NaH, Na H, 2.1 2.1 eq. 205, DMF, 20 h, rt 89% 89%
o
o
L r
206
Q
207
O_
Scheme 58
1.3.8 Application of2,I-Benzothiazines of 2,1-Benzothiazines in Natural Products Syntheses Harmata group has shown that the benzothiazines prepared by the conjugate The Harrnata addition of sulfoximine carbanions to a,~-unsaturated ct,13-unsaturated esters <03JA5754> can be used as enantiomerically pure starting materials for the synthesis of natural products. The benzothiazine synthesis establishes a stereogenic center with complete fidelity at a postion alph to a benzene ring. There are a number of natural products that possess such stereogenic centers. The Harmata Harrnata group has successfully applied the methodology to the synthesis of such compounds including (+)-curcumene 208 <03TL7261>, (+)-curcuphenol 209 <03TL7261>, erogorgiaene 210 <05TL3847>, pseudopteroxazole 211 <040L2201; <04OL2201; 050L3581> 05OL3581> and several related natural products.
37
Recent progress in in the chemistry chemistry oJ2,I-benzothiazines of 2,1-benzothiazines
Me Me
Me. Me
~M' ~ ~~Me
MeN Me
Me. Me
Me~Me ~ , , M e .,Me
Me Me
Me
R
~,l
_ ,Me
st s
."H
":::
[.& -
208. 208. R R = = H, H, S-(+)-curcumene S-(+)-curcumene
209. RR = OH, OH, S-(+)-curcuphenol S-(+)-curcuphenol 209.
Na
I(,le Me
/
:
~k~'O
210. 210. erogorgiaene erogorgiaene
IVle
211. 211. pseudopteroX8zoie pseudopteroxazole
Figure 11. Natural product targets.
Pseudopteroxazole 211 is a member of the amphilectane class of diterpenes and was isolated from a marine soft coral Pseudopterogorgia Pseudopterogorgia elisabethae elisabethae <990L527>. <99OL527>. M tuberculosis Pseudopteroxazole 211 possesses considerable inhibitory activity against M. tuberculosis H j1g/mL (97% growth inhibition). Given continuing global H37Rv 12.5/~g/mL 37 Rv at a concentration of 12.5 problems with respect to the treatment of tuberculosis, both the structure of 211 and its biological activity provide an impetus for syntheis. The total synthesis commenced with the coupling of ester 212 with (R)-sulfoximine (R)-sulfoximine (R)-77b to afford enantiomerically pure sulfoximine, sulfoximine, which was then treated with LDA followed by a proton quench to produce benzothiazine 213 as a 10: 10:11 mixture of diastereomers in good yield. Subjecting 213 to a twostep reduction/oxidation and spontaneous epimerization sequence afforded aldehydes 214a and 214b in a 1.6:1 1.6:1 ratio (Scheme 59). 59). The mixture was treated with a Wittig reagent to provide 215a and 215b in 52% and 33% yields, respectively, as single stereoisomers. stereoisomers. Me [ COzEt Mei~CO2Et
Me
~ ¢'
a,b
":::
Mex I@
.&
Br
8, b
--
Br
OMe OMe
EtO2C....I~Me M e ~ H <,,.T~.,,,,,~ -..S. ' o OMe
212 212
OHC.~,~Me Me "::: ..,,H Me [
+
N"'?"O-
.&
OMe OMe
N"S"~
OMe Ph
213 213
Me
214a 214a
Me Me. Me Me
Me
MeM[ [ ~ . , , M e
-e e
M Me
I~~
e ~
·,'H H
+ -
'~S'I
N OMe OMe
1
Ph
215a 215a (52%) (52%)
0
Me
-:?'
Me
+ Me M e "::: ~
·,'H H
."Me
-:?'
Ph
214b 214b
OHC,,,I' ,Me c,d= M e ' . ~ ""J~I
+
.&
OMe OMe
+
'~S'I
N
1
Ph
0
2 1 5 b (33%) (33%) 215b
(a) Pd(OAch, BINAP, (R)-sulfoximine, LDA, 88%; LAH; (d) Swem, Pd(OAc)2, BINAP, (R)-sulfoximine, 81%; 81%; (b) LDA, 88%; (c) LAH; Swern, 81%, 81%, 1.68:1,2 1.68:1, 2 steps; steps; (e) Wittig Scheme 59
38
X Hong and M. Harmata y.
Interestingly, treatment of of diene 215a with methanesulfonic acid afforded 216 as a single diastereomer in 88% yield, the structure of of which was confirmed by X-ray analysis (Scheme 60). The transformation of 216 into 217 started with an alkylation, followed by reductive desulfurization and triazene formation to afford compound 217 in 92% yield. Upon treatment with diiodomethane, triazene 217 was smoothly converted to aryl iodide 218 in 75% yield. Pd-catalyzed intramolecular Heck coupling of 218 led to the desired product 219b in 62% yield. Me.
215a 215a
aa
Me
Me.
~l,,. / ~
.,Me
~,[,,.
~ H + =
Me
b c,d b,c,d
Me
'
..=
Me
OMe
216 Me .,Me ,,H
Me
I OMe
218
-
ff =
ee
NEt2 217
Me
l,.
e
:M "
OMe
Me.
.
ll
Me
e ·,'Me
, ..
Me M e
Me Me
~ ~
·,'H
I~
OMe CHz CH2
219a 219a (14%)
ll
Me Me
II"
+ +
Me
e
Me
OMe Me
219b (62%)
(a) MsOH, MsOH, 88%; LiHMDS, allyl bromide; (c) Na/Hg, NalHg, 92%, HONO, Et2NH, Et2NH, 100%; 88%; (b) LiHMDS, allyl bromide; 92%, 2 steps; steps; (d) HONO, 100%; (e) CH 212, 20 h, 75%; Pd(OAc)2, 4% (o-Tol)3P, CH212, 75%; (f) 2% Pd(OAc)2, (o-Tol)3P, TEA, TEA, 120°C, 120 ~ 38 h Scheme Scheme 60
Stereoselective reduction of2l9b of 219b was conducted using one ofPfaltz's of Pfaltz's chiral catalyst to deliver compound 220 in 90% yield (Scheme 61). Demethylation of220 of 220 with NaSEt afforded the phenol in 87% yield. Subsequent nitration of the phenol with concentrated HN0 HNO33 produced the corresponding nitrophenol in 84% yield. With the nitrophenol in hand, the last stage of the synthesis involved assembling the benzoxazole ring. Reduction of of the nitrophenol with Zn dust, followed by treatment with methyl orthoformate and catalytic of pseudopteroxazole 211 in 65% yield for the last two steps TsOH, completed the synthesis ofpseudopteroxazole (Scheme 61). 61 ). After the successful synthesis of pseudopteroxazole pseudopteroxazole 211, the synthesis of the structurally-related compound erogorgiaene 210, which also shows antituberculosis activity, was reported <01JNP100>. <01 JNP 100>. This synthesis was a formal synthesis of of erogorgiaene using essentially the same methodology (Scheme 62) as that used for the synthesis of211. of 211. Aniline 221 was converted into the iodide using triazene chemistry. A Sonogashira coupling reaction of the corresponding iodide followed by Swem Swern oxidation and Wittig reaction afforded the of
39
Recent progress in the chemistry chemistry of2,l-benzothiazines of 2,1-benzothiazines
intermediate 222 in excellent yield. This compound compound was convered to erogorgiaene erogorgiaene by Hoveyda and co-workers<04JA96>. co-workers<04JA96>. Me Me Me Me MeliMe ".
a 219b 219b
-
=
~
Me Me
·,'Me e H ."
I"::
b,c,d, e b, c, d, e •
Me
e
.0
N~___&
OMe OMe Me Me
Me
211 211
220 220
tQ3 ~
Me. Me Me>yMe
CF
I o (o-ToI)2P,] r. N...(/ B (0-TOI}zP)I(N-{ "'" ', ~tBu , ,tBu
o
-/;)) 44 CF
F3
~
3
~ P f a l t z Pfaltz chlral chiral catalyst
(a) 3% catalyst, 200 psi H2, Hz, rt, 1I h, CHzCl NaH, 6.0 eq. EtSH, DMF, CH2C12, 90%, 158:1; 158"1; (b) 7.0 eq. Nail, z, 90%, NH 4Cl, 90% MeOH, rt, I1 h; (e) overnight, reflux, 87%; 87%; (c) HN0 HNO3, min, 84%; 84%; (d) Zn, NH4C1, 3, Hexanes, 1.5 min, CH(OMe)3, CH(OMe)3, TsOH (cat), 65%, 65%, two steps
Scheme 61 Scheme
_IC02Me _
-
a, b
Me
ro Me
_
"Ph 0-
a,b_
94
M e . O H
Me
221
~ Me~
c,d,e,f,g
NH 2 OH
.0
c,d,e,f,g
Me
Me
222 222
TMS TMS
---
12 12 steps steps
Me Me
le Me M
"
-Me
Me Me
210; erogorgiaene (tranlsyn) (tran/syn)
(a) LAH: NalHg, (c) 4.5 eq. HCl, NaNOz, 5.0 eq K EtzNH, 90%; LAH: (b) Na/Hg, HC1, 3.4 eq NaNO2, K2CO3, 90%; (d) CH CH3I, ZC0 3, 5.0 eq. Et2NH, 3I, 130
°c, ~ 0.5 h, 80%; 80%; (e) 0.12 0.12 eq PPh PPh3, 0.06 eq PdCl PdC12, 0.06 eq. CuI, CuI, Et3N, Et3N, 2.0 eq. (trimethylsilyl)acetylene, (trimethylsilyl)acetylene, 3, 0.06 z, 0.06 96%; (g) Ph Ph3PCH3, 90%; (f) Swern oxidation, 96%; 3PCH 3, n-BuLi, THF, 98%. Scheme Scheme 62
40
x. X Hong and M. M Harmata Harrnata
In addition to these studies, the Harmata group also successfully achieved the total synthesis (+)-curcumene 208 and curcuphenol 209 utilizing the 2,1-benzothiazine 2,I-benzothiazine chemistry <03TL7261>. The synthesis of (+)-curcuphenol was accomplished by reduction of of benzothiazine 94, followed by protection, desulfurization, reductive deamination and deprotection to give diol 223 in good yield. The latter was then converted into (+)curcuphenol 209 (Scheme 63). The total synthesis of (+)-curcumene involved a similar approach to that of of (+)-cucurphenol.
-'"C 02Me
Me Me
a,b,e,d,e • Me
..... Ph 094 94
l
OH
223 223
1a,a, f,f,g9
.~
Me
~OB" H~ OBn
Me..~~N Me
~OH
Me Me
NH2
h, h, i,j, i,j, kk
209 (+)-eureuphenol (+)-cureuphenol 209;
208; (+)(+)- eureumene curcumene
224
(a) LAH; LAH; (b) DHP, DHP, TsOH; Na/Hg, 74%, three steps; nitrite, DMF, DMF, 50%; (e) H H++ (f) TsOH; (c) Na/Hg, 74%, three steps; (d) isoamyl isoamyl nitrite, NaH, BnBr; BnBr; (g) Na/Hg; NalHg; (h) HONO, HONO, NaBH3CN, NaBH]CN, 61%; Pd/C, H Br2; (k) 2-methylNail, 61%; (i) Pd/C, H2; (j) (Ph (PhzPCH2-)2, 2; U) 2PCH 2-)2, Br2; propene lithium Scheme 63
1.4 ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS We are grateful to Prof. Paul A. Wender, Prof. Andreas Pfaltz, Prof. Abimael D. Rodriguez and Dr. Jeff Zablocki (CY (CV Therapeutics) for their constant encouragement and informative conversations in the course of our work on benzothiazines. All those past and present members of our research group at the chemistry department at the University of of Missouri-Columbia as well as all individuals whose names are included in the references are gratefully acknowledged. Our work in this area has been supported by the NIH (IROI(1R01AI59000-0IAI) AI59000-01A1) and the donors of the Petroleum Research Fund, sponsored by the American (38288-AC1 and others), to whom we are extremely grateful. Chemical Society (38288-ACI REFERENCES 1.5 REFERENCES 64JOC1688 64JOC1688 65JOC3163 65JOC3163 66AC(R)728 66AC(R)728 66AC(R)741 66AC(R)741 66JOC3531 66JOC3531 66MIl 66MI1 66MI2 66MI2
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Recent progress in the chernistry chemistry of of 2, 2,1-benzothiazines I-benzothiazines
66MI3 66MB 67AC(R) I426 67AC(R)1426 67CB2151 67CB2164 67JHC403 67JOC506 67MI1 67MII 67MI2 67MB 67MI3 67MI4 68MII 68MI1 69M928 69MII 69MI1 71CBI880 71CB1880 71MI1 71MII 71OPP33 710PP33 I 134 72JCS(P2) 1134 72JHC315 75JA676 76JHC615 77MI1 77MII 78H(lI)377 78H(11)377 79TL3969 81CC927 8IJAI525 81JA1525 81JHC73 8IJHC73 82CCI060 82CC1060 82CC884 82JHC 1045 82JHCI045 82JOCI909 82JOC1909 I9 83JCS(P2) 17 1719 83JOC4275 84CPB4360 84JCS(PI )2429 84JCS(P1)2429 84JOC5124
84MI1 84MII 84T1919 84TI919 85JOC2066 86H(24)2739 86JCS(P I)483 86JCS(P1)483 86JCS(PI )483 86JCS(P1)483
86JCS(P1)491 86JCS(PI)491 86JCS(PI )497 86JCS(P1)497 86JCS(PI)501 86JCS(P1)501 86JCS(P2)645 87CC385 87TL5997 88TL5229 89MI1 89MII 90JCS(PI )2089 90JCS(P1)2089
41
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Fongers, H. Hogeveen, R.F. Kingma, 1. J. Org. Org. Chern. Chem. 1983,48,4275. 1983, 48, 4275. H. Shimizu, K. Matsuo, T. Kataoka, M. Hori, Chern. Chem. Pharm. 1984, 32, 4360. Pharrn. Bull Bull. 1984,32,4360. P. Hanson, T.W. Stone, 1. J. Chern. Chem. Soc., Perkin Trans. 11984,2429. 1 1984, 2429. R.A. Abramovitch, W.D. Holcomb, W.M. Thompson, S. Wake, 1. J. Org. Org. Chern. Chem. 1984, 1984, 49, 5124. JP 59164786,1984; 59164786, 1984; Chern. Chem. Abstr., 102, 78901. D.E. Ames, A. Opalko, Tetrahedron 1984, 1984, 40,1919. 40, 1919. R.A. Abramovitch, A.O. Kress, K.S. K.S. PilIay, Pillay, W.M. Thompson, 1. J. Org. Org. Chern. Chem. 1985, 1985, 50, 2066. D.R. Borthakur, D. Prajapati, J.S. J.S. Sandhu, Heterocycles 1986,24,2739. 1986, 24, 2739. R.S. Gairns, R.D. C.J. Moody, C.W. Rees, S.C. S.C. Tsoi, 1. J. Chern. Chem. Soc., Perkin Trans. 1 R.D. Grant, C.J. 1986,483. 1986, 483. R.S. Gairns, R.D. R.D. Grant, C.J. C.J. Moody, C.W. Rees, S.c. S.C. Tsoi, 1. J. Chern. Chem. Soc., Perkin Trans. 1 R.S. 1986, 483. 1986,483. R.S. Gairns, R.D. Grant, C.J. C.J. Moody, C.W. Rees, S.c. S.C. Tsoi, 1. J. Chern. Chem. Soc., Perkin Trans. Trans. 1 1986, 491. 1986,491. R.S. Gairns, C.J. C.J. Moody, C.W. Rees, S.c. S.C. Tsoi, 1. J. Chern. Chem. Soc., Perkin Trans. 11986,497. 1 1986, 497. R.S. Gairns, C.J. C.J. Moody, C.W. Rees, 1. J. Chern. Chem. Soc., Perkin Trans. 11986,501. 1 1986, 501. S.A. S.A. Glover, A. Goosen, C.W. McCleland, J.1. J.L. Schoonraad,1. Schoonraad, J. Chern. Chem. Soc., Perkin Trans. 2 1986, 645. 1986,645. M. Hori, T. Kataoka, H. Shimizu, K. Matsuo, A. Sugimoto, K. Ikedo, K. Hamada, H. Ogura, H. Takayanagi, 1. J. Chern. Chem. Soc., Chern. Chem. Cornrnun. Commun. 1987,385. 1987, 385. E.O. Schlemper, Tetrahedron Lett. 1987,28,5997. 1987, 28, 5997. M. Harmata, E.O. M. Harmata, Tetrahedron Lett. 1988,29, 1988, 29, 5229. S. Tamada, T. Fujioka, H. Ogawa, S. Teramoto, K. Kondo, JP 01061470, 1989; 1989; Chern. Chem. Abstr., 112,35887. 112, 35887. P. Hanson, S.A.C. Wren, 1. J. Chern. Chem. Soc., Perkin Trans. 1 1990,2089. 1990, 2089.
42
90TL7021
91 CC877 91CC877 9IJCS(P I) 1733 91JCS(P1)1733 91JMC2477
91J0C5059 91JOC5059 91T8855 91TL4359
92MI1 92MIl 92MIl 92MI1 93JMC2242
94JCS(P 1)1709 94JCS(PI)1709 94MIl 94MI1 94S 142 94S142 94TL2911 95TL4769 97JHCI693 97JHC1693 97T13855 97Tl3855 97TA909 97TL137 98JHCI449 98JHC1449 98JHC499 98JHC983 98JOC6845 98MI1 98MII 98T9995
98TL5731 98TL573I 99AG(E)2419 99BMCL673
99JOM(576) 125 99JOM(576)125 99JPR403 99OL527 990L527 99TL95 00JOCI69 00JOC169 00JOC8086 00JOC8391 00JOC839I 00JOC926 OOSI 00S1 00SL475 01JA3830 0lJA3830 01JNP 100 OIJNPIOO 010L3321 01OL3321 0lSLI878 01SL1878 01T5915 02MI1 02MIl
X. X Hong and M. M Harmata Harrnata
H. Shimizu, Shimizu, K. Ikedo, K. Hamada, H. Matsumoto, M. Ozawa, T. Kataoka, M. Hori, 1990, 31,7021. Tetrahedron Lett. 1990,31,7021. W.B. Motherwell, A.M.K. Pennell, J. Chern. Chem. Soc., Chern. Chem. Cornrnun. Commun. 1991, 1991, 877. H. Shimizu, K. Ikedo, K. Hamada, M. Ozawa, H. Matsumoto, K. Kamala, Kamata, H. Nakamura, M. Ji, T. Kataoka, M. Hori, J. Chern. Chem. Soc., Soe., Perkin Trans. Trans. 11991, 1 1991, 1733. J.L. Malleron, M.T. Comte, C. Gueremy, IF. J.F. Peyronel, A. Truchon, le. J.C. Blanchard, A. Doble, O. Piot, lL. J.L. Zundel, C. Huon, B. Martin, P. Mouton, A. Viroulaud, D. Allam, lJ. Chem. 1991,34,2477. 1991, 34, 2477. Betschart, J. Med. Chern. RJ. Claassen, e.L. M. Harmata, R.J. C.L. Barnes, J. Org. Org. Chern. Chem. 1991,56, 1991, 56, 5059. 1991, 47, 8855. M. Harmata, B.F. B.F. Herron, Tetrahedron 1991, H. Shimizu, K. Hamada, M. Ozawa, T. Kataoka, M. Hori, K. Kobayashi, Y. Tada, 1991, 32, 4359. Tetrahedron Lett. 1991,32,4359. Chem. Abstr., 117, M. Nakane, K. Satake, K. Ando, H. Wakabayashi, JP 04128276, 1992; 1992; Chern. 191879. Chem. Abstr., 117, M. Nakane, K. Satake, K. Ando, H. Wakabayashi, WO 9205164, 1992; 1992; Chern. 131207. J.-L. Malleron, e. C. Gueremy, Gu6r6my, S. Mignani, J.F. J.F. Peyronel, A. Truchon, J.-e. J.-C. Blanchard, A. Doble, P. Laduron, O. Piot, l-L. J.-L. Zundel, lJ. Betschart, H. Canard, P. Chaillou, O. Ferris, C. Huon, B. Just, R. Kerphirique, B. Martin, P. Mouton, A. Renaudon, l-e. J.-C. Szmigel, J. Med. 1993, 36, 2242. Chem. 1993,36,2242. Chern. H. Shimizu, M. Ozawa, T. Matsuda, K. Ikedo, T. Kataoka, M. Hori, K. Kobayashi, Y. Tada, J. Chern. Chem. Soc., Perkin Trans. 11994, 1 1994, 1709. 1709. D. Blondet, J.-C. Pascal, WO 9403425, 1994; 1994; Chern. Chem. Abstr., 121,255666. 121, 255666. M. Harmata, M. Kahraman, Synthesis 1994, 1994, 142. 1994, 35, 2911. D. Blondet, J.e. J.C. Pascal, Tetrahedron Lett. 1994,35,2911. M. Harmata, D.E. 1995, 36, 4769. D.E. Jones, Tetrahedron Lett. 1995,36,4769. F.T. Coppo, M.M. Fawzi, J. Heterocycl. Chern. Chem. 1997,34, 1997, 34, 1693. U. Chiacchio, A. Corsaro, G. Gumina, V. Pistara, A. Rescifina, M. Alessi, A. Piperno, G. Romeo, R. Romeo, Tetrahedron 1997, 1997, 53, 13855. J. Brandt, H.-J. Asyrnrnetry 1997, 8, 909. H.-J. Gais, Tetrahedron: Asymmetry 1997, 38, 137. M.L.E.N. da Mata, W.B. Motherwell, F. Ujjainwalla, Tetrahedron Lett. 1997,38, E. Fanghanel, H. Bartossek, U. Baumeister, M. Biedermann, H. Hartung, J. Heterocycl. Chern. Chem. 1998,35, 1998, 35, 1449. 1449. Chem. 1998,35,499. 1998, 35, 499. F.T. Coppo, M.M. Fawzi, J. Heterocycl. Chern. Fawzi, J. Heterocycl. Chern. Chem. 1998,35,983. 1998, 35, 983. F.T. Coppo, M.M. Fawzi,J. M. Harmata, M. Kahraman, J. Org. Org. Chern. Chem. 1998,63,6845. 1998, 63, 6845. Chem. Abstr., 129,175645. 129, 175645. H. Nie, K.L. Widdowson, WO 9834929, 1998; 1998; Chern. M. Harmata, M. Kahraman, D.E. S.E. Weatherwax, Tetrahedron 1998, 1998, 54, D.E. Jones, N. Pavri, S.E. 9995. e. Lett. 1998,39, C. Bolm, J.P. Hildebrand, Tetrahedron Let',. 1998, 39, 5731. M. Harmata, N. Pavri, Pavri, Angew. Chern., Chem., Int. Ed. Engl. 1999,38,2419. 1999, 38, 2419. R.R. Wilkening, R.W. Ratcliffe, KJ. K.J. Wildonger, L.D. Cama, K.D. Dykstra, F.P. DiNinno, R.R. T.A. T.A. Blizzard, M.L. Hammond, lV. J.V. Heck, K.L. Dorso, E. St. Rose, J. Kohler, G.G. Hammond, Bioorg. Med. Chern. Chem. Lett. 1999,9,673. 1999, 9, 673. B.H. Yang, S.L. Organomet. Chern. Chem. 1999,576, 1999, 576, 125. 125. B.H. S.L. Buchwald, J. Organornet. H. Bartossek, E. Fanghanel,J. /Chern-Ztg 1999, 403. Chem./Chem-Ztg 1999, 341, 341,403. Fanghanel, J. Prakt. Chern. A.D. Rodriguez, C. Ramirez, I.!. I.I. Rodriguez, E. Gonzalez, Org. Org. Lett. 1999,1,527. 1999, 1,527. H. Shimizu, T. Hatano, T. Matsuda, T. Iwamura, Tetrahedron Lett. 1999,40,95. 1999, 40, 95. Org. Chern. Chem. 2000,65, 2000, 65, 169. C. Bolm, J.P. Hildebrand, J. Org. e. V. Benin, P. Kaszynski, J. Org. Org. Chern. Chem. 2000,65,8086. 2000, 65, 8086. H. Togo, T. Nabana, K. Yamaguchi, J. Org. Org. Chern. Chem. 2000, 65, 8391. Org. Chern. Chem. 2000, 65, 926. H. Togo, Y. Harada, M. Yokoyama, J. Org. 1. M. Reggelin, C. Zur, Synthesis 2000, I. E. Bonfand, L. Forslund, W.B. Motherwell, S. Vazquez, Synlett 2000, 475. e. Arn. Chern. C. Bolm, O. Simic, Simic, J. Am. Chem. Soc. 2001, 123, 3830. A.D. Rodriguez, e. C. Ramirez, J. Nat. Prod. 2001,64, 2001, 64, 100. M. Harmata, S.K. S.K. Ghosh, Org. Org. Lett. 2001,3,3321. 2001, 3, 3321. e. 2001,1878. 1878. C. Bolm, O. Simic, Simic, M. Martin, Synlett 2001, A. Ryokawa, H. Togo, Tetrahedron 2001, 57, 5915. W.W. Ogilvie, R. Deziel, J. Naud, lJ. O'Meara, WO 2002076982, 2002; Chern. Chem. Abstr., 137, 263074.
Recent progress in the chemistry chemistry of2,1-benzothiazines of 2,1-benzothiazines
02MI2
02MI3 02SL832 03ARK11 03ARKII 03JA5754 03JOC9574 03JSMC349 03MI1 03Mll 03OBC1342 030BC1342 030L427 03OL427 03TL726I 03TL7261 04JA96 04MI1 04Mll
04OL2201 040L2201 04SL101 04SLIOI 04TL5233 05OL3581 050L3581 05TL3847 06JOC3650
43
I. Yoshida, N. Yoneda, Y. Ohashi, S. Suzuki, Suzuki, M. Miyamoto, F. Miyazaki, H. Seshimo, J. 1. Kamata, Y. Takase, M. Shirato, D. Shimokubo, Y. Sakuma, H. Yokohama, WO 2002088107,2002; 2002088107, 2002; Chem. Chem. Abstr., 137,353066. 137, 353066. J.F. Hartwig, Handbook of of Organopalladium Organopalladium Chemistry for Organic Synthesis Synthesis 2002, 1, 1051. C. Bolm, M. Martin, L. Gibson, Synlett 2002, 832. K. Sakuratani, H. Togo, ARKIVOC. 2003, vi, II. 11. M. Harmata, X. Hong, J. Am. Chem. Chem. Soc. Soc. 2003, 125, 5754. J.T. J.T. Manka, F. Guo, J. Huang, H. Yin, J.M. J.M. Farrar, M. Sienkowska, V. Benin, P.Kaszynski, J. Org. Org. Chem. Chem. 2003, 68, 9574. M. Harmata, S.K. 2003,2,349. S.K. Ghosh, c.L. C.L. Barnes, J. Supramol. Chem. Chem. 2003, 2, 349. M. Harmata, Chemtracts 2003, 16, 660. Y. Misu, H. Togo, Org. Org. Siomol. Biomol. Chem. Chem. 2003, 1, 1342. 1342. C. Bolm, M. Martin, O. Simic, Simic, M. Verrucci, Org. Org. Lett. 2003,5,427. 2003, 5, 427. M. Harmata, X. Hong, C.L. Barnes, Tetrahedron Lett. 2003, 44, 7261. R.R. Cesati, 1. J. De Armas, A.H. Hoveyda, J. Am. Chem. Chem. Soc. Soc. 2004, 126, 96. C. Yoakim, J. O'Meara, B. Simoneau, W.W. Ogilvie, R. Deziel, WO 2004026875, 2004; Chem. Abstr., 140, 140, 303707. M. Harmata, X. Hong, C.L. Barnes, Org. Org. Lett. 2004,6,2201. 2004, 6, 2201. K. Hemming, C. Loukou, S. Elkatip, R.K. Smalley, Synlett 2004, 101. 101. M. Harmata, X. Hong, S.K. S.K. Ghosh, Tetrahedron Lett. 2004,45,5233. 2004, 45, 5233. M. Harmata, X. Hong, Org. Org. Lett. 2005, 7,3581. 7, 3581. M. Harmata, X. Hong, Tetrahedron Lett. 2005,46,3847. 2005, 46, 3847. M. Harmata, N.L. Calkins, R.G. Baughman, C.L. Barnes, Bames, J. Org. Org. Chem. Chem. 2006, 71,3650. 71, 3650.
44
Chapter 2 Porphyrins Diels-Alder and 1,3-dipolar Porphyrins in Diels-Alder 1,3-dipolar cycloaddition reactions Ana M. G. Silva and Jose Jos6 A. S. Cavaleiro* Department ojChemistry, of Chemistry, University ojAveiro, of Aveiro, 3810-193 Aveiro, Portugal E-mail: [email protected] [email protected]
2.1
OVERVIEW OVERVIEW OF OF THE THE CYCLOADDITION CYCLOADDITION REACTIONS REACTIONS OF OF PORPHYRINS PORPHYRINS
Interest in porphyrin chemistry started centuries ago with Man trying to understand why blood is red and plants are green <78MIl>. <78MI1>. However it was only in 1929 that the of a porphyrin was unambiguously demonstrated by Hans Fischer at his macrocylic structure of of such of protoporphyrin IX. The iron complexes of Munich school with the first synthesis of natural compounds play key roles in several vital functions (e.g., respiration and drug detoxification) and its magnesium complex is a precursor of chlorophyll a. As a result of of this pioneering synthetic work Fischer was awarded the Nobel Prize in 1930 <94MI1>. <94MIl>. Mainly after the second world war, chemists have looked for better synthetic methodologies leading to porphyrins and for the understanding of of their biosynthesis, mode of of action and catabolism. With the advent of of synthetic porphyrins, potential applications in medicine, in catalysis and in other areas have become possible. Several research groups have been dedicating their efforts to the synthesis of simple porphyrins containing groups on meso- and/or betapositions of of the macrocycle. Other topics of research have centred on the transformation of of the periphery of the macrocycle via functionalization reactions including electrophilic of alkyllithium reagents, peripheral reduction, oxidation substitutions, nucleophilic addition of <00COCI39; OOMIl>. chlorins and pericyclic reactions <00COC 139; 00MI 1>. Benzoporphyrins, (dihydroporphyrins) and bacteriochlorins (tetrahydroporphyrins) are important derivatives which can demonstrate significant medicinal applications. The search for new synthetic methodologies leading to such compounds is a target for many groups. Diels-Alder (DA) and 1,3-dipolar cycloaddition (l,3-DC) (1,3-DC) reactions are simple and Diels-Alder very versatile transformations to introduce a wide range of of substituents at the meso- and betapyrrolic positions of porphyrins, thus leading to promising derivatives obtained in many cases in one-pot transformations. The use of beta-vinylporphyrins beta-vinylporphyrins as dienes in DA reactions has been known for decades and has been recently reviewed <03A107>. <03AI07>. This review will focus only on the use of of porphyrins as dienophiles in DA reactions as well as on the use of porphyrins and porphyrinic derivatives in 1,3-DC reactions.
Porphyrins 1,3-~polar cycloaddition reactions Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
2.2 2.2.1
45
PORPHYRINS CYCLOADDITION REACTIONS REACTIONS PORPHYRINS IN CYCLOADDITION Porphyrins Porphyrins as dienophiles in Diels-Alder Diels-Alder reactions
The possibility of using porphyrins as dienophiles in DA reactions emerged in 1997 <97CC1199> found that meso-tetraarylporphyrins la-d can when Cavaleiro and coworkers <97CCI199> meso-tetraarylporphyrins la-d o-benzoquinodimethane, a highly reactive diene behave as dienophiles in the presence of o-benzoquinodimethane, situ by the thermal extrusion of S02 generated in situ SO2 from a sulfone by refluxing in 1,2,4trichlorobenzene, TCB, giving chlorins 2a-d in moderate yields (Scheme 1).
o2s
02S~ Ar
X Ar
Ar
Ar
5
TCB lTCB reflux reflux
+
[X) ]
-
ArAr
....
/'~-N
HN"~ Ar
1
2 a Ar= Ar= Ph, Ph, X=H X=H b Ar= m-MeOC rn-MeOC6H4, eH4 , X=H c Ar= p-MeOC X=H p-MeOC6H4, eH4 • X=H d Ar= C C6F eF55,• X=H e Ar= Ph, Ph, X=N0 X=NO2 2
Scheme 1. DA reactions of porphyrins 1 with o-benzoquinodimethane. o-benzoquinodimethane. As well as the synthesis of chlorins 2a-c, the DA reactions of of porphyrins la-c la-c with 0obenzoquinodimethane gave two naphthoporphyrins 3 and 4 (Figure 1) resulting from the dibenzoquinodimethane and tetradehydrogenation reactions of of the corresponding chlorins. On the other hand, the reaction with porphyrin lId d having pentafluorophenyl groups in the meso meso positions, afforded chlorin 2d and a diastereomeric mixture of of two bacteriochlorin bis-adducts Sd 5d and 6d the chiorin (Figure 2), showing that the presence of electron-withdrawing groups at the meso-position meso-position of the porphyrin greatly improve the DA reactions with o-benzoquinodimethane. o-benzoquinodimethane.
NH Ar--~ Ar /"--N
/~--Ar HN"~ Ar
N~, k //~---Ar HN"~
Ar--~ Ar /"--N
3
Ar Ar= Ph b Ar= m-MeOC m-MeOC6H4 eH4 c Ar= p-MeOC p-MeOC6H4 eH4
a a
Figure 1. Naphthoporphyrins 3 and 4.
4
46
A.M G. Silva Silva and and J.A.S. Cavaleiro Cavaleiro A.M.
Ph
~,,..1~y 06F5
~
C6 Fs 06F5
5d 5d
,i-
~
Ph
6d 6d
77
Figure 2. Bacteriochlorins Bacteriochlorins 5d and 6d and bis-naphthoporphyrin bis-naphthoporphyrin 7. Figure
A beta-substituted beta-substituted porphyrin, such as beta-nitro-meso-tetraphenylporphyrin beta-nitro-meso-tetraphenylporphyrin lIe, A e, also reacts with o-benzoquinodimethane o-benzoquinodimethane to give the corresponding nitrochlorin 2e, together with the naphthoporphyrin 4a and the bis-naphthoporphyrin (bisadduct) 7; the formation of of these 4a and 7 derivatives imply HN0 HNO22 elimination and dehydrogenation reactions <06TL8437>. Subsequently, other publications have appeared involving the DA reactions of other of porphyrins with dienes. For instance, the reaction of mesotetrakis(pentafluorophenyl)porphyrin lId d with the diene generated from pyrrole-fused 3sulfolene gave rise to the isoindole-fused chlorin derivative 8 accompanied by a mixture of of stereoisomeric bacteriochlorins bacteriochlorins 9 (Scheme 2) <98CC2355>. <98CC2355>.
Ar Ar
CO2Et C02Et
....L Ar--/k,\ Ar
Ar
O2,----J, 'NH
02SXNH
//Y---Ar Ar
~
.,. Ar---~ . . . . . . Ar
TCB, TCB,reflux reflux
IAr Ar ld Ar= Ar= CsFs C6F5 1d
//~NH r~//~._ A -
y
/jL-Ar +
~
Ar Ar
//~NH r ~ ~_--~..-
)-
Ar--/~ . . . . . . / ~ A r ~
EtO2C~
8 (32-39%) (32-39%) 8
Ar
FI I N"--./
Ar 9 (mixture (mixtureof of stereoisomers) stereoisomers) 9
Scheme 2 DA Reaction of porphyrin Id ld with a pyrrole-fused 3-sulfolene.
Furthermore, it was shown that porphyrin Id ld can also react with a pyrazine o-quinodimethane derivative ( Scheme 3) <05TL2189>. However, in this case the reaction did not afford the expected DA adduct, the product being the porphyrin derivative 10 resulting from the tetradehydrogenation of the corresponding adduct. The porphyrin derivative 11 was also obtained although in minor amount; this product must result from a cyclization reaction between the beta-fused quinoxaline ring and the adjacent meso-aryl group. Also, bisadducts 12 and 13 were isolated; these are the result of site specific bisaddition to opposite pyrrolic rings followed by oxidative processes.
47
Porphyrins Diels-Alder P o r p h y r i n s in D i e l s - A l d e r and a n d 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition reactions reactions
CN
CN
N~/ON AF Ar
Br~N
..CN
Br:):NJ(GN Br "I N GN Ar Ar Ar Ar-~N Nal, Nal, rGB, TCB, reflux reflux
.
Ar Ar
N~/ON
F
Ar
H N / ~ Ar +
Ar-~N
HN/~'~~~ x F
F
Ar
Ar
Ar
10 (34%)
1d ld Ar= Ar= GeF C6Fs5
9
Ar
I I (3%) 11
CN
N~"~ -.-ON J /F , ~ % ~,,
CN N~CN J /f N
Ar
" Ar
F
+
Ar
F F
N
Nc 1!, N! NC
F
.N '
...
NCJI
12 (6oYo)
~
.I 13 1%
NC
(
)
Scheme 3 DA reaction of of porphyrin 1d l d with pyrazine o-quinodimethane derivative. Ph Ph
C6F5 NH
Ph----(,, Ph
Ni_
Ph /~---Ph
C6F5
~
C6F5
C6F5
Ph 14 C6F5 C6F5 16 s 16 ,--------'--'-'_ [ ) ) ] ----.::...---=---------,CsF benzene, reflux
1. benzene, benzene, reflux reflux
2. DDQ
C6F5 N
Ph-- N N',N
Ph
Ph
P" (23%) 15 (23%)
C6F5 ..~
C6F5
C6F5
C6F5
C6F5 17 (55%) CsFs
Scheme 4. DA Reactions of of N-confused porphyrin 14 and hexaphyrin 16 with 0obenzoquinodimethane.
48
A.M. G. Silva and J.A.S. Cavaleiro Cavaleiro A.MG.
The DA reactions with o-benzoquinodimethane o-benzoquinodimethane have also been extended to nickel(II) Nconfused porphyrin 14 to yield nickel(II) N-confused isoquinoporphyrin isoquinoporphyrin 15 ( Scheme 4) <02CC1816>. The reaction occurred selectively in the peripheral carbonnitrogen bond, showing that this bond is more reactive than the other carbon-carbon carbon-carbon double bonds. This can be understood understood by the resonance contributions to the overall structures. Figure 3 shows two such resonance structures. In the canonical form II the C=N is both "cross conjugated" and in an iminium form which is known to be electron-deficient and an active dienophile <02CC 1816>.
Ph
Ph
p,\ Ph--& Ph
Ni
Ph /)---Ph
-~
=
~ N 7 \N.-J(
Phi, Ph
Ni_
~...N /
Ph I I
Ph /)~Ph
-\_NI~ Ph II "
Figure 3. Two canonical forms of of N-confused porphyrin 14. Figure
Similarly, the DA reaction of of o-benzoquinodimethane o-benzoquinodimethane with the hexaphyrin 16, followed by treatment with DDQ, gave rise to the naphthohexaphyrin naphthohexaphyrin 17 <05AC(E)932>. This result revealed that the first addition of of the diene took place selectively at the inner inverted betaof the pyrrolic double bond, suggesting that this double bond is the most reactive position of macrocyc1e. In minor amount the reaction also gave rise to a bisnaphthohexaphyrin. macrocycle. bisnaphthohexaphyrin. Curiously, this compound resulted from the selective addition of of a second 0obenzoquinodimethane benzoquinodimethane species to an outer beta-pyrrolic beta-pyrrolic double bond of of the naphthohexaphyrin 17, and is in agreement with the theoretical calculations that predicted that the second cyc1oaddition cycloaddition could not occur at the other side of of the inner double bond of of 17. F5
CCCO C6F5"
~
C6F5
1
ld 1d
C6F5"
~
C6F5
18d 8 h, 200 ce, ~ 22% MW, 3x10 min, 200 ce, ~ 83%
19d heat, no reaction MW, 3x15 3xl 5 min, min, 180 ce, ~C, 23%
of porphyrin 1d ld with pentacene and naphthacene. Scheme 5. DA Reaction of
49
Porphyrins in Diels-Alder Diels-Alder and 1.3-dipolar Porphyrins 1,3-dipolar cycloaddition cycloaddition reactions reactions
It has also been shown that polycyclic hydrocarbon derivatives can react successfully with porphyrins. In fact, meso-mono-, meso-mono-, meso-dimeso-di- and meso-tetraarylporphyrins meso-tetraarylporphyrins react with pentacene providing chlorin-type derivatives in moderate to good yields, depending on the number, steric hindrance and electron withdrawing character of the meso-aryl meso-aryl groups (Scheme 5) <00TL3065>. In the particular scenario of the DA reaction of mesomesotetrakis(pentafluorophenyl)porphyrin 1d 1d with pentacene (after 8 h at 200 ~ chlorin 18d was 200°C), obtained in 22% yield. This yield was improved to 83% and the reaction time reduced to 30 minutes by performing the reaction under microwave irradiation (after 3xlO 3x10 min at 200°C) 200 ~ <05TL4723>. Moreover, using microwave irradiation, the same porphyrin 1d l d reacted with naphthacene (after 3x15 min at 180°C) 180 ~ providing a synthesis of the corresponding chlorin 19d (as a mixture of of isomers), which could not be obtained by a procedure using conventional heating. DA reactions with polycyclic hydrocarbon derivatives have also been applied to other macrocycles. Lukyanets and coworkers have explored this methodology by adding the unsubstituted tetraazaporphine 20 to a series of of anthracene derivatives (Scheme 6). For instance, the reaction with naphthacene (after 6 h at reflux) afforded the chlorin 21 and a tetraazabacteriochlorin (bisadduct) in small amounts <00JPP525>. .
N~N (X):):) r;NN ~H N~ N C6H5Ci'reflux ~ H Y .&.&.&.&
N
Ny' "yN \=.f 20 20
CsHsCI. reflux
N~N ,-
0N
"~\ ~I
H
H H
NI' I/~"~
f
N"irN~' N N N
~U
\\
\
21 (39%)q 21 (39o/~
Scheme Scheme 6. DA Reaction of the tetraazaporphine 20 with naphthacene.
The same strategy provides a useful tool to derivatize corrole 22 and sapphyrin 25 (Scheme 7). In the case of corrole 22, the reaction with pentacene (after 6 h at 200°C) 200 ~ afforded mainly the dehydrogenated adduct 23; this is formed from the selective addition of pentacene to the beta-pyrrolic beta-pyrrolic double bond near to the direct pyrrole~pyrrole pyrrole-pyrrole link and subsequent dehydrogenation <04S <04S1291>. 1291 >. In minor amount, the reaction also gave rise to the dehydrogenated adduct 24 resulting from an unexpected thermal [4+4] cycloaddition reaction. In the reaction with sapphyrin 25, adduct 26 was produced with high selectivity (MW, 1 h, 200 200°C), ~ showing once again that the beta-pyrrolic beta-pyrrolic double bond close to the pyrrole-pyrrole link contains the most reactive position of this type of macrocycle <06TL3 13 1>. <06TL3131 >.
2.2.2
Porphyrins Porphyrins as 1,3-dipoles 1,3-dipoles in 1,3-dipolar 1,3-dipolar cycloadditions cycloadditions
In 1995, Boyd and co-workers <95TL7971> covalently linked a porphyrin to fullerene C C60 60 through a 1,3-dipolar cycloaddition reaction involving the porphyrinic azomethine ylide 28 (Scheme 8). The ylide was generated in situ from beta-formyl-meso-tetraphenylporphyrin beta-formyl-meso-tetraphenylporphyrin 27 and N-methylglycine, and provided the porphyrin-C porphyrin-C60 6o diad 29 in good yield.
50
A.M G. Silva and J.A.S. Cavaleiro A.M. Cavaleiro
C6F5
R C6F5
R
06
TCB 200 ~ C6F5
I
R=(CH2)3OAc MW TCB,200 ~
1
C6F5
(
~
R C6F5
R
5
23(23%) y
~
24(13%) ~ , ~
Scheme 7. DA reactions of corrole 22 and sapphyrin 25 with pentacene.
Ph Ph
CHO CliO
Ph Ph +
Ph Ph
HN-CH HN-CH2-CO2H 2 -C0 2 H [I
Me Me
Ph Ph 27 27 (M= (M= 2H) 2H)
jtoluene reflux toluene reflux
m
+
Ph Ph
--
m
HC=N-CH2 I Me
Ph N \
Ph Ph
Ph Ph
06o
Me
Ph Ph
Ph Ph
Ph Ph -
Ph Ph
28 28
29 29 (40%) (40%)
Scheme 8. 1,3-DC reaction of of the porphyrinic azomethine ylide 28 with C C60. 60 •
51
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
Subsequently, other research groups have used this strategy for the construction of other porphyrinic diads. As an example, the porphyrinic azomethine ylide 28 (M = = Ni) has been successfully trapped in 1,3-DC reactions with a range of dipolarophiles including Nphenylmaleimide, dimethyl fumarate, dimethyl acetylenedicarboxylate, trans-~-nitrostyrene, trans-~-nitrostyrene, 1,4-benzoquinone and 1,4-naphthoquinone. lA-benzoquinone lA-naphthoquinone. In general, the reactions afforded the expected adducts, e.g. 30, in very good yields (Scheme 9) <02JOC726>. Exceptions were found in the reactions with 1,4-benzoquinone and lA-naphthoquinone 1,4-naphthoquinone which only gave rise to the formation of the dehydrogenated adducts, e.g. 31. More recently, porphyrinic azomethine ylide 28 (M == Ni) has been trapped with isatin to give a spiro porphyrin derivative 32 (Scheme 9) <06SC2655>.
o ~
o 0
-Ph ~N-Ph
O ~ o~ =\N~
[28]
o
H
0
16 o
o
Mh-N ~ ~ _ p h
o
Me-~~
N
o
Ph Ph
P h Ph
Ph Ph
~
P
h
Ph Ph
Ph Ph
Ph
30(96%mixtureofdiastereomers)
30 (96% mixture of diastereomers)
31 (94%) (94%) 31
(13%) 32 (13%)
of porphyrinic azomethine ylide 28 with different Scheme 9. 1,3-DC reactions ofporphyrinic dipolarophiles It has also been demonstrated that in the absence of dipolarophiles, porphyrinic azomethine ylide 28 can participate in 1,5-electrocyclization reactions, to yield pyrroloporphyrins, e.g. 33 (Scheme 10) . <01JCS(PT1)2752>.
Ph ~/7...N -'Me
[28]
Ph Ph
h
Ph 33 33(55%) (55%) Ph Scheme 10. 1,5-Electrocyclization reaction of28. of 28.
52
A.M. G. Silva and J.A.S. Cavaleiro A.MG.
Numerous studies have been reported concerning the use of of 1,3-DC reactions as powerful of other systems employing porphyrins or chlorins as electron tools for the construction of donors and fullerene as electron acceptor, mimicking the photosynthetic reaction centres. One of these studies involves the preparation porphyrin-(C60)2 porphyrin-(C 6o )2 triads 34a and 34b from the 1,3-DC reaction of of a porphyrin having two formyl groups in the ppara a r a position of the 5,10- or 5,15phenyl groups, with N-methylglycine and C60 C60 (Figure 4) <98CL605>.
Me r '''='~ , N
m~=J r
''''''~ // \b
Me , N
Ar
Me
34b
of porphyrin-(C6o)2 triads 34. Figure 4. Examples ofporphyrin-(C60)2
1. pyridine, 100 ~C 0
2.._5% H H2SO 2. Me~H 2S044,, MeOH_...
O I
O
Phytyl
35
MeO MeO
O
OsO4, NalO4
M-N N-methylglycine, N-methylglycine, Ceo C60
....
MeO MeO
o
toluene, reflux
o O
38 (49%)
MeO
~-,,~n ,
0
Scheme 11. l l. Synthesis ofphytochlorin-C of phytochlorin-C60 6o diad 38.
~/
53
Porphyrins in Diels-Alder and 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition reactions reactions
<99JCS(PT1)2403> Hynninen and coworkers <99JCS(PTI )2403> used a similar approach to prepare phytochlorin-C60 diad 38 (Scheme 11). 11). The protocol employed the pyrolysis of the natural phytochlorin-C6o chlorophyll a molecule 35, followed by transesterification and demetallation to furnish derivative 36. Subsequent oxidation of 36 with OS04 NaI04 has allowed the synthesis of OsO4 and NaIO4 the formyl derivative 37, which was further used as precursor of the azomethinic ylide intermediate in the 1,3-DC reaction with C C60 60 leading to the formation of diad 38. Photochemical studies revealed that this diad underwent a fast intramolecular photoinduced electron transfer in polar solvents such a benzonitrile <99JACS9378>. Based on studies showing that the close proximity between the porphyrin and the C60 C60 is essential for the observation of an electron transfer process, Fukuzumi and co-workers have prepared the porphyrin-C porphyrin-C60 C60-pyrrolidinyl moiety is directly 6o diad 41, in which the C6o-pyrrolidinyl connected to the meso position of the porphyrin macrocycle (Scheme 12) <03JPC(A)8834>. The strategy adopted for the synthesis of the starting porphyrin involved the 2+2 condensation of a meso-unsubstituted meso-unsubstituted dipyrrylmethane with 3,5-di-tert-butylphenyl3,5-di-tert-butylphenylsubstituted dipyrrylmethane and 3,5-di-tert-butylbenzaldehyde, 3,5-di-tert-butylbenzaldehyde, to give 39, in 11.5% yield. Subsequent Ni(II) metallation, followed by Vilsmeier-Haack formylation and demetallation, gave rise to 40 which was used as the 1,3-dipole precursor; this dipole in the presence of Nmethylglycine and C C60, 60 , yielded the expected diad 41.
Ar AF CHO
A~ +
A=r=
J.
Ar
Ar
39
1. Ni(OAch. Ni(OAc)2, CHCI CHCI3, 3 , reflux 2. POCI POCl 33,, DMF, CH CH2CICH2Cl 2 CICH 2 CI 3. CH CH3COONa 3COONa (aq) 4. TFA, H H2SO 2S044,, CHCI 33
Ar Me
Ar
Ar N-methylglycine, Ceo C6o toluene, reflux
41
CHO
Ar Ar
Ar Ar
40
Scheme 12. Synthesis ofporphyrin-C of porphyrin-C60 6o diad 41.
Similar protocols have been followed for the synthesis of other porphyrin-C porphyrin-C60 6o diads where the linkage between C para C60 meta or para 60 and porphyrin moieties occurs through the ortho, meta positions of the phenyl ring of the porphyrin macrocycle <00PP598, 03JPC(A)8834 and 06SC2135>.
54 54
A.M.G. G. Silva Silva and andJ.A.S. J.A.S. Cavaleiro Cavaleiro A.M
Another interesting interesting strategy strategy for for the the construction construction of of aa porphyrin-C6o porphyrin-C60 diad diad linked linked by by aa Another disilane disilane chain chain was was devised devised by by Ito Ito and and coworkers coworkers (Scheme (Scheme 13) 13) <06BCSJl338>. <06BCSJ1338>. This This method method involves involves the the use use of of the the meso-iodo meso-iodo triphenylporphyrin triphenylporphyrin 42, 42, prepared prepared by by iodination iodination of of porphyrin porphyrin 39 39 using using aa mixture mixture of of bis(trifluoroacetoxy)iodobenzene-iodine bis(trifluoroacetoxy)iodobenzene-iodine . <00OL131>. An An iodo iodo porphyrin 42 42 was was reacted reacted with with I,2-diethynyl-l,1,2,2-tetramethyldisilane 1,2-diethynyl-l,l,2,2-tetramethyldisilane using using Sonogashira Sonogashira porphyrin coupling conditions conditions to give give rise to derivative 43; 43; this compound compound then then reacted with coupling
Ar AF
AF Ar
112, (CF3COO)21Ph, 2 , (CF 3COO)zIPh, CHCI CHCI33
Ar Ar
Ar Ar
Ar Ar
~~
39 39
I
Ar
42
" J Zn(OAc)2.2H20, MeOH, CH2CI2 ...-~"MMeMe
Ar
~"
MeMe [PdCI2(PPh3)2],Cul, THF, NEt3 MeMe MeMe I
Ar
I
==
Si- S I ~ /;}--~-~i-~i I I MeMe MeMe
Ar
43 I~~~--CHO I-o-CHO
Ar Ar
Pd(PPh3)4, Cul, THF, THF, NEt NEt3 Pd(PPh 3 )4, Cui, 3 MeMe
@_
Si-Si ~ CliO /;}--~-~i-~i~CHO ' '
Ar
I
I
MeMe
Ar
44 N-methylglycine, C6o C60 N-rnethylglycine, toluene, toluene, reflux
Ar
MeMe II II }--~-Si-Si----"'~---< Si-Si II II
Ar
Me
MeMe
MeMe Ar
45 45
Scheme 13. 13. Synthesis Synthesis of ofporphyrin-C diad 45. 45. Scheme porphyrin-C6o60 diad
yl
55 55
Porphyrins Porphyrins in in Diels-Alder Diels-Alderand and 1.3-dipolar 1,3-dipolarcycloaddition cycloaddition reactions reactions
p-iodobenzaldehyde using similar coupling conditions allowing the formation of porphyrin 44. This porphyrin was then allowed to react with N-methylglycine and C C60, 60 , giving rise to the final diad 45. Fukuzumi and co-workers <030L2719> <03OL2719> have developed another strategy aimed at a synthesis of imidazoporphyrin-C imidazoporphyrin-C60 14). Using the Crossley approach 6o diad 49 (Scheme 14). <95JCSCC2379> as for the synthesis of 17,18-dioxochlorin 47, the Cu(II) complex of betanitro-meso-tetraphenylporphyrin Ie l e was demetallated and reduced to the beta-amino beta-amino nitro-meso-tetraphenylporphyrin derivative 46, and this was photo-oxidised and hydrolysed to give 47. Condensation of 47 with the terephthalaldehyde in the presence of excess of NH NH4OAc 1:1I mixture 40Ac in a refluxing I: AcOH-CHC13 for 2 h, gave the expected derivative 48, which, with N-methylglycine and of AcOH-CHCh in the presence of C C60 imidazoporphyrin-C60 diad 49. 60 produced the corresponding imidazoporphyrin-C6o imidazoporphyrin-C60 diad has shown the longest Interestingly, the Zn(II) complex of that imidazoporphyrin-C6o lifetime in solution of the charge-separated state ever reported for donor-acceptor-linked diads.
Ar~Ar
Ar~Ar NH 2
1.hu.02
2.H+/H20
2. WI H20 or or
Ar ~
Ar
Ar ~
le = 1.~
Ar
silica silica gel gel
46
/H
46
4_~
~
47
C CHO OHCVCHO
/ NH NH4OA c 4 0Ac AcOH/CHCI AcOH/CHCI33
Me
N Ar ~ 49Ar 49
/
Ar N-methylglycine. N-methylglycine, C 060 60 toluene, reflux
"'t~ }
ff
~
N ~
\\
.
reflux~ N H~ N ~ N~~)-CHO :~CHO H
A r ~ A H48 r 48
Scheme ofporphyrin-C Scheme 14. Synthesis of porphyrin-C60 6o diad 49. of synthetic methodologies for the preparation of of porphyrinic azomethine azomethine In terms of ylides, the porphyrin moiety, in the examples above, was the carbonyl component. However, there are also examples where the porphyrin is used as the t~-amino a-amino acid component. have devised a protocol, in which the Lemmtyinen and coworkers <01JPP835> via phytochlorin 37 containing a formyl group was transformed into glycine derivative 50 via reductive amination (Scheme 15). In the final step, derivative 50 was reacted with C60 , and gave rise to the phytochlorin-C60 phytochlorin-C6o diad 51. benzaldehyde and C60,
56 56
A.MG. JA.S. Cavaleiro A.M. G. Silva and J.A.S. Cavaleiro
/CO2H HN
NaBH3CN
1. 1. GlyOt-Bu.HCI, GlyOt-Bu.HCI, NaBH 3CN
2. TFA 2.
Me
~-
MeO MeO
37
o
~ /)
MeO MeO
0
/
~ ~ nbenzaldehyde, ~ldehyde, C 06o 60 toluene, toluene, reflux reflux
51
Scheme diad 51. 51. Scheme 15. 15. Synthesis Synthesisofphytochlorin-C of phytochlorin-C60 6o diad
1. 1. HCI.NH HCI.NH2CH2CO2Me 2 CH 2C0 2 Me La(OTfh, La(OTf)3, K2CO toluene, reflux reflux CHO K 2C0 3, 3 , toluene, cliO 2. 2. NaBH NaBH4, MeOH 4 , MeOH CH CH2CI 0 ~C 2 CI 22,, O°C 3. NaOH NaOH (aq) (aq) 3.
Ph,~~Ph
Ph"
~
N/~CO2 H H Ph"
-Ph
~
Ph Ph 52
H..~HCHO, dimethyifumarate fumarate ~HO, dimethyl Ph
Ph
CO2Me
toluene, reflux reflux toluene,
"CO2Me
Ph"
~
Ph 53
Scheme 16. 16. Synthesis Synthesisof of diad diad 53. 53. Scheme
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
57
A convenient route to N-(porphyrin-2-ylmethyl)glycine 52 was described by Cavaleiro and coworkers <06JOC8352> <06JOC8352> (Scheme 16); 16); it involves the coupling of of the Ni(II) complex of of beta-formyl-meso-tetraphenylporphyrin beta-formyl-meso-tetraphenylporphyrin with an excess of of glycine methyl ester hydrochloride followed by reduction of the product imine with sodium borohydride and alkaline hydrolysis. Once synthesized, the Ni(II) complex of N-(porphyrin-2-ylmethyl)glycine, 52 was used as an azomethine ylide precursor; the latter was generated in the presence of of paraformaldehyde and dimethyl fumarate, allowing the formation of diad 53 in 74% yield. Besides the use of porphyrins as azomethinic ylide derivatives, the porphyrin macrocycle can also be used to generate porphyrinic nitrile oxides 55 (Scheme 17) <04RCB(E)2192>. Thus, the treatment of <04RCB(E)2192>. of oxime 54 with N-bromosuccinimide in the presence of triethylamine, led to the formation of nitrile oxide 55, which was trapped in 1,3DC reactions with dimethyl maleate and 2,5-norbomadiene 2,5-norbornadiene to afford 56 and 57, respectively. In the reaction with 2,5-norbomadiene, 2,5-norbomadiene, if an excess of of 55 was used, then the corresponding bis-adduct was obtained in good yield.
+
NBS, NBS NEt3 NEt3
--N 0
----"' 54 ~.~H:NOH ' -'--~--
-
f'M'
/~C02Me N~ O 7
C02Me
~
C02Me 56(91%) 56 (91%)
57 (97%) (97%)
Scheme 17. 1,3-DC Reactions ofporphyrinic of porphyrinic nitrile oxide 55 with dipolarophiles.
Another example with porphyrinic dipolar species uses pyridinium salt derivatives as precursors of porphyrinic pyridinium ylides (Scheme 18) <05TL5487>. The procedure involves the reaction of porphyrin 58 with methyl bromoacetate, in refluxing chloroform, to give pyridinium salt 59. The latter, in the presence ofK of K2CO3, 1,4-benzoquinone to 2C0 3, reacts with 1,4-benzoquinone yield only the mono-addition compound 60. Notably, when the reaction was performed in the presence of of DBU, bis-addition occurred and the porphyrinic dimer 61 was the only isolated addition product.
58
A.M. G. Silva and l.A.S. J.A.S. Cavaleiro A.M G.
Ph Ph
Ph
Ph 58 Ph Ph
C ~ H~ICH2CuOx2Me O
¢
+
Ph Ph
CH2CO2Me
~
+
Br Ph 59 Ph 59
/ ~
K K2COa 2C0 3 toluene, toluene, reflu re~/
°O
~~ DBU DBU
_~ene, uene, reflux reflux
Ph
Ph 0 Ph Ph
~
-...;::
h
0
Me
Ph Ph Ph Ph
Ph
Ph Ph
60(16%)
60 (16%)
MeO2C
O CO2Me ° 61(23%) 61 (23%)
Scheme 18. 1,3-DC reactions ofporphyrinic l,4-benzoquinone. of porphyrinic pyridinium ylide with 1,4-benzoquinone.
2.2.3 2.2.3 Porphyrins as dipolarophiles in 1,3-dipolar cycloaddditions Our first entry to the use of porphyrins as dipolarophiles in 1,3-DC reactions involved the reaction of of porphyrins with azomethinic ylides, generated in situ situ from a-amino acids and aldehydes, to yield chlorins and isobacteriochlorins (bisadducts) <99CC 1767, 05JOC2306>. meso-tetrakis(pentafluorophenyl)porphyrin In the particular scenario of of the reaction of of meso-tetrakis(pentafluorophenyl)porphyrin 1Id d with the azomethine ylide, generated in situ situ from N-methylglycine and paraformaldehyde, in refluxing toluene during 15 hours, the pyrrolidinochlorin derivative 62 was obtained as the main product (Scheme 19), 19), together with a small amount of isobacteriochlorin 63 (bis-adduct, Figure 5).
59
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions
H ~C=O + H
HN--CH2-CO2H I Me
C6F5
H
C6F5
-i-
-
H..'C=N-CH2 Me
C6F5 +
Me
C6 Fs5 ++ bisadduct /~C6F (11%) (11%)
= C6F5~k
6 Fs C6F5 62 (61%) (61%) C 1d C 62 C6F5 ld 6 Fs Scheme 19. 1,3-DC Reactions of porphyrin Id ofporphyrin ld with azomethine ylide.
When a larger excess of of the azomethine ylide precursors was used and the reflux was prolonged for 40 hours, the reaction afforded isobacteriochlorin 63 as the major adduct together with a small amount of of bacteriochlorin 64 (Figure 5). This result demonstrates that the attack of the second azomethine ylide species to the chIorin chlorin macrocycle occurs I]-pyrrolic double bond, yielding the isobacteriochlorin with preferentially at the adjacent ~-pyrrolic high site selectivity.
Me,Me C6F5 63
Me"
C6F5 64
Figure 5. Bis-adducts obtained in I,3-DC 1,3-DC reaction. Figure This strategy has been successfully applied to other porphyrins, however the best yields were obtained with porphyrins having electron-withdrawing groups at the meso m e s o positions of of the macrocycle <05JOC2306, 04JBCS923>. Knowing the great potential of I,3-DC with porphyrins, Gryko and co-worker of such 1,3-DC <05OL1749, 06JOC5942> predicted that if two electron-withdrawing groups were placed in <050Ll749, vicinal (~,P') (13,13') positions of the same pyrrolic unit of a porphyrin, then stable, locked chlorins could be synthesized in a regioselective way. As a result, they undertook the synthesis of of a range of porphyrins to be used as starting materials in 1,3-DC reactions with azomethine v i a 3+1 condensations of of a tripyrrane ylides. The starting porphyrins were synthesised via t~,t~'-diformyl pyrrole. Thus, (compound containing three pyrrolic units such as 65) with an a,a'-diformyl of the tripyrrane 65, they have performed the condensation of of the aryl for the synthesis of aldehyde with pyrrole (Scheme 20). On the other hand, the synthesis of the diformyl pyrrole I2 or cerium ammonium 66 involved the dimerization of esters of acetoacetic acid using Iz NH 3 , gave nitrate (CAN) to give the corresponding l,4-diketones; 1,4-diketones; these, when treated with NH3, rise to an a,a'-dimethylpyrrole ct,ct'-dimethylpyrrole derivatives, which were then transformed into the required
60 60
A.M. G. Silva Silva and and J.A.S. J.A.S. Cavaleiro Cavaleiro A.MG.
diformylpyrroles 66 66 by by selective selective oxidation oxidation of of the the methyl methyl groups groups using using CAN CAN in in MeCN/ MeCN/H20 diformylpyrroles H2 0 at room room temperature temperature (Scheme (Scheme 21). 2 l). at
ArCHO ArCHO ++
0
TFA TFA
N
H H 65 65 Scheme Scheme 20. 20. Synthesis Synthesis of of the the tripyrrane 65. 65.
1. NaOMe NaOMe 1.
O
/~~CO2R
2. 12 CAN 2.1 or CAN 2 or
RO2~.2R
R~R
°OIO°NH3aa q or jNH3, MeOH
R= Me, Me, Et, Et, t-Bu t-Bu R=
NH 3 q or NH 3 , MeOH
R0 RO2C, 2C
C0 CO2 R 2R . ~ OHC CHO OHC--«'N;\-CHO H H
CAN MeCN, H20
W
RO,,C R0 2C
A
CO2R C0 2R
N H H
66
Scheme 21. Synthesis of diformylpyrrole 66.
RO2C, R0 2C
h
~
CO2R C0 2R
CO2R CO2R
Ar
O H C ~ CNH OCHO + OHC + H 65
66 66
/
~
Ar
f~CHO / HCHO N-methylglycine N-methylglycine toluene, reflux reflux toluene, CO2R
67
M Me N', e
Ar
Ar 68 Scheme 22. Synthesis of of locked chlorins 68. Scheme Finally, Finally, the the condensation condensation of of the the tripyrrane tripyrrane 65 with with the the diformyl diformyl pyrrole pyrrole 66, in in a TFA/CHCI3 TFAlCHCb solution, solution, gave gave porphyrins porphyrins 67. Such porphyrins porphyrins were were then then used used in in 1,3-DC
61
Porphyrins in Diels-Alder and and 1,3-dipolar cycloaddition reactions 1.3-dipolar cycloaddition
reactions with azomethinic ylides affording the locked chlorins 68 (Scheme 22). The results 13-pyrrolic positions, obtained showed that if electron-withdrawing groups are introduced at p-pyrrolic the presence of electron-withdrawing groups at meso meso positions is no longer necessary for the success of of a 1,3-DC reaction. The usefulness of such 1,3-DC reactions was also demonstrated when C- and Nglycoconjugated pyrrolidine-fused chlorins 69 and 70 were synthesised via azomethinic ylide cyc1oadditions Id (Schemes 23 and 24) cycloadditions with meso-tetrakis(pentafluorophenyl)porphyrin meso-tetrakis(pentafluorophenyl)porphyrin ld of ld Id with the azomethinic ylide, generated in situ from the <05S857>. While the reaction of galactosyl configured aldehyde and N-methylglycine, afforded a diastereomeric mixture of of two chlorins 69, the reaction of Id l d with the N-substituted symmetrical azomethinic ylide, generated in situ situ from the galactose-substituted glycine derivative with paraformaldehyde, gave chiorin chlorin 70 as the only isolable product.
C6F5 "74O --1-0 O HO~.O, ~~ O N-methylglycine N-methylglycine
O
.O
OHC~YO
o/-0t-
[
1d ld
= C6F5
6F5
~ (~6F5 ~N'Me
)-0o .
o
o
0
69 69 (51% (51% mixture mixture of of diastereomers) diastereomers)
Scheme 23. Synthesis of of the C-glycoconjugated pyrrolidine-fused chlorin 69. Scheme
C6F5 ---1LO
--?Lo HCHO _--
NH
CH2-CO2H
O7C~
ld
-(~H2
= C6F5
6F5
O7t"]
--1-0
N~O 70(19%) 70(19%)
O-~ Of-
Scheme 24. Synthesis of of the N-glycoconjugated pyrrolidine-fused chlorin 70.
Another example illustrating the versatility of 1,3-DC reactions is concerned with the reaction of of [36]octaphyrin 71 with azomethine ylide generated in the usual way from Nmethylglycine and paraformaldehyde, to give mono- and bis-pyrrolidine-fused adducts 72 and 73 (Scheme 25) <060LlI69> <06OL 1169>
62
A.M. G. Silva and J.A.S. Cavaleiro A.MG.
Ar Ar
Ar'"x\ .... Ar "i~nH
Ar
N~\ N II ~q/,)II Ar Ar
,,., / / ' A rAr n!,~----(
Ar Ar
Ar= CsF C6Fs5
71 71
HCHO, N-methyigiycine HCHO, N-methylglycine toluene, reflux reflux
;?--N '
Ar A
r
~
Ar
Ar
Ar
Ar N
Ar
~~.~~-~
Ar-~/ Ar + \\
+
Ar
72 (3%)
Ar ."y,..-Ar //
.... ' " { .-~k II /~,~"" /" .-~ ~r'~---Z/~ .~'
Ar
73 73 (7%) (7%)
Scheme 25. 1,3-DC Reaction of [36]octaphyrin 71 with azomethine ylide.
--f-o "~0 0
Ar AF --
[_
4-
+
O-~=C:
1 HJ
Me H
I Ar
r
"Me (72%) 74 (72%)
-
+
I
Ar
Ar
Ar
Ar
0 O~
-O-N~~
H
H]
13n Bn
I
1d, Ar= CsF C6Fs5 1d,
0t-0
Ar
Ar
r
Ar
TN.Bn
,o o 75 (66%)
Scheme 26. 1,3-DC reactions of porphyrin ld Id with nitrones.
63
Diels-Alder and 1,3-dipolar cycloaddition reactions Porphyrins in Diels-Alder
Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fusedchlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the N-methylnitrone, generated in situ situ from N-methyl hydroxylamine and paraformaldehyde, with porphyrin Id ld . <00JPP532>. It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. In an attempt to explain the different behaviour of of azomethinic ylides and Nmethylnitrones in 1,3-DC reactions with porphyrins and chlorins, a theoretical study has been carried out. The results obtained showed that while in the cycloadditions of porphyrins and chlorins with azomethinic ylides the processes are irreversible and consequently are kinetically controlled, the cycloadditions of such macrocycles involving N-methylnitrone are clearly reversible, showing that the products from such reactions should be thermodynamically controlled <07MIl>. <07MI 1>.
C6F5 O--N",Me
C6F50..N -Me
C6F5
C6F5
06F50
C6F5
o \
C 6 F5 C6F5
Me" "
Me Me"N
76 76
C 6 F5 C6F5
77 77
Figure 6. Bacteriochlorins Bacteriochlorins 76 and 77.
Ph Ph
NO2
Ph Ph
Ph Ph
Ph N--N-CH2
le 1e
+-1Ph
P Ph
h
Ph Ph
~
~H N-N' ,.~7
Ph Ph ++ Ph Ph
Ph
Ph ++ Ph Phi/N
,%~_DB_U_~/
Ph
Ph Ph
78
DBU
Ph
79 79
//" toluene,reflux reflux toluene,
Ph
HN~Ph Ph Ph
//
~-~
Scheme 27. 1,3-DC Reactions of porphyrin Ie l e with diazomethane.
80 80
64
A.M G. A.M. G. Silva and J.A.S. J.A.S. Cavaleiro Cavaleiro
Glycoconjugated isoxazolidine-fused chlorins and bacteriochlorins were also elegantly synthesised using a 1,3-DC approach (Scheme 26). For instance, the galactosylnitrone reacted with porphyrin Id ld in a small volume of toluene, at 60°C, 60 ~ to yield chlorin 75, accompanied by a small amount of two related bacteriochlorins <02TL603>. Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of p-nitro-meso-tetraphenylporphyrin ~-nitro-meso-tetraphenylporphyrin Ie l e with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) <02S1155>. <02Sl155>. The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. The same approach was subsequently used by Dolphin and co-workers <02CC2622> and also by Robinson and co-workers <03T499> to prepare pyrazoline cycloadducts from porphyrins and chlorins. Scheme 28 shows new chlorin derivatives (81 and 82) which have been obtained in this way. "
hv, heat ,. ,. . . .
N
MeO
MeO MeO
36
0
MeO MeO
81
0
82
Scheme 28. 1,3-DC Reaction of phytochlorin 36 with diazomethane.
Carbonylic ylides represent other class of 1,3-dipolar reactive species to be used in 1,3la with DC reactions with porphyrins. For example, reaction of meso-tetraphenylporphyrin meso-tetraphenylporphyrin la carbonyl ylide derived from tetracyanoethylene oxide gave chlorin 83 (Scheme 29) <02TL7281>. Moreover, a large range of 1,3-DC reactions with carbonyl ylides has been patented <04MIl>. <04MI 1>. The resulting adducts containing one or more cyano groups can be further derivatized aiming to obtain photosensitizing agents of interest in photodynamic therapy.
oO
.c / \ c. NC--f-\-CN NC CN
Ph
NC CN Ph
~
[ o
Ph
Ph +
[NC-1~\-CN: NC
Ph
1a la
V~'O CN CN
Ph - - - Ph
CN
Ph
83 (20%)
la with a carbonyl ylide. Scheme 29. 1,3-DC Reactions of porphyrin la
65
Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition cycloaddition reactions
Nitrile oxides have been also widely applied in 1,3-DC reactions with porphyrins <05TLl555, 05S1030, 05S3632, 06H885>, <05TL1555, 06H885>. The reactions using unstable nitrile oxides, such as benzonitrile oxide, have failed or have given products in low yields; however reactions using stable nitrile oxides usually gave good results. In this way, the addition of 2,6dichlorobenzonitrile, to meso-tetra(p-chlorophenyl)porphyrin meso-tetra(p-chlorophenyl)porphyrin 84 afforded chlorin 85, together with a minor amount of related bacteriochlorins (Scheme 30). Ar Ar
Ar Ar
O--N
Ar
85 85 (53%) (53%)
(3-
°r:t4+
Cl
III
C Ar
Ar
+ CI~CI + CI'&CI
=-
Ar
1,&
Ar
p-CIC6H4 84, Ar= p-CIC sH4
Scheme 30. 1,3-DC Reactions of porphyrin 84 with nitrile oxide. 30.1,3-DC
Finally, it is important to mention that there are other related publications in which porphyrin macrocycles are not directly used as dipolarophiles but are transformed into new derivatives that can react with carbonyl ylides via ACE (alkene cyclobutene epoxide) reactions. This idea arose in 1997, 1997, when Russell and co-workers found that fused esteractivated cyclobutene epoxides 86 can be ring-opened to give carbonyl ylides 87, and that these can be trapped stereospecifically by ring-strained alicyclic dipolarophiles, such as 2,5norbornadiene, norbomadiene, to form hetero-bridged norbornanes norbomanes 88 in good yields, through ACE transformations (Scheme 31) <97CC <97CCI023>. 1023>.
~: 11O°C.3~ 110~
86
[J40] h. J:-J-~ O
,,.
E
87
88
E= C0 CO2Me 2 Me
Scheme 31. A typical ACE (alkene cyclobutene epoxide) reaction.
Gunter and co-workers have applied this methodology to the condensation of norbornene derivative 90 (block A, Scheme 32) with epoxide 94 (block B, Scheme 33) norbomene <98S593>. Thus, using the Crossley porphyrin-a-dione porphyrin-a.-dione 47, condensation with 1,2,4,5benzenetetramine tetrahydrochloride and then the product with a strained dione, gave 90 as block A. blockA.
66
A.M. G. Silva A.MG. Silva and and J.A.S. J.A.S. Cavaleiro Cavaleiro
-CI+H3N~NH3 +cl-
Ar~Ar
_CI+H3N/ ~
Ar~Ar NH2
-NH3+CI_ =
NH2
N
Ar 47
\
/
Ar
89
O ~ / /
Ar~Ar
N N:r(XD ~"I [
~/.
N
A(
~
N
Ar 90, block A 90, blockA
Scheme 32. Synthesis of of block A.
Typically, the synthesis of of block B involves the Diels-Alder reaction of of 1,4naphthoquinone with cyclopentadiene, followed by reduction and OH methylation to give 92 (Scheme 33). The next step involves a Ru-catalysed [2+2] cycloaddition of 92 with dimethyl acetylenedicarboxylate (DMAD), followed by epoxidation (MeLi, ButOOH) to give 94 as block B.
O
~
1.NaH,THF Nail,THF ¢ b e o 1. 2. Mel
O
O
91
MeO2C CO2Me
~h\.I02Me
~ ~MeO \~) MeO 0
•
ButOOH, ButOOH,MeLi MeLi -78°e -78~
"" '1.---:; ~ MeO MeO
~
MeO
/, 92 92
I DMAD RuH2CO(Ph3)3 CO2Me 93
CO2M e
94,blockB
94, block B
Scheme 33. Synthesis of block B.
Finally, the condensation of blocks A and B under thennal thermal conditions gave 96, where the porphyrin ring is rigidly linked to the dimethoxynaphthalene chromophore, through an ACE reaction (Scheme 34). The ACE reaction has proved to be an extremely versatile method for linking other chromophores to porphyrin macrocycles through a rigid spacer <99JOC4218, OIM406, 01M406, 02T3445>.
Diets-Alder and 1,3-dipolar cycloaddition reactions Porphyrins in Diels-Alder
67
MeO k 94, B-BLOCK B-BLOCK
heat heat
= ~'~)~7~/CO2Me
.._
II
II
95
~..Z.......-"-.-.~I
block A A 90, block
~
MeO2C
O/---:n /,
--<-""""---- -->------->------,-
MeO MeO2C
MeO
N
-N Niv
N
N Ar
96, ACE-coupled ACE-coupled product product 96,
Scheme Scheme 34. ACE Reaction.
2.3 CONCLUSIONS CONCLUSIONS This survey has highlighted importance of reactions as powerful tools highlighted the importance of cycloaddition cycloaddition reactions functionalisation of of meso beta-positions of of a porphyrin meso and beta-positions porphyrin macrocycle. macrocycle. for the functionalisation porphyrins can be used as dienophiles dipolarophiles in DA DA dienophiles and as dipolarophiles As shown above, porphyrins 1,3-DC reactions of reactive dienes and 1,3-dipoles 1,3-dipoles to achieve and 1,3-DC reactions with a wide range of monoadducts monoadducts of of the chiorin chlorin type, as the main products, products, or related compounds. compounds. Furthermore, Furthermore, under bis-adducts of bacteriochlorin types can be obtained under certain conditions, conditions, bis-adducts of the iso- or bacteriochlorin depending depending on the 41t 4n species used. Porphyrins can also be used as precursors precursors of Porphyrins of 1,3-dipolar 1,3-dipolar species, and this has been widely explored, mainly when targets are concerned with the synthesis ofporphyrinic of porphyrinic diads. Several novel porphyrin porphyrin derivatives can then be obtained by following the mentioned cycloaddition methodologies; methodologies; many of of the new products products fulfil the requirements requirements to be cycloaddition considered considered as potential new drugs mainly for the detection and treatment treatment (PDT) of of cancer cancer situations photo-inactivation of situations and in the photo-inactivation of microorganisms. microorganisms.
2.4
ACKNOWLEDGEMENTS ACKNOWLEDGEMENTS
Thanks are due to all colleagues colleagues and students who co-authors in our our cited publications. publications. Thanks who are co-authors Thanks para a Ciencia Thanks are also due to our University, to "Fundayao "Fundaqgo para Ci~ncia e a Tecnologia" Tecnologia" (FCT, Portugal) and POCI (FEDER) for funding the Organic Organic Chemistry Chemistry Research Unit. Portugal) POCI 2010 (FEDER) A.M.G.S. A.M.G.S. thanks thanks FCT FCT for her SFRH/BPD/8374/2002 SFRH/BPD/8374/2002 grant.
2.5
REFERENCES REFERENCES
78MII 78MI1
94MI1 94MII 95TL797I 95TL7971 95JCSCC2379 97CC1199 97CCI199
Ed.; Academic Academic Press: Vol. I, D. Dolphin Dolphin In The Porphyrins I; Dolphin, Dolphin, D., Ed.; Press: New York, York, 1978; 1978; Vol. General Preface. General Preface. R.A., Ed.; Marcel R.A. Sheldon R.A. Sheldon In Metalloporphyrins in Catalytic Oxidations; Sheldon, Sheldon, R.A., Ed.; Marcel Dekker: New York, York, 1994; Dekker: 1994; Pp 6. C.A. Reed, P. Boyd, 1995, 36, 7971. 7971. T. Drovetskaya, Drovetskaya, C.A. Reed, P. Boyd, Tetrahedron Lett., 1995, M.J. Prashar,1. M.J. Crossley, Crossley, L.J. L.J. Govenlock, Govenlock, J.K. J.K. Prashar, J. Chem. Soc., Chem. Commun., 1995,2379. 1995, 2379. A.C. Tom6, J.A.S. Cavaleiro, Cavaleiro, Chem. Commun. 1997, 1997, Tome, P.S.S. P.S.S. Lacerda, Lacerda, M.G.P.M.S. M.G.P.M.S. Neves, Neves, lA.S. 1199.
68 97CCI023 97CC1023 98CC2355 98CL605 98S593 99CC1767 99CCI767 99JACS9378 99JCS(PTI )2403 99JCS(PT1)2403 99JOC4218 00COC139 00JPP525 00JPP532
00MI1 OOMII 00OL 131 000Ll31 00PP598 00TL3065 0IJCS(PTI)2752 01JCS(PT1)2752 0IJPP835 01JPP835 0lM406 01M406 02CC 1816 02CCI816 02CC2622 02JOC726 02S1155 02S 1155 02T3445 02TL603 02TL728I 02TL7281 03A107 03AI07 03JPC(A)8834
03OL2719 030L2719 03T499 04JBCS923
04RCB(E)2192 04S1291
04MI1 04MII 05AC(E)932 05JOC2306 050Ll749 05OL1749 05S857
05S 1030 05SI030
A.MG. A.M. G. Silva and 1.A.S. J.A.S. Cavaleiro
R.N. Warrener, A.C. Schultz, D.N. D.N. Butler, S. Wang, I.B. R.N. I.B. Mahadevan, R.A. Russell, Chern. Chem. Cornrnun. Commun. 1997,1023. 1997, 1023. M.G.H. Vicente, M.T. Cancilla, c.B. C.B. Lebrilla, K.M. Smith, Smith, Chern. Chem. Cornrnun. Commun. 1998,2355. 1998, 2355. Chem. Lett. 1998, 1998, 7, 605. S. Higashida, H. Imahori, T. Kaneda, Y. Sakata, Chern. 7,605. R.N. Warrener, M.R. Johnston, MJ. M.J. Gunter, Synlett 1998, 1998, 593. A.M.G. Silva, A.C. Tome, Tom6, M.G.P.M.S. Neves, A.M.S. Silva, JAS. J.A.S. Cavaleiro, Chern. Chem. Cornrnun. Commun. 1999, 1999, 1767. 1767. N.V. Tkachenko, L. Rantala, A.Y. Tauber, J. Helaja, P.H. P.H. Hynninen, H. Lemmetyinen, J. Arn. Chern. Am. Chem. Soc. 1999, 1999, 121, 121, 9378. Kilpel~iinen, P.H. Lemmetyinen, I. Kilpeliiinen, lJ. Helaja, A.Y. Tauber, Y. Abel, N.V. Tkachenko, H. Lemmetyinen, Hynninen,1. Hynninen, J. Chern. Chem. Soc., Perkin Trans. 1 1999,2403. 1999, 2403. R.N. Warrener, A.C. Schultz, M.R. M.R. Johnston, M.J. M.J. Gunter, Gunter, 1. J. Org. Org. Chern. Chem. 1999,64,4218. 1999, 64, 4218. M.G.H. Vicente, K.M. K.M. Smith, Smith, Curro Curr. Org. Org. Chern. Chem. 2000,4, 2000, 4, 139. 139. J. Porphyrins Phthalocyanines Phthalocyanines E.A. Makarova, G.V. Korolyova, O.L. Tok, E.A. E.A. Lukyanets, Lukyanets,1. 2000,4,525. 2000, 4, 525. A.C. Tome, Tom6, P.S.S. P.S.S. Lacerda, A.M.G. Silva, M.G.P.M.S. Neves, J.A.S. Cavaleiro, 1. J. Phthalocyanines 2000, 4, 532. Porphyrins Phthalocyanines M.G.H. Vicente and L. Jaquinod in The Porphyrin Handbook; Kadish, K. M., Smith, K.M., Guilard, R., Ed.; Ed.; Academic Press: Press: San Diego, 2000; Vol. 1, I, p 149-238. F. Odobel, F. Suzenet, E. Blart, J.-P. J.-P. Quintard, Org. Org. Lett. 2000, 2000, 2, 131. 131. Photochern. J.L. Bahr, D. Kuciauskas, P.A. P.A. Liddell, A.L. Moore, T.A. T.A. Moore, D. Gust, Photochem. Photobiol. 2000, 72, 598. Photobiol. A.M.G. Silva, A.C. Tome, Tom6, M.G.P.M.S. Neves, lA.S. J.A.S. Cavaleiro, Tetrahedron Lett. 2000, 41,3065. 41, 3065. A.M.G. Silva, M.A.F. Faustino, A.C. Tome, Tom6, M.G.P.M.S. Neves, A.M.S. Silva, JAS. J.A.S. Cavaleiro, J. Chern. Chem. Soc., Perkin Trans. 1 2001, 2752. Cavaleiro,1. A. Efimov, N.V. Tkatchenko, P. Vainiotalo, H. Lemmetyinen, 1. J. Porphyrins Phthalocyanines Phthalocyanines 2001, 5, 835. M.R. Johnston, Molecules 2001, 2001, 6,406. 6, 406. B.O. Patrick, D. Dolphin, Chern. Z. Xiao, B.O. Chem. Cornrnun. Commun. 2002,1816. 2002, 1816. A. Desjardins, lJ. Flemming, E.D. E.D. Sternberg, D. Dolphin, Chern. Chem. Cornrnun. Commun. 2002,2622. 2002, 2622. A.M.G. Silva, A.C. Tome, Tom6, M.G.P.M.S. Neves, A.M.S. Silva, JAS. J.A.S. Cavaleiro, J. Org. Org. Chern. Chem. 2002, 67, 726. A.M.G. Silva, A.C. Tome, Tom6, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Synlett 2002,1155. 2002, 1155. M.R. Johnston, MJ. M.J. Gunter, R.N. Warrener, Tetrahedron 2002, 58, 3445. A.M.G. Silva, A.C. Tome, Tom6, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, D. Perrone, Lett. 2002,43,603. A. Dondoni, Tetrahedron Lea. 2002, 43, 603. J. Flemming, D. Dolphin, Tetrahedron Lett. 2002,43,7281. 2002, 43,7281. J.A.S. Cavaleiro, M.G.P.M.S. Neves, A.C. Tome, Tom6, Arkivoc 2003, xiv, 107. 107. N.V. Tkachenko, H. Lemmetyinen, lJ. Sonoda, K. Ohkubo, T. Sato, H. Imahori, S. Fukuzumi,1. Fukuzumi, J. Phys. Chern. Chem. A 2003, 107, 8834. I.M. Blake, M.J. Y. Kashiwagi, K. Ohkubo, J.A. McDonald, I.M. MJ. Crossley, Y. Araki, O. Ito, H. Org. Lett. 2003,5,2719. 2003, 5, 2719. Imahori, S. Fukuzumi, Org. B.C. Robinson, Tetrahedron 2003,59,499. A.N. Kozyrev, lL. J.L. Alderfer, B.C. 2003, 59, 499. A.P.J. C.R. Neri, F.S. Vinhado, O.A. Serra, P.R. A.PJ. Maestrin, A.O. Ribeiro, A.C. Tedesco, C.R. Martins, Y. Iamamoto, A.M.G. Silva, M.G.P.M.S. Neves, A.C. Tome, Tom6, J.A.S. Cavaleiro, 1. J. Braz. Chern. Chem. Soc. 2004, 15,923. 15, 923. Y.V. Morozova, Z.A. Starikova, B.1. B.I. Maksimov, D.V. Yashunskii, G.V. Ponomarev, Russ. Chern. Chem. Bull., Int. Ed. 2004, 53, 2192. IF.B. J.F.B. Barata, A.M.G. Silva, MAF. M.A.F. Faustino, M.G.P.M.S. Neves, A.C. Tome, Tom6, A.M.S. J.A.S. Cavaleiro, Synlett 2004, 1291. 1291. Silva, JAS. E.D. Sternberg, D. Dolphin, USA Pat. 6,825,343 J.K. MacAlpine, E.D. 6,825,343 (2004) [http ://www.freepatentson Iine.corn/6825343 .html] [http://www.freepatentsonlinc.com/6825343.html] H. Hata, Hata, H. Shinokubo, A. Osuka, Angew. Chern. Chem. Int. Ed. 2005, 44, 932. Tom6, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, 1. J. Org. Org. A.M.G. Silva, A.C. Tome, Chern. Chem. 2005, 70, 2306. D.T. Gryko, M. Gal~zowski, 7, 1749. Gat~zowski, Org. Org. Lett. 2005, 7, 1749. Tom6, M.G.P.M.S. Neves, J.A.S. A.M.G. Silva, A.C. Tome, lA.S. Cavaleiro, D. Perrone, A. Dondoni, Synlett 2005,857. 2005, 857. X. Liu, Y. Feng, X. Chen, F. Li, X. Li, Synlett 2005, 1030. 2005,1030.
Porphyrins in Diels-Alder and 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition reactions
05S3632 05TLI555 05TL1555 05TL2189 05TL4723 05TL5487 06BCSJ1338 06BCSJ 1338 06H885 06JOC5942 06JOC8352
06OL 1169 060L1169 06SC2135 06SC2655 06TL313I 06TL3131 06TL8437 07MIl 07MI1
69
1. L. Xingang, F. Yaqing, H. Xiaofen, 1. L. Xianggao, Synthesis 2005, 3632. X. Li, J. Zhuang, Y. Li, H. Liu, S. Wang, D. Zhu, Zhu, Tetrahedron Lett. 2005,46, 2005, 46, 1555. S. Zhao, M.G.P.M.S. Neves, A.C. Tome, Tom6, A.M.S. Silva, J.A.S. Cavaleiro, M.R.M. AJ. Ferrer Correia, Tetrahedron Lett. 2005, 46, 2189. Domingues, A.J. Tome, M.G.P.M.S. Neves, J.A.S. Cavaleiro, C.O. A.M.G. Silva, A.C. Tom6, C.O. Kappe, Tetrahedron Lett. 2005, 46, 4723. Tom6, A.M.S. Silva, lA.S. J.A.S. Cavaleiro, Tetrahedron Lett. S. Zhao, M.G.P.M.S. Neves, A.C. Tome, 2005,46,5487. 2005, 46, 5487. H. Tsuji, M. Sasaki, Y. Shibano, M. Toganoh, T. Kataoka, Y. Araki, K. Tamao, O. Ito Bull. Chern. Chem. Soc. lpn. Jpn. 2006, 79, 1338. 1338. S. Ostrowski, P. Wyr~bek, Wyrctbek, A. Mikus, Heterocycles 2006, 68, 885. Gryko, JJ. Org. Chern. Chem. 2006,71,5942. 2006, 71, 5942. M. Gat~zowski, Galctzowski, D.T. D.T. Gryko, P.S.S. Lacerda, A.C. Tome, Tom6, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. A.M.G. Silva, P.S.S. Cavaleiro, E.A. Makarova, E.A. E.A. Lukyanets, Lukyanets,l. J. Org. Org. Chern. Chem. 2006, 71,8352. 71, 8352. H. Hata, Y. Kamimura, H. Shinokubo, A. Osuka, Org. Lett. 2006, 8, 1169. 1169. M.E. Milanesio, E.N. E.N. Durantini, Synth. Cornrnun. Commun. 2006, 36, 2135. H.1. Chen, Synth. Cornrnun. X.G. Liu, Y.Q. Y.Q. Feng, CJ. C.J. Tan, Tan, H.L. Commun. 2006, 36, 2655. J.P.C. Tome, Tom6, D.-G. Cho, J.1. J.L. Sessler, M.G.P.M.S. Neves, A.C. Tome, Tom6, A.M.S. Silva, JAS. J.A.S. Cavaleiro, Tetrahedron Lett. 2006, 47, 3131. Wyrqbek, Tetrahedron Lett. 2006,47,8437. 2006, 47, 8437. S. Ostrowski, P. Wyrctbek, G.J. Oses, Os6s, A.M.G. Silva, A.R.N. Santos, A.C. Tome, Tom6, M.G.P.M.S. Neves, J. A.S. Cavaleiro, GJ. J.1. J.I. Garcia, unpublished unpublished results.
70
Chapter 3
Three-membered ring systems
Stephen C. Bergmeier and Damon D. Reed Athens, OH, Department of of Chemistry & Biochemistry, Ohio Ohio University, University, Athens, OH, USA USA [email protected] bergmeis @ohio.edu and [email protected] dr 159303 @ohio.edu
3.1
INTRODUCTION INTRODUCTION
This review covers the chemical literature on epoxides and aziridines for the year 2006. As in previous years, this review is not comprehensive but rather covers a selection of synthetically useful and interesting reactions. Three-membered ring systems, epoxides and aziridines in particular, are excellent synthetic intermediates. This is largely due to their ability to be converted into other functional groups such as diols, diamines, and amino alcohols to name but a few. While the synthesis of aziridines and epoxides can be quite challenging, the rewards for a selective and high yielding synthesis can be substantial. The chapter has been divided into two sections, one covering epoxides and the other covering aziridines. Each of these sections has been further divided into two additional sections, one on the synthesis of the heterocycle and one on the reactions of the heterocycle. There is some overlap between methods for the synthesis of epoxides and aziridines and any overlap has been noted in the text.
3.2 3.2.1
EPOXIDES Preparation of Epoxides
Epoxides are possibly the most studied of the three-membered heterocycles. While a host methods for the synthesis of epoxides have been developed, work continues, especially in the development of more chemo-, regio-, and stereoselective methods. The development of new metal-based epoxidation catalysts continues to garner significant levels of activity. The use of the Mn-based catalyst, 1, with a water-soluble ligand provides excellent yields of the <06MI139>. A Mn-salen complex was modified by the addition of corresponding epoxides <06MIl39>. phosphonium groups at either end to render it water-soluble. The use of 5 mol% of this catalyst with NalO NaJ044 as the oxidant provided a quantitative yield of cyclohexene oxide from cyclohexene.
71
Three-membered Three-membered ring systems
o O
CI- +
NalO4, 11 (5 (5 mol%). mol%)=_ 0 [ ~ O0 Na104, 100% 100%
_N/~NN~
+ CI-
PhSP~o/~Mr~o~PPh3
A number of additional metal-catalyzed epoxidations have been reported in the past year. Platinum is a rarely used catalyst in oxidation reactions. The use of chiral Pt-catalyst 2 in the epoxidation of terminal alkenes provides the epoxide products in moderate yield and <06JA14006>. The chiral hydroxamide 3 is used with a Mo catalyst to enantiomeric excess <06JAI4006>. provide the epoxide product in excellent yields and moderate enantioselectivity <06AG(I)5849>. A bis-titanium catalyst, 4, has also been used to epoxidize the usual set of <06AG(I)5849>. alkenes with HP2 H202 as the oxidant <06AG(I)3478>. <06AG(I)3478>. Substrate
R~ R~
Conditions
Yield, "Ioee %ee
Product H H
2 2 (2 (2 mol%), mol%),H H202 20 2
O
R~, ~ Rx?
R R ==C C4H 9, 48%, 48%, 83% 83% ee ee 4Hg, R R =CH CH2Ph, 75%,66% 66% ee ee 2 Ph, 75%,
,,,_O ",9
CO [ ~ ~
30% H20 2 , 4 (5 mol%) 30%H202,4(5mol%)
OC ~ :
H H
Ph~ Ph'~
O
Ph>
79%, 98% ee 79%,98%ee 47%,82%ee 47%, 82% ee
,,,0_ ",9
CO Ph~ Ph~
[Mo0 [MoO2(acac)2] (2 mol%) mol%) 2 (acachl (2 3, 3, cumene cumenehydroperoxide hydroperoxide
r J 22
K ph/3~,J
95%, 85% ee 95%,85%ee
o
Ph
-
m
SO/LptP,' Cc6F5 i CF3SO Ph Ph
82%, 87% ee 82%,87%ee
H H
O~'~'C(4-t-Bu-C6H4)3 0~C(4-t-BU-C6H4b
Ph, Ph l + '" Ph P': Ph "'"'r"P~ .OH / CF P .OH Ph ph/
OC
3
3
,,N.oH
H, " ' ~ ,H
H, Q , H
aN'OH H N.OH "'WO
Q:l\:=P /N--~
3 0~C(4-t-BU-C6H4b O/~'~'/"c(4"t'Bu'c6H4)3
3
-
Ph ~
Ph
-- - 22
4
The use of supported catalysts to carry out epoxidation reactions has seen considerable activity in the past year. A primary rationale for the use of supported catalysts is the ease in the reuse of the catalyst. The solid supports used range from silica gel to polystyrene. Quinine and other Cinchona alkaloids were linked to a soluble PEG polymer to generate dimeric polymers such as 5 <06TA330>. Reaction of chalcone with 5 using t-BuOOH as the oxidant provides the product epoxide in good yield and with good enantioselectivity. The PEG-linked ligand was reused three times with only minimal degradation in the enantiomeric excess of the product.
72
S.C. Bergmeier and D.D. Reed S.c.
o0
Ph~Ph Ph Ph OMe OMe
t-BuOOH, t-BuOOH, 5, 5, KOH, KOH, 90%, 90%, 86% 86% ee ee _
~
~ ~
I "":
N....,;;;
'OH
H
If 0
Ph~Ph Ph Ph
K
_ . ~ C l -c, -
CIcl-
£~-) ,,+" _N-{ PEG
~ I
0 00
H
OMe 9Me
c~'\~ ) + I
2000 )-N,
IfHO
5
0
I
-:?'
:::,...N
Another method for generating an epoxidation catalyst on a solid support is to simply absorb or non-covalently attach the catalyst to the solid support <06MI493>, <06MI493>. Epoxidation of olefin 6 with mCPBA and catalyst 8 provides 7 in quantitative yields and with 89% ee. The immobilization of 8 on silica gel improves the enantioselectivity of the reaction providing 7 with 95% ee. Recycling experiments with silica-8 show a decrease in both yield and the enantiomeric excess for each cycle (45% ee after 4 cycles). This is attributed to a leaching of the catalyst from the silica gel. Two other solid supports, a Mg-Al-Cl-LDH Mg-A1-C1-LDH resin (LDH) and a quaternary ammonium resin (Q-resin) were also examined. It was expected that ionic attraction between 8 and the LDH or Q-resin would allow the catalyst to remain immobilized through multiple cycles better than with silica gel. Both of these resins showed improved catalytic properties upon reuse of the catalyst (92-95% ee after 4 cycles).
~O~
NC~ 6
NC
6
8, mCPBA, mCPBA, 100%, 100%, 89% ee ~ S, silicao8, mCPBA, mCPBA, 100%, 100%, 95% ee silica-S, LDHoS, LDH.8, mCPBA, mCPBA, 100%, 100%, 93% ee Q-resinoS, mCPBA, Q-resin.8, mCPBA, 100%, 100%, 97% ee
/=N\
.-., / #.~-...y~u....~ ~O~
NC~ 7
NC
"'-
7
N=~ SO 3 -
\t-Bu acac t-Bu/ 8
Vinyl epoxides epoxides are highly useful synthetic intermediates. The epoxidation epoxidation of of dienes using of dienes with sugaroccurs at the cis-olefin. cis-olefin, Epoxidations Epoxidations of Mn-salen type catalysts typically occurs of a diene. diene, A dioxiranes have previously been reported reported to react at the trans-olefin trans-olefin of derived dioxiranes new oxazolidinone-sugar oxazolidinone-sugar dioxirane, dioxirane, 9, has been shown to epoxidize epoxidize the cis-olefin cis-olefin of of a diene <06AG(I)4475>. A A variety of of substitution on the diene is tolerated in the epoxidation, epoxidation, <06AG(I)4475>. of these substitutions substitutions provided provided including aryl, alkyl and even an additional olefin. olefin, All of including moderate yields of of the mono-epoxide mono-epoxide with good enantioselectivity.
73
Three-membered ring systems
[' ~ ~ R ~R
O
a" ~'~'~" R ~R
0-4
1,
oxone, 9 (10-30 mol%), K K 22Ca CO 3 3 = axone, •
R = Ph, 66%, R = 85% ee R = nC nC5H11, SH 11 , 80%, 89%ee R = ca CO2Et, 2 Et, 64%, 94% ee CH=CHCO2Et R = CH=CHCa 2 Et (trans), 74%, 94% ee
0""
:
O
An exploration of structural modifications on the activity of prolinol catalysts has been <06T12264>. More electron-rich aromatic tings published <06Tl2264>. rings on the prolinol scaffold improve the activity in the epoxidation of o:,~-enones. t~,l]-enones. The reaction of 10 with an enone and t-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. Iminoiodinanes are not normally used as epoxidation reagents. An organocatalytic route to epoxides using an iminoiodinane as the oxidant has been reported <06Tl1413>. <06T11413>. The reaction of 11 and NsNIPh with o:,~-unsaturated t~,~-unsaturated aldehydes provides the target epoxides in excellent yield and with excellent enantioselectivity. A number of other oxidants had been examined with iodosobenzene being the optimal oxidant. However the substrate scope of this oxidant was not ideal. NsNIPh was found to slowly generate iodosobenzene under the reaction conditions and provide wide substrate scope. 0 RI.J~.~
Conditions
R2
Conditions
Substitution Substitution
% Yield,%ee Yield, % ee
93%, 89% ee 93%,89"1oee 55%, 83% ee 55"1o,83"1oee 80%, 71% ee 80%,71%
o HCI0 (20 mol"lo) NsNIPh, 11 11oHCIO4 mol%) R 11 = H, R22 = CH 33 NsNIPh, 4 R 1 = H, R2= R2 = Ph R1 n-C3H R 11 = H, R22 = n-C 3 H 77
=
~ H~ H3C"
R2
2 = Ph R2= R 11 = Ph, R R 11 = CH 33,, R22 = Ph 2 = CH R2= CH2CH2Ph R 11 = Ph, R 2CH 2Ph
Conditions Conditions t-BuOOH, hexane, 10
0 RI.JL~
~
88"1o,93"1oee 88%, 93% ee 92%, 92% ee 92"1o,92"1oee 72%, 88% ee 72"1o,88"1oee
=
CH 3
O OCH 3 ~~
H3C'N~B
~CH3
" ] / "CH 3 OCH 3
n
H 11
10
Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides, epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides <06JA2105>. Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields, yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example - Ph) in 97% ee while isobutyraldehyde provides 13 (R = = i-Pr) benzaldehyde provides 13 (R = with only 10% ee, ee. These epoxy amides could be converted to a number of epoxide-opened
74
S.c. S.C. Bergmeier and D.D. Reed
products using fairly standard chemistry. In a particularly interesting transformation, amide 14 was converted to ketone 15 in excellent yield by treatment with an organolithium reagent.
'~'Meo MeO
~
~ ~ +\;J NEt? NEt2
OMe z " ~ "z~OMe 12 12
O ....~ C O N E t 2
CI
O
ACHO RCHO KOH KOH R == Ph, Ph, 93%, 93%, 97% 97% ee ee A A i-Pr, 79%,10% R ==/-Pr, 79%, 10% ee
R,,'/---~CON Et2 13
Ali, -78°C. RLi _78oc,. A R = Ph, Ph, 88% R = Me, 81% A=Me,81%
14
~ CI
O Z_~
o, ~
O
R 15
A very interesting organocatalyzed one-pot Michael addition/aldol condensationlDarzens condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess.
O
oO
~O ~........-......~-.~O
+ +
0O CI v J J . V ~ O ally I CIJv)loaIlYI
16
17
18, 18, AcONa. AcONa
O
[CIJ!OailYI 1 CIv~oallyl
o~""~ J 19 lg
oO
K2C0 3 , DMF.
57% yield yield 57% 86% ee 86%ee
~
0O
o~OailYI O yl .... V""~ 20
~
F3
F3
18
3.2.2
Reactions of Epoxides
The primary type of epoxide reaction remains the nucleophilic ring-opening reaction. Research on the development of novel catalysts or catalytic systems for epoxide opening continues to be a highly active area of study. Epoxides have been found to cleanly react with acetic anhydride to provide the diacetate under solvent-free conditions <06TL6865>. Treatment of epoxides with ammonium-12molybdophosphate and a slight excess of acetic anhydride (1.2 equivalents) provides the corresponding diacetate in excellent yields. A number of epoxides were examined and all worked quite well. It was also found that N-tosyl aziridines participate in this reaction providing the corresponding acetoxysulfonamides.
75
Three-membered Three-memberedring ring systems systems
~ O
AC20' (NH;);[o/PM01204016= ~ / ' ~ O A c 93%
~~]~
NTs Ac20' (NH4)3[PM012040]6 93%
v
"OAc
CX
OAC
~_.~OAc v
"NHTs NHTs
The conversion of epoxides to other three-membered heterocycles is often a multi-step process involving an initial ring opening followed by a ring closure. Two recent reports detail a one step conversion of an epoxide to a thiirane. Treatment of an epoxide with KSCN in PEG-400 provides the corresponding thiirane in excellent yields <06TL8471>. A related SCN and catalytic cyanuric chloride to provide the thiirane in solvent-free approach uses NH NH4SCN 4 equally good yields <06TL4775>.
~~]~
O
PEG-400. PEG-400, KSCN. KSCN,93% 93% or or NH NH4SCN, cyanuric chloride chloride (2 (2 moi%), mol%), neat 4 SCN. cyanuric 90% 90%
~-
~:S
Typical epoxide ring-opening conditions with amine nucleophiles usually involves some type of acid catalyst. Consequently the development of milder catalysts for use with either sensitive epoxides or sensitive amines is of interest. Ring-opening reaction of epoxides with m-amino acid esters can be catalyzed by Ca(OTf)2 Ca(OTf) 2 <06TLl733>. <06TL1733>. Reaction of 21 with an a-amino alanine ester provides the ring opened product 22 in moderate yields. Of note, the t-butyl ester is retained. This is a significant improvement over previously reported procedures in terms of yields. The products, 22, were prepared as hydroxyethylamine dipeptide isosteres. The use of AI(OTf) Al(OTf),3 for the catalysis of epoxide opening by amines has also been reported <06TL6557>.
O o
PhO~ PhO,v,,,Z-& + H2N~ O -
21 21
O
R
OH 0 CH3C Nca(OTf)2 ,- P h O v . ~ H . v ~ o . . R R = Et, 68% R = t-Bu, 54% 22 R =Bn, 61% _
<06TAI638>. A polymeric version of Jacobsen's Cr-salen catalyst has also been reported <06TA1638>. This polymeric catalyst worked well with a variety of amines, showed excellent enantio- and of 90-98%. Most importantly the catalyst diastereoselectivity with an enantiomeric excess of was reusable with no loss in stereoselectivity of of the products. of ~,o~-disubstituted a,a-disubstituted amino acids is a difficult task and continues to attract The synthesis of of an epoxide with azide has been attention. An efficient route that utilizes the ring-opening of of the sulfoxide substituted epoxide 23 with NaN NaN,3 provides reported <06TL9268>. Treatment of intermediate azido aldehyde 24. This aldehyde was not isolated but oxidized to the acid and a,a-disubstituted amino acid 25. The regioselectivity of of then the azide reduced to provide the ~,c~-disubstituted this reaction was impressive with only one product reported.
76
S.c. Bergmeierand S.C. Bergmeier and D.D. Reed
o
N3
s,o,to, NAN3,MeOH/H2oo_ cHo O~S(O)tOI
Co
23
1) 1) NaCI0 NaCIO22,, NaH NaH2PO 2 P044
H H202, 86% 20 2 ,86%
•
2) Pd/C, 98% 2) H H22,, Pd/C, 98%
24
~H2 COOH 25
The addition of Grignard reagents or other organometallic reagents to epoxides is a highly useful reaction for monosubstituted epoxides. However, when the epoxide is 2,3disubstituted, the selectivity of the addition is poor and overall yields are generally poor as well. A recent report on the addition of propenyl Grignard to epoxides identifies a set of conditions that improves regioselectivity <06JOC5826>. In addition, this method provides better yields than the corresponding alkynylalane. The reaction of 26 or 28 with an excess of propenyl magnesium bromide and catalytic CuI provides the ring-opened products 27 and 29 in excellent yield. The reaction, as expected, proceeds with inversion of stereochemistry. A large group, such as a TIPS, is necessary to provide good regioselectivity in the ring opening reaction. When the TIPS group in 26 was replaced with Bn, a 75:25 mixture of regioisomers was obtained.
TIPSO'~---~ TIPSO~ O 26 26 0
T, SO TIPSO~
r
Cui Cul (130 (130 mol%) mol%)
'~'"MgBr (600 mol%) mol%) MQBr (600
TIPSO~"'" TIPSO.,"~k__7 ..... O o
OH OH 27,63% 27, 63%
T, so TIPSO~ OH OH
28
29,70% 29, 70%
An epoxide ring opening followed by a ring closing has been found to form the important 3-hydroxypyrrolidine ring system <06CC3226>. Treatment of amido epoxide 30 with dimethylsulfoxonium methylide initially opens the epoxide ring. The amide anion then closes on the carbon bearing the sulfoxonium group to provide the 3-hydroxypyrrolidine ring 31. Spiro- and bicyclic hydroxypyrrolidines were also prepared from the corresponding cyclic amido epoxides. NHTs
NHTs
~ O ~ 30
Me3S(O)l,nBuLi nBuLi = Me3S(O)I, 86% 86%
•
~OH T s ~ / -....~
z
31 OH
A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate <060L2771>. <06OL2771>. The reaction of MgI, MgI 2 with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed.
77
Three-membered Three-memberedring ring systems systems
CO2Me
ill
o O
MgO\/OMe ! j
Mgl2
n
O ~ A r = MeO MeO I
Ar~ Ar'~'~ .
°
Ii,,~
l 32
Ph, 78%, 78%, 4:1 4:1 Z:E Ar = Ph, Ar = = (4-0Me)C (4-OMe)C6H 74%, 5:1 5:1 Z:E 6 H4, 4 , 74%, Ar = 2-CI-C E 2-CI-C6H 76%, 10:1 Z: Z:E 6H44,, 76%,
Ar
OH
33
The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true MoritaBaylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment Me3P provides a good yield of the epoxide-opened of enone 34 with Me3P epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. ~ 1 ~ OH ~OH
O o
~ 34 34
0
35,67% 35, 67%
Me3P, Me3P, (-BuOH t-BuOH (0.025 (0.025 M) •
oO
O
~ 36
37, 60% 37,60%
Epoxides will also participate in radical reactions and this usually results in ring opening of the epoxide. The addition of a radical derived from xanthate 38 to butadiene monoepoxide EIZ mixture of olefins <06AG(I)6520>. provides the addition product 39 in good yields as an E/Z <06AG(I)6520>. This reaction presumably proceeds through the addition of the xanthate-derived radical to the olefin, which then opens the epoxide. {\
O
{\ o
O
Q~ O
s
38
OEt OEt
~
o
Et3B, air 82%, EIZ75:25 E/Z 75:25 82%,
=
~ 39
OH
Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp,TiCI Cp2TiC1 generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2:1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a p-hydrogen [3-hydrogen elimination.
78
S. C. Bergmeier and D.D. Reed S.C.
O
OH Cp
40
OH OH
OH
TiC' --
o.y ¢CoyH
+
O
42,22% 42, 22% 0 O
41, 66%, 2:1 mixture 41,66%,2:1
~-Lactones [3-Lactones are highly useful intermediates in organic synthesis and are components of a variety of biologically active molecules. One of the primary routes to ~-lactones is the catalytic carbonylation of epoxides. Most carbonylation reactions require fairly high CO pressure (200-900 psi) in order to provide reasonable yields of product. These types of conditions make this reaction not particularly viable in the typical organic laboratory. A Crsalen catalyst has been developed that allows the carbonylation of epoxides to be carried out at only 1 atm. of CO pressure <060L3709>. <06OL3709>. Catalytic carbonylation of epoxides were performed with only 1 mol % of 43 in 1-2 hours at 100 psi of CO. More impressively, the carbonylation could also be carried out at 1 atm of CO (a balloon) and slightly longer reaction times with 2 mol% of 43. This method was compatible with a number of functional groups including esters, ethers, halides and olefins.
THF O
CO (1 (1 atm). atm)_ 43 (2 mol%) mol%)DME DME
;10 -L_J . O
(3--//-
R/ 44 R 44
co co,,-
_. t-Bu
= Me, 96% R= R = CH20SiMe2t-Bu, CH2OSiMe2t-Bu, 96% R = (CH (CH2)2CH=CH 2,, 95% 2hCH=CH 2
O"C+~o 43
I
t-Bu
THF
Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare ~;y-epoxyhydroxylamines, [3,y-epoxyhydroxylamines, 46, and oxazetidine, 47 <060L3923>. <06OL3923>. Upon deprotonation deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the ~,7-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional ~,y-epoxyhydroxylamine ]3,~/nitrones were examined as well and all provided similar yields of the ~,y epoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines 5-endo-tet cyclization were formed in this cyclization. from the 5-endo-tet
<[>-Ph Ph
sBuLi, TMEDA_ sBuLi. TMEDA. THF,-98~ THF, -98 DC -
Ph 1 + [00 Ph (.>L-Li
J
IJ Ph) ph / 45 45
Ph H O ~ ~ -J:'h h , "Ph NaOH = HO~-J ---,N"-,a.,,O~H-,---..... 60 DC 1 I ~ O-N 85% O-N 't-Bu "t-Bu 47
ohO-P -"~Php h
t-Bu " N ' O t-BU'N'O
~Ph
63%" -63-%-t-Bu/N'OH t-Bu f "OH
46 46
79
Three-membered Three-membered ring systems
The aza-[2,3] Wittig rearrangement of aziridines is an excellent method for the synthesis of substituted piperidines. The analogous reaction of an epoxide has recently been examined <06TL728 I>. Reaction of divinyl epoxide 48 with t-butyl diazo acetate provides the ylide <06TL7281>. intermediate 49, which then undergoes the [2,3] Wittig rearrangement to 50, Several catalysts were examined as catalysts for the formation of 49. It is noteworthy that the copper catalyst performed much better than the more widely used rhodium catalysts.
t-BU02C~N2 t'Bu02C~ N2,.
0
CU(hfacac)2 Cu(hfacac)2 72%
.... ~ 48
I,t-BU02C~ ooo+0o lj
l
-
]
,. ? ' ~
oo,ou
~~",,-;:? .... 49 49
50 50
The acid catalyzed rearrangement of an epoxide to an aldehyde or ketone is a useful and widely used reaction. Two useful examples of this rearrangement are reported below. An interesting conversion of a vinyl epoxide to a dihydropyridine has been reported using this rearrangement methodology <060L3473>. <06OL3473>. Treatment of the ester substituted vinyl epoxide 51 with Sc(OTf)3 catalyzes a ring opening of the epoxide to form an intermediate enol. This enol adds to the imine which subsequently cyclizes to form the dihydropyiridine 53. This reaction is limited by the need for a non-enolizable imine.
oo
I~
0o
E t O ~ EtO~
+
+
N
~
)t H ph.~,.
CH 3 CH3
Ph
51
Sc(OTf)a Sc(OTf)3(15 (15 mol%). mol%) 5A MS " 5AMS 51% 51 '/o
H3C~"~-~
,,,..~~.J
~ ~ J " Ph
H 52 52
C02Et 53
An additional example of an oxonium ion generated via the acid catalyzed rearrangement has been used to prepare a dihydropyran <06TL6l49>. <06TL6149>. The oxonium ion 54 generated by the reaction of an epoxide with ZrCl ZrC144 can be trapped by a nucleophile such as butynol to prepare dihydropyran 55. A variety of mono- and disubstituted epoxides have been used in this reaction.
0
C?
ZrCI4
+ [ ~ 5 4 O'zrCI3
CI
+ +
~U CJ
o '0'
=
67%-" 67%
cP 55
~ 0
/
80
S.c. D.D. Reed S.C. Bergmeier and D.D.
3.3
AZIRIDINES
3.3.1
Preparation of Aziridines
Several reviews on the synthesis of aziridines have been published in the previous year. These publications include: a review on the silver catalyzed addition of nitrenes (among other intermediates such as carbene) across a double bond <06EJOC4313>; a review on sulfur ylide addition to imines to form aziridines <06SLl81>; <06SL181>; a review on nitrogen addition across ~,[~-unsaturated esters double bonds <06ACR194>; a general review on functionalization of a,~-unsaturated with some discussion of aziridination <06TAI465> <06TA1465> The addition of a nitrogen atom across a carbon-carbon double bond is a powerful method for the synthesis of aziridines in that two bonds are formed in a single step. The large amount of previous knowledge in the stereospecific synthesis of carbon-carbon double bonds also lends great utility to this general route of aziridine synthesis. The reactions of a nitrene, metal nitrene or nitrene equivalent with an olefin continues to attract attention. No doubt due to the potential payoff in terms of a generally universal aziridination method. The use of Rh,(NHCOCF')4 has been shown to be exceptionally useful in the catalysis of aziridination Rh2(NHCOCF3)" reactions using trichloroethoxysulfonamide (TcesNH,) (TcesNH2) as the nitrogen source <06Tl1331>. The Tces group is readily removed from the final compound. In addition, this aziridination process works well on both styrene as well as aliphatic olefins. This reaction is rare in that similar aziridination methods only work well for styryl olefins. While nitrogen sources such as chloramine-T and PhI=NTs have been used for TsNC12 has not been explored until now. The reaction of TsNCl, TsNC12 with aziridination reactions, TsNCI, Pd(OAc),2 and ~CO, Pd(OAc) K~CO3 provides the expected N-tosyl aziridines in good yields <06TL7225>. This reaction presumably proceeds through an initial amidohalogenation reaction catalyzed by palladium. The chloroamide is then converted to the aziridine via an intramolecular substitution reaction. Gold-based catalysis has attracted considerable attention in recent years. A gold-catalyzed aziridination reaction has recently been reported <06JOC5876>. A series of gold catalysts were examined for their ability to catalyze the aziridination of styrene with p(NsNH2). Styrene and phenyl-substituted styrenes provided the Nnitrophenylsulfonamide (NsNH,). nosyl aziridines in good to excellent yields. Cinnamate however provided the aziridine product in only 25% yield. The use of other sulfonamides (e.g. tosyl, trichloroethyl) gave much lower yields of the aziridine product. Diphenylphosphorylazide (DPPA) has also been shown to be an excellent nitrene source in aziridination reactions <06JOC6655>. The reaction of styrene and substituted styrenes with DPPA and tetraphenylporphyrin cobalt (CoTPP) provided the N-diphenylphosphinyl aziridines in moderate yields. The use of metal-catalyzed aziridination methods with chiral ligands has also been reported. The copper-based system paired with ligand 56 provides the expected cinnamyl aziridine in good yield and excellent ee <06MI4568>. It is interesting to note that the t-butyl ester is obtained with 99% ee while the smaller methyl ester is obtained in only 88% ee. The binaphthyl ruthenium catalyst 57 has been found to aziridinate a number of olefins with moderate enantioselectivity <06TLl571>. <06TL1571>. Both p-nitrophenyl (Ns) and trimethylsilyloxy (SES) sulfonamides work well with this catalytic system. As is usually seen, the aziridination of aliphatic olefins proceeds in only 32% yield and 56% ee.
81
Three-membered Three-membered ring systems
a2
a2
conditions conditions
R1 N ~ R 3
RI-~../R3
R4
Yield
Conditions
2 = H, R3 Rh2(NHCOCF3) mol%), Phl(OAcb Phl(OAc)2 R1 1= = Ph, R R2= 3= = Me, R4 4= = Tees, Tces, 85% 85% Rh 2(NHCOCF 3)44 (1 mol%), CI3CCH2OSO2NH 2, MgO MgO 1= = Me, R2 2= = Me, R3 R3 = = (CH (CH2)2CH(Me)(CH2)2OH, 70% CI3CCH20S02NH2, R1 2bCH(Me)(CH 2bOH, 70% Pd(OAc)2 (2 mol%), K2CO 3, TsNCl 2
R 1 = Ph, R 2, R 3 = H, R 4 = Ts, 70%
[Au(tBu3Tpy)]OTf [Au(tBu3Tpy)]OTf (3 mol%), mol%), NsNH NsNH 2 2
1= = Ph, R2 2,, R3 R3 = = H, R4 R4 = 88% R1 =Ns, 88% 1 4 = Ns, 25% = Ph, R2 2= = H, R3 R3 = = C0 CO2Me, 25% R1 = 2Me, R4 =
CoTPP (10 mol%), mol%), (PhO)2P(O)N3 (PhO)2P(O)N 3 CoTPP
R 1 = Ph, R 2, R 3 = H, R 4 = P(O)(OPh)2, 50%
[Cu(MeCN)4]CI0 [Cu(MeCN)4]CIO 4 4,, 56, PhlNTs PhlNTs
1= = Ph, R R2 2= = H, R3 R3 = = C0 CO2tBu, R4 4= = Ts, 99%, 99%, 99% 99% ee (2S,3R) R1 2tBu, R 4 = Ts, 97%, R1 = = Ph, R2 R2 = = H, R3 R3 = = C0 CO2Me, 97%, 88% 88% ee (2S,3R) R1 2Me, R4 =
NsN NsN 3 3,, 57 (0.1 mol%) mol%) NsN NsN 3 3,, 57 (2 mol%) mol%) SESN SESN 3 3,, 57 57 (0.1 mol%) mol%)
1= = Ph, R2 2,, R3 R3 = = H, R4 R4 = = Ns, 70%, 70%, 81% 81% ee R1 2 3 = H, R4 1= = n-C n-C6H13, 4= = Ns, 32%, 32%, 56% 56% ee R1 6 H13 , R2,, R3 = 1= = Ph, R2 2,, R3 3= = H, R4 4= = SES, SES, 26%, 26%, 91% 91% ee R1
~11111 .i.it1;-Q. .
Ar = 3,5-CI2-4-(CH3)3SiC6H 2 N\O, ~,'N = ~
CI>=(N
N>=.
V C CI I
o - ' R U - o ~
CI I - \ J C
r
A
~
56 57 Non-metal catalyzed aziridinations have also been reported. These methods are often more broadly applicable than the metal-catalyzed methods. The use of N-methylpyrrolidine-2-one chloramine-T is an effective route for the synthesis of N-tosyl hydrotribromide (MPHT) and chloramine-Tis <06MI16>. The aziridination of olefins using t-BuOI and sulfonamides appears to aziridines <06MIl6>. be a general method for aziridination <06CC3337>. The t-BuOI is prepared in situ from tBuOCl and NaI. This is a broadly applicable method in that a wide variety of sulfonamides BuOCI (tosyl, nosyl, SES) can be used with roughly equivalent yields. a2 a2
conditions conditions R3
Conditions
Yield
MPHT (10 mol%), mol%), Chloramine-T Chloramine-T MPHT
R 1 = Ph, R 2, R 3 = H, R 4 = Ts, 85%
t-BuOCI, t-BuOCI, t-BuOCI, t-BuOCI, t-BuOCI, t-BuOCl, t-BuOCI, t-BuOCI,
R1 = = Ph, R2 R2== Me, Me, R3 R3 = = H, R4 R4 = = Ts, 81 81% R1 % 2 3 4 1= n-C6H13, 2, 3 = 4 = Ts, 77% R1 = n-C H , R , R = H, R = Ts, 77% 6 13 1= = Ph, R2 2,, R3 3= = H, R44 = = o-Ns, 66% 66% R1 2, R3 1= = Ph, R2, R3 = = H, R4 4= = SES, SES, 97% 97% R1
Nal, Nal, Nal, Nal, Nal, Nal, Nal, Nal,
TsNH TsNH22 TsNH 22 TsNH o-NsNH o-NsNH 2 2 SESNH SESNH 2 2
82
S.c. D.D. Reed S.C. Bergmeier and D.D.
The ability to directly prepare N-H aziridines through the addition of nitrogen to an olefin is quite rare. A recent report provides a method for the conversion of chalcones to the corresponding N-H aziridines <06SL2504>. The use of the hydrazinium salt 58 as a nitrogen transfer agent in combination with base proved to be a synthetically useful method for the synthesis of aziridine 59. Hydrazinium salt 58 can be readily prepared as either the iodide or nitrate salt, although the iodide synthesis was more convenient. The counterion of the hydrazinium salt as well as the base used were shown to be important factors. For electronrich aryl groups the iodide salt and t-BuOK gave significantly better yields.
(0)
o
Ar--Ph
N N+ X H 2 N' 'CH H2N" 'CH3 s 58 58
_
base
,.
° Ph Ar~Ph
Ar
59
HN
Ar Ph Ph p-MeOC p-MeOC6H sH44 p-MeOC p-MeOC6H sH44
X I NO3 NOs I NOs NO3
Base Yield (%) t-BuOK 61 t-BuOK 61 NaOH 95 NaOH t-BuOK 56 t-BuOK NaOH 2 NaOH
Intramolecular aziridination reactions overcome many of the inherent limitations associated with intermolecular aziridinations. The ring strain associated with the resulting bicyclic aziridines leads to increased reactivity and instability. Sulfamate-linked bicyclic aziridines can be readily prepared using rhodium catalysis <06T11331>. <06Tl1331>. Treatment of sulfamate 60 with Rh2(oct) Rh,(oct).4 and PhIO provides sulfamate-linked fused-ring aziridine 61. The stereoselectivity was moderate in this cyclization and was explained by a chair-like transition 13 • interactions. Interestingly the seven-membered ring 62 state that minimized gauche and A ''3 could also be formed in good yield and with improved diastereoselectivity.
02 o"S" NH2 M e ~ ' ~ -. 60
02 Rh2(oct)4 (2 mol%) Phl(OAcb Phl(OAc)2, MgO MgO 84%,4:1 84%, 4:1
o"S"N Me~ H 61
02
o"S'NH2 TBSO
SiMe3
Rh2(NHCOCF3)4 Rh 2(NHCOCFs)4 (2 mol%) Phl(OAch, Phl(OAc) 2, MgO 66%,10:1 66%, 10:1
~""SN~ TBS(~
H '"~ 62
Allylic carbamates have also been cyclized to carbamate-linked fused-ring aziridines. The cyclization of homoallylic carbamates to the corresponding aziridines has not been successful <06CC4501>. until a recent report <06CC450 1>. The reaction of homoallylic carbamate 63 with a rhodium catalyst and iodosobenzene provides moderate yields of the fused-ring aziridine 64. The major byproduct of this reaction is the C-H insertion product 65. The relative amounts of the aziridine to the C-H insertion product could be modulated by the choice of rhodium catalyst. Rh,(OAc). provides a 68:14 ratio of aziridine : C-H insertion product, while The use of Rh2(OAc)4 Rh,(oct). Rh2(oct)4 provides a slightly better 71:6 ratio.
83
Three-membered ring ring systems systems Three-membered
oO
O
Q>--; 63
64 Rh Rh2(OAc)4, 2 (OAc)4, PhlO Rh2(oct)4, Rh 2 (oct)4, PhlO
o
}--NH
O~
H H
65 14 14 6
68 9 71 71
The conversion of azidoformates to fused-ring aziridines via the thermal generation of a nitrene has previously been reported. More recently, the photolytic conversion of a sugarderived azidoformate has been used to prepare fused-ring aziridines <06JOC8059>. Photolysis of azidoformate 66 at 254 nm provides aziridine 67 in excellent yield. The resulting bicyclic aziridine was reduced to provide oxazolidinone 68 in 95% yield. Oxazolidinone 68 was subsequently converted to L-daunosamine. OCH OCH33
..... ..O .,,OCH3 nm)_ hv (254 nm). 79% 79%
O'"
O/~N3
O -;;;r--o~
H H22,, Pd/C. Pd/C
O~
yN o o
66
.....
~_.O~ OCH3
95% 95% O"" .-"
67
68
The synthesis of aziridines though an aza-Darzens or Darzens-like approach is a conceptually useful method for the formation of two bonds of an aziridine ring in a single reaction step <06T3694, 06JOC5881>. There are of course a number of variations on this theme. One very useful approach is the addition of of a sulfur ylide to an imine. The addition of S-allyl derived sulfur ylides has been shown to be a good route to diastereomerically pure vinyl aziridines <06CC1833>. of the chiral N-sulfinyl imine 69 with an S-allyl <06CCI833>. The reaction of sulfur ylide provides aziridines 70 and 71 in good yield as a 25:75 mixture. The diastereomeric excess of of the major isomer (71) was >95%. t-BU,s~O t-Bu,,s~O
Me-..,r~N-. _s~O MeyN,?~o Ph
tBu 69
JI
tBuOLi THF 72% ratio 70:71, 25:75
N\ Me~/ Me~.,,~ ,,
Ph' Ph"
.... ~
,/'
70
t-Bu,,s<.O I
Me~/ N\ ,,
Ph" 71
The intramolecular intramolecular addition of of sulfur ylides to imines lmmes (e.g. 72) has proven proven to be an excellent route to fused-ring aziridines (e.g. 73) <06AG(I)7066>. <06AG(I)7066>. The addition addition of of a of the sulfur ylide 72. The The ylide sulfonamide to a vinylsulfonium salt leads to the formation of undergoes an intramolecular intramolecular addition to form the product product fused-ring aziridine 73. This then undergoes method has also been used for the synthesis of of fused-ring epoxides.
84
S. C. Bergmeier and D.D. Reed S.C.
q, %
0-
,S-t-Bu = NH ~
N Ts Ts
o% -t+ ~ S--t-Bu ~SPh2 ~"~SPh2 1\~S-t-Bu
-..V
l.... ::'N NHTs
NaH NaH
O
/ -68%..,-
Y L N_._~/-- SPh2 +'taul Ts
,N,..N" ~ \t.Bu
68%
J
Ts
72 72
73
The addition of halomethyl metal reagents provides another Darzens-like route to ICH 2Cl with MeLi generates a chloromethyllithium aziridines <06JOC9373>. Reaction of ICH:C1 reagent, which then adds to the imine 74. A subsequent intramolecular N-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene.
~~.OMe K...~.N
O
O
ICH2CI, ICH2CI, LiBr, LiBr, MeLi MeLi 97%, 97%, d.L d.r. 87:13
'<;\~OM' %--~N%OMe
~ , I /ONN tz~.
74
0 O
75
A new methodology for the synthesis of aziridines via an intramolecular cyclization <06CC3513>. reaction at nitrogen has been reported <06CC35 13>. Typical ring closing methods for the formation of aziridines rely upon a basic nitrogen displacing a leaving group on a beta-carbon as in the approaches above. The conversion of a hydroxylamine to an a-acyl O-acyl hydroxylamine renders this nitrogen relatively electrophilic. Formation of the enolate of 76 initiates a 3-exotet ring closure by reaction of the nucleophilic enolate carbon upon the electrophilic 0Oacylated nitrogen. The yields of this process are quite good. The reaction also proceeds with very good diastereoselectivity, providing 77 and 78 in a 90:10 mixture. The reaction has also been shown to proceed with a chloramine <06CC4338>. Ph,(" ph/~N..OCOtB u Ph...]..... LHMDS. / LHMDS,-20 -20 DC ~ •,,. N N 93%
] CO2tfBu 76
Z_X D
Ph,(" Ph....].....
N N
/ \
"'C0 '"CO2tBu 2 IBu
77
9 0 : 1: 010 90
L\.. C02 IBUu ~CO2tB 78
One of the most well used methods for the synthesis of aziridines involves a two (or sometimes more) step process in which an epoxide is opened by a nitrogen nucleophile. The resulting ~-amino [3-amino alcohol (e.g. 79) is then converted to an aziridine via a number of different processes. This method is generally not broadly applicable when a variety of different groups on the nitrogen of the aziridine are desired. A useful method to convert an epoxide to a number of different N-sulfonyl aziridines (e.g. 80) has been reported <06S425>. Simple addition of a sulfonamide to an epoxide provides high yields of 79 which is readily closed to form the aziridine.
85
Three-membered ring systems Three-membered
[ ~
19 equiv. equiv9RS0 RSO2NH2,. 1.2 2 NH 2 0.1 equiv equiv K K2CO • 0.1 2C0 33
O
0 1 equiv equiv BnNEt3CI BnNEt3CI 0.1 9 dioxane, 90 dioxane, 90 DC ~
",~OH
79
N "SO2R H
R 6H44,, 91% R == 4-MeC 4-MeC6H 91% R R == t-Bu, t-Bu, 83% 83%
1) 1) 55 equiv equiv Pyridine Pyridine 55 equiv equiv MsCI MsCI •CH CH2CI reflux 2 CI 22,, reflux 2) 2) 44 equiv equiv KK2CO 2 C0 33 CH3CN, 45 ~ CH 3CN, 45 DC
[ ~ N-SO2R 80
R == 4-MeC6H4, 4-MeC6H4, 82% 82% R R= = t-Bu, t-Bu, 77% 77% R
A rather interesting approach to aziridines involves a reductive ring-opening of an azetidinone followed by ring closure <060L11Ol>. <06OL 1101 >. Treatment of 81 with LiAIH. LiA1H4 leads to an intermediate amino alcohol. This is followed by the subsequent formation of the aziridine ring via displacement of the adjacent halogen to form 82.
'tf
BnO,, BnO
° 3.3.2
l
!
equiv LiAIH LiAIH44 • 5 equiv
N, N. R R
I
OBn~ ?Bn
HO~ .•' N H" N,
H
'R
R= = i-Pr, i-Pr, 57% 57% R= = Bn, Bn, 62% 62% R R= = allyl, allyl, 43%
R
82 82
81 81
Reactions of Aziridines
The reactions of aziridines (like epoxides) are largely dominated by nucleophilic ring opening reactions. In the past year two reviews that cover ring opening reactions of aziridines have been published, including a review on ring opening reaction of aziridines with carbon nucleophiles <06EJOC4979>, and a review on the reactions of N-sulfonylaziridines <06JOC8993> which includes discussion of their ring opening reactions. The reaction of aziridines with oxygen nucleophiles is a common route to vicinal amino alcohols. The use of aldehydes as oxygen nucleophiles has been reported as a route to acyloxy amines <06OL1521>. <060L152l>. N-Heterocyclic carbenes (NHC) have also been used to catalyze the ring opening of aziridines by carboxylic acid anhydrides to produce 83 in NRC has also been reported to catalyze the moderate yields <06EJOC4787>. The same NHC opening of aziridines by TMSX reagents where X -= N C1, and I <06TL4813>. N"3, Cl, [ ~
NTs
18-crown-6 50 50 DC, ~ air R ==Ph, 70% R =CH3,75% R=CH 3 , 75% 9
~]~NHTs v i,
NHC,RCHO NHC'RCHO" K C0 3 • K2CO 2 3
°
NHC, NHC, (RCO)20 (ACO) DC 80 ~ R A= =CH3, 3 , 96% R= Ph, 91% A=Ph,91%
O O/~R #
NHC
Nv N
83
/
of mono- and disaccharides that lend themselves Amino sugars are important component of well to synthesis through aziridine opening reactions. Glycal derived aziridines have been of 4-amino-2,3-unsaturated sugars found to be useful intermediates for the synthesis of <06JOC1696>. Epoxide 84 was converted to the trans-dimesylate 85 through a series of of <06JOC1696>. Treatment of of 85 with base base and an excess excess of of a glycosyl acceptor, 87, standard transformations. Treatment provides provides the glycoside 88 88 in excellent yield. The The aziridine aziridine 86 was not isolated isolated due to its
86
S.C. s.c. Bergmeier and D.D. Reed
reactive nature. A number of simply glycosyl acceptors such as MeOH and i-PrOH were examined in this reaction and provided the expected 1,4 addition products in high yield. It is quite impressive that the use of a monosaccharide such as 87 as the glycosyl acceptor also provides the product in very good yields.
u
BnO_ _ ' ~ ~ Bno
steps ,. 33 steps.
B n O ~ , , O~ Bno!o)
0'" 8,"
T
MSO"'Y NHMs 85
84
O~ ~ lO l "'0>(
+ H0)O"'O HO '"O~ -
+
t-BuOK
° ---To ~ O
___. 73%
[BOO))] BnO
0 1
MsN
86
0 0 ) 0 " ," 0>( BnO~Uy
°
U~I~
MsHN
87
--\-0
'0
88 - \
Typically, the stereospecific formation of quaternary centers is as problematic as selective nucleophilic attack at the more substituted carbon of aziridines. Interestingly, a copper <06OL5105>. Although N-tosyl mediated methodology has been reported that does both <060L5105>. aziridines show favorable results, N-nosyl aziridines gave the best results. The reaction of 89 with a variety of phenols yielded 90 in moderate yields.
° N/~CO2t-Bu ~N~C02t-Bu N H "
N Ns Ns
H
+ +
D I
R R
. .-::-
OH
CuOAc, DBU.= toluene toluene R == H, H, 64% 64% R
~CO2t_B u
R =OMe, = OMe, 59% = CHO, 71% 71% R =CHO,
89
90
Another problem with the reaction of phenols with aziridines is the selectivity between 0Oalkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B (ArO)3B selects for <06OL2627>. Most of the examples reported in this paper showed less than 5% C-alkylation <060L2627>. of the O-alkylation product. What is interesting about this report is the stereochemistry of the SN1 type product. product. While the mechanism is not known, the product is formally an SNI configuration (the SN2 product). In Generally less than 5% was the product of inversion of configuration addition to the N-tosyl, both the N-Cbz and N-Dpp aziridines gave excellent yields of aziridine-opened product.
phj~'~Ts
+
73% 73%
"£' ...-::-
Ph
OH OH
NHTs NHTs
Typically in ring-opening reactions of aziridines, the amine functional group is retained in the product molecule. An example of such a reaction where the amine group has been lost has recently been reported <06TL977>. An intramolecular Friedel-Craft reaction of aziridine 91 leads to the expected product as an intermediate. Under the rather drastic reaction conditions, the sulfonamide is lost leading to formation of the naphthalene ring.
87
Three-membered Three-membered ring systems
_-..
H H2SO (300 mol%) mol%) 2 S0 44 (300 benzene, benzene, reflux reflux • 85% 85%
H3C
~CO2Me NHTs
91
H3C
~
[~~
CO2Me NHTs
CH3
93
92
/CO2Me
94
CH3
It has been found that N-tosyl aziridines undergo oxidative addition to palladium <06JA15415>. Reaction of aziridine 9S 95 with complexes to form azapalladacyclobutanes <06JAI54l5>. Pdidba)3 Pd2(dba) 3 and l,lO-phenanthroline 1,10-phenanthroline provides the palladacycle 96 in 45% isolated yield. This compound is an air stable solid. Treatment the palladacycle 96 with catalytic CuI is believed to open the palladacycle to form a copper intermediate, which cyclizes to cyclopentyl alkylpalladium intermediate 97. Loss of CuI then provides the product palladacycle 97 as an air stable solid. Several different aziridines were examined in this reaction. Only a limited set of olefin substituted aziridines provided the azapalladacyclobutanes (e.g. 96).
<,,. A .,<-NTs ~TS "~
v
",4
95
Ts ms
Pd2(dba)3 (50 mol%) moP/o) •= ~ ,. _ /N Pd(phen) Pd /N'Pd(phen) 2 (dba)a (50 1,1 O-phenanthroline (phen) 1,10-phenanthroline (phen) ~~ 45% 96 L
( ~ ('p/ h(phen) en)
Pd"l «Pd~1 ~Nwe'u "C'u I
Ts
-"
~/~P,~J(phen) I N'Cu I Ts
I
-Cui. -Cul
"
Cui Cul (20 (20 mol%) mol%) • 72%
~ N ~
l
£t;~~Pd(Phen) va~, n ~ , --'p-en" 97 Ts Ts' 97
A novel C-3 functionalization of methylene aziridines has also been reported <06T8447>. Selective deprotonation of 98 to form 99 and the reaction 99 with an electrophile yielded 100 in good yields. In this way, a variety of alkyl groups could be selectively placed on the (S)-o~-methylbenzyl substituted methylene aziridine. These researchers also found that (S)-a-methylbenzyl aziridines, 101, when deprotonated and reacted with a variety of electrophiles gave 102 in moderate yields and with good diastereoselectivity.
88
S. C. Bergmeier and D.D. Reed Reed S.C.
~n
.l
Bn I, N N
Bn
s-BuLi, MEDA. s-BuLi, T TMEDA
::Y
Electrophile
]
Li~
gBn n iI I
N
R7 R
R %Yield Mel Me 79 PhCHO PhCHOH 74 TMSCI TMS 63 CI(CH 2)44 70 CI(CH 2)4 1 CI(CH2) C1(CH2)41
H MeyPh Me.~r / Ph N
~
1/--O0~ ' "
H M e . ~ Ph MeVPh I N
TMEDA = • s-BuLi, TMEDA Electrophile Electrophile
~
R
N
~
102
EI ectrop h'lIe Electrophile R %Yield %de Mel Me 47 80 Ph2CO Ph2COH 43 88 TMSCI TMS 80 90 -------------
In an extension of previous work, additional examples of fused-ring aziridines were prepared through the cycloamination of olefins with an aziridine nitrogen <06JOC6067>. Fused-ring aziridines 104 and 105 were obtained through the cycloamination of aziridine 103. While 104 and 104 were obtained as an -3:1 mixture, they were converted to exocyclic olefin 106 in excellent yields. These fused-ring aziridines will react with a variety of nucleophiles providing cyclic imine 107 in excellent yields. H 0 'I 0 N
~Ph
NBS NBS • "
(~H N 0O
103 103
~H
"••O
Y-N
yO
~n H N 0O
Br~..." Br.......",'
104
Br Br
PI~ Ph
KOH KOH MeOHffHF MeOH/THF •
105
Ph Phi n = = 1, 1, 98%, 9 8 % , 104:105 104:105 = 74:26 n = n = = 2,88%,104:105 2, 8 8 % , 1 0 4 : 1 0 5 = = 78:22 n
O~_
-
Nu Nu
~ ~ . N
Ph
.H3C
u 107
106 Ph n=1,99% n = 1,99% n =2, = 2, 95%
n = 1, TMSN 33,, Nu = N33,, 99% n = 1, H2 2,, Pd/C, Nu = H, 99% HBF4, 4, Nu = OMe, 99% n = 1, MeOH, HBF n = 2, TMSN 33,, Nu = N33,, 81 % 81% n = 2, H H2, 2, Pd/C, Nu = H, 82%
In a related example, a cycloamination of an olefin was carried out with an N-t-butyl aziridine to prepare morpholine derivatives <06JOC4678>. Upon an initial bromoamination reaction an aziridinium ion 110 is formed. This readily undergoes ring opening with bromide to form dibromomorpholine 111. While this is an interesting reaction, it does not appear to be general, as other groups on the nitrogen provided little to no product.
* [
N
108 108
~ NBS ~N~f1r r ~O~+ I09 109
_
~
~ N~
Br
Br
Br] \'N (_
Bf'<0 Br ""L,,,.~ 0 110 110
Brae Br
43%
Br~o 111 111
89
Three-membered ring systems Three-membered
Researchers have found that the reduction of a variety of aziridine esters yields the corresponding aziridine aldehyde which dimerizes diastereoselectively <06JA14772>. The reduction of 112 with excess DIBAL yields the dimer 113, which is in equilibrium with the monomer 114. This molecule reacts as the monomer and both reduction to 115 or reductive amination to 117 proceed in quantitative yields. In a very interesting reaction, treatment of 113 with N-benzyl tryptamine provides the pentacyclic 116 in excellent yield. H
H N N
P "'C02Et Ph ph~---&"'CO2Et
N H N H DIBAL (200 (200 mol%) mol%) •,.~/---~ -n_ C~ DIBAL ..)-~,.7~o 83% PhOH 83% Ph~ H' H~ ~N~~..OH
tJ
112 112
113 113
~ H
N ph~--~,,
',/
115
.OH
~g~:.
NaBH4 ~ 100%
~
ph~--&,,,CHO 114
y H "14 r
Ph
~
~:mll ~ N-benzyltryptamine -20 DC, toluene 94% (20:1, syn:anti))
H
N
H
N N NaCNBH3. PhP",,/NHPh ~ .... aniline Ph /NHPh aniline 100% 100% 117 117
.~.' cr Bn Bn
HH H NN ..H i
[ ": ~ ""~ H J
o
,,,Ph
Ph N H
N H H
116
The reactions of N-acyl aziridines can sometimes involve nucleophilic attack at the acyl group rather than the aziridine ring. This change in the more typical pattern of reactivity is dependent on a number of factors. An example of this type of change in reactivity has recently been reported <06TL2065>. Treatment of 118 with benzylamine provided a low yield of 119, the product of nucleophilic attack at the carbonyl. An examination of reaction Et20 or THF conditions found that the use of a Lewis acid and a coordinating solvent such as Et,o provided significantly better yields of 119.
O.~.OBn N
BnNH2
F3C~--~CO2 Et Solvent Solvent (temp.) (temp.) Lewis acid acid Yield Lewis CICH 118 CICH2CH2CI (reflux) none 25% none 25% 2CH 2 CI (reflux) THF THF (reflux) (reflux) Yb(OTf)3(20 (20 mol%) rnol%) 52% 52% Yb(OTfb Et BF Et20 (reflux) BF3,Et20 (100 mol%) tool%) 67% 67% 2 0 (reflUX) 3oEt20 (100
~
O.~NHBn N F3C~-~CO2 Et 119
In a highly unusual reaction, treatment of 120 with an organolithium reagent provides <06JOC8510>. amine substituted homoallylic alcohol 122 <06JOC85 10>. This reaction presumably proceeds via a metalation/ring opening sequence to generate intermediate 121. This then undergoes a beta-elimination to 122. A number of other examples were also reported.
90
s.c. Bergmeier and D.D. Reed S.c. Bergrneierand
O•NTs ~r O~NLiTS Li
O~NTS
RLi =
R
C ~
NLiTs
121
120
3.4
1- :X
R
HO
NHTs
= nBu, nBu, 82% R= = Ph, 69% R= = CH2SiMe3, CH2SiMe3, 92% R=
122 122
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Three-membered ring systems
060L3923 06OL3923 06OL5105 060L5105 06S425 06SL 181 06SLl81 06SL2504 06T3694 06T8447
06T11331 06TI1331 06T11413 06T12264 06TA330 06TAI465 06TA1465 06TA1638 06TA1638 06TL977 06TLl571 06TL 1571 06TLl733 06TL1733 06TL2065 06TL4775 06TL4813 06TL6149 06TL6557 06TL6865 06TL7225 06TL7281 06TL728I 06TL7755 06TL847I 06TL8471 06TL9268
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91
92
Chapter 4 Four-membered ring systems Benito Alcaide Departamento de Quimica Organica Org~knica1.I. Facultad de Quimica, Universidad Complutense de Madrid, 28040-Madrid, Spain [email protected] Pedro Almendros Instituto de Quimica Organica Orggmica General, General CSIC, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain lnstituto [email protected]
4.1
INTRODUCTION INTRODUCTION
The importance of four-membered heterocycles in many fields of Science (including Organic Chemistry, Inorganic Chemistry, Medicinal Chemistry, and Material Science) can hardly be overemphasized, and justifies a long lasting effort to work out new synthetic protocols. Condensing the vast amount of published material to less than 20 pages is an extremely demanding task. This, obviously, can only be done by strict selection and by applying a very dense style of writing. Oxygen- and nitrogen-containing heterocycles, in particular ~-lactams, [3-1actams, dominate the field in terms of the number of publications. This chapter covers selected relevant aspects in this area.
4.2
AZETIDINES, 3-AZETIDINONES, AND AZETIDINES, AZETINES, AZETINES, 3-AZETIDINONES, AND DIAZETINES DIAZETINES
2-( I-Adamantyl)-2-methyl-azetidines have been synthesized and tested for their 2-(1-Adamantyl)-2-methyl-azetidines antiviral activity against influenza, being markedly active against influenza A H2N2 virus <06BMC3341>. The biological activities of of an aqueous fraction extracted from Polygonatum of odoratum of L-2-azetidinecarboxylic acid 1, purified from the extract, on the growth of several types of algae have been tested <06MI1>. <06MII>. Electrophilic amination of of ketones and aldehydes in the presence of dibenzyl azodicarboxylate in dichloromethane, using L-2azetidinecarboxylic acid 1 as a catalyst, has been described <06TL 1117>. The structure of of 3fluoroazetidinium hydrochloride 2 has been explored both by X-ray diffraction analysis and DFT calculations, and the conformation of of this molecule was shown to be significantly C-F'" W§ interaction <06CC3190>. Aqueous phosphoric acid influenced by the through space C-F ......N (85 wt%) is an effective, environmentally benign reagent for the deprotection of of tert-butyl l-benzhydrylazetidin-3-ylcarbamate 3 <06JOC9045>. The carbamates, including tert-butyl 1-benzhydrylazetidin-3-ylcarbamate of aminonitrofluorenes such as azetidine derivative 4, structure-property relationship of C-N bond formation between the free amine synthesized by copper-mediated Ullmann-type C-N and the corresponding iodoarene, has been described <06S3425>. tert-Butyl hypoiodite (tBuOI) has been found to be a powerful reagent for the cyclization of of N-alkenylamides leading to a variety of of N-heterocycles, including 2-(iodomethyl)-l-tosylazetidine 2-(iodomethyl)-I-tosylazetidine 5, under extremely mild conditions <06OL3335>. <060L3335>.
93
Four-membered ring ring systems systems
BocHN
L--N
"H
I
1
'H
_
qY y
2 H Cl
33
Ph ,Ph
Ts
Ph Ph
4
5
N,N-Carbonyldiimidazole-mediated N,N'-Carbonyldiimidazole-mediated cyclization of amino alcohols to substituted azetidines has been developed <06JOC4147>. N-Tosyl-3-halo-3-butenylamines underwent CuI/N,N'-dimethylethylenediamine to efficient Ullmann-type coupling with the catalysis of CuIlN,N-dimethylethylenediamine afford 2-alkylideneazetidines 6, which could be readily converted into the corresponding ~ 13<06OL5365>. 6-Vinyl oxazinanones undergo catalytic, lactams by oxidation with 0O33 <060L5365>. diastereoselective, decarboxylative ring contraction to form vinyl azetidines 7 in good yield <060L3211>. <06OL3211>. N-(Alkylidene or l-arylmethylidene)-2-propenylamines 1-arylmethylidene)-2-propenylamines have been 1-arylmethylidene)-3-bromo-2regiospecifically functionalized to novel N-(alkylidene or l-arylmethylidene)-3-bromo-2fluoropropylamines, which proved to be excellent precursors for 3-fluoroazetidines 8 <06JOC7100>. The one-pot formation of 1,3-disubstituted azetidines via the reaction of amine nucleophiles with in situ prepared bis-triflates of 2-substituted-l ,3-propanediols have 2-substituted-l,3-propanediols been demonstrated <06JOC7885>. X
NHTs NHTs
J..A ~R
0
-- Jt i
R
)l
Ts, N
Tss
6 (86-99%)
R2 H
R1
R3''
"Ts
R2 F F-q
-- R;~-T' ii
0 R3
R1 R4 R1~R4 R22 R
. . / RR11
'-./
8
R44 R 7 (60-93%)
Key: i) CuI, DMEDA, dioxane, 100 DC. ~ ii) 5 mol% tool% Pd(PPh Pd(PPh3)4, CH2C12, 3)4, CH 2Cb, RT. The use of monochloroalane has been shown to be an efficient method for the reduction of 4-aryl-3,3-difluoro- as well as trans-2-aryl-3-chloro-~3-1actams to their trans-2-aryl-3-chloro-~-lactams corresponding azetidines 9 <06SL2039; 06T6882>. The resulting chloroazetidines were excellent building blocks for the synthesis of different 3-substituted azetidines through nucleophilic substitution of the chlorine by different carbon, nitrogen, sulfur and oxygen nucleophiles in good to high yields <06T6882>. Azetidine-2-carboxylic acid 10 has been obtained by treating a trichloromethyl ketone-derived Mannich adduct with aqueous NaOH in 1,2-dimethoxyethane. The reaction is considered to proceed via a gem-dichlorooxirane gem-dichlorooxirane intermediate. Intramolecular ring opening affords the azetidine ring <06AG(E)3146>. Enantio- and diastereomerically pure cis-2,3-disubstituted cis-2,3-disubstituted azetidinic amino acid derivatives have been obtained by intramolecular anionic ring-closure <06SL781>. The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine afforded the four-membered cyclized product 11, a mixed ketal of of cis-2,4-disubstituted cis-2,4-disubstituted azetidine-3-one, stereospecifically <06OL1323>. <060L1323>. The of N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol in the asymmetric application of ethylation and arylation of of arylaldehydes has been described <06SL3443>. 0II X R 2 X R 2 Ph21~ NH O~ PH,~__]e,.,~/CO2Me o~N, ' ~N ~, .Ph TMSO, R1
,R1 99 (82-97%) (82-97%)
° Ph;:):~CCI3 ~ HO2C,," )=t:h" PPh2ph Ph CCI3 I
H0 2C
II
o O (72%) 10 (72%)
2
,,"
AlH 2Cl, Et20, Et20, 34 ~DC ((X CI), 0 ~DC (X = F). ii) aq. NaOH, NaOH, DME, DME, RT. Key: i) A1H2C1, X -= C1),
"
11 11
Bz
94
B. Alcaide and P. Almendros
Pyranoid and furanoid spiro-N-mesyl azetidines, a new type of water-soluble spiro-Cnucleoside, have been prepared from easily available sugar spiroacetals <06T915>. The first results concerning thermally induced and silver-salt-catalyzed [2+2] [2+2] cycloadditions of imines to (alkoxymethylene)cyclopropanes to afford spirocyclic azetidines 12 have been published <06AG(E)5176>. A two-step reaction sequence using a one-pot a-aminoallylation reaction of spirocyclic diamines, followed by ring-closing metathesis to make a diverse collection of including azetidines, has been developed <06TL8977>. The dominant secondary fragmentation of a series of of 1,3-di- and 1,2,3-trisubstituted N-arylhexahydropyrimidines under electron impact has been described to involve loss of imines or azetidines BHrSMe2 in THF under <06ARK57>. The treatment of an oxopiperazino-~-Iactam oxopiperazino-13-1actam with BH3"SMe2 <06TL89 I I>. The reflux gave rise to the bicyclic azetidine 13 as the major product <06TL8911>. crystalline cis,cis,cis,cis-[5.5.5.4]-I-azafenestrane cis,cis,cis,cis-[5.5.5.4]-l-azafenestrane borane adduct 14 has been efficiently isolated using a Mitsunobu reaction as the key cyclization step followed by treatment with <06JAI1620>. Triplet-sensitized irradiation of 8-thia-9-azatricyclo[7.2.1.0]dodecaBhEt20 <06JA11620>. BF3"Et20 2,4,6,IO-tetraenes in acetone solution gives rise exclusively to tetracyclic suitams 2,4,6,10-tetraenes sultams bearing a bridgehead azetidine ring <06JOC2456>. The synthesis of of novell',2'-azetidine-fused novel l',2'-azetidine-fused bicyclic pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks for automated solid-phase oligonucleotide synthesis has been reported <06JOC299>. It has been shown that the reaction of azetidines with chloroformates gives highly functionalized y-chloroamines 7-chloroamines in high yields and selectivities under mild reaction conditions <060L5501>. <06OL5501>. The ring opening of activated cyclic amines, including fourmembered, foIIowed followed by an intramolecular expansion of of cyclopropanol to cyclobutanone via a carbocation intermediate has been reported. In the case of a N-tosylazetidine ester, the cyclobutanone 15 was formed by treatment of the crude Kulinkovich product with CaS04 CaSO4 <060L4335>. <06OL4335>. A formal [4+2] cycloaddition of 2-aryl-N-tosylazetidines with nitriles in the presence of Zn(OTf)2 has been described for the synthesis of substituted tetrahydropyrimidines <06TL5393>. N-Activated 2-phenylazetidines have been opened regioselectively at the benzylic carbon with various aIIylsilanes allylsilanes or propargylsilane in the presence ofBF of BF3"Et20, carbonylative polymerization 'EhO, providing amino olefins <06TL2205>. The carbonylative polymerization 3 of azetidines tetrahydrofuran azetidines catalyzed catalyzed by [Co(CH3CO)(CO)3P(O-tOI)3], [Co(CH3CO)(CO)3P(o-tol)3], and the participation participation of the tetrahydrofuran polymerization to give ester units polymer products been described described solvent in the polymerization give ester units in the polymer products has been <06AG(E) I29>. Insights into the regioselective nucleophilic ring-opening of azetidinium <06AG(E)129>. ions has been reported <06EJ03479>. <06EJO3479>. It has been shown that efficient ring expansions, selectively leading either to pyrrolidines or to azepanes through [1,2] [1,2] or [2,3] [2,3] sigmatropic <06EJO4214>. 14>. shifts, respectively, can be performed from 2-alkenylazetidinium salts <06EJ042 OR 1
[~/
+
H R~N,Bn
R2
'X=--N
'R~
R2
"R3
12 (71-97%)
..../ o H L~~",,/aH
A 13
-B,F3
-
H H'"
H '''H
cazEt
Q -N
"Ts Ts 14
/ONHTs (t NHTs
N,F ffi B
~)-J aO
15 (70%)
4 2,5-Dimethoxyphenyi. ii) (a) CITi(O-i-Pr)3, Key: i) 10 l0 mol% tool% Ag(fod), MeCN, 30°C. 30 ~ R R 4 == 2,5-Dimethoxyphenyl. C1Ti(O-i-Pr)3, EtMgBr, THF, RT; (b) CaS04, CaSO4, CH CH2C12, 2Cb, RT. The direct, stereoselective conversion of alkynes to N-sulfonylazetidin-2-imines 16 by the initial reaction of of copper(I) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] [2+2] cycloaddition of of a postulated N-sulfonylketenimine intermediate with a range of imines has been described <06AG(E)3157>. The synthesis of N-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been
95
Four-membered ring systems
achieved <06EJ02440>. <06EJO2440>. I-Benzhydryl-3,3-difluoroazetidin-2-thione 1-Benzhydryl-3,3-difluoroazetidin-2-thione has been prepared and converted into y-aminodithioesters 7-aminodithioesters <06S2327>. The [2+2] [2+2] cycloaddition of an N-acyl-2azetine to dichloroketene has been described as a new entry to azetidines fused to cyclobutanes <06TL6377>. The conversion of 4-vinyl-substituted ~-lactams into 4-vinylsubstituted l-azetines 1-azetines 18 and their subsequent reaction with dipheny1cyclopropenone diphenylcyclopropenone resulted in the formation of a highly functionalized 7-azabicyclo[4.2.1]nonene <06TL425>. The xXray structure of an azetine-containing Ni0I) Ni(n) porphyrin derivative has been elucidated <06OBC4059>. <060BC4059>. The preparation of 1,2-diazetidines 19 from 1-(1-hydroxypropan-2yl)hydrazine-l,2-dicarboxylate under very mild conditions has been accomplished AZ-l,2-diazetines <06TL6835>. The regioselective acylation reactions of f121,2-diazetines 20 as well as their rearrangements into 4H-l,3,4-oxadiazines 4H-1,3,4-oxadiazines or pyridazines have been reported <06S514; 06S2885>. It has been proposed that azetine and f13 -1 ,2-diazetine intermediates may be A3-1,2-diazetine <06OL1983>. A stereoselective synthesis of 4involved in the thermolysis of aza-enediynes <060Ll983>. hydroxyalkyl-I,2-oxazetidines hydroxyalkyl-l,2-oxazetidines 21, based on the addition of a-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, has been described <060L3923>. <06OL3923>. 4 3 R3,~,NSO2 R4 R )=fNS0 2 R
2
N,
R
R 16
4.3
1
°ifCO'R' -{fSEI CO2R2
Ny 1
17
R
2
R
~_~SEt N
R1 18
HQ R1 ArHN~NHAr R2~ 2 p ~ ....Ar HQ R1
R2
R2
ArHNTI-fNHAr
n
RV
N-N 'R
1
19
N-N\
N-N" 20
R Ph""
""Ar O-N 'R 3
O-N,,R3 21
MONOCYCLIC MONOCYCLIC 2-AZETIDINONES 2-AZETIDINONES (~-LACTAMS) ([~-LACTAMS)
[3-1actams has been reviewed The polymer-supported and combinatorial synthesis of ~-lactams <06MI109>. A review on the synthesis of new classes of heterocyclic C-glycoconjugates <06MIl09>. including C-glycosyl ~-lactams [3-1actams by asymmetric multicomponent reactions has appeared [3<06ACR451>. The asymmetric synthesis of active pharmaceutical ingredients including ~ lactams such as ezetimibe and SCH 58053 has been reviewed <06CRV2734>. An overview on recent developments in isocyanide based multicomponent reactions in applied chemistry including ~-lactam [3-1actam formation, has appeared <06CRV17>. Ketene chemistry including ketene-imine cycloadditions to form ~-lactams, ~-lactams, has been reviewed <06EJO563>. <06EJ0563>. A review on the biocatalytic preparation of ~-amino ~-amino acids including the ring opening of ~-lactams, ~-lactams, has appeared <06T5831>. A convenient and general method of synthesis of NH-~-lactams NH-p-Iactams via Grubbs' carbene-promoted isomerization of the respective N-allyl ~-lactam followed by RuC13-catalyzed RuCh-catalyzed enamide cleavage has been developed <06CEJ2874>. The [2+2] carbonylative cycloaddition of substituted imines with allyl bromide leading to heteroaryl ~ 13lactams has been reported <06Tl565> <06T1565> <06Tl2064>. <06T12064>. The reaction of enantiopure 4oxoazetidine-2-carbaldehydes with unmodified ketones catalyzed by L-proline or D-proline has been reported to give the corresponding y-amino-p-hydroxy y-amino-[3-hydroxy ketones 22 <06JOC4818>. (l'R,3S,4~)-3-[l'-(tertThe synthesis of the novel carbapenem precursor (1 'R,3S,4S)-3-[1 '-(tertbutyldimethylsilyloxy)ethyl]-4-(cyclopropy1carbonyloxy)azetidin-2-one has been described butyldimethylsilyloxy)ethyl]-4-(cyclopropylcarbonyloxy)azetidin-2-one <06EJO3755>. <06EJ03755>. Ethyl difluoro(trimethylsilyl)acetate and difluoro(trimethylsilyl)acetamides have been used as precursors of 3,3-difluoroazetidinones <06EJ04147>. <06EJO4147>. The activation of the C-CI C-C1 bond of (E)-a-chloroalkylidene-p-lactams (E)-~-chloroalkylidene-[Mactams via the Suzuki cross-coupling reaction to achieve 2-azetidinones 23 has been reported <06MI2114>. The diruthenium-catalyzed formation of p-Iactams [3-1actams via carbenoid C-H insertion of a-diazoacetamides ~-diazoacetamides has been described [3-1actams by Staudinger cycloaddition has <06MI2203>. The synthesis of novel N-sulfonyl ~-lactams
96
B. Alcaide and P. Almendros
been achieved <06MI49>. Results on chiral induction during photocyclization within achiral (z-oxoamides to ~-lactams <06OBC4533>. A model that p-Iactams have been presented <060BC4533>. zeolites of a-oxoamides explains the relative stereoselectivity in the Staudinger reaction based on a kinetic analysis of the cis/trans ratios of reaction products has been proposed <06JA6060>. The effects of solvents, additives, and pathways of ketene generation on the stereoselectivity of the Staudinger reaction have been investigated <06JOC6983>. Staudinger reaction of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions have been employed to synthesize 3-ethoxycarbonyl p-Iactams 13-1actams <06JOC8l5>. <06JOC815>. The y-heteroatom directed stereocontrolled Staudinger cycloaddition reaction of of vinylketenes and imines has been achieved <06TL5993>. The diastereoselective synthesis of trans-p-Iactams trans-~-lactams on soluble polymer support has been described <06Sl829>. <06S1829>. Functionalization of N[(silyl)methyl]-p-Iactam [(silyl)methyl]-~-lactam carbanions with carbon electrophiles to give 2-azetidinones 24 has been reported <06JOC6368>. Experimental and theoretical evaluation of the unexpected four-membered (phosphono-p-Iactams (phosphono-13-1actams 25) over six-membered ring formation during the synthesis of azaheterocyclic phosphonates has been documented <06JA6368>. O
~
R3
X 1
22
R2
O/~'--N~ E 24
23
R1 Ph~ ' ~ P ( O R 2 ) 2 O
Ph
.P(OR )2 "R' 25 (62-90%)
Key: i)Nail, i) NaH, THF,~. THF, A. p-Lactam 13-Lactam analogs of combretastatin A-4 have been synthesized and their cytotoxic L1210 leukemia <06MI544>. The design, effects have been evaluated in vitro against LI210 synthesis, and antibacterial activity of 4-alkylidene-azetidin-2-ones 26 as new antimicrobial agents against multidrug-resistant pathogens have been reported <06JMC2804>. (Benzothiazol-2'-yl)azetidin-2-one derivatives have been prepared and screened for antibacterial and antifungal activities <06IJC(B) 1762>. Several pyrimidine-based 2<06IJC(B)1762>. azetidinones have been synthesized and tested for their antibacterial, antifungal and [3-Lactamantituberculosis activities against different microorganisms <06IJC(B)773>. p-Lactamdihydrofuran hybrids 27 have been prepared by a novel palladium0l)-catalyzed palladium(II)-catalyzed 1>. The synthesis heterocyclizative cross-coupling of of two different a-alIenoIs (z-allenols <06AG(E)450 <06AG(E)4501>. of of 3-(aryl)alkenyl-p-Iactams 3-(aryl)alkenyl-13-1actams by application of olefin cross-metathesis on solid support has been reported <060L4783>. <06OL4783>. The synthesis of 3-phenylthio p-Iactams 13-1actams has been carried out using a-diazocarbonyl (z-diazocarbonyl compounds as precursors of ketenes <06S659>. A Lewis acidmediated method for the C3 epimerization of of 3-halo-3-phenylthio-p-Iactams 3-halo-3-phenylthio-13-1actams has been developed <06H749>. The stereoselective synthesis of cis- and trans-3-alkoxy-3trans-3-alkoxy-3phenyl/benzylthioazetidin-2-ones has been described <06T829l>. <06T8291>. p-Lactams 13-Lactams 28 have been isolated as the major products of the reaction of dimethoxycarbene with isocyanates <060L3121>. <06OL3121 >. oO
MeO~o Meo~o
RO~ RO~"~OMe~""'~C02Bn " ~ O ~ cO2BnR2"-I~ OMe
O
H H-O:/~
J--N,..'H o 26 26
o
Key: i) RN=C=O, chlorobenzene, heat.
"R3
R4
MeOOMe MeO MeO~~/OM OMe OMee '+---loMe N,~O i.~ F-T~OMe O)--N'R
27 27
28 (49-68%) (49-68%)
97
Four-membered ring systems
Azetidin-2,3-diones have been used as synthons for the stereoselective synthesis of cis- and trans-C3-alkyl/aryl azetidin-2-ones <06S <06S115>. 115>. It has been reported that the threecomponent reaction of of N-substituted hydroxylamines, aldehydes, and phenylacetylene catalyzed by Cu(!) p-Iactams 29 Cu(I) under neat conditions afforded the corresponding [3-1actams <06MI203>. The reactions of nitrones with terminal alkynes (Kinugasa reaction), catalyzed iPr-trisoxazoline/Cu(C104)z'6H20 [3-1actams in by a chiral iPr-trisoxazoline/Cu(CI04)z·6H zO complex in air, afforded p-lactams reasonable yields with up to 85% ee <06JOC3576>. The direct, palladium-catalyzed, multicomponent synthesis of 3-amido-substituted p-lactams [3-1actams 30 from imines, acid chlorides, 4-Oxoazetidin-2-yl benzoate has and carbon monoxide has been accomplished <06OL3927>. <060L3927>. 4-0xoazetidin-2-yl been resolved by an inclusion complexation with a chiral host compound, (R,R)-(-)-trans4,5-bis(hydroxydiphenylmethyl)-1 ,4-dioxaspiro[4.5]decane <06TA2216>. The Rh(II)4,5-bis(hydroxydiphenylmethyl)-l,4-dioxaspiro[4.5]decane [3-1actams has catalyzed intramolecular C-H insertion of diazoacetamides in water to afford p-lactams been mentioned <06JOC5489>. The reaction of N-acylimidazoles possessing an electronwithdrawing group in the (J. a position with diarylimines produces p-lactams [3-1actams 31 in high yields <06JOC5804>. Studies on the effects of the distance between the aromatic rings and the (J.a[3-1actams derived from stereogenic reaction center on the memory of chirality of p-lactams phenylalanine have been performed <06TL5883>. The synthesis of C3 unsymmetrically [3-1actams as well disubstituted azetidin-2-ones by Lewis acid mediated functionalization of p-lactams as a mechanistic study have been published <06TL5255>. The generation of acyloxyketenes 1,3-dioxolium-4-olates and their reaction with ketenophiles to give from unstable mesoionic 1,3-dioxolium-4-0Iates [3-1actams has been reported <06JOC5162>. A strategy for the [2+2] cycloadducts, including p-lactams synthesis of differently C3-substituted p-lactams ~-lactams involving the reaction of p-lactam ]3-1actam carbocation equivalents with active substrates in the presence of a Lewis acid has been described <06T5054>. A new route to enantiopure 4-aryl-substituted p-lactams ]3-1actams through [3-1actams has lipase-catalyzed enantioselective ring cleavage of the corresponding racemic p-lactams been developed <06MI917>. The enantioselective synthesis of trans-p-lactams trans-~-lactams using a chiral auxiliary under Reformatsky reaction conditions has been described <06SLl 113>. A new <06SL1113>. class of glycoconjugated p-lactams [3-1actams has been accessed by direct glycosidation of a suitable 4alkylidene-azetidin-2-one acceptor with several perbenzylated (N-phenyl)trifluoroacetimidate <06EJ069>. The synthesis and biological evaluation donors activated by catalytic Yb(OTf)3 <06EJO69>. of azido- and aziridino-hydroxy-p-lactams aziridino-hydroxy-[3-1actams through stereo- and regioselective epoxide ring opening have been reported <06JOC9229>. O
Ph ih + R1CHO ~ i O y
-i
R1 " Me 29 (55-95%) (55-95%) 29
R1
-iiii
2 ~ + RScocI __ R2 N.H
R3LN"R1R 2 Ro2~ N , " R1 30 (27--66%) (27-66%) 30
EWG,,~Ar
EWG'" O ' S ~NAr A orN'Arr 31 31
KHC0 3, NaOAc, neat, 70°C. Key: i) MeNHOH'HCl, MeNHOH.HC1, 5 mol % CuCl, CuC1, 2,2'-bipyridine, KHCO3, 70 ~ ii) 1.4 mol% Pd Pdz(dba)3"CHC13, iPr2EtN, MeCN/THF (1:1), 55°C. 55 ~ z(dbakCHCI3, iPrzEtN, p-Lactams [3-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiA1H4 LiAIH4 is a powerful method for the synthesis of stereodefined aziridines and azetidines <060Ll101>. <06OL 1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cis-disubstituted pyrrolidines and piperidines 32 <060LlI05>. <06OL1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of of a peptide-
98
B. Alcaide and P. Almendros
inhibitor has been described using as the key transformation the aminolysis of a deformylase inhibitor ~-Iactam <06SL3 179>. Reductive ring opening of 2-azetidinones promoted by sodium 13-1actam <06SL3179>. borohydride gives 3-aminopropane-l,2-diols 3-aminopropane-l,2-diols <06TL2209>. The stereoselective conversion of 2-azabicyclo[2.2.0]hex-5-en-3-one into aminodienes has been described <06S633>. Using a 13-1actam ring opening-allene opening-allene sodium methoxide/methanol system, an unprecedented domino ~-Iactam cyclization reaction gives pyrroles 33 <06CC2616>. An enzymatic method has been developed for the synthesis of enantiomeric benzocispentacin and its six- and sevenmembered homologues through the lipase catalyzed enantioselective (£>200) (E>200) ring opening of bicyclic ~-lactams 13-1actams <06CEJ2587>. The ring opening of ~-lactam-fused 13-1actam-fused pinenes gave y-amino alcohols, alcohols, which have been used as catalysts for the enantioselective addition of diethylzinc to aldehydes <06TA199>. A novel procedure has been developed for the preparation of 2,3disubstituted 4, 4,1-benzothiazepines, 13-1actam<06TL5665>. disubstituted l-benzothiazepines, via the ring transformation of a ~-lactam
x
R20~- ~ n X o L I N,R1
R 2 0 ~X i~ R20~ ii lL',.N.-~)n .N.J)n --" ii R1 32 (44-98%) (44-98%)
3 OP 2 R3Hs p~, R
iii R2~R H: Ph ~ 0
N
'R1
2 ~ R
Ph Ph
R~;:..Q-N\ MeOOC R1 ~1 33 (50-54%) (50-54%)
MeOOe
Key: i) AlHzCI, A1H2C1, EtzO, Et20, RT. ii) MeCN, reflux. reflux, iii) MeONa, MeOH, RT.
4.4
SPIROCYCLIC P-LACTAMS ~-LACTAMS FUSED AND SPIROCYCLIC
A review on antibacterial antibacterial natural products including ~-lactam 13-1actam formation has appeared [~-Lactamase nomenclature has been reviewed <06MIlI23>. <06MIl123>. New <06AG(E)5072>. ~-Lactamase 1022> as well as their use as approaches to the inhibition inhibition of metallo-~-lactamases metallo-13-1actamases <06AG(E) <06AG(E)1022> novel weaponry for antibiotic antibiotic resistance in bacteria have been reviewed <06ACR721>. A review on the application of alicyclic ~-amino 13-amino acids in peptide chemistry including enzyme[3-1actams has been published <06CSR323>. An catalyzed ring opening of cycloalkane fused ~-Iactams overview on free radical chemistry including fused ~-lactams [3-1actams has appeared <06CC4055>. Large-scale oxidations oxidations in the pharmaceutical industry including ~-lactams 13-1actams have been reviewed <06CRV2943>. The synthesis and biological activity of spiro ~-Iactams [3-1actams incorporating quinones have been reported <06PS2483>. The Cu(I)-catalyzed Cu(0-catalyzed coupling of [3-1actams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides producing the spiranic ~-lactams e n route r o u t e to chartellines chartellines <060Ll779>. <06OL 1779>. corresponding ~-haloenamides has been accomplished en In work directed toward a total synthesis of chartelline A, a strategy investigated to construct 10-membered ring of this marine alkaloid was an intramolecular aldehyde/spiro-~-Iactam aldehyde/spiro-13-1actam the 10-membered cyclocondensation to form the macrocyclic enamide functionality <06JOC3159>. A biosynthetically inspired and strategically designed lO-step 10-step sequence synthesis of (±)(+)chartelline C has been reported <06JAI4028>. <06JA14028>. The synthesis of spiro-linked ~-Iactam [3-1actamchartelline dihydropyridines 34 through the cyclization of lithiated lithiated pyridine carboxamides has been I]-lactam 35 in the preparation of achieved <06OL5325>. <060L5325>. The utility of the spiro ~-lactam peptidomimetics as analogues of melanostatin was demonstrated <06JOC7721>. The chirospecific synthesis synthesis of spirocyclic ~-lactams [3-1actams and their characterization as potent type II ~ [3turn 06CEJ6315>. tum inducing peptide mimetics have been accomplished <06JOC97; 06CEJ63 15>. Yhermolysis spiro[13-1actam-4,2'-oxadiazolines] in the presence of aryl isocyanates Thermolysis of spiroW-lactam-4,2'-oxadiazolines]
99
Four-membered ring systems
afforded both N-lactam and O-lactam substituted substituted spiro[azetidine-2-one-4,3'-indol-2'-one] spiro[azetidine-2-one-4,3'-indol-2'-one] derivatives <06JOC44 I8>. <06JOC4418>. R
~
0
c,
N
r,
R'
R'
N H
Br
X X
XV",B"
Br
Br
~fi/~" ~I ~ ,~~
E E
R-
0o
N But ii Ph Ph -+ L,,ph i-~ O,/~lN, lph
o
Y
/;
~~P
Y
- PMP
N,Bu Butt
35
34 34 (39-91%) (39-91%)
R == R' R'== Br Br (charteIline (chartelline A) A) R R == R' R'== HH (chartelline (chartelline C) C) R Key: i) LDA,-40 LDA, --40 DC. E-Cl. ~ ii) E-C1.
Spiranic ~-lactams [~-lactams have been prepared by the reaction of N-protected cyclic keteneN,S-acetals with vinyl isocyanates <06SL201>. The synthesis of spiro-~-lactams spiro-~-lactams through halogen-mediated intrasulfenyl cyclization of cis-3-benzylthio-3-(prop-2-ynyloxy/-enyloxy)cis-3-benzylthio-3-(prop-2-ynyloxy/-enyloxy)[3-1actams has been achieved <06EJ04943>. <06EJO4943>. The one-pot three-component reaction for the ~-lactams direct conversion of certain alkylhydroxylamine hydrochlorides (alkyl = benzyl, pmethoxybenzyl, benzhydryl, tert-butyl), formaldehyde or an alkyl glyoxylate and bicyclopropylidene to furnish the 3-spirocyclopropanated 2-azetidinones 36 has been developed by microwave heating <06EJOI251>. <06EJO1251>. The acid-catalyzed fragmentative rearrangement of tricyclic isoxazolidines yields cyclopropane-fused ~-lactams ]3-1actams <06SLl125; <06SL1125; 06EJ05485>. 06EJO5485>. The highly diastereoselective synthesis of fused oxopiperazino-~-lactams oxopiperazino-i3-1actams 37 by Staudinger reaction between functionalized ketenes and 5,6-dihydropyrazin-2(lH)-ones 5,6-dihydropyrazin-2(1H)-ones 11>. has been carried out <06TL89 <06TL8911 >. O
+
R1
+! ~ [R,R~] _
R'RlcHo eHO + R'R2NHOH.HCl NHOHHe, + ~
i__..~ 2-
:)=t:
"--~" R
36 (49-78%)
R~L-N-Bn O/~--N.~ . /OTBDMS R1 37
Key: i) NaOAc, EtOH, MW. The synthesis of a series of macrocyclic bis-[~-lactam bis-~-lactam derivatives via a highly stereoselective [2+2] Di-exo-3-amino-7[2+2] cycloaddition has been described <06TL8855>. Di-exo-3-amino-7oxabicyclo[2.2.l ]hept-5-ene-2-carboxylic acid, five aldehydes and two isocyanides were oxabicyclo[2.2.1]hept-5-ene-2-carboxylic reacted both in methanol and in water to prepare a 10-membered lO-membered ~-lactam J3-1actam library via a Ugi4-centre-3-component reaction <06TL9113>. 4-Formyl-l-(2- and 3-haloalkyl)azetidin-2-ones 3-haloalkyl)azetidin-2-ones have been prepared as valuable starting materials for the synthesis of different optically 1,4-diazepane annulated ~-lactam [3-1actam active bicyclic azetidin-2-ones, such as piperazine and 1,4-diazepane ]3-1actam-fused enediynes involved an derivatives 38 <06JOC7083>. A synthetic route to ~-lactam-fused intramolecular Kinugasa reaction <06CC2992>. A ~-lactam-azasugar [3-1actam-azasugar hybrid (polyhydroxylated carbacephem) has been designed and synthesized as a potent glycosidase inhibitor <06TL7923>. 7-Amino- and 2-ethoxycarbonyl-5-dethia-5-oxa-cephams were prepared from 1,3-alkylidene-l-erythritol <06Tl0928>. <06T10928>. Synthetic approaches towards a new class of strained lactenediynes, compounds where a 10-membered enediyne ring is fused with a ~-lactam J3-1actam have been described <06ARK15; 06ARK261>. The stereoselective synthesis of functionalized tricyclic [3-1actams ~-lactams via intramolecular nitrilimine nitrilimine cycloaddition has been achieved <06TA1319>. Strained tricyclic ~-lactams 39 were prepared via intramolecular
100 1O0
B. Alcalde Alcaide and P. Almendros
[2+2] cycloaddition reactions in 2-azetidinone-tethered enallenols with control of the regioselectivity by choice of alkene substitution <06CEJ1539>. <06CEJ 1539>.
R10
O
-i
R10
"R2
1
OH 2 H H : R
iii
ii
X
--
OH H H R2
"
38 (41-87%) (41-87%)
339 9 (52-57%) (52-57%)
2
NH 2 , MgSO4, MgS0 4 , CH NaBH 4 , MeOH, reflux. Key: i) R R2NH2, CH2C12, reflux, iii) Toluene, 220°C, 220 ~ sealed 2Cb, RT. ii) NaBH4, tube.
New C-3' hydroxamate-substituted and more lipophilic cyclic hydroxamate cephalosporin derivatives were preppared as a potential new generation of selective antimicrobial agents <060BC4178>. <06OBC4178>. The positive effect of natural and negatively charged cyclodextrins on the stabilization of penicillins towards ~-lactamase ~-Iactamase degradation due to inclusion and external guest-host association has been studied <060BC1297>. <06OBC1297>. The first step of the deacylation reaction of benzylpenicillin in the E. coli TEMI TEM1 ~-Iactamase 13-1actamase has been <060BC206>. A strategy for the solid-phase synthesis of penicillin derivatives has modelled <06OBC206>. been reported <06S3297>. Studies on the hydrolysis of of oxacillin have been carried out <06CEJ7597>. A theoretical proposal for the synthesis of carbapenems from 4-(2propynyl)azetidinones promoted by [W(CO)s] [W(CO)5] as an alternative to the Ag+-assisted process has been reported <06CEJ7929>. A stoichiometric molecularly imprinted polymer for the class-selective recognition of ~-Iactam ~-lactam antibiotics in aqueous media has been described <06AG(E)5158>. An amide derived from penicillin V and racemic (R/S)-2-aminobutanol has been prepared and shows significantly higher toxicity than the pure diastereomers <06TLI 737>. The synthesis and siderophoric activity of conjugates of methyl 6<06TL1737>. aminopenicillanate with biscatechol-hydroxamate chelators have been reported <06T7799>. An efficient method for the deprotection of tert-butyldimethylsilyl tert-butyldimethylsilyl ethers was TiCl TiC14-Lewis 4-Lewis base complexes; it was applied in the synthesis of l~-methylcarbapenems l~-methyIcarbapenems<06JOC5380>. The reactivity of cephalosporin sulfones has been studied <06JHC 183>. OXETANES, 4.5 OXETANES, LACTONES) LACTONES)
DIOXETANES, DlOXETANES,
OXETENES OXETENES
AND
2-OXETANONES 2-0XETANONES
([~(~-
Ketene chemistry including ketene-aldehyde cycloaddition to form ~-lactones [3-1actones and ketene-alkene cycloaddition to form oxetanes has been reviewed <06EJ0563>. <06EJO563>. It has been reported that the attachment of the oxetane motif to molecular scaffolds results in remarkable improvements of key physicochemical characteristics and provides valuable opportunities for property-guided drug discovery <06AG(E)7736>. Oxetanes have also been utilized as synthons for the preparation of different compounds. The synthesis of 5-hydroxyfunctionalized 2-trifluoromethyl-l-alkenes was achieved by l-(trifluoromethyl)vinylation 1-(trifluoromethyl)vinylation via oxetane ring-opening <06S <06S128>. 128>. A convenient route to tetrahydropyran-based liquid crystals from oxetane precursors has been described <06EJO3326>. <06EJ03326>. The asymmetric synthesis of of y~,hydroperoxyalkanols involved regiospecific and stereoselective acid-promoted opening of oxetanes with hydrogen peroxide. This was used as the core of the first asymmetric synthesis of 1,2-dioxolane-3-acetic acids 40 <06JOC2283>. An aniline glycosyl carbamate spacer linked to the 2'-OH of paclitaxel has been obtained <06JOC9628>. The synthesis of 7- and 10-spermine conjugates of paclitaxel and IO-deacetyl-paclitaxel 10-deacetyl-paclitaxel were synthesised as potential
101
Four-membered ring systems
prodrugs <06TL2667>. Noncytotoxic taxanes as novel antituberculosis agents have been discovered <06JMC463>. A 4-methyl-5-oxo docetaxel analogue was prepared starting from 10-deacetylbaccatin III <06OL2301>. <060L2301>. Bridging converts the noncytotoxic nor-paclitaxel derivative 41 into the cytotoxic analogue 42 by constraining it to the T-taxol conformation <060L3983>. <06OL3983>.
R, '~O . .... 8stepsR ~ . ] . ~ co .
AcQ OOH OO ~ " o . < _ .0. o6 o
O ACO AcO OOH OOH O ~
P,C H ON,".,,L
o,
~ : ° °
° a"= .
:H: o
PhCH 200
~_
41 41
o
°
42
A C,D-seco-paclitaxel derivative was prepared from taxine and tested for biological A activity <06TL8503>. A 36-step synthesis has been carried out in automated synthesizers to provide a synthetic key intermediate for taxol <06MI370>. The bicyclic oxetane 43 which was obtained by the [2+2] [2+2] photocycloaddition (Patemo-Btichi (Patern6-BiJchi reaction) of a methylthymine derivative with benzaldehyde, showed, in model studies, efficient photosensitized splitting of of thymine oxetane units by covalently linked tryptophan in high polarity solvents <060BC29 I>. The Patern6-BiJchi Patemo-Biichi reaction of 1,3-dimethylthymine or 1,3-dimethyluracil <06OBC291>. with benzophenone benzophenone and its six 4,4'-disubstituted derivatives generated two series of regioisomeric oxetanes, head-to-head head-to-head and head-to-tail isomers <06EJOI790>. <06EJO 1790>. The efficient photosensitized splitting of of the thymine dimer/oxetane unit on its modifying ~-cyclodextrin 13-cyclodextrin by a binding electron donor has been reported <060BC2576>. <06OBC2576>. Thymine oxetanes have been tested as charge traps for chemical monitoring of nucleic acid mediated transfer of excess electrons <06AG(E)5376>. The pathways of excess electron transfer in DNA with flavindonor and oxetane-acceptor modified DNA hairpins 44 has been investigated <06CEJ6469>. Patem6-Biichi reaction of 2,3A temperature effect on the stereoselectivity in the Patern6--Bachi dihydrofuran-3-ol derivatives with benzophenone was noted <06TL2527>. A new terpenoid, the tricyclic oxetane amentotaxone, has been isolated from Amentotaxus formosana <060L753>. <06OL753>. The spirocyclic oxetane lactone 45 has been synthetized <06T7747>. An oxetane-fused benzene was proposed as intermediate in the mass spectrometric fragmentation of of even-electron negative ions from hydroxyphenyl carbaldehydes and ketones <06TL4601>. <06TL4601 >. 0
HNly oANJ
l C02Bn
~
0
HNJ4-0
oAN~Ph I l C0 H CO2Bn 2Bn
43 (21%) 43(21%)
0
0-0LNH Ph¥NAO Ph j
0==\ NH ~H 44 G (~ 44
~ (NH ~
G
=
1 R10 R 0
0
~NAo jJ a2 -bR2
0 45 45
0 O
Key: i) PhCHO, hv, MeCN, RT. An acid-catalyzed ring-closing ynamide-carbonyl metathesis, which would proceed through ring opening of of an amide-substituted oxetene intermediate 46 formed through a stepwise hetero [2+2] cycloaddition pathway, has been described <06OL23 <060L23 l>. I>. The synthesis of tetrasubstituted enol ethers by E-selective olefination of esters with ynolates has been reported to occur via lithiated oxetene species <06JA1062; <06JAI062; 06CEJ524>. A dioxetane-based selective chemiluminescent probe for singlet oxygen has been employed to detect and
102
B. Alcaide and P. Almendros
quantify singlet oxygen in the reactions of superoxide with organic peroxides <06JOC796>. <06JOC796>. The synthesis and fluoride-induced chemiluminescent decomposition of bicyclic dioxetanes substituted with a 2-hydroxynaphthyl group have been described <06T5808>. The synthesis of dioxetane 47 has been achieved during abortive attempts to synthesize ent-premnalane A ent-premnalane A <06T53 13>. Bicyclic dioxetanes bearing a 2-hydroxy-l,I'-binaphthyl-5-yl <06T5313>. 2-hydroxy-l,l'-binaphthyl-5-yl moiety are active towards charge-transfer-induced chemiluminescent decomposition intramolecular modulation intramolecular <06T12424>. Color for charge-transfer-induced chemiluminescence of bicyclic dioxetanes bearing a 3-hydroxy-5-naphthylphenyl moiety in coordination sphere been reported 4-(3-tertthe has <06TL8407>. Butyldimethylsilyloxyphenyl)-4-methoxyspiro[I,2-dioxetane-3,2'-adamantane] Butyldimethylsilyloxyphenyl)-4-methoxyspiro[ 1,2-dioxetane-3,2'-adamantane] was <06S1781>. The dioxetanone intermediate 48 was synthesised by two different approaches <0681781>. isolated in studies on the possible biogenetic precursors of pyrrole-2-aminoimidazole <06OL2421>. alkaloids <060L242 I>. A dioxetanone intermediate has been proposed as supporting the bioluminescence mechanism for the chemiexcitation process to generate the singlet-excited state of of neutral oxyluciferin <06TL6057>. A spirocyclic dioxetanone intermediate was proposed in investigations of the unimolecular reactivities of a range of of perbenzoate anions in the gas phase by electrospray ionization tandem mass spectrometry <06JOC7996>. <06JOC7996>.
R30C
o
o
o
...,
-i
Y
46
47
48 48
Key: i) 02, hv, CH2C12, RT. ]3-1actone-type The structure and absolute configuration of the unusual fused 13-lactone-type metabolite vibralactone 49, which was found to inhibit pancreatic lipase with an IC ICs0 of 0.4 so of gg/mL, from the cultures of the Basidiomycete Boreostereum Ilg/mL, Boreostereum vibrans have been established by spectroscopic and computational methods <06OL5749>. <060L5749>. A detailed mechanistic investigation of epoxide carbonylation by the catalyst [(salph)Al(THFht [(salph)Al(THF)2] + [CO(CO)4r [Co(CO)4]- (salph = N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), THF = tetrahydrofuran) to form 13[3<06JAI0125>. A readily prepared Cr-Co lactones has been carried out <06JA10125>. Cr-Co bimetallic catalyst is capable of effecting epoxide carbonylation to produce 13-lactones ]3-1actones at substantially lower CO pressures than previously reported catalyst systems <060L3709>. <06OL3709>. A chiral oxazaborolidinecatalyzed enantioselective synthesis of ~-lactones ]3-1actones from ketene and aldehydes has been developed <06OL4943>. <060L4943>. A catalytic asymmetric synthesis of 3,4-dialkyl-cis-~-lactones, 3,4-dialkyl-cis-~3-1actones, inhibitors of the thioesterase domain of fatty acid synthase, via a sequential ketene dimerization/hydrogenation process has been achieved <06JOC4549>. <06JOC4549>. 3-Alkylidene-oxetan2-ones 50 have been prepared in good to excellent yields, with high Z-selectivity, by olefin 3-methyleneoxetan-2-ones in the presence of Ru-based second cross metathesis with 3-methyleneoxetan-2-ones generation metathesis catalysts <06OL2139>. [3<060L2139>. Molecular recognition of lactones, including including~ lactones, can be achieved by inclusion complexation with optically active hosts derived from tartaric acid <06TA1678>. <06TAI678>. The Walden cycle which interconverts the stereochemical configurations of chlorosuccinic and malic acids involves a ~-Iactone ~3-1actone intermediate rather than ~-lactone intermediate because the Onue Onuc C CI C1 angle in the transition structure for the an a-lactone (174 ~ is more favorable than that for the latter (139°), (139~ as determined by a former (174°) computational study <06CC1106>. <06CC 11 06>. An efficient chiron approach to the total synthesis of (-)-
103
Four-membered ring systems
tetrahydrolipstatin 51 starts from tri-O-acetyl-D-glucal, tri-O-acetyI-D-gIucal, and uses copper-mediated C-C bond formation, Frater alkylation, and Barton-McCombie deoxygenation <06SL3888>. Stereoselective syntheses of (-)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclizations as the key steps <06TL4995>. The stereoselective synthesis of (-)-tetrahydrolipstatin via a radical cyclization based strategy has also been reported <06TL4393>. An expeditious enantioselective total synthesis of valilactone has been accomplished <06JOC5748>. Concise syntheses of valilactone and a two-carbon transposed aldol-lactonization process as a key step orlistat derivative employed a tandem Mukaiyama aldol-Iactonization <060L4497>. <06OL4497>. An efficient protocol has been developed using D-(2R)-Oppolzer sultam as a chiral auxiliary for generating anti/syn anti/syn diastereomers with high enantiopurity and were utilized in an efficient synthesis of natural product belactosin C 52 and its synthetic congeners <06JOC337>. A concise and straightforward 14-step total synthesis of (±)(+)<060BC2845>. Enantioselective total syntheses of salinosporamide A 53 has been described <06OBC2845>. lactacystin ~-lactone J3-1actone 54 have been achieved <06JA68 <06JA6810; 06JOC1220; 060BCI93>. 06OBC193>. The 10; 06JOCI220; reaction of acryloyl chloride with an amino ketone in the presence of pyridine produces a bicyclic ~-lactone [3-1actone rather than the corresponding acrylamide, which can be the major product <060Ll7I7>. A diastereoselective organonucleophile-promoted bisunder other conditions <06OL1717>. cyclization process provides access to bicyclic- and tricyclic-~-lactones tricyclic-13-1actones bearing tertiary carbinol centers and quaternary carbons and employed keto acid substrates <060L4363>. <06OL4363>. A synthetic strategy for construction of the novel spiro-bicyclic ~-lactone-y-Iactam 13-1actone-3,-lactam system present in oxazoiomycin >. The ~-lactone oxazolomycin has been demonstrated <06TL603I <06TL6031>. [3-1actone nucleus has been used as a synthon for the preparation of different compounds such as (-)deoxyharringtonine <06JA10370>, the CrC <060L7>, and C7-C20 zo fragment of amphidinolide B <06OL7>, (-)-pironetin <06JA7438>. SN2' ~-lactone has provided the requisite SN2' Ring opening of a [3-1actone pyrrole-substituted allene for the enantioselective total synthesis of (-)-rhazinilam ~-lactones yielded a-amino <06JA10352>, while ring opening of amino J3-1actones m-amino acids <06CCI757; <06CC1757; 06TLlOI9; 06TL1019; 06TL370I>. 06TL3701>. Yttrium initiators have been used for the polymerization of racemic ~-butyrolactone 13-butyrolactone <06AG(E)2782>. Different syntheses of functionalized ~-keto [3-keto esters have been carried out starting from 4-methyleneoxetan-2-one <06EJOllI7; <06EJOll17; 06TA2672; 06Tl0497>. 06T10497>. HO
~H
nC6H13~ .....~RC11H23
)=(
RI+
H
o
+
R)jR
1 ~ i__ R22
R',]
o
I
1
-~
OHCHN"~
o 50 50 (55-94%) (55-94%)
49 49
-
51 O
O
CI
..... , ~ _ _ / / ~ , /
~ 52
OH 53
54
O
CH2C12,reflux. Key: i) 5 mol% Ru-based cat., CHzCh, 4.6 4.6
THIETANES, TAMS, AND RELATED RELATED SYSTEMS THIETANES, ~-SUL [3-SULTAMS,
I,2-thiazetidine 1, I-dioxides (~ A stereoselective one-pot synthesis of substituted 1,2-thiazetidine 1,1-dioxides (13<06OL5513>. sultams) 55 started from heterocyclic pentafluorophenyl (PFP) sulfonates <060L55 13>.
104
B. Alcaide and P. Almendros
Thermolysis of of the pentacoordinate pentacoordinate 1,2-thiazetidine 1,2-thiazetidine 1-oxide I-oxide 56, which was synthesized synthesized for characterized by X-ray crystallographic crystallographic analysis, gave the corresponding corresponding the first time and characterized aziridine 57 and a cyclic sulfinate sulfinate almost quantitatively <06OL4625>. <060L4625>. aziridine
OO:S?'('-NP PFp )-r-
R"
_i
Hl_';'~ '~_;' R It O-t- N ,
c8
FsC F s
o
55 (26-58%)
~
~"~~Fs
S- N -",\'0 'Ph
~
II
56
~h
ii
-
+ N FsC--P'-Ph FsC (94%) 57 (94%)
cd FSC
I
/-/
CF
s
0
~ 0
(quant)
MO(CO)6, MeCN-H20, MeCN-HzO, 90 90°C. 160°C, Key: i) Mo(CO)6, ~ ii) Toluene, 160 ~ sealed tube. spironucleosides, including the spiroannulated spiroannulated thietane 58 were Four-membered spironucleosides, L-thietanose nucleosides which have showed synthesized <06TL3875>. Various D- and L-thietanose moderate anti-HIV activity were synthesized from D- and L-xylose <06JMC1635>. A synthesis of of isothiazolidines isothiazolidines 60 via sulfonium ylides formed by the reaction of of thietanes 59 <06TLl109>. The 2-(diphenylmethylene)thietan-3-one 2-(diphenylmethylene)thietan-3-one 61 and nitrene has been achieved <06TLl109>. reacted with 1,2,4,5-tetrazines 1,2,4,5-tetrazines in KOH/MeOH/THF to give 4H-pyrazolo[5,1-c]thiazines <06TL7893>. A model for the prediction of the homolytic bond dissociation enthalpy and adiabatic ionization ionization potential potential of fused four-membered heterocycles, including benzothiete 62, <060BC846>. has been developed using calculations at B3LYP/LANL2DZ level <06OBC846>. Ph S~O,,,,/,,, O Ar Ar O,,~Ph ~~ ]
q
BnO 58
+ Phl=NTs
59 59
- Q-TS i ,_
"Ts 60 (56-67%) (56-67%) 60
O~Ph ~ SS 61 61
62
62
Key: i) Cu(acac)z, Cu(acac)2, benzene, reflux.
4.7
SILICON AND PHOSPHORUS PHOSPHORUS HETEROCYCLES. HETEROCYCLES. MISCELLANEOUS
The preparation and reactivity of heterocyclic compounds with a silicon atom and another non-adjacent different heteroatom including 1,3-oxasiletane, 1,3-oxasiletane, 1,3-azasiletane, 1,3-azasiletane, 1,31,3thiasiletane, thiasiletane, and 1,3-phosphasiletane 1,3-phosphasiletane have been reviewed <06T7951>. <06T7951 >. An overview on novel silicon-based reagents for organic synthesis including silacyclobutanes and 1,31,3disilacyclobutanes has appeared <06CEJ1576>. 3,4-Dibromo-1 ,2,3,4-tetrakis( di-tert3,4-Dibromo-l,2,3,4-tetrakis(di-tertbutylmethylsilyl)cyclotetrasilene 63 was prepared in 81 % yield by reduction of the 81% corresponding tetrabromocyclotetrasilane with 2.1 equivalents of KCg KCs in THF <06AG(E)3269>. Calculations Calculations on a series of polycyclic silicon molecules confirm that the introduction of a double bond into into four-membered cyclic silanes lowers the ring strain by the cyclic delocalization of 1t-electrons ~-electrons through hyperconjugation with the (J cy bonds <06T4491>. <06T4491 >. The first thermally stable four-membered heterocycle chlorosilylene 64 has been synthesised and characterized <06AG(E)3948; 06AG(E)424 1>. The four-membered heterocycle 65 has 06AG(E)4241>. been prepared and unambiguously identified by multinuclear NMR spectroscopy <06AG(E) 1643>. Nickel-catalyzed ring opening reaction of silacyclobutanes 66 with <06AG(E)1643>. aldehydes afforded the corresponding alkoxyallylsilanes 67, while ring expansion of benzodimethylsilacyclobutene with aldehydes occurred under nickel catalysis to give oxasilacyclohexenes <060L483>. <06OL483>. Oxidation of benzylidene acetals that incorporate a siletane ring at the para position creates a deprotection pathway without affecting other important chemical properties of the benzylidene acetal <06JOC420>.
105
Four-membered ring systems
f-Bu2MeSi, ,SiMef-Bu2 t-Bu2MeSi, ` ,SiMet-Bu 2 Si=Si Si--Si
[
t-Bu,
,CI
Tip,,T ip ,,Tip Si--Si
"t-Bu
Sn--Si +ip "Tip Tip"
N--Si
I
Br-Si-Si-Br
B r - S[i - - S i -[ B r t_Bu2MeS i SiMet.Bu 2 f-Bu2MeSi SiMef-Bu
P
63
64
65
R2
R3 "3 R1 (~) Si-R 1 R1 '
S
66
Tip = 2,4,6-triisopropylphenyl 2,4,6-triisopropylphenyl
" --
~'R 2
67 (47-87%) (47-87%)
Key: i) Ni(cod)2, PPh2Me, PPh2Me, toluene, 100°C. 100 ~ The structure of of a four-membered phosphapalladacycle has been established by a single-crystal X-ray structural analysis <06JA6376>. The thermal conversion of the cyclic 5 carbodiphosphorane 68 into 1,2-A -azaphosphete 69 proceeds almost quantitatively and 1,2-~,5-azaphosphete regioselectively <06AG(E)7447>. The reaction of aryl nitriles with [1,3,2,4]diselenadiphosphetane (Woollins' reagent) 70, followed by water affords a variety of of <060L5251>. A single-crystal X-ray diffraction primary arylselenoamides in 60-100% yield <06OL5251>. study of a bicyclic four-membered phosphorus-containing product showed the bicycle to 5 adopt envelope-type topology <06AG(E)6685>. A 1,3,2-1. -oxazaphosphetidine reaction 1,3,2-~,5-oxazaphosphetidine intermediate, in which the p-o P-O bond order is 0.47, has been found on studying the aza-Wittig reaction between phosphazenes and aldehydes <06JOC2839>. It has been postulated that betaine 71 can be formed upon treatment of the corresponding iminophosphorane with phenyl isocyanate through an abnormal aza-Wittig reaction <06EJ04170>. <06EJO4170>. Various other fourmembered azaphosphaheterocyclic intermediates have also been proposed <06CEJ7178; 06T4128>. The fragmentation of C-amino four-membered phosphorus ylides to carbenes has been proposed <06JA459>. The preparation and characterization of the air-tolerant 1,3diphosphacyclobuten-4-yl radical 72 has been achieved <06AG(E)4341>. A fluorous analogue of Lawesson's reagent for thionation of carbonyl compounds has been developed and its use demonstrated on a series of amides, esters, and ketones <06OL1093>. <060Ll093>. Several structures of cationic P-S-halogen cages containing a four-membered heterocycle have been characterized <06CEJ <06CEJl703>. 1703>. ,R R
(:~~+/NR2
W~ P- NR2 _ I_ N=-( ~ "..NR 2 R Ph
68 68
<w -- wP;t' -N R
i
__~
-P-NR 2 N
I
R
Ph/
69 69
Se II Se Se-P-Ph / ~ e ~ [e Ph-P-Se [/
Se 70
Me CO2Et ~C02Et Me N-PPh N-PPh3 )-[ 3 N o N'Ph "Ph 71
t-Bu% f-Bu,
Mes Mes
5=i
Mes' Mes
72
Key: i) Benzene, 80°C, 80 ~ 60h. Mes = 2,4,6-t-Bu3C6H2. N-Sulfonyl aziridines underg oxidative addition to palladium(0) palladium(o) complexes resulting in azapalladacyclobutane complexes 73, which after intramolecular carbopalladation in the presence of copper(I) iodide gave azapalladabicyclo[3.2.l]octanes azapalladabicyclo[3.2.1]octanes <06JAI5415>. <06JA15415>. A titanacyclobutane has been proposed as intermediate in the olefin cyclopropanation with the Ti-Mg-CCI Ti-Mg-CC144 system <06JOC4325>. The existence of oxaarsetanes 74 during an arsa-Wittig 170 <06EJO4934>. The syntheses, H and 17 0 NMR spectroscopy <06EJ04934>. reaction has been proved by I1H structures, and thermolyses of pentacoordinate 1,2-oxastibetanes, which are considered as formal [2+2]-cycloadducts in the reaction of a stibonium ylide and a carbonyl compound, have been described <06JOC659>. A tricyclic intermediate containing a four-membered metallacycle has been proposed for the Rh-catalyzed alkylation-cycloaddition of 3-haloalkyl1,6-enynes <06JA14818>. <06JAI48l8>. A planar metallacycle bearing a relatively short Hf-Sb bond has been study by X-ray diffraction <06CC4030>. Reversible alkene extrusion from platinaoxetanes has been reported <06JA12088>. Synthetic and structural studies of germanacycle 75 have been reported <06CC3978>. Homogeneus, titanocene-catalyzed
106
Alrnendros B. Alcaide and P. Almendros
dehydrocoupling of of amine-borane adducts into four-membered azaboracycles has been accomplished <06JA9582>. Formation of (bistriphenylphosphine)-2-(2,2,4,4<06JA9582>. of (bistriphenylphosphine)-2-(2,2,4,4tetramethylpentan-3-ylidene)-1 ,3-dithiolato-platinum 76 and its X-ray crystaIIographic tetramethylpentan-3-ylidene)-l,3-dithiolato-platinum crystallographic <06CEJ7742>. Synthesis and X-ray analysis of of the 1,2analysis have been carried out <06CEJ7742>. dialuminacyclobutene 77 have been published <06AG(E)2245>. <06AG(E)2245>. The synthesis of of an Nheterocyclic carbene-Pd(lI) carbene-Pd(II) four-membered complex and its application in the Suzuki and Heck-type cross-coupling reaction have been documented <06T6289>. <06T6289>. Intramolecular C-H C-H of molybdenacyclobutanes have been performed <06JA9038>. <06JA9038>. activation reactions of via carbon monoxide and isocyanide insertion has been Formation of of aluminacyclobutenes via accomplished <06CCI763>. N2 to give <06CC1763>. Experimental results have shown that Tb Ti2 reacts with N2 a D2h-symmetric D2h-symmetric TbN Ti2N22 molecule which has a planar, cyclic structure with alternating Ti and N atoms <06AG(E)2799>. <06AG(E)2799>. Studies on ruthenium metallacycles derived from 14-electron complexes as possible olefin metathesis intermediates have been carried out <06JA16048>. <06JAI6048>. The reaction of of phosphaalkenes with electrophiles has provided an effective route to 1,3diphosphetanium salts containing a P2C2 P2C2 ring <06JAI5998>. <06JA15998>.
r
Ph Ph P Pd(phen) VAsPh3 d(phen) ro~SPh3 I
}- N
R22
R
"R11
'R
73
- o ) ph/ Ph
74
phen O-phenanthroline phen = 1,1 1,10-phenanthroline
4,8 4.8
S-Pt(PPh3)2 Ar S-Pt(PPh3 h Me3Si .~--' S ~AI"
t-Bu,, ,Dipp t-BU"--NPiPP N~N Ie I ,
_ . N-Ge' Dipp~ "CI Dipp 'CI
1--8
tu t-Bu--( t-Bu t-Bu
75
Me3Si 76
"Ar 77
Dipp = 2,6-/-Pr2C6H3
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Org. Chern. Chem. 2006, 71, 5804. C. Palomo, J.M. Aizpurua, A. Benito, L. Cuerdo, R.M. R.M. Fratila, J.1. J.I. Miranda, A. Linden, 1. J. Org. Org. Chern. Chem. 2006, 71,6368. 71, 6368. Y. Wang, Y. Y. Liang, L. L. Jiao, D.-M. Du, 1. J. Xu,J. Xu, J. Org. Org. Chern. Chem. 2006, 71,6983. 71, 6983. Y.
Four-membered ring systems
06JOC7083 06JOC7100 06JOC772I 06JOC7721 06JOC7885 06JOC7996 06JOC9045
06JOC9229 06JOC9628 06MI 1 06MIl 06MI49 06MI 109 06MIl09 06MI203 06M1370 06MI370 06MI544 06MI917 06MI 1123 123 06MIl 06MI2114 06MI2203 06OBC193 060BCI93 06OBC206 060BC206 06OBC291 060BC29I 060BC846 06OBC846 060BCI297 06OBC1297 060BC2576 06OBC2576
06OBC2845 060BC2845 06OBC4059 060BC4059 06OBC4178 060BC4178 060BC4533 06OBC4533 06OL7 060L7 06OL231 060L23I 060L483 06OL483 06OL753 060L753 060LI093 06OL 1093 060LI 101 06OL 1101 060LI 105 06OLl105 06OL1323 060L1323 06OL 1717 060L17l7 060LI779 06OL1779 06OL1983 060LI983 060L2139 06OL2139 060L2301 06OL2301 060L242I 06OL2421
06OL3121 060L3121 06OL3211I 060L32I 060L3709 06OL3709 06OL3335 060L3335 06OL3923 060L3923 06OL3927 060L3927
109
W. Van Brabandt, M. Vanwalleghem, M. D'hooghe, N. De Kimpe, 1. J. Org. Org. Chem. Chem. 2006, 71, 7083. Vemiest, D. De Smaele, G. Duvey, N. De Kimpe, 1. W. Van Brabandt, G. Verniest, J. Org. Org. Chem. 2006, 71, 7100. 71,7100. Gonzfilez, 1. J. Org. Org. Chem. 2006, 71, A. Macias, A.M. Ramallal, E. Alonso, C. del Pozo, J. Gonzalez, 7721. M.C. Hillier, C.-y. Chen, J. Org. Org. Chem. Chem. 2006, 71,7885. 71, 7885. D.G. D.G. Harman, A. Ramachandran, M. Gracanin, S.J. S.J. Blanksby, 1. J. Org. Org. Chem. 2006, 71,7996. 71, 7996. B. Li, M. Berliner, R. Buzon, C.K.-F. Chiu, Chiu, S.T. S.T. Colgan, T. Kaneko, N. Keene, W. Kissel, T. Le, K.R. Leeman, B. Marquez, R. Morris, L. Newell, S. Wunderwald, M. Witt, lJ. Weaver, Z. 71,9045. Zhang, Z. Zhang, 1. J. Org. Org. Chem. Chem. 2006, 71, 9045. F. Benfatti, G. Cardillo, L. Gentilucci, R. Perciaccante, A. Tolomelli, A. Catapano, 1. J. Org. Org. 71, 9229. Chem. 2006, 71,9229. A. E1Alaoui, Schmidt, C. Monneret, J.-c. J.-C. Florent, J. Org. Org. Chem. 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Chem. 2006,4,193. Org. Biomol. 2006, 4, 193. lC. H.-D. H61tje, HolDe, A.J. A.J. Mulholland, Org. Siomol. Chem. 2006, 2006,4,206. J.C. Hermann, L. Ridder, H.-D. Org. Biomol. 4, 206. Q.-H. Song, H.-B. Wang, W.-J. W.-J. Tang, Q.-X. Siamal. Chem. 2006, 2006,4,291. Q.-X. Guo, S.-Q. S.-Q. Yu, Org. Org. Biomol. 4, 291. D. Shanks, H. Frisell, H. Ottosson, L. Engman, Org. Org. Siamal. Biomol. Chem. Chem. 2006,4,846. 2006, 4, 846. D. Maffeo, L. Leondiadis, I.M. l.M. Mavridis, K. Yannakopoulou, Org. 2006,4, Org. Siamal. Biomol. Chem. Chem. 2006, 4, 1297. W.-J. Tang, Q.-H. Song, H.-B. H.-B. Wang, J.-y. W.-J. J.-y. Yu, Q.-X. Q.-X. Guo, Org. Org. Siamal. Biomol. Chem. Chem. 2006, 4, 2576. N.P. Mulholland, G. Pattenden, I.A.S. Waiters, Org. Org. Biomol. Chem. 2006, 4, 2845. l.A.S. Walters, Siamal. Chem. 2006,4,2845. T. KOpke, Kopke, M. Pink, J.M. J.M. Zaleski, Org. Siamal. Chem. Org. Biomol. Chem. 2006,4,4059. 2006, 4, 4059. M.J. Miller, G. Zhao, S. Vakulenko, S. Franzblau, U. 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Florio, R. Luisi, A. Salomone, C. Cuocci, Org. R. Dhawan, R.D. Dghaym, D.J.St. Cyr, B.A. Amdtsen, Arndtsen, Org. Org. Lett. 2006,8,3927. 2006, 8, 3927.
110 060L3983 06OL3983 060L4335 06OL4335 060L4363 06OL4363 06OL4497 060L4497
06OL4625 060L4625 060L4783 06OL4783 060L4943 06OL4943 06OL5251 060L525I 06OL5325 060L5325 060L5365 06OL5365 060L5501 06OL5501 060L5513 06OL5513 060L5749 06OL5749 06PS2483 06S115 06S 128 06S128 06S514 06S633 06S659 06S 1781 06S1781 06S1829 06S2327 06S2885 06S3297 06S3425 06SL201 06SL781 06SL1113 06SLlI13 06SL1125 06SLlI25 06SL2039 06SL3179 06SL3443 06SL3888 06T915 06T1565 06T 1565 06T4128 06T449I 06T4491 06T5054 06T5313 06T5808 06T583I 06T5831 06T6289 06T6882 06T7747 06T7799 06T7951 06T829I 06T8291 06TI0497 06T 10497 06T10928 06T 10928
B. Alcaide and P. Almendros S. Tang, C. Yang, P. Brodie, S. Bane, R. Ravindra, S. Sharma, Y. Jiang, lP. J.P. Snyder, D.G.I. Kingston, Org. Lett. 2006,8,3983. Org. Lett. 2006, 8, 3983. S. Baktharaman, S. Selvakumar, V.K. Singh, Org. Org. Lett. 2006,8,4335. 2006, 8, 4335. Lett. 2006,8,4363. H. Henry-Riyad, Henry-Riyad, C. Lee, V.c. V.C. Purohit, Daniel Romo, Org. Org. Lett. 2006, 8, 4363. G. Ma, M. ZancaneIla, Lett. 2006, 2006,8, Zancanella, Y. Oyola, R.D. Richardson, Richardson, J.W. Smith, D. Romo, Org. Org. Lett. 8, 4497. 2006,8,4625. N. Kano, Y. Daicho, T. Kawashima, Org. Org. Lett. 2006, 8, 4625. S.A. Testero, E.G. Mata, Org. Lett. 2006,8,4783. Org. Lett. 2006, 8, 4783. EJ. Corey, Org. Lett. 2006,8,4943. V. Gnanadesikan, Gnanadesikan, E.J. Org. Lett. 2006, 8, 4943. Org. Lett. 2006,8,5251. 2006, 8, 5251. G. Hua, Y. Li, A.M.Z. A.M.l. Slawin, J.D. Woollins, Org. S.D. Hamilton, Org. Org. Lett. 8, 5325. G. Arnott, J. Clayden, S.D. Lett. 2006, 2006,8,5325. H. Lu, C. Li, Org. Lett. 2006,8,5365. Org. Lett. 2006, 8, 5365. Vargas-Sanchez, S. Lakhdar, F. Couty, G. Evano, Org. Lett. 2006,8,5501. M. Vargas-S~inchez, Org. Lett. 2006, 8, 5501. Lett. 2006,8,5513. A.K. de K. Lewis, BJ. B.J. Mok, D.A. Tocher, J.D. Wilden, S. Caddick, Org. Org. Lett. 2006, 8, 5513. D.-Z. Liu, F. Wang, T.-G. Liao, l-G. J.-G. Tang, W. Steglich, H.-J. Zhu, l-K. J.-K. Liu, Org. Org. Lett. 2006, 8,5749. Phosphorus, Sulfur A.K. KhalafaIlah, Khalafallah, N.A.A. EI-Kanzi, E1-Kanzi, H.A. Soleiman, M. Younis, Phosphorus, Relat.Elem. 2006, 181,2483. 181, 2483. D.K. Tiwari, V.K. Gumaste, A.R.A.S. Deshmukh, Synthesis 2006, 115. 2006,115. R. Nadano, J. Ichikawa, Synthesis 2006, 128. H.-l Flammersheim, H. GorIs, lJ. Fleischhauer, Fleischhauer, R. Beckert, lJ. Weston, M. Schmidt, H.-J. G6rls, Synthesis Synthesis 2006,514. 2006, 514. R. A. Youcef, C. Boucheron, S. Guillarme, S. Legoupy, D. Dubreuil, F. Huet, Synthesis Synthesis 2006, 633. L. Jiao, Y. Liang, Q. Zhang, S. Zhang, lJ. Xu, Synthesis Synthesis 2006, 659. E.L. Bastos, L.F.M.L. Ciscato, D. Weiss, R. Beckert, W.J. WJ. Baader, Synthesis 2006, 1781. Synthesis 2006,1829. 2006, 1829. S.-Z. Jian, Q. Yuan, Y.-G. Wang, Synthesis S. Lacroix, V. Rixhon, J. Marchand-Brynaert, Marchand-Brynaert, Synthesis Synthesis 2006, 2327. lJ. Fleischhauer, Fleischhauer, R. Beckert, W. Gunther, Giinther, H. GorIs, G6rls, Synthesis Synthesis 2006, 2885. D.B. Boggian, Boggi~in, E.G. Mata, Synthesis Synthesis 2006, 3297. M. Sarkar, A. Samanta, Synthesis Synthesis 2006, 3425. A. Zhou, L. Cao, H. Li, Z. Liu, C.U. Pittman Jr, Synlett 2006, 201. M. Sivaprakasam, Sivaprakasam, F. Couty, G. Evano, B. Srinivas, R. Sridhar, K.R. Rao, Synlett 2006, 781. Q. Yuan, S.-Z. Jian, Y.-G. Wang, Synlett 2006, 1113. M. Marradi, A. Brandi, A. de Meijere, Synlett 2006, 1125. W. Van Brabandt, N. De Kimpe, Synlett 2006, 2039. Repic, TJ. X. Jiang, K. Prasad, M. Prashad, lJ. Slade, O. Repi6, T.J. Blacklock, Synlett 2006, 3179. M.-C. Wang, W.-X. Zhao, X.-D. Wang, M.-P. Song, Synlett 2006,3443. 2006, 3443. J.S. Yadav, K.V. Rao, A.R. Prasad, Synlett 2006, 3888. lS. 2006,3888. FJ. F.J. Sayago, M.A. Pradera, C. Gasch, J. Fuentes, Tetrahedron 2006, 62, 915. 62, 1565. L. Troisi, L. Ronzini, C. Granito, L. De Vitis, E. Pindinelli, PindineIli, Tetrahedron 2006, 62,1565. N. Kanomata, S. Yamada, T. Ohhama, A. Fusano, Y. Ochiai, J. Oikawa, M. Yamaguchi, F. Sudo, Tetrahedron 2006,62,4128. 2006, 62, 4128. Y. Naruse, lJ. Ma, K. Takeuchi, T. Nohara, S. 1nagaki, Inagaki, Tetrahedron 2006, 62, 4491. BhaIla, S. Madan, P. Venugopalan, A. Bhalla, Venugopalan, S.S. S.S. Bari, Tetrahedron 2006, 62, 5054. I. Margaros, T. Montagnon, M. Tofi, Vassilikogiannakis, Tetrahedron Toil, E. Pavlakos, G. Vassilikogiannakis, Tetrahedron 2006, 62,5313. 62, 5313. N. Hoshiya, N. Fukuda, H. Maeda, N. Watanabe, M. Matsumoto, Tetrahedron 2006, 62, 5808. A. Liljeblad, L.T. Kanerva, Tetrahedron 2006, 62, 5831. T. Chen, lJ. Gao, M. Shi, Shi, Tetrahedron 2006, 62, 6289. Dejaegher, N. De Kimpe, Tetrahedron B. Van Driessche, W. Van Brabandt, M. D'hooghe, Y. Dejaegher, 2006,62,6882. 2006, 62, 6882. F.A. Macias, V.M.I. Vifiolo, Vinolo, F.R. Fronczek, G.M. Massanet, lM.G. J.M.G. MoliniIlo, Molinillo, Tetrahedron 2006, 62, 7747. 2006,62,7747. R. Schobert, A. Stangl, K. Hannemann, Hannemann, Tetrahedron 2006, 62, 7799. G. Rousseau, L. Blanco, Tetrahedron 2006, 2006,62,7951. 62, 7951. A. Bhalla, BhaIla, P. Venugopalan, Venugopalan, S.S. S.S. Bari, Tetrahedron 2006, 62, 8291. B.L. Ashfeld, S.F. Martin, Tetrahedron 2006, 62,10497. 62, 10497. Chmielewski, Tetrahedron 2006, 62,10928. 62, 10928. T.T. Danh, K. Borsuk, lJ. Solecka, M. Chmielewski,
ring systems Four-membered ring
06T12064 06TI2064 06T12424 06TI2424 06TA199 06TAI99 06TA1319 19 06TA13 06TA1678 06TAI678 06TA2216 06TA2216 06TA2672 06TL425 06TL 1019 06TLIOl9
06TL 1109 06TLII09 06TL 1117 06TLI 117 06TL1737 06TLI737 06TL2205 06TL2209 06TL2527 06TL2667 06TL3701 06TL3875 06TL4393 06TL4601 06TL4995 06TL5255 06TL5257 06TL5393 06TL5665 06TL5883
06TL5993 06TL6031 06TL6057 06TL6377 06TL6835 06TL7893
06TL7923 06TL8407 06TL8503 06TL8855 06TL8911 06TL8977 06TL9113
III 111
L. Troisi, L. L. Ronzini, C. C. Granito, Granito, E. E. Pindinelli, A. A. Troisi, Troisi, T. T. Pilati, Tetrahedron Tetrahedron 2006, 2006, 62, 62, L. 12064. 12064. N. Hoshiya, N. N. Watanabe, H.K. H.K. Ijuin, Ijuin, M. M. Matsumoto, Tetrahedron Tetrahedron 2006, 62, 12424. 12424. Z. Z. Szakonyi, Szakonyi, A. it. Balazs, Bal~izs,T.A. T.A. Martinek, F. F. FulOp, FtilOp,Tetrahedron: Tetrahedron. Asymmetry 2006,17,199. 2006, 17, 199. P. I9. P. Del Del Buttero, G. G. Molteni, Tetrahedron: Asymmetry 2006, 2006, 17, 17, 13 1319. K. K. Tanaka, D. D. Kuchiki, Kuchiki, M.R. M.R. Caira, Caira, Tetrahedron: Asymmetry 2006, 17, 17, 1678. 1678. Koichi Tanaka, Tanaka, Hiroko Takenaka and and Mino R. R. Caira, Caira, Tetrahedron: Asymmetry 2006, 17, 2216. C. Chu, K. Morishita, T. T. Tanaka, M. Hayashi, Tetrahedron: Tetrahedron." Asymmetry 2006, 17, 2672. Hemming, P.A. P.A. Q'Gorman, O'Gorman, M.1. M.I. Page, Tetrahedron Lett. 2006,47,425. 2006, 47, 425. K. Hemming, A. Schneider, Q.E.D. O.E.D. Rodrigues, M.W. Paixao, Paix~o, H.R. Appelt, A.L. Braga, L.A. Wessjohann, 2006, 47, 1019. Tetrahedron Lett. 2006,47,1019. V. Nair, S.M. S.M. Nair, S. S. Devipriya, D. Sethumadhavan, Tetrahedron Lett. 2006,47, 2006, 4 7, 1109. 1109. Prim, C. C. Greek, Greck, Tetrahedron Lett. 2006,47, 2006, 47, I1117. I 17. C. Thomassigny, D. Prim, S.S.F. Chong, Tetrahedron Lett. 2006,47, 2006, 47, 1737. 1737. P. Styring, S.S.F. M. Domostoj, I.I. Ungureanu, A. A. Schoenfelder, P. Klotz, A. Mann, Tetrahedron Lett. 2006, 47, 2205. P. Del Buttero, G. G. Molteni, M. M. Roncoroni, Tetrahedron Lett. 2006,47,2209. 2006, 47, 2209. M. Abe, M. Terazawa, K. K. Nozaki, A. A. Masuyama, T. T. Hayashi, Tetrahedron Lett. 2006, 47, 2527. A. Battaglia, A. Guerrini, E. Baldelli, G. Fontana, G. Varchi, C. Samori, E. Bombardelli, 2006, 47, 2667. Tetrahedron Lett. 2006,47,2667. N. Valls, Vails, M. Borregan, Borreg~in, J. Bonjoch, Tetrahedron Lett. 2006,47,3701. 2006, 47, 3701. S.B. MandaI, Mandal, Tetrahedron Lett. 2006,47,3875. 2006, 47, 3875. A. Roy, B. Achari, S.B. J.S. J.S. Yadav, K.V. K.V. Rao, M.S. Reddy, A.R. Prasad, Tetrahedron Lett. 2006,47,4393. 2006, 47, 4393. 2006, 47, 4601. A. Attygalle, J. Ruzicka, D. Varughese, J. Sayed, Tetrahedron Lett. 2006,47,4601. 2006, 47, 4995. J.S. Yadav, M.S. Reddy, A.R. Prasad, Tetrahedron Lett. 2006,47,4995. A. Bhalla, S. Rathee, S. Madan, P. Venugopalan, S.S. S.S. Bari, Bari, Tetrahedron Lett. 2006,47,5255. 2006, 47, 5255. A. Bhalla, S. Rathee, S. Madan, P. Venugopalan, S.S. S.S. Bari, Tetrahedron Lett. 2006,47,5257. 2006, 47, 5257. M.K. M.K. Ghorai, K. Das, A. Kumar, A. Das, Tetrahedron Lett. 2006,47,5393. 2006, 47, 5393. P. Csom6s, L. Fodor, J. Sinkkonen, K. Pihlaja, G. Bernath, Bern/lth, Tetrahedron Lett. 2006,47,5665. 2006, 47, 5665. M.A. Bonache, C. Cativiela, M.T. M.T. Garcia-L6pez, R. Gonzalez-Muniz, Gonz/dez-Mufiiz, Tetrahedron Lett. 2006, 47, 5883. 47,5883. A.L. Shaikh, V.G. Puranik, A.R.A.S. Deshmukh, Tetrahedron Lett. 2006, 47, 5993. 2006,47,5993. M.S. Chorghade, M.K. M.K. Gurjar, Tetrahedron Lett. D.K. Mohapatra, D. Mondal, R.G. Gonnade, M.S. 2006, 47, 6031. 603 1. Y. Takahashi, H. Kondo, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2006,47, 2006, 47, 6057. A.C.B. Burtoloso, C.R.D. C.R.D. Correia, Tetrahedron Lett. 2006,47,6377. 2006, 47, 6377. W. Miao, W. Xu, Z. Zhang, R. Ma, S.-H. S.-H. Chen, G. Li, Tetrahedron Lett. 2006,47,6835. 2006, 47, 6835. M.H. Nantz, M.J. MJ. Haddadin, M.J. MJ. Kurth, Tetrahedron Lett. 2006, 47, Y.F. Suen, H. Hope, M.H. 7893. S.G. Dumbre, M.I. M.1. Khan, M. Shabab, V.G. Puranik, Tetrahedron Lett. 2006, 47, G. Pandey, S.G. 7923. H.K. Ijuin, Tetrahedron M. Matsumoto, K. Yamada, H. Ishikawa, N. Hoshiya, N. Watanabe, H.K. Lett. 2006, 47, 8407. 2006,47,8407. J.P. Snyder, V. Trajkovic, R.N. Saicic, Z. Ferjancic, R. Matovic, Z. Cekovic, Y. Jiang, J.P. Tetrahedron Lett. 2006, 47, 8503. 2006,47,8503. 2006,47,8855. N. Arumugam, R. Raghunathan, Tetrahedron Lett. 2006, 47, 8855. Fernandez de la Pradilla, A. Flores, Tetrahedron Lett. 2006, 2006,47,891 I. A. Viso, R. Fernfindez 47, 8911. Akritopoulou-Zanze, S.W. S.W. Djuric, Tetrahedron Lett. V. Gracias, A.F. Gasiecki, J.D. Moore, I. Akritopoulou-Zanze, 2006, 47, 8977. Sillanp1Ui, F. Ftil6p, Fiilop, Tetrahedron Lett. 2006, 2006,47,9113. I. Kanizsai, Z. Szakonyi, R. Sillanp~i~i, 47, 9113.
112
5.1 Chapter 5.1
Five-membered ring systems: thiophenes and Se/Te analogues Tomasz Janosik and Jan Bergman Department of of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, SE14157 141 5 7 Huddinge, Sweden (Y. 1.), J.), [email protected] (1. (J. 8.) B.) [email protected] (T.
5.1.1
INTRODUCTION INTRODUCTION
This chapter summarizes the advances in the chemistry of thiophenes, selenophenes and tellurophenes reported during the year 2006. The remarkable productivity in this field is manifested not only in all contributions devoted to fundamental reactivity and properties, but also by the numerous papers dealing with applications of thiophene containing molecules, for instance in medicinal chemistry and materials science. With the objective of providing an overview of general interest, selected examples illustrating the progress in these specialized areas will also be discussed briefly. However, the main focus will be directed towards general ring synthesis and reactions of thiophene derivatives. Several useful specialized reviews have appeared during the reporting period of of this chapter. The chemistry of thienothiophenes <06AHC(90)125> and thienopyrimidines <06AHC(92)83> has been discussed in detail, whereas accounts of related interest highlight of thiaheterohelicenes <060BC2518> <06OBC2518> as well as similar fused thiophene systems the field of <06AG(E)8092>. 5.1.2
THIOPHENE THIOPHENE RING RING SYNTHESIS SYNTHESIS
The boronic ester 1, a useful partner for Suzuki couplings, has been prepared by exposure of the 2-fluorobenzaldehyde 2 to ethyl mercaptoacetate in the presence of a base under microwave irradiation <06JOC3959>. In addition, base induced reactions between ethyl mercaptoacetate and 2-aryl-l-chloroacrylonitriles <06RJ0238>, <06RJO238>, hetarylacetonitriles <06CHC594>, or 6-chloropyrimidine-5-carbaldehydes <06JHCI629> <06JHC1629> resulted in series of ethyl 3-amino-5-arylthiophenene-2-carboxylates, 2-amino-3-hetaryl-4(5H)oxothiophenes, or thieno[2,3-d]pyrimidine-6-carboxylates, respectively. Annulation of 3-(phenylsulfonyl)thieno[2,3-dJpyrimidine-6-carboxylates, pyrazine-2-carbonitrile with ethyl mercaptoacetate gave ethyl 3-aminothieno[2,3-b]pyrazine2-carboxylate in excellent yield <06Tl <06T11124>. of 1124>. A stepwise sequence involving substitution of electron deficient 2-nitrobenzamides with methyl mercaptoacetate, followed by conversion of of
113
systems: thiophenes Five-membered ring systems: thiophenes and Se/Te analogues
the amide unit to a nitrile and final base induced cyclization gave rise to substituted methyl 3b]thiophene-2-carboxylates <06H(68) 1109>. I 109>. aminobenzo[ aminobenzo[b]thiophene-2-carboxylates
t
"J... @/' 9 V:J--
HS/'-..COzEt HS~CO2Et
9
W, 140°C, #W, 140 ~ 30 30 min min !1
o O/SyyCHO
~
0
X _:
K K2CO MeCN 2C0 33,, MeCN
0
b - - B~ ~ c oIt2 E '\t
74% 74%
F
S
2
C~B
1
A one-pot variant of of the Gewald thiophene synthesis involving aryl alkyl ketones provided a series of 2-amino-4-arylthiophene derivatives <06SL2559>, whereas new conditions for the Knoevenagel/Gewald sequence have also been established. This approach utilized hexamethyldisilazane and acetic acid for the condensation step, followed by NaHC03, giving for treatment of the resulting intermediate with sulfur in the presence of NaHCO3, 13 I 1>. The Gewald reaction has also instance 2-amino-3-cyanothiophene 2-amino-3-cyanothiophene derivatives <06TI <06T11311>. been employed for preparation of of 2-amino-5-(phosphonomethyl)thiophenes 2-amino-5-(phosphonomethyl)thiophenes <06PSS601>. In addition, a variant using a functional ionic liquid as a soluble support leading to 2aminothiophene-3-carboxylates has been developed <06H(68)375>. <06H(68)375>. Yet another "classical" thiophene synthesis, namely the reaction of 1,4-diketones with Lawesson's reagent, has been employed for the construction of I ,2-b]thiophene skeleton <06JHC629>. of the indeno[ 1,2-b]thiophene of trisubstituted thiophenes in a The precursor 3 served as a starting material for a series of study towards progesterone receptor modulators, giving for example the product 4 upon reaction with an appropriate bromoketone. The fact that rather complex thiophene derivatives could be prepared in a straightforward manner compensates for the low overall yields <06JHC1391>.
/~" N
~ N,~
O"v~
S
+ CI c
o
~ '-":::
1. Et3N, 65°C
2. p-TsOH, p-TsOH, acetone 2. acetone CI CI Sr _ _re_fi_ux _ gr reflux 21% 21%
---..._
//
o 4
An approach to dibenzothiophenes dibenzothiophenes involving a benzyne intermediate has been developed, wherein the required precursor 5, which is available in three steps from 2-fluorothiophenol, 2-fluorothiophenol, underwent lithiation giving the species 6, which could thereafter be treated with various electrophiles rendering the final products 7 <06JOC6291 <06JOC6291>. >. F I
O--s:O 5
I-BuLi t-BuLi (3.3 equiv) (3.3 equiv) THF, -78°C THF,-78 ~ to to 00 °C ~
" 0] [~ ~ .~
E+, -78 ~ to 20 ~_•_ _E_+,_-7_8o_C_to_20_oC
LSi
6
E
=
75-79% 75-79%
~
Vs-V
E SPh, Br, E = H, H, SPh, Br, 4-MeC 4-MeCsH4C(H)OH 6 H4 C(H)OH
7
7
Electrophilic cyclization of of the precursors 8, which are available from 3(methylthio)pyridine by regioselective lithiation, followed by introduction of CBr4, CBr4, and a subsequent Sonogashira coupling, has resulted in a series of of thieno[3,2-b]pyridines 9
1 14 114
T. Janosik and and J. Bergman T. Bergman
<06T6036>. It should also be mentioned that an isomeric series ofthieno[2,3-b]pyridines of thieno[2,3-b]pyridines has been prepared by base induced annulations involving for instance 2-mercaptopyridine-3carbonitrile precursors and ethyl chloroacetate <06SC97>.
o::: SMe
~ I N
~
8 8
E+ E* (12, (12, Br2' Br2, or NBS) CH CH2CI rt, 30 30 min min _-2 CI 22,, rt, 42-88% 42-88%
R R
IN E jNit---{E ~'/~"~..._~S ~
R ~->S R
E=Br, E =Br, I R= R = Ph, Ph, TMS
9
Intramolecular palladium catalyzed thio-enolate S-arylation has been used in a route to a set of fused benzo[ b]thiophenes, as illustrated by the conversion of the substrate 10 into the benzo[b]thiophenes, product 11 <06TlI513>. <06T 11513>.
I
",,51!
[ ~ g
(XB~
Pd Pd2(dba)3 (2.5 mol%), mol%), DPEphos (6 mol%) 2(dbah (2.5 CS Cs2CO PhMe, 100 °C ~ ,. 2C0 3, 3 , PhMe, 57%
OeD S
r
11 11
10
A series of benzo[b]benzo[2,3-d]thiophen-6,9-diones benzo[b]benzo[2,3-d]thiophen-6,9-diones 12 has been prepared in modest yields by palladium mediated cyclization of the precursors 13. However, the necessity to use stoichiometric amounts of the palladium source precludes cost effective preparation of the targets. The required substrates 13 may be constructed by palladium catalyzed reactions <06SC3319>. between the appropriate phenols with 2,3-dimethylbenzoquinone <06SC33 19>.
o Me~.. Me
S
O
Me ;3 o
~ .
13
R3
Pd(OAch, Pd(OAc)2, AcOH AcOH reflux, reflux, 1 d
R2
23-51%
,. Me
R'
R2
o
1 RI=H,F R =H, F 2 H, R2= H, CI CI R OMe, F, CI R33 = H, Me, OMe,
=
R1 12
Gold catalyzed reactions are currently enjoying considerable interest, interest, and have also found applications in thiophene ring synthesis. A series of (u-alkoxyalkyl)(o-alkynylphenyl) (a-alkoxyalkyl)(o-alkynylphenyl) AuC1, giving the sulfides 14 was subjected to treatment with catalytic amounts of AuCl, benzo[b]thiophenes 15 in excellent yields. Some additional, more complex examples were also provided <06AG(E)4473>.
AuCI(2 (2 mol%), mol%),PhMe, PhMe,25 25 °C. ~ AuCI OMe 14
85%-quant. 85%-quant.
o
Me ~OMe
~->-~ S R
R = Pr, Ph, Ph, cyciohexyl, cyclohexyl, t-Bu, t-Bu, C0 CO2Et, 2Et, 4-F 4-F3CC6H 4-MeOC6H sH44 3CC sH44,, 4-MeOC
15
The first gold catalyzed C-S bond formation was demonstrated in a route to the 2,5via cycloisomerization of the allene 17 which occurred with high dihydrothiophene 16 via chirality transfer (d.r. > 95:5) <06AG(E)1897>. <06AG(E) 1897>.
115
Five-membered ring systems: thiophenes and Se/Te analogues Five-membered
Me Me
Me Me
~f~-~, r=< /OBn OBn
, rt AuCI (5 i-Pr@"~_ ....~OBn AuCI (5mol%), mol%),CH CH2CI rt 2CI 22, i-prJJ"""-OBn 86% SH 86% : H 17
i-pr~s)"''/ i-Pr '"
H
16
The intriguing circulene 18 has been prepared from the precursor 19 by initial exhaustive C-2 metalation, followed by introduction of elemental sulfur, and quenching with aqueous hydrochloric acid. This set of operations resulted in a polythiol, which was eventually converted to the target heterocycle 18 by vacuum pyrolysis <06AG(E)7367>. S,
LDA(16
'/' S
S
S
Et20
1. 1. LOA (16 equiv.), equiv.), Et2 0 2. 2. S8, $8, then then aq. aq. HCI HCI 3. 3. Vacuum Vacuum pyrolysis pyrolysis
,S'~ /'~S ,,
S~ S
/~S
y s--4.sYS S 18
19
A series of 3-oxothiophene derivatives has been prepared by intramolecular thia-antiMichael addition of a thiol anion to an enone functionality, resulting for instance in preparation of the target 20 by treatment of the precursor 21 with an amine <06JOC8006>. 0o
CI cI
0o
I~NHPh ~NHPh 21
S S ~/ LJ
~
BnNH 2, DMSO,120~ 1h. ~ ~ I 87%
BnNH 2 , DMSO, 120 °C, 1 h.
/ CI CI
87%
oo oO ~ N H PNHPh h
'\
~
\ SS / ~NHBn NHBn
20
It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3"OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also BF3·OEt2 found to give minor amounts of lactone or dithiolactone side products <06TL6067>. Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,51,4-dithiane-2,5diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction <06TL8087>.
S~C6H13 S C6H13 ee) 22 (98% eel
BF 33 Et Et20 (10 mol%) mol%) 20 (10 PhMe, reflux Ph Me, reflux 70% 70%
=
/ ~
O '"C6H13 O~"'C6H13 23 (97% (97% ee)
A series of functionalized tetrahydrothiophenes has been prepared by acid induced organocatalytic reactions involving a,p-unsaturated a,13-unsaturated aldehydes and 2-mercapto-l2-mercapto-1phenylethanone 24. This procedure led to good yields of products displaying useful enantiomeric excess, as illustrated by construction of the target 25 in the presence of the catalyst 26 <06JA <06JAI4986>. 14986>.
116 116
T. Janosik and and 1. J. Bergman T Bergman
o O
pr~ C H O + ~ Pr~CHO+ U ~HH ~ S
OH .CHO 26 (10 26 (10moI%) m~176176P hQH ~ CHO PhC022 H, H, PhMe. PhMe PhC0 74% (95% (95% eel ee) 74%
Phti S
24
Pr Pr
~r
/\
~ ' ~ A r Ar 'NJH OTMS OTMS 26
Ar = Ar = 3,5-(CF3h-C6H3 3,5-(CF3)2-C6H3
25
Formation of partially saturated thiophene derivatives has also been observed as products resulting from radical reactions of of thiophenol with S-4-pentynylcarbamothioates <06JOC3192>, irradiation of <06JOC3192>, of the sultam 27 at 300 nm in hexane, which leads to the fused <06JOC8438>, or photoisomerization of 4-anisyl-4-methylsystem 28 as the major product <06JOC8438>, 2,6-diphenyl-4H-thiopyran-l,1-dioxide <06JHC167>. 2,6-diphenyl-4H-thiopyran- 1,1-dioxide <06JHC 167>. Routes to L-~-3'-deoxy-3',3'-dif1uoro L-[3-3'-deoxy-3',3'-difluoro4'-thionucleosides <060L6083> <060L4593> have also <06OL6083> and a ketone analogue of biotin <06OL4593> been devised.
H
~) oo"~ 0 27
28
Generation and trapping of tropothione 29 with dienophiles has been utilized in an approach to partially saturated fused thiophene molecules. For example, treatment oftropone of tropone with Lawesson's reagent in benzene, followed by introduction of of N-phenylmaleimide gave the adduct 30 in excellent yield <06TL9329>.
o
Ph
,awessonsrea0ent Phil, rt
S H
&O
~
90% 29
0
~v1i_Ph
= /~ H ~ / N . . p h ~~
o 30
Heating of the sulfoxide 31 causes a Pummerer rearrangement generating the ylide 32, which could be trapped with dimethyl acetylenedicarboxylate (DMAD) giving the dihydrothiophene derivative 33 <06HC648>.
,,. M e O 2 C ~ cO2Me -] DMAD 59%
TMS/~S/~TM S DMPU, DMPU,100 100~"C. [[ ~s/ %~/- ] TMS/'-~/'-TMS iio 31
5.1.3
32
DMAD 59%
33
REACTIONS OF THIOPHENES THIOPHENES REACTIONS OF
Again, the ease of of bromine-lithium exchange at the 2-position of thiophenes has been demonstrated by conversion of the tetrabrominated trithiophene 34 (available by exhaustive bromination of the parent tricyclic compound) into the system 35, which is a useful building <06JOC3264>. Regioselective metalation has block for extended fused thiophene systems <06JOC3264>. also been employed en en route r o u t e to 2,3-bis(phosphanyl)benzo[b]thiophene 2,3-bis(phosphanyl)benzo[b]thiophene ligands for <06EJO2100>. Metalated thiophenes have stereoselective transition metal catalyzed reactions <06£J02100>.
117
Five-membered ring systems: systems." thiophenes and Se/Te analogues
also been reacted with aromatic nitriles, followed by reduction with NaBH4, NaBH4, giving 2thienylmethylamine derivatives <06S1858>. <06S 1858>. Br fu
Br fu
M
Br Br
y"
1.BuLi(2.1equiv.)THF,-78'C,3h Br Br _2_._T_M_S_C_I(;....2_.5_e.....:q_ui_v.-' 2. TMSCI (2.5 equiv.),--),_-7_8_' -78 ~_C
'-':::
Sh~S
M Br fu
= TMS
80% 80%
S
Br fu
y"
'-':::
Sh~S
TMS MS
S
34 M
35 ~
An interesting example of trilithiation has been reported, wherein 3(methylthio)thiophene 36 was exposed to the powerful base system LICKOR (tBuOKlBuLi), giving direct access to the products 37 after quenching of the intermediate 38 BuOK/BuLi), with suitable electrophiles. Reactions involving 2-(methylthio)thiophene gave 2,5disubstituted products resulting from a dilithiated intermediate <06S3855>.
Li
riSMe IL.._'SJ>
E
S J S---/ Li] 2.1.1"E+E*~+(6(6 equiv.), 8 ri equiv')'HTHF, THF' -78 -78 'C ~ THF, -78 'C --<_' 5 >--2 H' ----"'-"--'-'--''---'='---.- Li S Li -·---4-8--8-4-%---Li 48-84% -" rLi LICKOR THF, UCKOR(6equi ~ (6~ _equiv.) v') 7
36
38
rl
S J S---/
E.-J(S>--'E E E
E allyl, C02H, E = Me, Me, allyl, CO2H,CHO, CHO, TMS TMS
37 37
Transition metal catalyzed coupling reactions constitute some of the most powerful and versatile tools for manipulation of thiophene derivatives and are clearly one of the most dominant fields in current thiophene chemistry. Several potentially useful strategies of this type have been elaborated during the past year. An interesting synthesis of 2,3diarylthiophenes has been described, wherein for instance the 3-thiophenemethanol derivative 39 was subjected to treatment with aryl bromides in the presence of a palladium catalyst, leading to the product 40, as well as many similar molecules. The series of events leading to this outcome features cleavage of the C-H and C-C bonds at the 2- and 3-positions of the thiophene substrates <06JOC8309>. CI
~~~ it h
~
/
Ph
- OH OH
4-CIC 4-ClC6H4Br eH4 Br Pd(OAch, Pd(OAc)2,P(biphenyI-2-yI)(t-Buh P(biphenyl-2-yl)(t-Bu)2 CS Me, reflux 0s2003, PhMe, reflux 2C0 3 , Ph
---=-----"'---8'-60;.-0- - - -
86%
S
39
CI
40
A tandem palladium catalyzed multi-component approach has been devised providing direct access to for instance trisubstituted thiophenes from the simple starting material 3iodothiophene 41. In a representative experiment, the substrate 41 was converted to the product 42 by treatment with ethyl acrylate and iodobutane in the presence of a catalytic system consisting of Pd(OAc)2, tri(2-furyl)phosphine (TFP), norbomene, and a base. A mechanistic rationale accounting for this outcome was also proposed <06013939>. <06OL3939>.
1 18 118
T. Janosik and and J. Bergman T Bergman
o
I
B"tf::
Pd(OAc)2 (10 mol%), mol%), TFP (20 mol%) Pd(OAcl2 Bul (10 equiv.), methyl methyl acrylate (2 equiv.) norbornene norbornene (6 equiv.), equiv.), CS 0s2003, CH3CN, ~ 1d 2C0 3 , CH 3CN, 80 'C,
S 40
96% 96%
COzEt ~~,~/''O2Et
Bu
/
S
9
-
Su Bu
41
It has been demonstrated that bromothiophenes bromothiophenes may undergo palladium catalyzed C-H C-H 2,2'-bithiophenes, an important class of of homocoupling providing a new route to halogenated 2,2'-bithiophenes, building blocks for oligothiophene synthesis. For example, the alcohol 42 could be converted to the 2,2'-bithiophene 2,2'-bithiophene derivative 43 in good yield, suggesting useful functional group tolerance <06JA 10930>. (CH2)4OH
HO(H2C)4 (CH2)4OH HO(HZC)4~(CHZ)40H
PdCI PdCI2(PhCN)2 mol%) 2(PhCNl2 (3 mol%) AgN0 AgNO3/KF, DMSO, 60 'C ~ 3/KF, DMSO,
J-K~ o ~ Br S S Sr
70% 70%
Br
Br" Sr
43
42
Exposure of the benzo[b]thiophene benzo[b]thiophene derivative 44 to a palladium catalyst in the presence of of tri(2-furyl)phosphine (TFP) as the ligand led to the product 45, which incorporated two heterocyclic units from the starting material. The mechanistic aspects of of this transformation were also discussed, which appears to involve palladacycle intermediates <06JA722>.
B , . ~ - - - - ~ ,~r
Q{ S
CONHMe CONHMe
Pd(OAc)2 Pd(OAc)2 (5 mol%), mol%), TFP (10 mol%) mol%) K K2CO DMF, 105 'C, ~ 20 h 2C0 33,, DMF,
75%
44
O 45
The dithienyldienyne 46, which was prepared by sequential palladium catalyzed couplings, underwent intramolecular annulation to compound 47 in excellent yield. Similar <060LlI97>. cyclizations involving closely related substrates were also studied <06OL 1197>. Pd(OAcl2 Pd(OAc)2 (0.2 (0.2 equiv.), equiv.), PPh PPh3 (0.4 equiv.) 3 (0.4 BU4NBr, Bu4NBr, K K2CO DMF, 80 'C ~ 2C0 33,, DMF,
87%
46
47
of 3-iodothiophene-2-carboxylic 3-iodothiophene-2-carboxylic acid 48 with two Palladium/copper catalyzed reactions of equivalents of a terminal alkyne gives selective access to 5-substituted 4-alkynylthieno[2,3c]pyran-7-ones, for example the system 49 <06TL83, 06T9554>.
119 119
Five-membered ring systems: thiophenes and SelTe Five-membered Se/Te analogues
.OPh OPh OPh OPh
=--.// I
equiv.) (2 equiv.) OPh
PdC1 PdCI2(PPh3) Cul (cat.) 2 (pPh 3 h2 (cat.), Cui Et Et3N, ~ 3 N, DMF, 70-80 °C
C02H
75% 75%
o 48 48
49 49
Other new studies studies involving thiophenes in transition metal catalyzed couplings couplings encompass generation and coupling of thiophene-3-boronic acid acid derivatives giving 3,4di(thien-3-yl)maleimides di(thien-3-yl)maleimides <06RJ01490>, <06RJO1490>, and Suzuki Suzuki couplings of 3,4-bis(5-iodo-2methylthien-3-yl)-2,5-dihydrothiophene methylthien-3-yl)-2,5-dihydrothiophene <06SL737> or benzo[b]thiophene boronic acid <06TL3365>. Thiophene boronic boronic esters esters have also also been prepared by iridium iridium catalyzed borylation, and were converted to regioregular poly(alkylthiophenes) poly(alkylthiophenes) using Suzuki Suzuki reactions <06TL5143>. Synthetic sequences sequences featuring Kumada and Suzuki Suzuki reactions have also also been used for construction of thiophenes bearing four thienyl substituents <06AFM917>. Negishi coupling involving 2-iodo-(3,4-ethylendioxythiophene) 2-iodo-(3,4-ethylendioxythiophene) 5-carbaldehyde has been used during synthesis of a thiophene backbone amide amide linker for solid solid phase chemistry <06JOC6734>, en route whereas Negishi reactions of 2-bromothiophene have found found use en route to fused fused thiophenephenylene chromophores <06OL5033>. <060L5033>. Applications of the Sonogashira reaction encompass coupling of brominated 2,2'-bithiophenes 2,2'-bithiophenes leading to two-photon absorption chromophores central 2,2'-bithiophene motif <06T8467>, and preparation of oligo(2,5containing a central thienyleneethynylene) thienyleneethynylene) materials by repetitive Sonogashira reactions <06EJ0405, <06EJO405, 06S1009>. 06S 1009>. Sonogashira coupling of halothiophenes may also also be conducted in water solution solution using palladium on charcoal charcoal as the catalyst in the presence of PPh PPh3, CuI, and 2-aminoethanol 3 , CuI, <06BMCL6185>. A study on the reactivity of bromothiophene carboxylates in palladium catalyzed amination with hetaryl amines amines has also also been conducted <06S2794>, whereas copper catalyzed reactions of thienylboronic acids acids with azo compounds compounds gives rise to 2,8thienylhydrazine derivatives <060L43>. <06OL43>. Palladium catalyzed amination of 2,8dibromodibenzothiophene-S,S-dioxide dibromodibenzothiophene-S,S-dioxide with diarylamines provided access access to materials for organic light emitting devices <06AM602>. Several bromothiophenes have also also been aminated with various azoles in the presence of CuI in the ionic 4, as ionic liquid liquid [Bmim]BF [Bmim]BF4, illustrated by the synthesis synthesis of compound 50 <06T4756>.
n
ZS/--Br Br
benzimidazole benzimidazole Cul/L-proline,K Cul/L-proline,K2CO _- ~ 2C0 33 [Bmim]BF 4, 105-115 [Bmim]BF4, 105-115 °C ~
76% 76%
m 50
A protocol for palladium catalyzed direct C-H arylation of thieno[2,3-b]thiophenes thieno[2,3-b]thiophenes has been developed <06SL2423>. Likewise, 3-cyanobenzo[b]thiophene 3-cyanobenzo[b]thiophene 51 51 undergoes coupling with aryl bromides in the presence of a palladium catalyst to provide a series series of 2-aryl derivatives, for example the product 52 <06SL2016>. <06SL2016>. Direct C-H arylation catalyzed by also been carried out employing 3-methoxythiophene, leading to 2palladium acetate has also aryl-3-methoxythiophene derivatives. derivatives. Extensions involving 2-bromothiophenes as the aryl-3-methoxythiophene coupling partners enabled preparation of new oligothiophene systems <06TL9249> Thiophenes may also also be arylated using aryl iodides iodides in the presence of a rhodium catalyst <06JAl1748>. <06JA11748>.
120
T. Janosik and and J. T. J Bergman Bergman
CN 3-(i-PrO)C6H4Br, Pd(OAc)2(5(5mol%) mol%) 3-(i-PrO)C sH4 Br, Pd(OAcb K2CO DCH-18-C-6,DMF, DMF,140°C 140~ .. , DCH-18-C-6, K 2C0 33, ~-~ 82% 82% S r\--/CN
51
~ CN
~
h
~
CN~
--..;: Oi-Pr Oi Pr
\ ~
S
52
Irradiation of the readily available diamide precursor 53 in DMF solution gave the fused system 54 in excellent yield. This material could be subsequently chlorinated using POCb, POC13, and dehalogenated by catalytic hydrogenation to the parent ring system bis[ 1]benzothieno[2,3-c:3 1]benzothieno[2,3-c:3',2'-i][ 1,10]phenanthroline 10]phenanthroline <06S 1402>. Photocyclization reactions ',2'-i] [1, have also been employed in a route to new tetrathia[7]helicenes <06S3670>. Some other related helical aromatics have been prepared by intramolecular coupling of adjacent thiophene units via their 3-positions using FeC13 FeCb in chloroform and nitromethane <06TLl551>. <06TL1551>.
S~O
CI CI~s
hv,DMF=
hv, DMF
900/0 90%
•
0 53
0
54
Interconversion of functional groups at the thiophene ring is a common strategy to access further useful derivatives. A set ofthiophene-2-isocyanates of thiophene-2-isocyanates has been obtained by N-silylation of the corresponding 2-aminothiophenes, followed by treatment of the resulting intermediates with phosgene <06RJG 110>. Thiophene-2-carbaldehydes may be transformed to their <06RJGll0>. corresponding 1,3-diselenanes <06RJGl123> <06RJG1123> or dithioacetals <06RJ0256> <06RJO256> by exposure to propane-1,3-diselenol or ethane-1 ,2-dithiol, respectively, in the presence of TMSCI. ethane-1,2-dithiol, TMSC1. A study of Sharpless asymmetric dihydroxylation of thienyl- and (benzothienyl)acrylates has also been published <06TA29l9>. <06TA2919>. Nucleophilic displacement of of both bromine atoms in 3,3'dibromo-2,2'-bithiophene with NaS(i-Pr), followed by S-dealkylation and oxidative cyclization of the resulting thiol functionalities gave dithieno[3,2-c:2',3'-e][1,2]dithiin 1-b:3,4-b']dithiophen-4-one resulted <06PSS 191>. Studies on a synthesis of 4H-cyclopenta[2, 4H-cyclopenta[2,1-b:3,4-b']dithiophen-4-one <06S 1760>. in isolation of the unexpected product bis[bis(2-iodo-3-thienyl)methyl]ether <06S1760>. Moreover, chiral diamino-thiophene derivatives have been prepared by reduction of imines generated from thiophenecarbaldehydes and (R,R)-1,2-cyclohexanediamine, (R,R)-l,2-cyclohexanediamine, and were investigated as ligands for asymmetric catalysis <06ASC1521, 06CEJ667>. Additional contributions worth mentioning in this context encompass preparation of of [n ](2,5)thiophenophane-1 ,n-diones <06JOC6516>, [3,3]dithiacyclophanes featuring thieno[n](2,5)thiophenophane-l,n-diones [2,3-b]thiophene motifs <06TL5599>, 3,4-dicycloalkoxy-2,5-diethoxycarbonylthiophenes <06JHClOl>, as well as synthesis <06TL4635>, a thieno analogue of a cooked food mutagen <06JHC101>, of styryl substituted oligothienylenevinylenes using Wittig reactions <06T2190>. of thiophene derivatives detail biohydrolysis of (S)Additional studies featuring reactions of 3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of 1,1-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee
Five-membered ring ring systems: systems: thiophenes Five-membered thiophenes and Se/Te Se/Te analogues analogues
121
of the thiotetronic acid aroma component <06TL787>. A new route to 5-vinyl derivatives of Homer-Wadsworth-Emmons natural product thiolactomycin has also been elaborated using Horner-Wadsworth-Emmons reactions for the key transformations <06TL3447>. It should also be mentioned that a study of of 1,3-dipolar cycloadditions of benzo[b]thiophene-S,S-dioxide benzo[b]thiophene-S,S-dioxide with azomethine ylides has b]thiophene been performed, leading to formation of partially saturated pyrrolo-fused benzo[ benzo[b]thiophene derivatives, for instance 56, as mixtures of of isomers <06TL5139>. Cyanation ofthiophenes of thiophenes at C-2 has been achieved using TMSCN in combination with a recyclable polyvalent iodine(III) reagent based on an adamantane core <06CPB1608>. <06CPB1608>. In addition, syntheses of several partially hydrogenated 4,6-dimethyldibenzothiophenes 4,6-dimethyldibenzothiophenes have been reported <06HCAI623>. <06HCA1623>.
~ S
Me
55 56
Some theoretical aspects of of thiophene reactivity and structure have also been discussed, for example the kinetics of proton transfer from 2,3-dihydrobenzo[b]thiophene-2-one 2,3-dihydrobenzo[b]thiophene-2-one <06JOC8203>, the configuration of imines derived from thiophenecarbaldehydes <06JOC8203>, <06JOC7165>, and the relative stability of benzo[c]thiophene <06JOC7165>, benzo[c]thiophene <06Tl2204>. <06T12204>. The kinetics of 2-substituted-5-nitrothiophenes in room nucleophilic aromatic substitution of of some 2-substituted-5-nitrothiophenes temperature ionic liquids have also been investigated <06JOC5144>. 5.1.4
NON-POLYMERIC NON-POLYMERIC THIOPHENE THIOPHENE ORGANIC ORGANIC MATERIALS MATERIALS
The field of thiophene containing diarylethenes continues to attract considerable interest. Many of of the structures display interesting properties, and could be useful in design of new electronic devices. For example, it has been shown that the photochromic properties of the system 57 may be modulated by addition of fluoride ions, which shifted the absorption I>. Diarylethenes featuring thiophene units bearing maximum from 655 to 490 nm <060L391 <06OL3911>. pKa phenolic and pyridyl substituents have been prepared, and were demonstrated to exhibit pKa changes upon irradiation <06CEJ4283>. Self assembly at different temperatures was observed during studies of of dithienylethenes possessing aryl substituents extended with hexaethylene glycol chains in aqueous solution, resulting from different aggregation properties of of the open and closed forms of the system <06JOC7499>. <06JOC7499>. Further extensions involve design of dithienylmaleimide switches incorporating ferrocene moieties controllable by irradiation or electrochemical redox reactions <06TL9227>, or molecular switches based on dithienylperfluorocyclopentene bearing imidazo[4,5-J][1,10]phenanthroline imidazo[4,5-j] [1,1 O]phenanthroline units <06T10072>. <06Tl 0072>. In addition, it has been demonstrated that photochromic cyclopentenes based on benzo[b]thiophene-S,S-dioxide <06CCI881, benzo[b]thiophene-S,S-dioxide units display high fatigue resistance <06CC1881, 06T5855>. Studies of of the photochromic properties of of an unsymmetrical benzo[b]thiophene system and an indene unit perfluorocyclopentene bearing one benzo[b]thiophene <06TLI267> or symmetrical systems with two thiophene units bearing fluorophenyl groups <06TL1267> <06TL3 I67> have also been carried out. <06TL3167>
122
T. Bergman T. Janosik and and 1. J. Bergman
~Qr \ ~~ (MeshB~~B(Mesh
I
Vis
(Mes)2B
B(Mes)2
~
Jb
UV
I
(Mes)2B (MeshB
57
S
\
S
B(Mes)2 B(Mesh
The unsymmetrical system 58 incorporating donor and acceptor motifs has been prepared by sequential nitration, iodination, and Stille coupling from the parent 1,2-bis(2methylbenzo[b]thiophen-3-yl)perfluorocyclopentene, methylbenzo[ b]thiophen-3-yl)perfluorocyclopentene, and was investigated as a device for <06T68 14>. Upon coordination of the 1,10photo induced electrochemical switching <06T6814>. 1,10phenanthroline ligand 59 to a rhenium(I) tricarbonyl complex, a system was obtained where the photochromism was extended from intraligand excitation to metal-to-ligand chargetransfer excitation <06CEJ5840>. The photochromic reactions in single crystals of 1,2-bis(51,2-bis(5carboxyl-2-methyl-3-thienyl)perfluorocyclopentene, as well as co-crystals with bipyridines with intermolecular hydrogen bonding networks have also been studied <06CEJ4275>. Intramolecular hydrogen bonding has also been established to play a major role during diastereoselective cyclization of a dithienylhexafluoropentene carrying (R)-N-phenethylamide substituents <06OBC1002>. <060BC I002>. The fulvene 60 has been shown to participate in a Diels-Alder reaction with an electron deficient alkene, and the resulting adduct was thereafter locked by closing the dithienylethene unit by irradiation at 313 nm. The reverse reaction occurred upon opening the system by irradiation at wavelengths over 434 nm, whereupon the alkene was released <06AG(E)6820>. E
F
--N
N--
CI CI
58
CI CI
59
60
The benzothieno[3,2-b]benzothiophene 61 is a new semiconductor for air stable organic field effect transistors (FET) <06JA12604>. <06JA I2604>. A set of fused benzene-thiophene structures have been included in a study evaluating their vibronic coupling characteristics <06CEJ2073>. Likewise, the molecule 62 and two closely related structures have been investigated as materials for organic thin film transistors <06AFM426>. A series of related ring fused thiophenes have been investigated in connection with their solid state properties <06CM3470>. S S
s
iii-in
.s.
.s ~s~s~ 61
62
The dithieno[3,2-b:2',3'-dJphosphole dithieno[3,2-b:2',3'-d]phosphole 63 has been designed as a very sensitive material dithieno[3,2-b:2',3'-d]phospholes <060L495>. Cationic dithieno[3,2-b:2',3'-dJphospholes for detection of fluoride ions <06OL495>. alkylated at the phosphorus atom have also been prepared for application as building blocks
123
Five-membered ring Five-membered ring systems: systems: thiophenes thiophenes and SeiTe Se/Te analogues
<06OL5893>. Derivatives of of this skeleton for luminescent conjugated polyelectrolytes <060L5893>. <060L503>. The impact on the electronic bearing SiMe2H groups have also been studied <06OL503>. properties of di(2-thienyl)phospholes by modification of the phosphorus substitution has been monitored using Raman spectroscopy <06CEJ3759>. <06CEJ3759>. Some other examples of of studies concerning thiophene containing materials encompass preparation of the donor-acceptordonor-acceptordonor type liquid crystal 64 <060L4699>, <06OL4699>, evaluation of the properties of the thienoquinoid system 65 <060L5235>, <06OL5235>, and probing of the solvatochromic behaviour of of some thienylpyrroles, for example 66 <06OL3681 <060L368 I>. >.
~q
S
p~
S
~O/B~B'oK
C12H2So i~],~,N=N L./o
/p,
0/ Ph 63
o
64
NcACN 0o
NC
NC .CN NC~CN
\ s ~$'~] i~~ /, / ~L~
CN
CN CN
CN CN
Pr Pr
66
65
5.1.5
12H2s
THIOPHENE OLIGOMERS OLIGOMERS AND POLYMERS POLYMERS THIOPHENE
Numerous studies have been devoted to 2,2'-bithiophene based systems. Several diborylated structures, for example 67, have been included in a study investigating electronic communication between the boron centers and binding pyridine rings <06JAI6554>. <06JA16554>. The of the electronic properties of the dimer 68, as well as the synthesis and evaluation of corresponding trimer have been described <06CEJ2960>. <06CEJ2960>. 2,2'-Bithiophenes bearing perfluoroaryl groups have also been prepared and studied as blue light emitting materials <06CM3261>. Other studies of push-pull 2,2'-bithiophenes of related interest encompass push-pull + possessing amino and cyanovinyl groups <06JOC7509>, <06JOC7509>, fluorescent indicators for Ca22+ o-aminophenol-N,N,Obased on the 2,2'-bithiophene core substituted with the chelator o-aminophenol-N,N,Otriacetic acid <06T684>, and an octaethylporphyrin-dihexyl-2,2'-bithiophene-pyridine octaethylporphyrin-dihexyl-2,2'-bithiophene-pyridine system interlinked with diacetylene units <06TL5585>.
Q
~/F5
r~
F50~~ YB B ~/, h
o
S
O
~ F5 F5
S
V
I
67 67
F5
F5
0
~ b o0
68 68
0
0
,~
Likewise, a number ofterthiophenes of terthiophenes have been prepared and studied. For example, radical cations of the system 69 end-capped by bicyclo[2.2.2]octane units have been found to form centrally attracted bent ~-dimers n-dimers <06JAI4470>. <06JA14470>. The trimer 70 has been included in a
124 124
T. Bergman T. Janosik and 1. J. Bergman
of a series of related molecules <06JA5792>. High systematic probing of the properties of resolution electronic spectra of several ethylenedioxythiophene oligomers, among others the <06JAI7007>. A thiophene silyl terminated compound 71, have been recorded and discussed <06JA17007>. tetramer end-capped with 2-pyridyl units has also been reported in connection with syntheses of several related oligomers <06H(68) 1349>. Incorporation ofhexafluoropentene <06H(68)1349>. of hexafluoropentene units in the system 72 enabled lowering of the LUMO level without disturbing the conjugation efficiency. The construction of this molecule involved preparation and coupling of of 1,3dibromohexafluorocyclopenta[c]thiophene <060L538 I>. Other studies include a,co-capped <06OL5381>. sexithiophenes bearing fluorenyl <06CM3151> or tricyanovinyl <06CEJ5458> units, whereas the self assembly of oligothiophenes with chiral oligoethylene chains attached via ester linkages has been investigated <06JA5923>. The parent sexithiophene has also been demonstrated to form inclusion complexes upon mixing with polysaccharides, in which the oligothiophene adapts a twisted conformation in the chiral channel formed by helical wrapping of the polysaccharide hosts <060L235>. <06OL235>. A one pot procedure for construction of symmetric octithiophenes from 4-(alkylthio)-2,2'-bithiophene derivatives has also been described <06MAC8293>. Finally, several reports of of various aspects of quinoid oligothiophene derivatives have appeared <06TL5375, 06JAI0134, 06JA 10134, 06CMI539>. 06CM 1539>.
F
69 /~k / \
0
0
0
F
F
/--k / \
0
F
F
70
TMS MS
TMS 0
0 k__/ "----I
0O,k~/0 0
F
"----I
71 71
C6F13 F13 C6
F
Y~
F. F F
F F C6F13
S F F
F F
F F
72
There are also many examples of of materials containing thiophenes in combination with other conjugated units, for instance decyl end-capped thiophene-phenylene oligomers with improved oxidation stability for semiconductor applications <06CM579>. A molecule incorporating octithiophene, quaterthiophene, and fullerene units linked by saturated <06JOC1761>. fragments has been investigated as a long distance charge separation system <06JOCI761>. Liquid crystalline field effect transistors based on 5,5"-bis(5-alkyl-2-thienylethynyl)2,2':5',2"-terthiophenes have been devised <06JA2336, 06AM896>. The system 73 has been designed as a molecular wire which displayed electrochemical switching between an insulating and a conducting state <060Ll83>. <06OL 183>. In addition, a synthetic route to monodisperse oligo[1 ,4-phenyleneethynylene)-alt-(2,5-thiopheneethynylene)] systems has been described oligo[1,4-phenyleneethynylene)-alt-(2,5-thiopheneethynylene)] <06T2576>.
125
Five-membered ring systems: systems." thiophenes thiophenes and SeiTe Se/Te analogues
06H13 CN.~ ~ ~
~
CN
06H13 ~
S
~
NC
NC
73 Numerous publications include studies of thiophene containing polymers, for instance materials based on thieno[3,4-b]thiophene units <06MAC3l18>, <06MAC3118>, or the polymer 74 <06CEJ8075>. Visualization of enzymatic cleavage of single-stranded DNA has been achieved using the cationic polythiophene 75 <06JA14972>. The popular poly(3,4ethylenedioxythiophene) has been employed for design of transparent, plastic, low-workfunction electrodes <06CM4246>. A theoretical study has enabled accurate prediction of HOMO-LUMO gaps for polythiophene and polyselenophene based on extrapolation using HOMO-LUMO long ( > 20-mer) oligomers <060L5243>. <06OL5243>. The polymer 76 has been developed as a highmobility semiconductor for thin-film transistors <06AM3029>. A polymer composed of 1(thiophene-2-yl)benzothieno[2,3-b]benzothiophene units has also been prepared <06SM256>. Additional selected contributions to this field encompass for instance <06AG(E)6152>, construction of postfunctionalizable phosphole modified polythiophenes <06AG(E)6l52>, alternating thiophene-perfluoroarene copolymers <06JA2536>, regioregular copolymers containing 3-alkoxythiophene units <06JA8980>, a thiophene-benzobisthiazole copolymer <06SM38>, and a polythiophene containing cyclobutadiene cobalt cyclopentadiene complexes <06SM784>. The side chain conjugated material 77 displayed a very broad absorption band <06CC871 <06CC871>. >.
C8H17
s
S ":::
~ ~
Me
n n
74 74
5.1.6
M 75 75
+ + NEt3
"~-/NEt3 o~ CIo,
015H31 .S. 4.,,.s \~
-S
"C1sH31
,
n n
n
76 76
77 77
THIOPHENE DERIVATIVES CHEMISTRY THIOPHENE DERIVATIVES IN MEDICINAL MEDICINAL CHEMISTRY
As in previous years, the thiophene moiety, which is a common isostere of benzene, has been incorporated in a great number of biologically active compounds targeting a wide 2-amino-3-(3 ',4',5 'variety of potential medical applications. For example, a series of 2-amino-3-(3',4',5'trimethoxybenzoyl)-5-arylthiophenes <06JMC3906> or 3-amino-2-(3',4',5'-trimethoxybenzoyl)-5-arylthiophenes <06JMC6425> has been identified as a new type of antitubulin agents, whereas it was shown that (S)-1-(2-aminocarboxyethyl)-3-(2-carboxythiophene-3(S)-l-(2-aminocarboxyethyl)-3-(2-carboxythiophene-3ylmethyl)pyrimidine-2,4-dione displayed high potency towards GLUKs-containing GLUKs-containing kainate receptors <06JMC2579>. Other studies led to development of the molecule 78 as a hepatitis C virus polymerase inhibitor <06JMC1693>, 2-aminothiophene-3-carboxylates as adenosine AI A1 allosteric enhancers <06BMC2358>, N-glycolsyl-thiophene-2-carboxamides for <06BMCL1316>, 5-(pyrazol-5-yl)thiopheneproliferation of bovine aortic endothelial cells <06BMCL13l6>, 2-carboxamides as selective calcium-release-activated calcium channel inhibitors
126
T. Janosik and 1. J. Bergman T. Bergman
<06BMC4750>, 2-pyrimidyl-5-amidothiophenes as inhibitors of the kinase AKT <06BMCL4l63>, and arylsulfonylthiophene-2-carboxamidine inhibitors of the serine <06BMCL4163>, protease CIs Cls <06BMCL2200>. A series of monocyclic thiophenes, for instance 79, displayed lB inhibitors <06BMCL494I>. activity as tyrosine phosphatase 1B <06BMCL4941 >. A related set of 5-substituted 3-aryl-4-cyanothiophene-2-carboxylic acids was designed as AMPA receptor allosteric modulators <06BMCL5057>. It should also be mentioned that 2,5-diphenylthiophene derivatives bearing hydroxy and amine substituents have been studied as compounds for p13amyloid plaque imaging <06BMCL <06BMCLl350>. 1350>. In addition, a theoretical investigation probing the structure-activity relationships in a series of nitrothiophenes has also appeared <06BMC8099>.
OH .S.
H HO2C
]1 [
CO2H
~ N CO2H /'-"O Br NHCONHCH2(2-CICsH4) HO2C 79
78
A number of benzo[ blthiophene compounds have also attracted attention. benzo[b]thiophene attention. The system 80 has been studied as as a a7 nicotinic receptor partial agonist <06JMC4374>, whereas the b]thiophene derivative 81 displayed antitumor effects < 06JMC3l43>. benzo[ benzo[b]thiophene 06JMC3143>. A collection of benzo[b]thiophene-2-carboxamides was evaluated as antagonists of the human H H3-receptor 3-receptor <06BMCL3l62>. <06BMCL3162>. In addition, (arylamino) benzo[b]thiophenes were investigated as antioxidants <06BMCLl384>. <06BMCL1384>. It has also been shown that the molecule 82 displayed high affinity for the dopamine D3 D3 receptor <06BMC5898>. Other related work involves design of benzothieno[2,3-c]pyran derivatives for inhibition of hepatitis C virus NS5B RNA-dependent benzothieno[2,3-clpyran RNA polymerase <06BMCL457>, 9-benzylidene-naphtho[2,3-b]thiophen-4-ones as anti16>, and some cytotoxic thioaurone based structures microtubule agents <06JMC78 <06JMC7816>, <06CPB350>. Studies oftetrahydrobenzo[b]thiophene of tetrahydrobenzo[b]thiophene derivatives as inhibitors of hepatitis C <06BMCL100>, and 2-acylamino-tetrahydrobenzo[b]thiophene-3virus NS5B polymerase <06BMCLlOO>, 2-acylamino-tetrahydrobenzo[blthiophene-3carboxamides as FLT3 tyrosine kinase inhibitors <06BMCL3282> have also appeared. MeO MeO
O O MeO'~~OMe ~----T ~Me ~ 80
81
H iq~,,, N~.~N~~/,clCl 82
There are also many fused thiophene derivatives incorporating other heterocyclic units which exhibit interesting pharmacological properties. The thieno[2,3-b]pyrrole 83 has been identified as an allosteric inhibitor of hepatitis C virus NS5B polymerase <06BMCL4026>, whereas a series ofthienopyrroles of thienopyrroles has been investigated as glycogen phosphorylase inhibitors <06BMCL5567>. A study on thienopyrazole compounds as kinase inhibitors has also been reported <06BMCL96>. The thieno[2,3-b]thiophene thieno[2,3-blthiophene fragment may be found in the antitumor compound 84 <06BMC2859>, and protein tyrosine phosphatase 1B inhibitors <06BMC2l62>. <06BMC2162>. Other interesting developments in this context include studies of2-amino-3of 2-amino-3-
127
Five-membered ring systems: thiophenes and Se/Te SelTe analogues Five-membered
aroyl-thieno[2,3-c]pyridine derivatives derivatives as allosteric enhancers enhancers at the adenosine adenosine AI receptor receptor aroyl-thieno[2,3-c]pyridine <06BMCL5530>, antimicrobial antimicrobial 4-(phenylamino)thieno[2,3-b]pyridines 4-(phenylamino)thieno[2,3-b]pyridines <06BMC5765>, <06BMC5765>, and <06BMCL5530>, 3-aminothieno[2,3-b]pyridine-2-carboxamide kinase inhibitors inhibitors <06JMC2898>. <06JMC2898>. The 3-aminothieno[2,3-b]pyridine-2-carboxamide thieno[2,3-b]pyridone 85 represents a series of of similar compounds compounds that has been identified identified as thieno[2,3-b]pyridone inhibitors of of [3H]glycine eH]glycine binding binding to the NMDA NMDA receptor receptor <06JMC864>, <06JMC864>, whereas a set of of inhibitors thieno[2,3-b]pyridine-4-ones has been evaluated as non-peptide luteinizing hormonethieno[2,3-b]pyridine-4-ones <06JMC3809>. A nice example of of bioisosterism bioisosterism was releasing receptor antagonists <06JMC3809>. of the thieno analogue 86 of of the alkaloid febrifugine, which demonstrated by preparation of <06JMC4698>. Studies of of related interest feature displayed potent antimalarial effects <06JMC4698>. thienopyrimidine structures as melanin concentrating concentrating hormone receptor 1I antagonists <06JMC7108>, 06JMC7095>, 06JMC7095>, antibacterial compounds compounds <06BMCL4951 <06BMCL4951>, <06JMC7108>, >, or partial agonists hormone receptor <06JMC3888>. <06JMC3888>. In addition, the molecule 87 for the thyroid stimulating hormone potassium channels channels of of pancreatic beta cells was established to activate ATP-sensitive potassium <06JMC4l27>. <06JMC4127>. yHzCONMez CH2CONMe2 ~ C I CI N / , ~ p h Jj):Ph "S/ )-NH HO2C :5 /~NH HOzC S
nY
0
Ph OPh
0Q o
84
83
I
CI~s~N
CN
H
oH~ c
0
H
',s...-.,<.s..N
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85
87
SELENOPHENES SELENOPHENES AND TELLUROPHENES TELLUROPHENES
At present, the chemisty of selenophenes and tellurophenes is a relatively scantily studied area. Nevertheless, a number of new valuable contributions dealing with their chemistry have emerged. Electrophilic cyclization of of 1-(l-alkynyl)-2-(methylseleno)arenes 1-(1-alkynyl)-2-(methylseleno)arenes provides a route to a variety of2,3-disubstituted benzo[b]selenophenes, as illustrated by the preparation of the of 2,3-disubstituted benzo[b]selenophenes, system 88. Other useful electrophiles for similar reactions are b I2 or NBS <06JOC2307>. Similar chemistry has also been employed in preparation of 2,3-disubstituted 2,3-disubstituted benzo[b]selenophenes benzo[b]selenophenes on solid phase <06JCCI63>. <06JCC163>. In addition, syntheses of 2,3dihydroselenolo[2,3-b]pyridines have been achieved using radical chemistry <060BC466>. <06OBC466>.
SeMe
I""" h-
#
PhSeBr,CH2CI2, rt= r\--!sePh ~SePh
PhSeBr, CH 2 CI 2 , rt
95%
95%
.
~-~ ,I \S~"-'Ph Se Ph 88
(Me2A1)2Se gave the Selenation of the 1,4-dicarbonyl precursor 89 using the reagent (Me2AlhSe benzo[c]selenophene derivative 90 in good yield <06TL2887>. The synthesis and structural studies of 4,7-dimethoxybenzo[c]tellurophene 4,7-dimethoxybenzo[c]tellurophene have also been reported <06AG(E)5666>.
128
T. Janosik and 1. J. Bergman T. Bergrnan
~ Fe
0 0
Q
Fe
Q
(Me2AI)2Se 75% 75%
(MezAlhSe
~ Fe Fe
Se
Q
89
Fe
Q
90
In similarity to their thiophene halogenated selenophenes thiophene counterparts, counterparts, halogenated selenophenes or tellurophenes tellurophenes are useful substrates transition metal catalyzed Apart from a protocol protocol for substrates for transition catalyzed reactions. Apart preparation preparation of of 2-arylselenophenes 2-arylselenophenes by Suzuki Suzuki coupling coupling of of 2-iodo- or 2-bromoselenophene 2-bromoselenophene with aryl boronic acids, a route to 2-aroylselenophenes with 2-aroylselenophenes has been been devised. For For example, example, treatment of 2-iodoselenophene 91 with (4-methoxyphenyl)boronic acid under atmosphere treatment of2-iodoselenophene with (4-methoxyphenyl)boronic under an atmosphere of product 92 in good yield <06JOC3786>. <06JOC3786>. A of carbon carbon monoxide gave the product A copper copper mediated mediated amidation protocol involving 2-iodoselenophene has also appeared <06JOC1552>. amidation protocol involving 2-iodoselenophene <06JOC1552>. Moreover, Moreover, it has been shown shown that variants variants of of Sonogashira Sonogashira coupling coupling of of 2-bromo2-bromo- or 2iodotellurophene derivatives iodotellurophene derivatives offer efficient routes to a variety of of 2-alkynyltellurophenes 2-alkynyltellurophenes <06SL316l, been demonstrated <06SL3161, 06TL2l79>. 06TL2179>. It has also been demonstrated that homocoupling homocoupling of of 5-aryl or 5heteroaryl-2-bromoselenophenes heteroaryl-2-bromoselenophenes in the presence presence of of the system (Bu3Snh/Pd(PPh3)4 (Bu3Sn)z/Pd(PPh3)4 provides excellent excellent yields of of the corresponding corresponding 5,5'-diaryl-2,2'-diselenophenes 5,5'-diaryl-2,2'-diselenophenes and their heteroaryl substituted substituted analogues analogues <06TL795>. <06TL795>.
~ ~
fJ-~ Se ~e I
4-(MeO)C6H4B(OH)2,Pd(PPh3)4(cat.) Na2CO3,PhMe,co CO
4-(MeO)CeH4B(OHh, Pd(PPh 3)4 (cat.) NaZC03, Ph Me,
I
91 5.1.8 5.1.8
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,,OMe oMe
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~
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==--
o O
92
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06BMCL494I 06BMCL4941
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06BMCL5530
06BMCL5567
06BMCL6185 06CC871 06CC 1881 06CCI881
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T. Bergman T. Janosik and and J. Bergman
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T. T Janosik Janosik and andJ. J. Bergman Bergrnan
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Five-membered ring systems: thiophenes and Se/Te analogues Five-membered analogues
06S2794 06S3670 06S3855 06SC97 06SC3319 06SC3319 06SL737 06SL2016 06SL2423 06SL2559 06SL3161 06SM38 06SM256 06SM784 06T684 06T2190 06T2576 06T4756 06T5855 06T6036 06T6814 06T8467 06T9554
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134 06TL6067 06TL6067 06TL7163 06TL8087 06TL8119 06TL9227 06TL9249 06TL9329
T. T. Janosik and and J. J. Bergman
J.-J. J.-J. Filippi, X. X. Fernandez, E. E. Dufiach, Dufiach, Tetrahedron Tetrahedron Lett. 2006,47,6067. 2006, 47, 6067. K. K. Toyama, Toyama, T. T. Tauchi, N. N. Mase, Mase, H. H. Yoda, K. K. Takabe, Tetrahedron Tetrahedron Lett. 2006,47,7163. 2006, 47, 7163. A. A. Barco, Barco, N. N. Baricordi, S. S. Benetti, C. C. De Risi, Risi, G. G. P. P. Pollini, Tetrahedron Lett. 2006,47, 2006, 47, 8087. 8087. M. Gelo-Pujic, Gelo-Pujic, C. C. Marion, C. C. Mauger, M. M. Michalon, T. T. Schlama, Schlama, J.J. Turconi, Tetrahedron Tetrahedron M. 2006, 4 7, 8119. Lett. 2006,47,8119. L. Sun, Sun, H. H. Tian, Tetrahedron Lett. 2006,47,9227. 2006, 47, 9227. L. A. A. Borghese, G. G. Geldhof, L. L. Antoine, Tetrahedron Lett. 2006,47,9249. 2006, 47, 9249. V. Nair, K. K. G. G. Abhilash, E. E. Suresh, Tetrahedron Lett. 2006,47,9329. 2006, 47, 9329.
135
Chapter 5.2 systems: pyrroles and benzo analogs Five-membered ring systems" Erin T. Pelkey Colleges, Geneva, Geneva, NY NY 14456 14456 Hobart and William Smith Colleges, [email protected] Jonathon S. Russel WI 54115 St. Norbert College, De Pere, W154115 [email protected] Jonathon.Russel @snc.edu
5.2.1
INTRODUCTION INTRODUCTION
The synthesis and chemistry of pyrroles, indoles, and additional fused pyrrole and indole ring systems reported during the past year (2006) are the subjects of this review. Pyrroles and indoles are amongst the most studied heterocyclic ring systems due to their diverse biological activity and materials science applications. Page restrictions limit this review to selected advances. In keeping with the past few years, pyrroles and indoles are treated separately. Review articles will be mentioned at the beginning of the relevant sections.
5.2.2
SYNTHESIS SYNTHESIS OF PYRROLES PYRROLES
Pyrrole syntheses have been organized systematically into intramolecular (type I) and intermolecular (type II) approaches and classified by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below).
(') N [
c
type Ie Ic
e~a
type IIae
Intramolecular Approaches IntramolecularApproaches
~
Intermolecular Approaches Intermolecular Approaches
~ii~
.; "
;. "
""N""
R
5.2.2.1
Intramolecular Intramolecular Approaches
Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type Ia approaches to functionalized pyrroles. A platinum-catalyzed (PtCI ) cyclization of homopropargyl azides provided an entry to 2,5(PtC14) 4 disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <060L5349>. <06OL5349>. The addition of a carbonylation step extended a pyrrole synthesis to pyrrole-2-acetic acid <06ASC2212>. derivatives <06ASC22 12>. Treatment of enyne amine 1 with palladium diiodide in the presence of CO and methanol produced pyrrole-2-acetic ester 2 via a 5-exo-dig cyclization, oxidative carbonylation, and isomerization.
136
E.T. Pelkey and J.S. J.S. Russel
Et <~NH~~
/==\.
Pdl2 (cat.), KI
Et
~N~
\\
Bu/ Bu
Et
Pdl 2 (cat.), KI [ Et CO, 02, MeOH CO'O2'MeOH ~
D. ---63-0;'-0--.'
Bu Bu
63%
A
Et Et
]
C02Me "~~C02Me I ,
~
, Qy N
COMe /C02Me 2
[
Bu Bu Bu Bu
Bu Bu Bu Bu
2
1
A ring opening reaction of B-lactams ]3-1actams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles <06CC2616>. MeONa led to pyrrole-2<06CC2616>. In the event, treatment of B-lactam [3-1actam 3 with MeONa acetic ester 4 after cleavage of the amide bond, 5-exo-dig 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required.
PhO PhO --"
OMe OMe F O_Me «Me MeO Ph Ph q Ph Ph PhO" : Ph MeQ. PhO,,. 2. . Ph Ph "-.? PhMeONa MeONa MeO eO2C,~RNH ~ - - Pho,,;;f' - - P h O , , ! 1 ' N = PhO,,~M = P h O. , , . / N~ l Me Me 2: ~ N e l Me R [ [ O" ~ II MeOH MeOH50%l M Me02C R UeO2C R ~ aeO2C RR Me02C 50%
hl
°
R
~~ lH
.
3 (R (R = p-OMePh) p-OMePh) 3
4
A thermal ring opening reaction of an imine-substituted cyclopropene led to a mixture of 2,3,4-trisubstituted and 3,4,5-trisubstituted pyrroles <06TL5793>. Two type Ia syntheses of B-hydroxypyrroles ]3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones -bipyrroles 1-azapenta-l,4-dien-3-ones produced B-hydroxypyrroles ~-hydroxypyrroles including 2,2' 2,2'-bipyrroles <06EJ05339>. <06EJO5339>. A second approach to a B-hydroxypyrrole ]3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone <06JOC5560>. <06JOC5560>. On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. Intramolecular condensation reactions of unsaturated y-aminocarbonyl compounds provide regiospecific methods for the preparation of highly functionalized pyrroles. This strategy was utilized to prepare pyrrole-fused tetrathiafulvenes <06S2815>. In the event, a two-step reductive amination of aldehyde 5 gave sulfonamide 6. Treatment of 6 with Amberlyst 15 promoted an intramolecular condensation leading to fused pyrrole 7. Intramolecular condensation reactions of substituted y-aminoacetals followed by oxidation with DDQ provided the corresponding pyrroles <060L3585>. <06OL3585>. The former were prepared by nucleophilic additions of ketene silyl acetals onto imines. An intramolecular aza-Wittig reaction of unsaturated y-azidoketones provided a regiospecific route to 4-amino- and 4alkyoxy-2-trifluoromethylpyrroles <06JOC6996>. Similarly, an aza-Wittig sequence <06JOC6996>. involving y-azido-B-hydroxyketones y-azido-[3-hydroxyketones provided pyrrole-2-acetic esters <06JOC4965>. <06JOC4965>.
OHC OHC\/SS Et0)C;=S EtO OEt OEt 55
1. 1. TsNH TsNH22,, MS, MS,toluene toluene 2. NaBH NaBH4, EtOH 2. THF, EtOH 4, THF,
75% (2 (2 steps) steps) 75%
NHTs ~ . / == EtO,.~ OEt 6
Amberlyst15 15 ~C SS Amberlyst : T s - N ~ >=S ~==S ----.. Ts-N 99% 99%
..-::
S S
7
uThioether pyrroles have been prepared utilizing a type Ib condensation <06Tl708>. ~-Thioether <06T1708>. Treatment of ketene N,S-acetal 8 with the Vilsmeier-Haack reagent (POCl, (POC13 + DMF) led to 5-
137
Five-membered ring ring systems: pyrroles and benzo analogs
4-fonnylpyrrole-2-carboxylate 4-formylpyrrole-2-carboxylate 9 via an iminium-type cyclization. Interestingly, attempts to promote the cyclization with POCl POC133 alone or different Lewis acids did not yield any pyrrole products. On the other hand, treatment of 8 with the non-nucleophilic base DBU gave the 4unsubstituted pyrrole product 10. In a different study involving a structurally related TsOH, AcOH, or POC13) POCI 3) intramolecular vinylogous amide (no S), an acid-promoted (p(p-TsOH, condensation reaction produced a 2-benzoylpyrrole derivative <06T8243>.
CI
0' K_
OHC
O
EtS" EtS
"N" N "CO2Me C0 2 Me H H
CI CI
!j ": POCI POCI3 3
SEt SEt
DBU DBU toluene, ~A toluene,
DMF, DMF, 80°C 80 ~
88% 88%
MeO2C~NH
99
°O
~ ~
8
34%
-
'I \ EtS
Me H
H
I a CI
10
A base-mediated type Ib cyclocondensation of imino chlorides, derived from treating the corresponding N-allylamides with triphenylphosphite-chloride, triphenylphosphite-chloride, provided 2-aryl- and 2,3diarylpyrroles <06S995>. A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to <06OL4031>. For example, photolysis an interesting type Ib entry to functionalized pyrroles <060L4031>. of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction.
oO
~ l)l~~ N~ . ~ _ . . H
O
[
hv -8-7-%-
87%
H H
11 11
12
Ring closing metathesis (RCM) continues to enjoy significant attention directed at the Ic syntheses of pyrroles. 2-Phosphonopyrroles preparation of heterocycles including type Ie <06JOC4006>. For example, were prepared utilizing an oxidative RCM as the key step <06JOC4006>. ,6-diene 13 with Grubbs' second-generation catalyst in the presence of treatment of 4-aza-l 4-aza-1,6-diene the oxidant, tetrachloroquinone (TCQ), produced pyrrole 14. Microwave-assisted RCM reactions involving diallylamines were utilized to provide amino acid pyrrole derivatives (i.e., 15) and N-arylpyrroles <06TL3893>. A synthesis of N-(3-fluorophenyl)pyrrole also was reported utilizing a RCM reaction <06S 1823>
Ph Ph Me MeJ
~
l. ~_ N I
Bn ~ 13
Orubbs2nO Grubbs 2nd
0
o
Me
TCQ, CH CH2CI2. 2 CI 2 TCa, P(OMeh 84% (OMe)2 84% II II
h(.~ N AI
n ~
14
P(OMeh P(OMe)2 II II
0
MeO\ ~ C( M e~ oy
If
o 0 15 15
138
E.T. E. T. Pelkey and J.S. Russel
A McMurry coupling reaction involving 3-aza-I,S-dicarbonyl 3-aza-l,5-dicarbonyl compounds gave 2,S2,5dihydro-3,4-diarylpyrroles <06SL490>. The latter were converted into the corresponding 3,4-diarylpyrroles by irradiation (Rg (Hg lamp, SOO 500 W) in acetonitrile. Intramolecular condensation reactions involving enaminones and carbonyls (or their synthetic equivalents) provides another class of type Ie Ic approaches to pyrroles. Treatment of enaminone 16 with TFA provided fused pyrrole 17 <06TL2IS1>. <06TL2151>. 16 was prepared utilizing an aza-Wittig reaction between 1,3-cyclohexanedione and 2-azido-l, l-diethyoxyethane. An 2-azido-l,l-diethyoxyethane. 13-hydroxy enaminone alternate synthesis of 17 was achieved utilizing an oxidation of a ~-hydroxy palladium(O) and mesityl bromide <06T8S33>. promoted by palladium(0) <06T8533>. A number of different fused pyrroles were prepared utilizing this methodology.
°O
6::t O
E OEt '
N
16
5.2.2.2
TFA,CH 0H2012 TFA, 2CI 2 ' 95% 95%
..
H H
°O
60
pd(PPh3) Pd(PPh 3)44 MesBr, K .,MesBr' K2003, DMF 2C0 3, DMF •
O I
63% 63%
N'" H
H
17
18
Intermolecular Intermolecular Approaches
No type IIab approaches were abstracted. A type IIac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <060LS837>. For example, treatment of iodoacrylate 19 and <06OL5837>. trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-219 was prepared by iodinating (Ncarboxylate 21 with excellent regioselectivity. iodosuccinimide) the corresponding commercially available dehydroamino ester.
l
"~NI
i
Me02C MeO2C
19
NHAc HAc
+ +
SiMe3 SiMe3 Ii IIII Ph Ph 20
Pd(OAc)2 Pd(OAc)2 LiCI, LiCl, KK2CO 3 2C0 3 DMF, 65°C
DMF, 65~ 81% 81%
...
(> (> 25:1 25:1 regioselectivity) regioselectivity)
n
SiMe3 SiMe3
. ~
Me02C MeO2C
N H H
Ph Ph
21
A Knorr-type pyrrole synthesis involving the condensation between a-amino-~-ketoesters c~-amino-13-ketoesters I]-ketonitriles provided ~-cyanopyrroles I]-cyanopyrroles <060PRD899>. <06OPRD899>. The former amine substrates and ~-ketonitriles were prepared by reduction of the corresponding a-isonitroso-~-ketoesters ~-isonitroso-[~-ketoesters with ZnlHOAc. Zn/HOAc. Following the communcation in 2004, a full report appeared that described type IIac cyclocondensation reactions between dihydroisoquinolines and a-nitrocinnamates ~-nitrocinnamates leading to complex fused pyrroles <06JOC9440>. The latter were converted into the lamellarin alkaloids and related analogues. An oxidative radical coupling promoted by tetra-n-butylammonium cerium(IV) nitrate (TBACN) between ~-aminocinnamate 22 and enamine 23 provided pyrrole-3,4-dicarboxylate 24 <06T223S>. <06T2235>. Dimerization of the ~-aminocinnamates [3-aminocinnamates provided symmetrical pyrroles.
139
Five-membered ring systems: pyrroles and benzo analogs
/ CO2Et jC 02 Et
Et02C EtO2
1
+
Ph
TBACN, TBACN, CHCI CHCI3 3
NH I Ar Ar
H2N H2 N
22
Me Me
..
92% 92%
Et0 2 C EtO2C / ~
C02 Et CO2Et
h
Ph N Me Ph/%N Me I ~ Ar /~r
24 24
23 23
Had syntheses of pyrroles that were reported both involved cyclopropane Two unique type IIad fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with n-BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of intramolecular condensation, and loss of dibenzylamine. ketimine intermediate, intramolecular 1. n-BuLi PhCN 2. PhCN 3. AcOH
?
.. SnBu 3
Bn2N
80%
Ph .... ~ NLi
?
~
Bn2N
25
=
n
ZNAph Ph H H
26
The second IIad Had synthesis provided a route to 2,3,4-trisubstituted pyrroles <06CC2271>. Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation.
Ph Ph
H--~ H~ o 0
27
27
Cr(CO)5 Cr(CO)5
+
+
HN)lMe HN"J~Me
A
28
28
MS 4A MS4A toluene, tel uene, '"A,. 94% 94%
[
Ph OHC / ~ Ph OHCf)( HN Me Me HN
J.. A
proposed proposed intermediate intermediate
n A
Ph
,-
.
N
/..
Me Me
29 29
The preparation of 2-aminopyrroles was accomplished with type Hae IIae zinc-catalyzed cyclocondensation reactions between p-cyanoketones ~-cyanoketones and primary amines <06Tl452>. <06T1452>. Type Hae IIae cyclocondensation reactions between primary amines and l,4-dicarbonyl 1,4-dicarbonyl compounds (Paal-Knorr) or 2,5-dialkoxytetrahydrofurans (Clauson-Kaas) continue to remain the most utilized de novo approaches to functionalized pyrroles. An investigation into the utility of metal triflates in promoting the Paal-Knorr synthesis identified 1 mol% Sc(OTf)3 Sc(OTf) 3to be superior <06TL5383>. The preparation of a library of tetra-substituted pyrrole-3carboxamides was accomplished utilizing a Paal-Knorr cyclization within a parallel solutionphase sequence <06JCC491>. A few novel approaches for generating l,4-dicarbonyl 1,4-dicarbonyl compounds appeared in reports aimed at preparing substituted pyrroles. The 1,41,4carbonylative addition reactions of arylboronic acids to methyl vinyl ketone catalyzed by a Rh(COD\BF Rh(COD)2BF 44 provided l,4-diketones 1,4-diketones <06Tl1740), <06T11740), while the reductive ring opening of 3Hfuran-2-ones with DIBAL gave 1,4-ketoaldehydes <06H(68) I 121>. <06H(68)1121>.
140
E.T. Pelkey and J.S. J.S. Russel E.T.
/~]j~./.,~ PhO2S
02 PdCI2, CuCI
TiCI TiCI44
t~ tOluene~ 78% 78%
DMF/H2O ~ /~.~ 80%
O
(>
allylamine allylamine
PhO2S
30
O
N
~ ~ ~
N
~
PhO2 2S
Ph0 S 32
31
32
Me
Me
Pyrrole-substituted 1,4-diketones were prepared utilizing the Tsuji-Wacker oxidation of the corresponding homoallylic ketones <060L6l07>. <06OL6107>. The success of the reaction depended on protection of the pyrrole nitrogen as a sulfonamide. In the event, treatment of 2ketopyrrole 30 with PdCI, PdC12 and CuCI CuC1 in an oxygen atmosphere gave l,4-diketone 1,4-diketone 31. The latter underwent a cyclocondensation with allylamine in the presence of stoichiometric TiCl TiC144 2,2'-bipyrrole giving 2,2' -bipyrrole 32 which was converted into a 4-aminoprodigiosin analogue. The Paal-Knorr cyclocondensation has been exploited to prepare a number of biologically <06AP670>, anti-inflammatory agents active 1,2-diarylpyrroles including analgesics <06AP670>, <06BMCL3657>, and antimycobacterial agents <06JMC4946>. <06BMCL36S7>, The retro-Paal-Knorr ring opening reaction leading to l,4-dicarbonyl 1,4-dicarbonyl compounds was accomplished by heating N-substituted pyrroles in a citrate buffer <06SLl428>. <06SL1428>. The sequence was coupled with a forward Paal-Knorr reaction enabling the exchange of the Nsubstituent on pyrroles. (PG) support The Clauson-Kaas pyrrole synthesis was adapted to a soluble polyglycerol (PO) <060L403>. <06OL403>. Electrochemical oxidation of furan 33 in the presence of methanol followed by 2,5-dimethoxytetrahydrofuran 34. Cyclocondensation with primary hydrogenation gave 2,S-dimethoxytetrahydrofuran arylamines gave N-arylpyrroles 35. Removal from the PO PG support was then accomplished by treatment of 35 with LiOH which gave 2-pyrrolepropanoic acids 36.
1.MeOH dioxane electrolysis 2. H 2. H2, Pt/C 2 , PVC MeOH MeOH 1. MeOH dioxane electrolysis
OI~
r
O 33
Ar-NH2 NaOAc OI
~OMe O
AoOH
R
O
O o
OMe 34
ROrrJ?
LiOH UOH
~
Ar
{,-- 35 R R = PG PG support (35 support
aq. dioxane dioxane ~ aq.
36 36 R R == H H
Clauson-Kaas pyrrole synthesis was reported reported that alleviated the need for acid or A milder Clauson-Kaas heat <06TL799>. <06TL799>. The The innovation involved the hydrolysis of of 2,5-dimethoxytetrahydrofuran 2,S-dimethoxytetrahydrofuran 2,S-dihydroxytetrahydrofuran. The The latter was converted converted into pyrroles by treatment giving 2,5-dihydroxytetrahydrofuran. Clauson-Kaas pyrrole synthesis was studied with primary amines in an acetate buffer. The Clauson-Kaas K-lO montmorillonite montmorillonite acid catalyst and microwave irradiation <06OPP495>. <060PP49S>. Mild Mild utilizing a K-10 reaction conditions p- TsOH) allowed for the preparation preparation of of pyrrole-3-carboxaldehydes pyrrole-3-carboxaldehydes conditions (cat. p-TsOH) from 2,5-dimethoxytetrahydrofuran-3-carboxaldehydes 2,S-dimethoxytetrahydrofuran-3-carboxaldehydes <06S <06S 1494>. A mixture of of metals was utilized to promote a type IIae synthesis of of penta-substituted penta-substituted A <060L21S1>. Treatment of of enyne 37 with a Ag(I) catalyst followed by BnNH BnNH,2 and pyrroles <06OL2151>. a Au(I) catalyst gave pyrrole 38 via a Claisen-type rearrangement rearrangement and cyclocondensation. cyclocondensation.
141 141
Five-membered Five-memberedring ringsystems: systems:pyrroles pyrrolesand andbenzo benzoanalogs analogs
Ph o~CO2et
Ph o~CO2e
AgSbF6 AgSbF 6
1.BnNH BnNH22 1. 2. 2 (Ph (Ph3P)AuCl 3 P)AuCI
•
•
~
37
~
Et0 EtO2C 2C
Me Me
Ph Ph
N Me Me J 13n Bn
Me
Me
h
38 38
A mixture of of gold gold and and silver silver reagents was also also utilized in aa type type IIae cyclocondensation [3-alkynyl ketones and primary amines amines <06JOC4525>. <06JOC4525>. For example, example, treatment of of between ~-alkynyl cyclopentanone 39 and and benzylamine with AuCI AuC1 and and AgOTf gave fused fused pyrrole 40. A coppercoppercyclopentanone domino approach to complex pyrroles was developed <06AG(I)7079>. For catalyzed domino example, treatment of iodoenyne 41 with BocNH22 in the presence of CuI and N,Ndimethylethylenediamine (DMEDA) gave fused pyrrole 42 via an amidation followed by a 5endo-dig cyclization. Several higher yielding examples were also reported.
O~~, ~ 39
BnNH BnNH2, PPh33 2 , PPh AuCl,AgOTf AgOTf AuCI, CICH CICH2CH2Cl 2CH 2CI
°
79% 79%
•
rn~ %
'------/( N I
R1 R1
R2 R2
..
~
BocNH BocNH22,, Cui Cul DMEDA DMEDA CS Cs2CO3, THF 2C0 3 , THF
52% 52%
R I ==BBn; n ; R R22 ==MMe e 40 R1 R1 = = Boc; R R22 = = Ph 42 R1
~ 41
Ph Ph
A type IIae cyclocondensation of silyloxy enynes catalyzed by TMSOTf produced highly <06OL3881>. substituted pyrrole-2-acetic esters <060L3881>. The increasingly common theme of developing new pyrrole syntheses that involve cyclopropane fragmentations appeared in a type IIae pyrrole synthesis <060L835>. <06OL835>. Treatment of doubly activated cyclopropane 43 with benzylamine in the presence of magnesium sulfate led to complex pyrrole 44 via a nucleophilic cleavage of the cyclopropane ring, intramolecular condensation, and isomerization of the exocyclic 1t-bond. n-bond. Bn-NH2, MgS04 Bn-NH 2 , MgSO4
C7H15C~==Me~O2Et O 43
CH 3CN, !l
•_ CH3CN,A =. 78% 78%
--1
C7H15v,,'&, CO2Et| O l| B~N kk/~( H M~ee
C8H17 CO2Et .~
6n
Me
44
of pyrrolo[2,1-b]thiazoles pyrrolo[2, lob]thiazoles A type IIbc approach to pyrroles was employed in the synthesis of <06S 1433>. The key step involved a formylation with the Vilsmeier-Haack reagent followed <06Sl433>. by a cyclocondensation of of the putative iminium intermediate. (l) Hinsberg-type; (2) Type IIbd pyrrole syntheses fall into three general categories: (1) azomethine The azomethine ylide cycloadditions; and (3) isocyanide-based isocyanide-based cyclocondensations. The Hinsberg Hinsberg pyrrole synthesis, the cyclocondensation cyclocondensation between between iminodiacetates iminodiacetates and oxalates, oxalates, has been further exploited of the lamellarins lamellarins <06T594, <06T594, 06TL3755>. 06TL3755>. exploited in the total synthesis of Azomethine prepare a number number of of novel fused Azomethine ylide cycloadditions have have been been utilized to prepare including pyrrolo[2,1-a]isoquinolines <06CHJC279, <06CHJC279, 06TL1469> 06TLl469> and pyrrolo[1,2pyrroles including b]pyridazines <06SL804>. <06SL804>. Fused Fused hydroxypyrroles hydroxypyrroles were were obtained obtained in in cycloaddition cycloaddition reactions reactions b]pyridazines with with trimethylsilylketenes trimethylsilylketenes (TMS (TMS ketene) ketene) <06TL1469>. <06TLl469>.
142
E. T. Pelkey and 1.5. E.T. J.S. Russel
S S
MeO2C ~
CO2Me ~ benzene,1i benzene,A
/'-A
BU3Sn ~ Ph Bu3Sn~N"~Ph Me Me 45 45
81% 81%
G
t,
s~SnBu
\ ~ / ' ~ Ph Me
e
MeO2C" ~
|
CO2M Ph
Me
_.l
46
The generation of azomethine ylides generated by the ring-opening of aziridines has been studied in supercritical CO22 <06TLS47S>. <06TL5475>. The generation of non-stabilized azomethine ylides was realized utilizing an unprecedented 1,4-stannatropic shift <06CCS26>. <06CC526>. For example, heating thioamide 45 in the presence of DMAD produced pyrrole 46 via a cycloaddition of the azomethine ylide intermediate followed by loss of the sulfanyl group. Highly functionalized pyrroles continue to be prepared utilizing type IIbd cyclocondensation reactions between activated isocyanides and alkenes/alkynes. Cyclocondensations Cyclocondensations reactions involving tosylmethyl ioscyanide (TosMic) have been utilized to prepare pyrroles for study as reverse transcriptase inhibitors <06CMCI379> <06CMC1379> and neurotransmitters <06BMCLS203>. <06BMCL5203>. The preparation of 2-tosylpyrroles was realized via triphenylphosphine reactions between TosMic and alkynes run in the presence of triphenylphosphine <06HCA923>. <06HCA923>. An important solvent effect was discovered during an investigation into the Barton-Zard pyrrole synthesis (isocyanoacetates + nitroalkenes or p-nitroacetates) [~-nitroacetates) <06TLS481>. <06TL5481>. It appears that the THF stabilizing agent, BHT (butylated hydroxytoluene), inhibits this cyclocondensation. Much higher yields were obtained using distilled THF or MTBE MTBE as the solvent. Finally, the Barton-Zard pyrrole synthesis has been utilized to prepare pyrrole Weinreb amides <06JOC6678>, <06JOC6678>, a useful precursor precursor to pyrrole-2-carboxaldehydes and 3-pyrrolin-2-ones. The reaction between isocyanide 47 with nitroalkene 48 in the presence of DBU gave pyrrole Weinreb amide 49. The latter was converted into the corresponding corresponding pyrrole-2-carboxaldehyde 50 by treatment with LiAIH pyrrole-2-carboxaldehyde LiA1H 44.• Oxidative cleavage of the formyl group gave 3-pyrrolin-2-one 51. Ph Ph\
Me Me
!
Ph Ph
~ N0 "==<
2 48 48 NO2 CN~N'OMe CN N..OMe--------
[
o O
47 47
DBU, DBU,THF THF
71% 71%
Ph Ph
Ph LiAIH Ph Ph Ph Ph H202 Ph 4 H ~~o M elife LiAIH4 Ph N ~ O THF THF ~~ H NaHCO3 N - 72% N.OMe 80% N 'OMe 72% N
~ H 49
0
H 50
0
Ph H
O
51
Treatment of p-methoxyphenylethylamine with a stoichiometric amount of CU(OAC)2 Cu(OAc) 2 and in the presence of a catalytic amount of Pd(OAc)2 Pd(OAc) 2 produced a 3,4-diarylpyrrole via an unexpected three-component cyclization process <06JACSI2046>. <06JACS12046>. Another threecomponent sequence was exploited to prepare S-aryl-2-oxopyrrole 5-aryl-2-oxopyrrole derivatives via cyclocondensation reactions between malonates, aldehydes, and primary amines <06T6018>. 5.2.2.3
Transformations of other Heterocycles Transformations Heterocycles
A novel ring opening reaction of isoxazoles led to the formation of functionalized pyrroles <06S1021>. For example, treatment of isoxazole 52 with DBU DBU led to the formation of <06S1021>. pyrrole 53. A solid-phase synthesis of 3-amino-2,S-dicarboxylates 3-amino-2,5-dicarboxylates was accomplished by transformation of pyrrol-3-one 54 <06JCCI77>. <06JCC177>. The reaction between 54 and secondary amines led to the corresponding corresponding resin-bound aminopyrroles after enamine formation and loss
143
Five-membered ring ring systems: systems: pyrroles and benzo benzo analogs
of the phenylfluorenyl group. A similar solution-phase sequence was utilized to prepare <06OL6107>. pyrrole 30 <060L6107>.
HO CO2Bu
MeO2C~NHB n ph.J',~N-O
DBU THF,A~
DBU THF, !l
..
55% 55%
°O
~co,-Q
,OH C0 2 Bu N"OH CO2Bu
DJ
Ph
~
N I
Bn Bn
~
53 53
52
5.2.3
REACTIONS OF REACTIONS OF PYRROLES PYRROLES
5.2.3.1
Substitution Substitution at Nitrogen Nitrogen
54
The introduction of N-protecting groups (i.e., (i.e., Boc, sulfonyl, benzyl, trialkylsilyl, N-amino, and N-amido) attenuates the reactivity of the pyrrole nucleus and this topic has been <06Tl1531>. The N-alkylation of pyrrole has been investigated in an extensively reviewed <06Tl153l>. ionic liquid (l-n-butyl-3-methylimidazolium (1-n-butyl-3-methylimidazolium tetrafluoroborate) using potassium carbonate as the base <06TL2435>. Treatment of pyrrole-2,4-dicarboxylates with chloramine (NH,Cl) (NH2C1) in a biphasic system and in the presence of Aliquat 336 (phase-transfer agent) provided the <06TL5341 >. corresponding N-aminopyrroles <06TL5341>. The conjugate addition of pyrrole to o~,[3-unsaturated a,p-unsaturated esters catalyzed by potassium pyrrolate led to the formation of p-pyrrolyl J]-pyrrolyl esters <06SL77>. Nucleophilic aromatic substitution of N-pentafluorophenylpyrrole with the sodium salt of pyrrole provided the first access to hexapyrrolylbenzene derivatives <06ARK(ii)124>. The asymmetric allylic alkylation (AAA) reaction has been adapted for use with pyrrole nucleophiles <06JACS6054>. For example, treatment of pyrrole 55 and cyclopentene 56 with a palladium catalyst in the presence of a chiral additive gave pyrrole 57 in up to 92% ee. The latter was elaborated into piperazinone-pyrrole natural product, agelastatin A 94.
.~ MeO2C
o l{ ~
H
55
Br
+
OBoe OBoc
Pd2(dba)3-CHCl 3
Pd 2 (dbah-CHCI 3 ehiral chiraladditive
0s2003' 2_C_O_3 _,C0H2012 _c_s_ _H_2_C_12..
OBoc
OBoe 56
75% 75%
~"
nQ"
/,~ Me02C MeO2C
N
57
5.2.3.2
Br
>,. ~
94 . agelastatin A
,ge',"",," A
OBoe OBoc
Substitution at Carbon Carbon Substitution
Functionalization of the electron-rich pyrrole ring is often accomplished utilizing standard electrophilic aromatic substitution reactions. N-bromosuccinimide (NBS) is the reagent of choice for preparing bromopyrroles <06BMC4627, 06BMC8l62, 06BMC8162, 06BMCL5432, 06S3883, 06EJM1439>. The preparation of rhanzinal and related pyrrole natural products required the preparation of a 4-iodopyrrole-2-carboxaldehyde <06ARK(iii)163>. Introduction of the iodine was done by treatment of the corresponding pyrrole-2-carboxaldehyde with iodine and silver trifluoroacetate. The sulfonation of pyrrole 58 with chlorosulfonic acid in acetonitrile gave pyrrole-3-sulfonyl chloride 59 <06Tl699>. <06T1699>. Treatment of 59 with morpholine followed
144
E.T. Pelkey and J.S. Russel
pyrro1e-3-sulfonamide 60. The by base-mediated removal of the protecting group gave pyrrole-3-sulfonamide preparation of anti-HIV 5-arylthiopyrroles was achieved utilizing arylsulfenyl iodide generated in situ by the combination of arylthiophenol, iodine, and potassium iodide <06CMC1367, 06CMC1379>. A method exploited for preparing 2-alkylthiopyrroles involved treating 2-thiocyanatopyrrole with an alkyl Grignard reagent <06JOC903>. Additional examples of the direct cyanation of pyrroles utilizing oxidative conditions (hypervalent iodine and trimethylsilyl cyanide) were reported <06CPB1608>. The preparation of formylpyrroles has been investigated with the Vilsmeier-Haack formylation (POCl" (POC13, DMF) <060BC1032, <06OBC1032, 06TL3693>. With 2-(2'-thienyl)pyrrole <06T3493> and pyrrole-2-carboxylate <06TL4631>, this reaction proved to be unselective.
~
SO2CI 1.1.morpholine, morpholine,CH CH2CI 2 2CI 2 2. 2"KK2CO3' aq"MeOH MeOH 2C0 3 , aq.
HOSO2CI'CH3CN ~ ~ 46%
~ SO2Ph
SO2Ph 58
77% (2 steps) steps)
~O
~ H
59
60
New electrophilic substitution reaction methods for the preparation of dipyrromethanes have been reported. The condensation of N-methylpyrrole with benzaldehyde leading to the corresponding dipyrromethane was promoted by the addition of the organic catalyst, pyrrolidinium tetrafluoroborate <06T12375>. The reaction between pyrrole and N-tosyl imines promoted by metal triflates gave dipyrromethanes whereas tripyrromethane byproducts were not observed <06T10130>. Different catalysts including bismuth-trichloride <06SC1373> and copper bromide <06TL7323> have been evaluated for promoting the Michael addition of pyrroles onto electron-deficient alkenes. Organic catalysts including azirdin-2-yl methanols <06TA3135> and chiral pyrrolidinium salts <06TA107> have been utilized for stereoselective conjugate addition reactions by pyrroles. For example, treatment of N-methylpyrrole 61 and (E)crotonaldehyde 62 in the presence of aziridin-2-yl methanol 63 gave alkylated pyrrole 64 with relatively good enantiomeric excess (ee). Ph Ph
Me~Ph MeN ' ~ - - ~ ~ p h
o
N I Me
61
H OH 63 + +
Me
H
O 62 62
CH CH2CI 2,, i-PrOH i-PrOH 2CI 2
(75% eel ee) 51% (75%
~
~H ,,H
Me Me Me
O 0
64 64
A Nazarov-type cyclization was exploited to prepare annelated pyrroles <060Ll63>. <06OL163>. Acylation of N-tosylpyrrole 65 with carboxylic acid 66 promoted by trifluoroacetic anhydride gave intermediate 2-ketopyrrole 67 which underwent a Nazarov-type cyclization to give cyclopenta[b]pyrrole 68. Another route to cyclopenta[b]pyrroles involved a novel cyclization involving pyrrole-substituted enones and isocyanides <060L3975>. <06OL3975>.
145
Five-membered ring ring systems: benzo analogs systems: pyrroles and benzo
0o
HO~Me .o.[14 Me
+
NE I Ts 65
0 O
(CF3 C0 2)2 0
CICH2CH2CI, A CICH 2CH 2CI. '" 73% 73%
66
•.
[WMe] Me
Ts 67
0 O
1
•.
|
c::r
Me Me
Y '\
~
0
Ts 68
J
A gallium metal-mediated allylation of pyrrole led selectively to the formation of the 3substituted pyrroles <06TL3535>. In contrast, a palladium-catalyzed allylation of pyrrole with allylic alcohols performed in the presence of triethylborane led to 2-substituted pyrroles <06H(67)535>. Palladium-catalyzed cross-coupling reactions continue to play a central role for the preparation of highly substituted pyrroles and this subject has been reviewed <06EJ03043>. <06EJO3043>. The regioselectivity in the cross-coupling of polybromopyrroles can be predicted from the corresponding 'H IH NMR chemical shifts of the parent non-brominated parent systems <06CC299>. The positions containing protons that are shifted the farthest downfield in the IH 'H NMR correspond to the more reactive bromine atoms in the cross-coupling reactions of polybromopyrroles. A one-pot, regioselective double Suzuki cross-coupling reaction appeared <060L1537>. <06OL1537>. Sequential treatment of 4,5-dibromopyrrole 69 with p-methoxyphenylboronic acid and Pd(OAc)2 Pd(PPh3)44 gave 4,5-diarylpyrrole 70. Pd(OAc) 2 followed by p-fluorophenylboronic acid and Pd(PPh3) In a separate study, the regioselectivity of Suzuki reactions with 3,4-dibromo- and 2,4dibromopyrroles was evaluated <06S3883>. A two-step Negishi/Suzuki cross-coupling sequence provided a regioselective synthesis of 4,5-diarylpyrroles <06BMC4627> F.E
Br Br Br
h
N
I~t Et I
69
p-OMePhB(OH)2 1. p-OMePhB(OHb Pd(OAcb, Pd(OAc)2, K K2CO DMF.. 2 C033,• DMF CHO
2. p-FPhB(OHb p-FPhB(OH)2, Pd(PPh Pd(PPh3) 4 3 )4 45%
Y '\ ~
N
CHO
I
h-~ MeO...><...~
MeO
Et Et 70 7O
Palladium-catalyzed cross-coupling reactions have been exploited for the preparation of the lamellarin natural products <06T594, 06TL3755> and related analogues <06JMC3257>. For example, the Suzuki cross-coupling of symmetrical bistriflate 71 with boronic acid 72 of 73 with boronic acid gave 3-arylpyrrole 73 <06TL3755>. A second Suzuki cross-coupling of73 74 then produced 3,4-diarylpyrrole 75 which was converted in several steps to lamellarin a 20-sulfate 76, a selective inhibitor of HIV-1 integrase.
146
E.T. J.S. Russel E. T. Pelkey and l.S.
MeO MeO
i-prODB(OHb iPrO~ B(OH)2 TfO
OTf TfO OTf . ~ E N EE E L
MeO" ~ v MeO 72
h
~Ar]
-,.
i-proD 0 A
BnO" BnO
~ ~
"OMOM OMOM
74
~.
/
~
L... 1 Ar Ar
E = C0 CO2Me 2Me = 3,4-diOMePh 3,4-diOMePh Ar =
MeO MeO
MeO~ B(OH)2 MeOaB(OH)2
Y ~ E E N "N" E "E
80% 80%
71 71
f
OTf
Pd(PPh Pd(PPh3) 4, Na2COS, Na2CO3, THF THF S)4,
Ar
MeO MeO
>P~~
/-PRO
Pd(PPh3) 4, Na2COS, Na2CO3, THF THF Pd(PPh s)4, 90% 90%
73
OBn OBn
MeO MeO
/-PRO
MeO MeO
i - P r O ~ OMOM
OMOM
E E N "N" E E
t...
-~-
~Ar1
MeO~N/~,
O
O
MeO
Ar
75
76
A total synthesis of the pyrrole natural product, rhazinal, utilized a Suzuki cross-coupling cross-coupling reaction to install a 3-aryl moiety <06ARK(iii)163>. <06ARK(iii)163>. Suzuki cross-coupling cross-coupling reactions were exploited for the preparation of a number of pyrrole materials including a prodigiosin analogue <060L495l>, <06OL4951>, a bipyrrole building block <06TL2605>, fluorescent bis(pyrrol-2yl)arenes <06TL7541>, <06TL7541>, and BODIPY dyes <06EJ04658>. <06EJO4658>. The Heck cyclization of bromopyrrole 77 and the corresponding corresponding oxidative Heck cyclization of desbromopyrrole 78 was studied <06SL3081>. While the Heck cyclization of 77 led to a mixture of [3.3.1 ]bicycle 79 and [3.2.2]bicycle 80 under a variety of conditions, [3.3.1]bicycle the oxidative Heck cyclization of 78 led solely to the desired building block 79. The latter has previously been utilized in a total synthesis of dragmacidin F.
0
Me Me
X
TBSO~rQ
TBSO
~ '"1 HO HO 0O
77 77 X == Br Br
SEM SEM
for 77: 77: for Pd[P(t-Bubb, Pd[P(t-Bu)3]2,Pd2dbas Pd2dba3 CY2NMe, CY2NMe,THF THF -for -78: ------78:
Pd(OAc)2, t-BuOH t-BuOH Pd(OAc)2' AcOH, DMSO AcOH, DMSO
T B S O ~ ~ N /H~ TBSO~O
+
O
~
0tQMe
HO" 0 H
yN ~ ~"~'N';" O LEM ~ 0 SEM 79 79
+
y
HO NO
~
N /7- "lkl" i oO SEM SEM
80
78X=H 78 X =H An enantiospecific, gold-catalyzed pyrrole annelation reaction was utilized in a <06JACS 10352>. Specifically, treatment of allene 81 with synthesis of rhazinilam 95 <06JACS10352>. triflate - triphenylphosphine led to the formation of annelated pyrrole 82, which subsequently converted into 95. A gold-catalyzed direct coupling of pyrroles with [3-(pyrrol-2-yl)enones <06ASC331>. <06ASC331>. dicarbonyls led to the formation ~-(pyrrol-2-yl)enones
total gold was 1,3-
147
Five-membered ring ring systems: pyrroles and benzo analogs
Me MeO2C~,~:/~H
Me JY1e _
PPh33•9AuOTf PPh AuOTf
Et _
97:3 97:3(dr) (dr) 92% 92%
.~~N ~ Meo2C~ MeO2C
•
95 95
Et Et...-U
rhazinilam rhazinilam
82
81
A regiochemical outcome of a palladium-catalyzed direct C-H bond functionalization of the pyrrole ring can be directed by choice of N-substitution with bulky groups directing to C3. The oxidative alkenylation of N-(Boc)pyrrole led selectively to a 2-vinylpyrrole whereas the same reaction with the N-(TIPS)pyrrole produced a 3-vinylpyrrole <06JACS2528>. A tandem coupling reaction/intramolecular direct C-H arylation leading to the pyrrolo[2,1<06OL2043>. For example, treatment of Na]isoquinoline ring system was investigated <060L2043>. bromoalkylpyrrole 83 and iodoarene 84 with the reagents shown provided fused pyrrole 85. The authors proposed a mechanism that includes a Heck reaction between norbornene norbomene and 84, an ortho C-H functionalization of the iodoarene, and a C-H arylation of the pyrrole ring.
o
+ +
N
~
"-,]
Me M[~
~ /./
83 83 Br
PdCI PdCI2, tri2furylphosphine 2, tri-2-furylphosphine Cs2CO3, norbornene,CH CH3C N ,.. CS2C0 3, norbornene, 3CN.
I I~
Me W~ Me
y
91%
I~
N
~ C0 Me CO2M 2 e
C0 2Me CO2M e
84 ~
85 ~
SmI2-induced reductive cyclization of N-(alkylketo)pyrroles provided an entry into A SmI,-induced medium ring 1,2-annelated pyrroles <06EJ04989>. <06EJO4989>. An oxidative radical alkylation of pyrroles with xanthates promoted by triethylborane provided access to a-(pyrrol-2~-(pyrrol-2yl)carboxylic acid derivatives <06TL2517>. An oxidative coupling of pyrroles promoted by a hypervalent iodine(III) reagent provided bipyrroles directly <060L2007>. <06OL2007>. Concerted reactions involving the 1t-bond ~-bond of the pyrrole ring have been reported. The stereoselectivity in the cyclopropanation of pyrrole and other 5-membered ring heterocycles with rhodium carbenoids has been investigated <06JOC5349>. Diels-Alder cycloadditions of pyrroles (and indoles) with cyclopentadienone acetal gave the bicyclic cycloadducts in <06BCJ 1288>. fairly good yields <06BCJl288>. A synthesis of highly-substituted tetracenes was developed starting from isoindole (benzo[c]pyrrole) <060L273>. <06OL273>. For example, treatment of dibromonaphthalene 87 with phenyllithium in the presence of isoindole 86 followed by deamination of the intermediate cycloadduct provided tetracene 88. Separately, the synthesis and cycloaddition chemistry of oxadisilole-fused isoindoles was investigated <06SL251 0>. <06SL2510>.
F* F F
F ~
F F
""
:;..- N-Me N-Me ::--
F F
86
+ +
O06H13 Br~~~~]
B'~ I /./ /./ Br Br
OC O06H13 6 H 13
87
F
1. 1. PhLi PhLi 2. 2. NaOH, NaOH,CHCI CHCI33
O06H13
F .
35% 35%
F
F
O06H13 88
Cycloaddition reactions involving dithione intermediates derived by the reductive extrusion of sulfur atoms from [1,2,3,4,5]pentathienopino[6,7-b]pyrroles [1,2,3,4,5]pentathienopino[6,7-b]pyrroles provided access to 1,4-dithin-fused pyrroles (i.e., 89) <060L4529>. 1,4-dithin-fused <060L4529>.
148
E. T. Pelkey and 1.S. E.T. J.S. Russel
5.2.3.3 5.2.3.3
Functionalization of of the Side-Chain Side-Chain Functionalization
The preparation of 3-vinylpyrroles was investigated utilizing the Horner-WadsworthHomer-WadsworthEmmons reaction with 3-formyl-N-tosylpyrrole <06S1494>. <06S 1494>. The intramolecular acylation of pyrrole-2-Weinreb amides provided access to novel indolizinone derivatives <06T6182>. The amidation of pyrrole-2-carbonyl chloride was utilized as a key step in the preparation of pyrrole-oxazole analogue 90 of the insecticide Pirate <06S 1975>. A Mitsunobu reaction of 3,4-dihydroxypyrroles was utilized to prepare 3,4dialkylenedioxypyrroles (i.e., 91) <06TL3521>. Et Et
A r<--('M' 0--4?-Q 0 C02Me
S
N
,
[
Me Me
89
S
o0
N
"N
)
EtO EtO)
90
~
/;
~OM'
0
N H
'I N ~
t-BuO
o
91
H
OBn
0
92
The large scale preparation of orthogonally protected pyrrole tricarboxylic acid derivatives m-chlorination of a 2,4-dimethylpyrrole (i.e., 92) was reported. A key step was the selective a-chlorination intermediate that was derived from the Knorr pyrrole synthesis.
5.2.4 5.2.4
PYRROLE NATURAL PRODUCTS AND MATERIALS MATERIALS PYRROLE NATURAL PRODUCTS AND
5.2.4.1
Natural Products Molecules Natural Products and Biologically Biologically Active Small Small Molecules
Pyrrole rings are important structural subunits and recognition elements found in a number of bioactive materials including small molecule natural products and tetrapyrroles (i.e., porphyrins) and related macrocycles. The biosynthesis of naturally occurring pyrroles has been comprehensively reviewed <06NPR517>. <06NPR517>. The first five proteins involved in the biosynthesis of the prodigiosin pyrrole natural products have been identified <06JACS12600>. The total synthesis and anti-tumor activity of 3,4-diarylpyrro1e 3,4-diarylpyrrole natural <06JACS12600>. products and related analogues have also been reviewed <06THC53, 06T7213>. Novel halogenated pyrrole natural products continue to be isolated from different marine organisms. Examples of recently isolated pyrroles include 4-bromopyrrole-2carboxyarginine <06JNP125> and the stylissadines (tetrameric dibromopyrrole-imidazoles) Agelas sponge <06TL4675> from Stylissa Stylissa caribica caribica and agesamide A 93 from an Agelas <06OL4235>. <060L4235>. The combination of diverse biological activity and structural complexity make pyrrole natural products popular targets in the heterocyclic community. Selected highlights of developments in de novo pyrrole synthesis or reaction methodology developed en route to total syntheses of natural products have been mentioned in previous sections. Pyrrole marine natural product total syntheses that have been published during the last year include <06OL1443, 060L4083>, 06OL4083>, 12,12agelastatin A 94 <06JACS6054>, ageladine A <060L1443, dimethylageliferin <06T1 0182>, cyclooroidin <06TL5561>, <06T 10182>, <06TL5561 >, dibromophakellstatin <06JOC9431>, dragmacidin F <06CC3769, 06SL3081>, lamellarins (i.e., 76) <06T594,
149
Five-membered ring ring systems: pyrroles and benzo benzo analogs
06TL3755, 06JOC9440>, manzacidin A <06JACS2l74>, <06JACS2174>, oroidin <060L2961>, <06OL2961>, and the rigidins <06T8243>. The thermal cyclodimerization of oroidin provided a direct route to rac-cyclooroidin rac-cyclooroidin <060L819>. <06OL819>. Non-marine pyrrole natural product total syntheses that have been published during the last year include rhazinilam 95 <06ARK(iii)163, 06JACS10352>, 06JACS 10352>, rhazinal 96 <06ARK(iii)163>, and the polygonatines A and B <060BC1032>. <06OBC1032>. The total synthesis of the latter helped to confirm their structural assignment. Br gr
JyyoO
B-!}yo r~ O
:eN" "ix" Br~
o'
B'
H,,. H,
NH
HN~
o 0 93
~,H
HO\"'1~ NH Me/ Me.-I'N~\<--~ o 0
94 94
0
~
/;
~~H". y "'.
Et
BocHN
BocHN
'I
N
R=H
95 R = H 96 R R = CHO CHO 96
R
R
~ ~CO2Me N H
H
C0 2 Me
97
Unnatural lamellarin analogues have been prepared and evaluated as anti-cancer agents <06BMC4627,06JMC3257>. <06BMC4627, 06JMC3257>. Additional small molecule pyrroles demonstrating anti-cancer activity include pyrrolopyrrolizinones <06BMC8162> and prodigiosin analogues <06OL4951>. <060L495 I>. Additional types of biological activity investigated include anti-HIV <06CMCI367, <06CMC1367, 06CMC1379>, anti-inflammatory <06BMCL3657, 06AP670>, and antimycobacterial <06JMC4946>. Syntheses of the rigid pyrrole amino acid derivatives 97 and the corresponding 5-amino congener were reported <06TL4631>. 5.2.4.2
Macrocycles and Oligopyrroles Macroeycles
The synthesis and biological evaluation of pyrrole macrocycles (i.e., (i.e., porphyrins, expanded porphyrins, and calixpyrroles) and linear oligopyrroles comprise perhaps the largest body of work published each year that can be classified as pyrrole chemistry. Unfortunately, due to space limitations, the discussion of selected advances in this area could not be included. 5.2.4.3
Non-Oligomeric Materials Non-Oligomeric
The preparation and evaluation of novel borondipyrromethane (BODIPY) derivatives continues to be well studied. Selected types of BODIPY that have been investigated include dyes <06EJ04658, <06EJO4658, 06CAJl76>, 06CAJ176>, fluorescent sensors <06CC1503, 06JOC3093, 060L4445, 06OL4445, 06OBC776, 06JACSlO640>, 06JACS10640>, intracellular phospholipase activity sensors <06ACB65>, 060BC776, (i.e., 98) <06JACSlO, <06JACS10, 06JOC2881>, DNA sequencers <06JACS2542>, copper sensors (i.e., photosensitizers <06CC4398>, and luminescent gels <06JACS4548>. To close out the pyrroles section, the pyrrole moiety has been incorporated into novel nonlinear optical chromophores (i.e., (i.e., 99) <06JACS2142, 060L3681>. 06OL3681>.
150
E.T. Pelkey and 1.S. J.S. Russel
Et Et
L,..Me
S
oN CN
F~
N C NC-\\
~ ,8,
n
~N/
Et
5.2.5
99
98
~L..1
SYNTHESIS OF OF INDOLES INDOLES SYNTHESIS
As a distinct feature of mother nature's fundamental amino acid scaffold, and emanating from a variety of biogenic processes, it is no surprise that the indole nucleus has been intimately woven into the diverse and evolving fabric of the natural world. And while a wealth of dedication and precision has been brought to bear by the community of synthetic chemists in efforts to prepare the elaborate interlacing frameworks in which nature has embedded the indole core, the simple five-six fused skeleton of the molecule also continues <00JCS(Pl)1045>. The to inspire the development of creative strategies for its construction <00JCS(P1)1045>. latter point is well illustrated in a recent series of reports by the Funk group whose imaginative approach to the indole ring system has the delicate aromatic materialize through a well conceived electrocyclic transformation of trienecarbamate precursors, e.g., 100-102 100-102 <06JACS4946, 060L2643, 06OL2643, 060L3403, 06OL3403, 060L4775>. 06OL4775>. 1. 1. TFA, TFA, 93% 93%
&0 I 1//
0
N/ I
100 100
BOC
110°C,3h 110 ~ 3h
DDQ, rt, rt, 16h 16h DDQ, 88% 88%
&:0 0
//
N/
~
I
101
BOC
2. K2CO S, DMF 100~ 100°C ICH %= ICH2CO2Me, 71% 2 C02 Me, 71
3. 4 M NaOH; NaOH; HCI HCI 3. 93% 93%
OJ ~
N \\
102 102
This section of the chapter will highlight recent activity in the implementation of traditional methods and the development of novel strategies for the synthesis of indole alkaloids. A review of practical methods for indole synthesis has appeared <06CR2875>. A few special topics in indole chemistry that have been reviewed include heterocyclic synthesis via palladium-catalyzed oxidative addition <06CR4644>, 1-hydroxy-substituted l-hydroxy-substituted indoles, via tryptamines, and tryptophans <06THC77>, oxidative C-C bond formation in heterocyclic <06ARK(xi)310>, and monoterpene indole alkaloid biosynthesis <06NPR532>. chemistry <06ARK(xi)31O>, Other brief monographs of topical interest have appeared including a discussion of the Nicholas approach to natural product hybrids <06CEJ6403> an overview of new principles in medicinal organometallic chemistry <06AG(I)1504>, an account of the synthesis of twelve fluoroindolecarboxylic acids <06EJ02956>, <06EJO2956>, a survey of methoxy group directed augmentation of indoles <06ARK(vii)67>, the synthesis of indole derivatives via isocyanides <060BC757>, <06OBC757>, and a kinetic study of indole nucleophilicity <06JOC9088>. Work by the Stoltz group on the synthesis of the pyrazinone dragmacidins has also been documented <06CC3769>. As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,
151
systems: pyrroles and benzo Five-membered ring ring systems: benzo analogs analogs
and carbazoles will be treated separately. Oxindole synthesis will be covered in tandem with natural product synthesis.
IntramolecularApproaches(typeI) ~edl cc Jbb << type typeIaIa
GcJ ~
W N'a
e H H a
5.2.5.1
IntermolecularApproaches(type type IIac type Ilac ;>;' ~e- -_c._J ~-:! bb
Intermolecular Approaches (type II)
Intramolecular Approaches (type I)
~~eCj ~ dl b
~.,~b e N Naa
Grdl
H
H
Intramolecular Approaches Intramolecular Approaches
The classic intramolecular condensation of ortho-(2-oxoalkyl)anilines continues to be a useful strategy for accessing indoles via Ia type cyclization chemistry. Smith and co-workers employed acid-catalyzed cyclodehydration of ketoanilines on route to members of the nodulisporic acid family <060Ll665, <06OL1665, 060Ll669>. 06OL1669>. For example, treatment of ketoaniline 103 with l,l,l-trifluoroethanol 1,1,1-trifluoroethanol at reflux provided mild access to 2-substituted indole 104, a precursor to the heptacyclic core of (-)-nodulisporic acid D <060Ll669>. <06OL1669>. A variation of this methodology has been reported by Butin who has prepared indoles via acid catalyzed cyclization of anilines onto ortho-pendant ortho-pendant furans, which served as 1,3-diketone equivalents <06TL4113>. Kearney and Vanderwal observed the cyanogen bromide initiated <06TL4l13>. intramolecular cyclization of pyridinyl anilines to afford substituted indoles <06AG(I)7803>. OH OH
OH OH CF3CH 2OH
~ o
,S
.,,.
~
0 NH 22 ..- -NH 103
CF3CH2OH "~
.,LIJ,.I
v
'~OBn
........ , \ reflux,6h reflux, 6h ••, OBn
o=~
••••.......OBn
OTES "OTES
H
OTES
104
Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a o-amino protocol solvent-free conditions to Heck-Jeffery under prepare dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous Ia cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used o-vinyl-N-p-toluenesulfonylanilide to Nby the Okuma group to promote the cyclization of o-vinyl-N-p-toluenesulfonylanilide tosylindole <06CL I1122>. I 22>. A number of iodine promoted Ia type cyclization reactions have been utilized for indole ring construction. Iodocyclization of o-ethynylanilines, prepared by the Pd/Cu-catalyzed coupling of iodoanilines and terminal acetylenes, was employed by the Larock group in their synthesis of 3-iodoindoles <06JOC62>. Kobayashi and co-workers prepared l-arylindoles 1-arylindoles via iodine-mediated endo-cyclization of 2-(arylamino)-a-methylstyrene 2-(arylamino)-~-methylstyrene derivatives <06BCJI580>. <06BCJ1580>. An interesting solvent effect has been observed by Hessian and Flynn who reported selective 5-exo or 6-endo-digonal iodocyclization pathways leading to indoles 106 or quinolines 107, respectively, from common aniline precursors 105 <06OL243>. <060L243>.
152
E. T. Pelkey and l.S. E.T. J.S. Russel
R' ~
~I ~-~IR
U~}, 107 107
HQ HO
R' ~
~ )112'CH3CN ~~ 2, CH 3CN
N R Me Me 1 I-
U~I ..~RR NMe2
105 105
12'etOH
12, EtOH
R' ~
~ ~
/?
(,lrRR 106 106
\ IVle Me
Several examples of metal-mediated intramolecular ring closures have been reported. Iwasawa and co-workers have accessed the tricyclic core of the mitosenes, e.g., 110, in one pot from N-(o-alkynylphenyl)imines 108 via [3+2] [3+2] cycloaddition of the Pt(I1) Pt(II) or Au(III)<06OL289>. In a related containing azomethine ylides 109 with electron rich alkenes <060L289>. investigation, tungsten-containing vinylazomethine ylides were used to generate indoles with <06OL895>. a variety of pendant N- to C2 seven-membered ring systems <060L895>. Ph
Ph ir~Ph PtCl2(3tool%) ~"'O-t-Bu r//~Ph 1~-t_BU~P: i~.1/N MS5A, toluene= ~ O+Nt'l -~~-:?'O[ - t'lt - BO-t-Bu u 50°C ~[..~~ 50~ ~ ~ OTIPS ~ TIPS OTIPS [PtJ 110 OTIPS 108 ~ ~../OTIPS 109 --[Pt] 110 '~-OTIPS 108 109 (Ph PtCI 2 (3mOI%). MS5A, toluene
~I
r(r:hl
The Nakamura group was able to prepare 2,3-substituted indoles by the electrophilic trapping of indole C3-cuprates that had been generated by the sequential treatment of 0oCuCNo2LiC1 <060L2803, <06OL2803, 06AG(I)944>. In an alkynylanilines with n-BuLi, ZnC12, ZnCl" then CuCN·2LiCI Pd(OAc),2 to facilitate a one-pot alternative strategy, Lu and co-workers employed Pd(OAc) Sonogashira-Cacchi domino reaction between o-iodoanilines, terminal alkynes, and 1>. The Cacchi group arylbromides in their preparation of 2,3-substituted indoles <060L327 <06OL3271>. Pd,(dba)33 to couple o-(phenylethynyl)trifluoroacetanilide with aryl chlorides in made use of Pd2(dba) their synthesis of 2,3-disubstituted indoles <06ASC130 l>. A palladium catalyzed tandem <06ASC1301>. Buchwald-Hartwig/Heck reaction provided Lautens and co-workers with efficient access to 2-vinylic indoles from gem-dibromovinyl gem-dibromovinyl aniline precursors <060L4203>. <06OL4203>. Various strategies for indole ring synthesis have relied on the reductive cyclization of 0osubstituted nitroaryl groups. A synthesis of 7-formyl indoles from 3-methyl-2-nitrobenzyl alcohol has been reported by Satyam and co-workers that employs the Ia type BatchoBatcho-Leimgruber reductive cyclization <06SC1051>. The Belley group found that catalytic hydrogenation of (2-nitrophenyl)acetonitriles over Pd/C and (Ph3P)4Pd (Ph3P)4Pd afforded N-hydroxy-2aminoindoles <06TLl59>. <06TL159>. An alternative path to N-hydroxyindoles has been reported by the Nicolaou group who observed SnCl,-promoted SnC12-promoted cyclization of nitroaromatic a,~-unsaturated oql3-unsaturated ketoesters with the trapping of nucleophiles by the incipient a,~-unsaturated o~,~3-unsaturated nitrone intermediates <06AG(I)5364>. The Hossain group has reported a nice complement to the Reissert indole synthesis that allows for access to 3-substituted, rather than 2-substituted, ethoxycarbonyl indoles. The synthesis proceeds via catalytic reduction of 2-nitroaryl-3hydroxypropenoic acid esters over Pd/C <06JOC4675>. Davawala and co-workers have prepared 3-allylindoles from o-nitrobenzaldehydes using a sequence of Wittig olefination of FeS044 and NH 33 the aldehyde followed by a Claisen rearrangement in the presence of FeSO <06TL 1003>. <06TLl003>. As illustrated in the conversion of 111 to 112 below, a variety of indoles bearing chirality at C3 was accessed by O'Shea and co-workers by means of a (-)-sparteine directed enantioselective carbolithiation of 2-propenyl anilines, followed by electrophilic trappingcyclization of the lithio intermediates <06JACS 10360>.
153
Five-membered ring ring systems: systems: pyrroles and benzo benzo analogs
Ph~NH
Ph PhLi, rt, cumene 1. PhU, 2 U, (-)-spartene 2. 29 R R2Li,
N =
R1
R3
-X)
3 3. Electrophile (R (R3-X) 4. 2 M Hel HCI
R1 111
'" 112
A few type Ib intramolecular strategies for construction of the indole core have appeared. Opatz and Ferenc have prepared derivatives of indole-3-acetic acid via 5-exo-trig cyclization cz-deprotonated aminonitriles onto the ortho-pendant cinnamic acid side chains of a-deprotonated <060L4473>. <06OL4473>. Minakata, Komatsu, and co-workers have accessed 2,3-substituted indoles from o-stannylmethylated thioanilides 113 or related o-stannylmethylated aryl isothiocyanates through a sequence of 1,5-dipole generation to 114 and subsequent intramolecular cyclization to indole 115 <060L3693>. <06OL3693>. An interesting aza-Pauson-Khand reaction of alkynecarbodiimides has been employed by the Mukai group in an approach to the pyrrolo[2,3-b]indol-2-one system on route to (±)-physostigmine (+)-physostigmine <060L83>. <06OL83>.
R2
R2
[~NH3nBu3
~ -
SSnBu3
113 R1
114 R 1
S
S
R2
115
The Yao group has made use of a Ic type intramolecular Heck reaction to prepare the C22-<06OL4919>. A solvent-free variation of the symmetric dimeric indole core of chloptosin <060L49l9>. Bischler indole synthesis, electrophilic cyclization of a-arylamino 0~-arylamino imine tautomers prepared from aniline derived a-arylamino Menendez and co-workers for tz-arylamino ketones, has been used by Men6ndez the preparation of 2-arylindoles <06SL91>.
R3
R3
R,bNr~: R,R' ·~' R'Z'::C:R' --;&:~: 116
H
R1
117 117
H H
118 118
R'
H H
Zhao and Larock have described the synthesis of carbazoles, indoles, and dibenzofurans 118 via a Ic Ie type cyclization that follows a sequence of Pd-catalyzed cross-coupling of alkynes and aryl iodides 116, then nitrogen-directed palladium migration to an arylpalladium intermediate 117 that undergoes an intramolecular Mizoroki-Heck ring closure <06JOC5340>. A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac Iac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <060L3573>. <06OL3573>. cz-aryl azirines that Taber and Tian have employed the Neber protocol to prepare a-aryl underwent thermal rearrangement to afford substituted indoles via a unique Ie type ring closure <06JACS1058>. A variety of substituted N-alkyl and N-aryl indoles have been prepared by Zhao and co-workers who observed Ie cyclization of 2-aryl-3-arylamino-2-
154
E.T. J.S. Russel E. T. Pelkey and l.S.
<06OL5919>. alkenenitriles promoted by phenyliodine bis(trifluoroacetate) <060L59 19>. A nice synthesis of stereodefined 3-aryl indolines has been reported by the Pineschi group that involves the intramolecular copper-mediated ring closure of sulfonamidic aryl triflates <060L2627>. <06OL2627>. 5.2.5.2
Intermolecular Intermolecular Approaches
IIac ring syntheses have been reported. The Fischer indole synthesis, A vast array of type Hac the tried and true acid catalyzed rearrangement of arylhydrazones derived from the intermolecular condensation of ketones or aldehydes with arylhydrazines, continues to find broad application in synthetic design. Zard and Sharp have applied the Fischer method in a total synthesis of (±)-aspidospermidine (_+)-aspidospermidine <060L831>. <06OL831>. The Rawal group made use of the Fischer protocol to prepare model vindoline substrates to assess a Pd cross-coupling strategy for the synthesis of C-15 vindoline analogues<06JOC7899>. A regioselective Fischer indole synthesis has been reported by Christoffers in which the regiochemistry across the 2,3-bond of the annulated indole products, 120 or 122, is dependent on the relative configuration (cis/trans) of the bicyclic starting ketones 119 or 121 respectively <06SL3l8>. <06SL318>. Liu and coworkers have described a synthesis of 2,3-substituted indoles involving the rearrangement of 3,3-disubstituted indolenines generated from phenylhydrazine and a-disubstituted (z-disubstituted aldehydes. <06OL5769>. ZnC12 in anhydrous triethylene <060L5769>. Microwave-assisted Fischer indolization using ZnCl, Czarnocki in their syntheis of 2-(2-pyridyl)indoles on glycol was applied by Lipinska and Czamocki route to derivatives of sempervirine <060L367>. <06OL367>. Microwave technology was also applied by Kapoor and co-workers in their silica-based, solvent-free approach to pyrazolines, tetrahydrocarbazoles, and indoles <06SC2727>. Novel access to arylhydrazones from o~-diazoesters has been reported by the Takamura group <06TL743>. aryllithiums and a-diazoesters NH H
O ~ a)
O
HN
H
a)
O2R
O2R ~ n 119
120 120
H,,,
"CO2R
CO2R
121 121
122
PhNHNH2 AcOH, TFA. TFA, 100°C 100 ~ a) PhNHNH equiv), AcOH. 2 (2 equiv),
Sonogashira cross-coupling reactions provided strategic entry into a few type IIac Hac annulations. A heterogeneous palladium-catalyzed cross-coupling was used by Djakovitch and co-workers to prepare 2- and 2,3-substituted indoles from 2-iodoaniline and acetylene precursors <06ASC7l5>. <06ASC715>. Dorow and co-workers employed a 10:1 10:1 ratio of Cul:Cl,Pd(PPh), CuI:C12Pd(PPh3)2 in their preparation of pyrroloquinolones via Sonogashira coupling/heteroannulation methodology <060PRD493>. <06OPRD493>. McLaughlin and co-workers have described a one-pot copper-free Sonogashira alkynylation and base-mediated indolization reaction to access 1,2-disubstituted indoles 125 and azaindoles from o-chloroanilines 123 <06OL3307>. <060L3307>. A ligand-, copper, and amine-free variant of the Sonogashira coupling was used by Srinivasan and co-workers to access 2substituded indoles <06T5l 09>. <06T5109>. R2 a!.~,...NH \Zs CI 123 123
H ~ R33 H R PdCI2(MeCN)2 2(MeCN)2 PdCI (1 mol%) (1 mol %) • X-Phol X-Phol (3 mol %) K2C0 K2CO33,• MeCN MeCN
-----==-
lid
l
R22 R1 I R R!.~....NH ~~NH 0-
Z
124 124
R22 R R1 I R1 KOt-Bu ~J=}-N i ~ \ ~ KOt-Bu
I
----.
(50 mol %) ~ (50mol%)
~ 3
R "R3
125 125
I /;
3
R
155
Five-membered ring ring systems: pyrroles and benzo analogs
A few additional Pd-catalyzed schemes have been employed for IIac type cyclization chemistry. Palladium-phenanthroline complexes were used by the Ragaini group to prepare indoles via the intermolecular cyclization of nitroarenes and alkynes in the presence of carbon monoxide <06JOC3748>. Jia and Zhu employed Pd-catalysis for the annulation of 0ohaloanilines with aldehydes <06JOC7826>. A one-pot Ugi/Heck reaction was employed in the preparation of polysubstituted indoles from a four-component reaction system of acrylic aldehydes, bromoanilines, acids, and isocyanides <06TL4683>. Other examples of type IIac indole syntheses include the Thummel group's application of the Bartoli reaction for the synthesis of 7-bromoindole from 2-bromonitrobenzene and vinylmagnesium bromide <06JOC761l>, <06JOC7611>, the use of Zn(OTf), Zn(OTf) 2 by Kumar and Liu for the catalytic cyclization of propargyl alcohols with various substituted anilines <06JOC495l>, <06JOC4951>, and the preparation of N-methoxyindoles by Penoni, Nicholas, and co-workers via treatment of nitrosoarenes and alkynes with K~CO3/(CH3)2SO ~CO/(CH)2S044 <06JOC823>. Aoyama and co-workers have reported a unique entry into substituted indoles 128 from o-acyl-N-tosylanilines 126 that concludes with an intramolecular N-Li insertion of alkylidenecarbene intermediates 127 <06S 1249>. <06S1249>. O
R 2 ~ R
1
R3" ~ 'NHTs 126
R1
TMSCHN TMSCHN 22 (1.2 (1.2 equiv) equiv)
.
R1
C.
LDA or n-BuLi (2.2 equiv)
i 127
Ts
~
~
E R31~-,~,,/~N Ts 128
Select examples examples of Electrophiles Electrophiles = PhCHO, AC20, Ac20, and allyl bromide bromide
Gong and co-workers employed an intermolecular Nenitzescu reaction, a type IIce transformation, for the condensation of a p-amino-a,p-unsaturated [3-amino-a,~-unsaturated ester with 1,41,4benzoquinone to afford a 5-hydroxyindole derivative <06BMC91l>. <06BMC911>. A type IIae reaction has been reported by Willis and co-workers who prepared Nsubstituted indoles via Pd-catalyzed coupling of 2-(2-haloalkenyl)-aryl halides with a variety of amines <06ASC85 1>. In an alternative intermolecular approach to ring construction, <06ASC851>. Tang and Hu have reported a Pd-catalyzed coupling of o-alkynylhalobenzenes with amines to afford 1,2-disubstituted indoles <06ASC846>. 5.2.6 5.2.6 5.2.6.1
REACTIONS OF INDOLES Substitution at C-3/C-2 C-3/C-2 Substitution
The development of asymmetric variants of the Friedel-Crafts alkylation at indole C3 has received considerable attention. attention. In this regard, an assortment of chiral bisoxazolines have found steady use in conjunction with copper or zinc Lewis-Acid catalysts. Examples included the use of Zn(II) complexes for the alkylation of indoles with nitroalkenes <06JOC75, 060L2115>, 06OL2115>, the use of Cu(II) complexes for promoting the addition of indoles to N-sulfonyl aldimines <060Ll62l>, <06OL1621>, ethenetricarboxylates <06JOC739>, or benzylidene malonates as illustrated for the conversion of indole 129 to 130 with chiral azabisoxazoline ligand 131 <060L6099>. <06OL6099>. A review of chiral bis(oxazoline) ligand chemistry has appeared <06CR3561>. <06CR356l>.
156
E. T. Pelkey and 1.S. E.T. J.S. Russel
C02 Et
[~N
~ ~l 129 129
H H
H
Ph'/-~CO2 CO2Et = ~ Cu(OTfb/ligand Cu(OTf)2/ligand EtOH, EtOH, 20°C 20 oC
~~(l~
Ph'~CO2 CO2EtEt ~ ; / N ' ~ NN~5"-.
p F C 02 Et
~ ~N 130 H
\
---{ ~
131 131
/
/
Example Exampleligand ligand
A collection of other chiral agents have been employed in efforts to install asymmetric side-chains at C3. Deng and co-workers made use of bifunctional cinchona alkaloids to promote the enantioselective Friedel-Crafts Friedel-Crafts addition of indoles to aldehydes and a-ketoesters t~-ketoesters <06OL4063>. <060L4063>. Cinchona alkaloid-catalyzed enantioselective addition of indoles to imines has also been reported <06JACS8156>. <06JACS8l56>. In an alternative approach to chiral indoles, the Evans group has employed a bis(oxazolinyl)pyridine-scandium(III) triflate complex to promote the enantioselective addition of 4,7-dihydroindole to a,p-unsaturated t~,~-unsaturated 2-acyl imidazoles <060L2249>. <06OL2249>. In the latter case, oxidation of the substituted dihydroindole products with p-benzoquinone afforded the chiral indole products. Enantioselective Michael addition to a,p-unsaturated ct,[3-unsaturated ketones was achieved using D-camphorsulfonic acid as a catalyst <06EJO5225>. Enantiomerically pure aziridin-2-yl methanols were used by Bonini and co<06EJ05225>. workers as organocatalysts for the C3 alkylation of N-methylindole with a,p-unsaturated t~,~-unsaturated aldehydes <06TA3135>. A variety of Pd-catalyzed couplings have been used to set new bonds at indole C3. Trost and Quancard employed Pd with an anthracene derived chiral ligand and trialkylboranes to promote the enantioselective C3 coupling of 3-substituted-l-H-indoles and allyl alcohols for the installation C3 quaternary centers <06JACS63 <06JACS6314>. 14>. This methodology was applied in the synthesis of (-)-esermethole, a key intermediate on route to the Alzheimer's drug candidate (-)-phenserine. The Ma group has employed Pd in the regiospecific C3 coupling of indoles to electron-deficient alkenes bearing a 2-acetoxymethyl group <06JOC9865>. The 1313hydroxytryptophan subunit of cyclomarin A was constructed by Spinella and co-workers via <06SL 1319>. Pd-mediated vinylation of N-substituted indole to afford a key C3 acrylic ester <06SLl3l9>. An indolylboron species, prepared using Pd-catalyzed borylation of 3-iodoindole on solid support, was used by Kasahara and Kondo to prepare bisindolymaleimides <06H(67)95>. A number of other metal-mediated strategies for C3 functionalization have been described. Platinum was utilized by Han and Widenhoefer in the study of the intramolecular asymmetric hydroarylation of C2-tethered unactivated alkenes to generate 2,3-annulated indoles <060L380l>. <06OL3801>. Related arylationlcarboalkoxylation arylation/carboalkoxylation investigations with Pd have been disclosed <06CEJ237I>. <06CEJ2371>. Baba and co-workers used indium trichloride to promote the direct C3 coupling of indoles to benzyl or allylic alcohols <06AG(I)793>. Silver ion was used by the Banwell group to facilitate the coupling of N-methylindole to dibromocyclopropane derivatives in their approach to the polycyclic core structures of hapalindole and <06OL4959>. fischerindole alkaloids <060L4959>. In an interesting variation of a-amido ~-amido sulfone chemistry, the Petrini group has observed the formation of 3-(l-arylsulfonylalkyl) 3-(1-arylsulfonylalkyl) indoles via a clay-promoted Friedel-Crafts Friedel-Crafts reaction <060L4093>. <06OL4093>. Other reported routes to C3 substituted indoles include two independent reports of three-component aza-Friedel-Crafts aza-Friedel-Crafts reactions <060L4939, <06OL4939, 06SL96>, the Tudge group's synthesis of 3-sulfenyl indoles using N-alkyl or arylphthalimides in the presence of catalytic MgBr, MgBr 2<060L565>, <06OL565>, a photoinduced 1A-addition 1,4-addition of indoles to enones reported by Beauchemin and co-workers <06JOC676>, and the work of Tse and co-workers on the synthesis ofbisindoles of bisindoles via ring opening of N-sulfonylaziridines <060L576l>. <06OL5761>.
157 | 57
Five-membered ring systems: pyrroles and benzo analogs
The investigation of methods for the 2-arylation of indoles received significant attention. Examples include a report by Sanford and co-workers of a mild oxidative method for C2 aryl coupling that involves treatment of indoles 132 with [Ph-I-Ph]BF44 complex 133 under Pd<06JACS4972>, the use of palladium complexes of imidazolyl catalysis at room temperature <06JACS4972>, carbenes by the Sames group to arylate SEM-protected indoles <060Ll979>, <06OL1979>, and a report by Denmark and Baird on the cross-coupling of C2 silanolates with aryl iodides and bromides <06OL793>. In an approach that did not involve direct coupling at C2, Bremner and co<060L793>. 2-aryl-5-nitro-lH-indoles from N-acylated indoles via an intramolecular workers prepared 2-aryl-5-nitro-lH-indoles Pd-promoted oxidative cyclization to set the C2 bond, followed by hydrolysis of the isoindolo-indolone isoindolo-indolone tetracyclic intermediates to free indole nitrogen <06BMC857>. BF4
~H ~N/+ 132 132
5 mal % Pd[[ AcOH, AcOH, 25 DC ~
\
133 133
CQ-O COO 134 134
\
The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2vinylindoles from N-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8l46>. <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an N-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. There have been various reports of efforts to construct indole fused polycyclic frameworks via annulation across N-C2 or C3-C2. Bergman, Ellman, and co-workers have disclosed details of the asymmetric cyclizations of N-allyl-substituted indoles bearing a C3 imine functionality. To promote the transformations, the N-C2 annulations were catalyzed by a chiral rhodium phosphoramidite complex <060Ll745>. <06OL1745>. The Frontier group made use of a heteroaromatic Nazarov type cyclization between C2 and a C3 pendent a,f3-unsaturated ~,~-unsaturated 13[~ketoester functionality <060L5661>. <06OL5661>. In a report by Beccalli and co-workers, seven and eight-membered lactam ring systems were fused across the indole 2,3-bond using Pdcatalyzed intramolecular cyclization of C3 tethered aryl amides <06S2404>. Ferrer and Echavarren employed a gold catalyst to prepare seven- and eight-membered ring systems from C3 tethered alkynes <06AG(I) 1105>. X X X
0"
~ \ XX ())-NCO NCO
135 135
I~le Me
N.-'< N.~X II[I ( 3 0
X,,-/X
/~
---
~I:
137
' Me Me
X
equiv. N~ N . ~ - 136 X = OMe, OMe, SPr 4 equiv. / \
The classic addition of C3 tethered amine derivatives onto C2 of indolium ions has been used to access hexahydropyrrolo[2,3-b]indole hexahydropyrrolo[2,3-b]indole frameworks <060L4303, <06OL4303, 060L60ll>. 06OL6011>. An alternative and unique strategy for accessing similar pyrrolo[2,3-b]indole pyrrolo[2,3-b]indole polycyclics 137 has
158
E. T. Pelkey and l.S. E.T. J.S. Russel
been investigated by Rigby and Burke who observed [4+1] [4+1] cyclization of indole-2isocyanates 135 with carbenes <06H(67)643>. An oxidative coupling of an imidazole and a macrolactamization across the indole 2,3-1t 2,3-7z transient indolium ion has been exploited in a macro1actamization <06OL1165>. Other annulation strategies are discussed below in the section on system <060Ll165>. natural product synthesis. 5.2.6.2
Substitution at Nitrogen
The relative acidity of NH-indoles continues to stimulate the development of convenient protocols for protection-deprotection schemes. Chakrabarty and Kundu have reported the cleavage of N-Boc indoles under basic conditions using a methanolic solution of potassium carbonate <06SC2069>. The deprotection of N-tosylindoles using cesium carbonate has been reported by Bajwa and co-workers <06TL6425>. The Padwa group has described a method for the photodesulfonylation of indoles <06TL2409>. Alkylation at nitrogen has been achieved by treating indole or pyrrole with alkyl halides in 1-n-butyl-3-methylimidazolium tetrafluoroborate ionic solutions of potassium carbonate in 1-n-butyl-3-methylimidazo1ium -biindoles with Me, Boc, [bmim][BF44]J <06TL2435>. Bis-protection of 3,3'-diiodo-2,2' 3,3'-diiodo-2,2'-biindoles CO2Et, SO2Ph has been described by Roy and Gribble <06SC3487>. C0 2Et, or S02Ph
~.. ,Rv , ~ ~
Me R3
Toluene Me Me R3 R 2reflux,5h= 3 ~ R ~Me0 : Toluene reflux, 5h
~XO-R2 c/
~~~, C O"Me ) \ Me Cr(COb
,i
Cr(CO)3
Xd::'" 2 HO
Me Me....,,.~HO,~HMe H = ,"~ ~ Ma3//N R2
Me 3
·~~R2--hN !j~};, R c/
--
138 3 _ . ~.M ~ . e\ 139 139 "'Cr(COb
138
R 33 = = 1,3-dioxolane 1,3-dioxolane R
~.
c/
"Or(CO)3 e 140 140""Cr(COb
Me
Singlediastereomer
Single diastereomer
A few asymmetric transformations have been orchestrated between the indole ring and Nsubstituents. substituents. An intriguing stereoselective synthesis of N-aryl indole chromium complexes 138 with axially chiral N-C bonds has been reported by Kamikawa, Demura, Uemura, and co-workers <060Ll097>. N-ary1138 <06OL1097>. Stereoselective chromium tricarbonyl migration from N-aryl 138 to the arene ring of indole 139 was observed, with subsequent installation of the asymmetric side-chain at indole C4 of 140 <060Ll 097>. Arai and co-workers have employed 2-(p<06OL1097>. tolylsulfinyl)indoles bearing a,~-unsaturated ~,~-unsaturated enones at indole nitrogen as chiral auxiliaries <06H(68) 1025>. for asymmetric Diels-Alder transformations <06H(68)1025>. An approach to N-C2 annulated indoles has been reported by Ishikura and co-workers that <06T1015>. A involved cyclization-intramolecular alkyl migration of N-tethered borates <06Tl015>. BF3oEt,o-promoted synthesis of 2-prenylindoles from N-prenylindoles has been described BF3oEt20-promoted <060BC3966>. lactone-to-Iactam rearrangement <06OBC3966>. Iodolactonisation used in tandem with a lactone-to-lactam was employed by Joseph and co-workers for the conversion of N-allylindole-2-carboxylic acids to N-C2 cyclized diazepine derivatives <06SL2755>. Black and co-workers have achieved N-C7 annulation in the preparation of pyrrolo[3,2,1,hi]indazoles pyrrolo[3,2,I,hi]indazoles via base promoted cyclization of the 2,4-dinitrophenyl ethers of indole-7-ketoximes <06T6343>. 5.2.6.3
Functionalization Funetionalization of the Benzene Ring
The ability to selectively direct chemistry at indole positions C4 to C7 remains a synthetic challenge. Takayama and co-workers have developed a procedure for masking the 2,3-1t 2,3-~ bond of indole as a bridged ethylene glycol system that allowed for functionalization of the
Five-membered ring ring systems: systems: pyrroles and benzo benzo analogs
159
resulting indoline at C5 with halogen, NO NO"2, or methoxy groups <060L5705>. <06OL5705>. The ethylene glycol masking procedure was applied to the synthesis of corynanthe type opioid receptor agonists. Selective C-C bond formation at C4 has been achieved by Kita and co-workers who employed a Pummerer-type reaction between 5-sulfinyl indoles and a variety of carbon nucleophiles <06TL1881>. An Ir-catalyzed borylation strategy has been employed by Maleczka, Smith, and co-workers for the selective C7 arylation of NH indoles <06JACS15552>. A synthesis of 7-haloindoles via thallation of N-formylindoline has been <06JACSI5552>. described <06CPB788>. The Volk Yolk group has observed the formation 3-alkyl-7methyloxindoles during the reductive 3-alkylation of isatin with i-BuOH over Raney Ni <06H(68)539>.
5.2.6.4
Functionalization of the Side-Chain
The nucleophilicity of the indole core, coupled with the relative acidity of indole NH, continues to dictate a need for the development of delicate methods for selective side-chain functionalization. A sequence of hydroboration with 9-BBN followed by Suzuki-Miyaura Pd-coupling has been employed by Ferreira and Stoltz for the elaboration of 3-vinyl indole side-chains <06TL8579>. Gribble and co-workers have described the synthesis of indolylarylmaleimides and heteroaryl varients, staurosproine type indolocarbazole buildingblocks, via treatment of N-methylindole-3-glyoxylamide with methyl aryl acetates in solutions of potassium t-butoxide <060L4975>. <06OL4975>. A report from the same group has appeared that describes the conversion of tryptamine to an intriguing bis(indolyl)oxazole analog of the pimprinaphine ring system <06S3948>. Indole-2- or indole-3-aldehydes were converted by Jaisankar and Srinivasan to the corresponding 2- or 3-cyanoindoles by treatment with sodium <06S2413>. I3>. A lipase-catalyzed enzymatic azide in the presence of aluminum chloride <06S24 resolution has been used to generate an optically enhanced (R)-ester pendant on the cyclopentyl ring of a tricyclic 2,3-fused indole <060PRD592>. <06OPRD592>.
5.2.7
CARBAZOLES AND AZAINDOLES
5.2.7.1 Carbazole Ring Synthesis and Annulation Several reports of carbazole ring synthesis have appeared. A total synthesis of the biscarbazole alkaloid murrastifoline-A has been reported by the Chida group who employed a palladium-catalyzed double N-arylation of 2,2' -dibromobiphenyls to set the carbazole core 2,2'-dibromobiphenyls <06T6792>. Structurally related murrayafoline-A has been prepared by Mai and co-workers via an anionic [4+2] [4+2] cycloaddition of furoindolones onto methyl crotonate to set the tricyclic <06TL1071>. Fusion of an aryl-iron complex with a polyfunctional carbazole skeleton <06TL107l>. aniline afforded the central carbazole unit in the enantioselective synthesis of neocarazostatin B by the KnOlker Kn61ker group <06CC71l>. <06CC711>. Oxidative cyclization of a diarylamine with catalytic Pd(II) was employed by the same group to afford several natural carbazole alkaloids bearing 7-hydroxy or -methoxy substituents <060BC3215>. or-methoxy <06OBC3215>. Lu and co-workers have reported the use of palladium-catalyzed intramolecular oxidative cyclization to access carbazoles from 3(3'-alkenyl)indoles <060L1319>. <06OL 1319>. Strategies for annulation of carbazole scaffolds have been investigated. Hexacyclic benzofuropyrano- or benzofurofurocarbazoles have been prepared by Chattopadhyay and coworkers via a cascade of sigmatropic rearrangements emanating from 2-hydroxycarbazole tethered aryloxy alkynyl ethers <06SL3358>. The same group reported the conversion of 2-
160
E.T. Pelkey Pelkey and Russel E.T. and l.S. J.S. Russel
N-Cl azepine annulated carbazoles hydroxycarbazoles to a variety of CI-C2 C1-C2 oxepine or N-C1 O-allyl ethers followed by Grubbs' using a sequence of Claisen rearrangement from C2 C20-allyl olefin metathesis chemistry <06TL6895>. An interesting light- and base-meditated ring closure was used to access the aryl fused skeletons naphtho[a]carbazoles and benzo[c]carbazoles from 2- or 3-arylindole precursors <06T2820>. 5.2.7.2 Azaindole Azaindole Ring Synthesis Synthesis
An intriguing synthesis of 7-azaindoles has been reported by Zheng and Kerr that involves the generation of a tristrifloxy pyridine derivative 142 that undergoes heteroannulation when treated with primary amines. Oxidation of the resulting azaindolines 143 with MnO, MnO 2afforded <06OL3777>. the fully aromatized ring system 144 <060L3777>.
O
~o ~H
141
OTf
OTt
ill'
O TfO~N TfO~N RNH2 M n2 O 2 ~ ~ 2 ~ RNH Mn0 Tt,,o I NH pyridine Tf20 •... ~[~L...OT f TfO TfO " TfO/\'N/-N ~ N " N OTt N R pyridine R TtO N ,R 142
143
!))1 144 144
R
The Leimgruber-Batcho reaction was employed by Wang and co-workers to prepare 3substituted-4- and 6-azaindoles in one pot from o-methylnitropyridine, N,Ndimethylformamide dimethyl acetal, and electrophilic alkyl or acyl groups <06TL5653>. Synthesis of 4-substituted 7-azaindoles has been achieved by the Thutewohl group via Pdcoupling of anilines or phenols to C4 chlorides <06S629>. A synthesis of 7-azaserotonin from 7-azaindole has been reported by Chou and co-workers <06JACSI4426>. <06JACS 14426>. 5.2.8 5.2.8.1
INDOLE NATURAL NATURAL PRODUCTS PRODUCTS INDOLE Natural Natural Products Products Isolation Isolation and Characterization Characterization
Isolation and characterization of new indole alkaloids remains a fruitful avenue for the discovery of agents with the potential for biomedical application. The virtues of this age-old process, in light of advances in combinatorial chemistry, were brought to the community as part of the 23 231I"s, ACS National Meeting symposium, Modern Natural Products Chemistry and Discovery <060RGN467>. Drug Discovery <06ORGN467>. Examples of indole natural products that have recently been identified include the indoloquinone containing indoleamine-2,3-dioxygenase inhibitor exiguamine A from the marine sponge Neopetrosia exigua <06JACSI6046>, <06JACS 16046>, the azepino-indole hyrtiazepine from <06JNP1676>, 676>, oxazinin-4, an isolate of the toxic the Red Sea marine sponge Hyrtios erectus <06JNPl mussel Mytilus galloprovincialis galloprovincialis <06T7738>, the oxazolone tethered indole almazolone from the red alga Haraldiophyllum sp. <06Tl165>, <06T1165>, the cytotoxic, tripeptide-derived chaetominine from the Chaetomium fungus <060L5709>, <06OL5709>, malbrancheamide, an brevianamide type indole with fused bicyclo[2.2.2]diazaoctane system from the fungus Malbranchea aurantiaca <06Tl S17>, the cytotoxic cytochalasan-type alkaloid chaetoglobosin U from endophytic <06T1817>, fungus Chaetomium globosum <06JNP302>, an antiparasitic pyrimidine-linked p-carboline ~-carboline from the plant Annona foetida <06JNP292>, three bridged polycyclic terpenoid alkaloids from the stem-bark and root of Winchia calophylla <06JNPlS>, <06JNP18>, three aspidospermidine-type alkaloids from the leaves of Kopsia officinalis <06HCA5 15>, the pentacyclic monoterpenoid <06HCA515>, <06OL1733>, four oxindole arboflorine, isolated from the stem bark of Kopsia arborea <060Ll733>,
161
Five-membered ring ring systems: pyrroles and Five-membered systems:pyrroles and benzo benzoanalogs analogs
alkaloids from the bark of Cinnamodendron axillare <06JNP1517>, four related monoterpenoid oxindole alkaloids from the leaves of Gelsemium elegans <060L3085, <06OL3085, 06JNP715>, the unique spiro thiazole containing antifungal agent erucalexin, isolated from 06JNP7l5>, the leaves of the dog mustard Erucastrum gallicum <060BC691>, <06OBC691>, and two indoloquinazoline indoloquinazoline alkaloids extracted from Wu-zhu-yu, the dried fruits of China's Evodia rutaecarpa <06H(68)1691>. <06H(68) 1691>. Indole Alkaloid Total Synthesis Synthesis
5.2.8.2 5.2.8.2
The diversity of architectural types and vast array of biological activities continues to stimulate intense interest in the area of indole natural product total synthesis. A selection of completed works in total synthesis includes the DNA alkylating antitumor agents (+) and ent<06JACS15683, 06JACS7l36>, 06JACS7136>, the bromo-indolinine (-)-yatakemycin and duocarmycin SA <06JACS15683, chartelline C with spyrocyclic ~-lactam [3-1actam and tethered imidazole functionality <06JACS14028>, the telomerase inhibitors dictyodendrin B, C, and E <06JACS8087>, the <06JACS14028>, <06OL1975>, cytotoxic (±)-subincanadine (+)-subincanadine F cyclic peptide stephanotic acid methyl ester <060L1975>, with its distinctive l-azabicyclo[4.3.I] 1-azabicyclo[4.3.1 ] skeleton <06JOC9495>, cytotoxic peduncularine with 6-azabicyclo[3.2.1 ]octene framework <06BCJ1552>, <06BCJ 1552>, the ergot-alkaloids (+)-setoclavine, (+)6-azabicyclo[3.2.I]octene lO-dihydroisosetoclavine <06H(67)291>, isosetoclavine, and (-)-9, (-)-9,10-dihydroisosetoclavine <06H(67)291>, the isoquinuclidine 19R)-ibogamin-19-01 <06HCA542> and (+)-catharanthine <06AG(I)5334>, containing (-)-( (-)-(19R)-ibogamin-19-ol the antibacterial N-methyl-2,4-dibromoindole <06JNP1596>, the bis-indole alkaloids dragmacidin A, B, and C <06S49>, the neuronal cell protecting carbazomadurin B <06SL651>, the antioxidant (-)-neoechinulin A <06SL677>, and (S)-Cypridina luciferin <06TL753>.
j~~
MoO-U n~ MoO-U n~ l o :"Et o~J a;tj -=. ~~" ~~ O
r
M MeO e
N
, Me Me C0 C02Me 2 Me
145
O
Et Et
180
MeO
oc
_-.
O
MeO
"Et
N/~'~OBn
Me Me/
Ac
Me Me/
146
C0 Me (~02Me 2
(-)-Vindoline 147
A virtue of the practice of indole natural product total synthesis is the concurrent development of general or fortuitous discovery of intriguing synthetic methodology. Boger and co-workers have disclosed the details of an intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles 1,3,4-oxadiazoles <06JACS10589> <06JACS 10589> that has been employed in the total synthesis of (-)- and ent-(+)-vindoline <06JACS10596, <06JACS10596, 06AG(I)620>. For example, the inverse electron demand Diels-Alder Diels-Alder cycloaddition ([4+2]) of the tethered oxadiazole 145 is followed, after loss of nitrogen, by a 1,3-dipolar cycloaddition ([3+2]) across the indole 2,3bond to stitch up the C ring of the core pentacyclic frame 146 of (-)-vindoline 147. In an alternative approach to annulation across the indole 2,3-1t 2,3-~ system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)promoted cycIization-cycIoaddition cyclization-cycloaddition cascade <060L3275, <06OL3275, 060L5l41>. 06OL5141>. As illustrated in their approach to (±)-aspidophytine (+)-aspidophytine 150, Rh/OAc)4-catalyzed Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-1t 2,3-n bond to generate 149 <060L3275>. <06OL3275>.
162
E. T. Pelkey Pelkey and 1.S. E.T. J.S. Russel
0
0 o
0 C02t-Bu
I
',,..'- 'r
u
~
OMe ~wu (~O2Me 148
l
o
~I (N(;'l
N:: ~
MeO::::-'"
121 [i H OMe OMe Me Me
/
OMe Me
0
149
Aspidophytine 150 150 Aspidophytine
In the course of their investigation of the enantioselective total synthesis of avarainvillamide and the stephacidins, the Baran group has developed a method for the dehydrogenation of tryptophan as well as a one-step tryptophan synthesis from pyroglutamate and substituted aniline precursors <06JACS8678>. On route to the Erythrina Erythrina alkaloid 3-dimethoxyerythratidinone, Wang and Padwa encountered the interesting acid catalyzed rearrangement of lactam 151 to the tetracyclic <06OL601>. hydroxyindole 153 via the lactone 152 <060L60l>.
TB o S O ~ 2 M e TBS~2Me
Meo~>"o MeO~~'~~N"~"O
Meo~ MeO" ~ V
~/~-~.~O ,,0-" TfOH H L ' ~ ~ TtoH +
40°C,1h 40~
~
O
HO HO OMe OMe
M e 152
151 151
OMe
":
"
v
OMe OMe
~ "OMe OMe ~Y
153 153
The Bennasar group has reported a regioselective 6-endo reductive cyclization of 2indolylacyl radicals, generated from 154, to afford entry into the tetracyclic ring system 155 found within guatambuine 156 <06JOC1746, 06OL561>. 060L561>. Me Me
' N
~ 0;/
I
::::-...
154 154
~
N,, Me Me
N
COSePh Ph
n-Bu3SnH ~ ,-B,,5,H AIBN AIBN
Me Me
crR?N ~ ' / ~ N N
0;/
I
~::::-... ~-N"
155 155
"'H O N, 0 Me 'Me
(2:1 (2:1 trans-cis) trans-cis)
05PN Me Me.
0;/
::::-...
[
Me Me I<1
; :/;
N H
Me
Guatambuine Guatambuine156
Strategies for the synthesis of the core structures of several natural products have been reported. In developing a biomimetic approach toward the synthesis of haplophytine, Corey and co-workers have investigated the direct coupling of two indole partners in the form of an aspidophytine mimic and a tetracyclic canthiphytine analog <060L3ll7>. <06OL3117>. A selection of other studies include a biomimetic approach to the pentacyclic substructures of <06OL2187>, an aza-ortho-xylylene aza-ortho-xylylene route to the perophoramidine and communesin <060L2l87>, communesin ring system <060L3995>, <06OL3995>, synthesis of the tetracyclic core of tronocarpine <06OL4561>, a synthesis of the western half of the tremorgenic lolicines <060L456l>, IoIicines and lolitrems IoIitrems <06OL2209>, an approach to the bicyclo[4.3.1 ]decane skeleton of welwistatin <060L5287>, <06OL5287>, <060L2209>, bicyclo[4.3. I]decane a route to the tetracyclic core of koumine <060Ll08l>, <06OL1081>, construction of the pentacyclic core of ~-carboline ~-carboline subincanadine B <060LlI5>, <06OL115>, a synthesis of the tryptophan core of the celogentin/morodin family of cyclic peptides <06AJC819>, an enantioselective synthesis of
Five-membered ring systems: pyrroles and benzo analogs
163
stereocenter bound to C7 of of lyngbyatoxin A A <06OBC4292>, <060BC4292>, an approach to the quaternary stereocenter pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine framework of of arnoamines A and B the pentacyclic pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine <06TL7819>, and a biomimetic approach to the furanobisindole core of of phalarine <06TL4839>. 5.2.8.3 [~-Carboline p-Carboline and and Tetrahydro-~-carboline Tetrahydro-p-carboline Total Total Synthesis Synthesis 5.2.8.3 ~ The ubiquitous presence in nature and medicinal value of the tryptophan derived 13carbolines has prompted a wealth of synthetic activity. Recent efforts in carboline synthesis have been documented by Love <06THC93>. A review of strategies for the synthesis of the manzamine alkaloids has appeared <06THC255>. Martin and co-workers have described a general approach to corynanthe indole alkaloids, including a total synthesis of dihydrocorynantheol <06JOC6547>. A strategy for preparing zwitterionic sempervirine type indolo[2,3-a]quinolizine alkaloids has been documented <06T5736>. Other select examples indolo[2,3-a]quinolizine tetrahydro-~-carboline total synthesis include, include, (S)of completed works in carboline and tetrahydro-~-carboline <060L3549>, (+)-macroline and alstonerine <06JOC8884>, (-)-normalindine brevicolline <06OL3549>, <06JOC8761>, (-)-vincapusine <06JOC3768>, (-)-subincanadines A and B <060L4605>, <06OL4605>, (±)-alloyohimbane <060L3033>, ent-dihydrocorynantheol (_+)-alloyohimbane <06OL3033>, ent-dihydrocorynantheol <060Ll533>, <06OL1533>, vallesamidine <06HCA249>, (+)-12b-epidevinlantirhine <06TL5737>, and (+)-N,-methylpericyclivine (+)-Na-methylpericyclivine <060Ll017>. <06OL 1017>. tetrahydro-~-carboline synthetic A few intriguing developments in the area of tetrahydro-~-carboline methodology include the report of a catalytic asymmetric Pictet-Spengler reaction <06JACS 1086> and an enantioselective Pd-catalyzed intramolecular allylic allylie alkylation of <06JACS1086> 1-substituted-~-carbo1ines from Lindoles <06JACS1424>. A one-step synthesis of 1-substituted-[3-carbolines tryptophan has appeared that bypassed the tetrahydro intermediate <06Tl0900>. <06T10900>.
5.2.8.4 5.2.8.4
Oxindole Oxindole Total Synthesis Synthesis
Oxindoles and spirocyclic variants represent another general class of indole alkaloids that have received considerable attention as synthetic targets as well as key intermediates in natural product synthesis. Trost and Brennan have constructed the stereogenic quaternary center of deceptively simple horsfiline using a palladium-catalyzed asymmetric allylic alkylation of an oxindole nucleophile <060L2027>. <06OL2027>. Weinreb and co-workers employed an 06OL1779>. The oxindole spiro-~-lactam in their approach to chartelline A <06JOC3159, 060Ll779>. Wood group has completed work on (±)-welwitindolinone (+)-welwitindolinone A isonitrile <06JACS1448>. <06JACS 1448>. As illustrated below, the spiro-oxindole framework 159 was set via a-deprotonation ~-deprotonation of the isonitrile 158 with subsequent cyclization of the resulting anion onto the isocyanate <06JACSI448>. <06JACS 1448>. Other completed works in oxindole or spiroindole natural product synthesis include convolutamydines Band B and E <060L677>, <06OL677>, (±)-strychnofoline (+)-strychnofoline <06CEJ8208>, (±)(_+)dehaloperophoramidine <06AG4317>, (-)-flustramines A and Band B and (-)-flustramides A and B <06CC420>, (+)-aUine (+)-alline <06TL5379>, and (R)-convolutamydine A.
164
E.T. Pelkey Pelkey and and l.S. J.S. Russel E.T.
\Me CI
. \\ . e c' ~
O
....
H
N'", ~ M e H/~"Me
COCI2 Et3N,0 ~
'"'
CI
H
CN'i~HMe
R21~_.)/~" <~Me
. THF THF
LiHMDS LiHMDS
-78°C -78 ~
~--NH2 157
157
\\~~e91 elll
CN
H
~
0"" ~N
H Me "Me
0
H H
158
159
Concurrent with efforts in the realm of oxindo1e oxindole natural products, a high density of work has been directed toward the development of supporting methodology for application to total synthesis. A selection from the multitude of reported works include the investigation of the diastereoselection in the formation of spirocyclic oxindoles by the intramolecular Heck reaction <06JOC2587, 06JOC2600>, the Lewis acid-catalyzed enantioselective C3 hydroxylation of oxindoles <06JACS 16488>, the stereoselective alkylation of oxindole <06JACS16488>, cyclization/carbonylation of enolates <06JOC8559>, the tandem intramolecular Heck cyclization!carbonylation acrylamides on route to perophoramidine and the communesins <06JOC8891>, the molybdenum-catalyzed asymmetric allylation of 3-alkyloxindoles for the formal synthesis of (-)-physostigmine <06JACS4590>, the addition of isatins to dimethoxycarbene-DMAD zwitterion to afford spirodihydrofurans <06JOC2313>, the diastereoselective synthesis of spirocyclic oxindoles via intramolecular Ullmann coupling and Claisen rearrangement <06AG(I)2274>, the rhodium-catalyzed asymmetric addition of aryl-and alkenylboronic acids to isatins <06AG(I)3353>, the synthesis of 2-phenylindoxyls via basic hydrolysis of 3acetoxy indoles <06ARK(xi)37>, the stereoselective synthesis of spiro-y-butyrolactones from <060L507>, the synthesis of 3-acyloxindoles via CuUL-proline-catalyzed isatins <06OL507>, CuI/L-proline-catalyzed intramolecular arylation of I]-keto ~-keto amides <06OL6115>, <060L6115>, a domino carbopalladation/C-H carbopalladation!C-H activation! C-C bond formation leading to the synthesis of unsymmetrically substituted 3activation/C-C (diarylmethylenyl)indolinones from anilides <06OL4927>, <060L4927>, the asymmetric synthesis of spirocyclic oxindoles via chiral indole-2-sulfoxides indole-2-sulfoxides <06OL4137>, <060L4137>, the rhodium-catalyzed addition of arylboronic acids to isatins for the preparation of 3-aryl-3-hydroxyoxindoles <06OL2715>, <060L2715>, and the synthesis of diversely functionalized oxaspirocyclic oxindoles using Barbier-type carbonyl-additions to isatins in sequence with metal mediated cyc1ization cyclization to spiro-dihydrofurans <06JOC2346>. <06JOC2346>. 5.2.9
BIOCHEMICAL CHEMISTRY BIOCHEMICAL AND AND MEDICINAL MEDICINAL CHEMISTRY
5.2.9.1 Indole Indole Alkaloid Alkaloid Biosynthesis Biosynthesis
Indole alkaloids have had a rich history in the designs of of chemists hoping to understand, understand, mimic, and regulate a varied host of of biochemical biochemical systems. Details regarding the biosynthetic pathway of of the tryptophan derived antitumor agents rebeccamycin and staurosporine staurosporine have <06JACS12289> been reported by the Walsh group <06JACS 12289> as well as by Sherman and co-workers <06JACS724>. May and Stoltz have evaluated commonalities commonalities in the structure and <06JACS724>. communesins, and biosynthetic origins of the cytotoxic calycanthaceous alkaloids, the communesins, of the antitumor-antibiotic antitumor-antibiotic nomofugin <06T5262>. An investigation of the biosynthesis of echinomycin has been been disclosed <06OL4719>. <060L4719>. Pedras Pedras and Okinyo have reported on the biosynthesis biosynthesis of of erucalexin, erucalexin, a member member of of the crucifer crucifer phytoalexins, phytoalexins, which which have a putative role
Five-membered ring systems: pyrroles and benzo analogs
165
in the regulation of carcinogen metabolism <06CC1848>. Related investigations of the metabolism of crucifer phytoalexins have appeared <060BC3526, <06OBC3526, 060BC2581, 06OBC2581, 06BMC4958>. A reverse prenyltransferase prenyitransferase has been investigated in conjunction with studies of the biosynthesis of the ergot alkaloid precursor fumigaclavine A <06CBC158>. <06CBC 158>. 5.2.9.2
Medicinal Applications Applications of Indole Alkaloids
In the realm of cancer chemotherapy, indoles have been screened as potential regulators of protein kinase activity <06JMC789, 06JMC1217, 06JMC268I, 06JMC2681, 06JMC310l, 06JMC3101, 06JMC4638, 06JMC4896, 06JMC7549>, 06JMC7549>, as antimitotic agents <06JMCI910, <06JMC1910, 06JMC6273, 06CMCI106>, 06CMC1106>, as angiogenesis inhibitors <06JMC1271, <06JMC 1271, 06JMC2143>, antivascular antivascular agents <06BMC44I0>, <06BMC4410>, as regulators of DNA function <06JMC1442, 06JACS143, 06AG(I)6570>, 06AG(I)6570>, and as ligands for various other protein and enzymatic targets <06JMC684, 06JMC6922, 06JMC7239, 06JMC7307, 06BMC464, 06BMCL6273>. 06BMCL6273>. A fundamental study of nucleophilic addition into a mitosene-like cyclopropyl quinone methide reductive alkylating agent has been described <06JOC5855>. Indoles have been investigated as potential regulators of a variety of other important disease states including Alzheimer's disease <06JMC459, 06JMC7588>, diabetes <06JMC6421>, <06JMC6421>, obesity <06JMC4023>, hypertension <06JOC2760, 06CMC96>, hepatitis B and C <06BMC911, 06JMC6950>, 06JMC6950>, HIV <06JMC3172, 06BMC2106, 06BMC2109>, 06BMC2109>, and malaria <060L2591, <06OL2591, 060L3407>. 06OL3407>. Several studies of anti-inflammatory agents have been disclosed <06JMC135, 06JMC26 11, 06JMC2858, 06JMC45 12, 06JMC4327, 06JOC3718, 06JMC2611, 06JMC4512, neuropsychiatric disorders, indoles were 06BMCL3241, 06BMCL4483>. In the area of neuropsychiatric investigated as ligands for dopamine/serotonin receptors <06JMC760, 06JMC4785, 06JMC6408, 06H(68)713, 06BMC3794, 06TL943>, galanin receptors <06JMC3757>, <06JMC2489>, and melatonin receptors <06JMC3509, 06CMCI099>. 06CMC1099>. GABA receptors <06JMC2489>,
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Five-membered ring systems: pyrroles and benzo analogs
06CL 1122 06CLlI22 06CMC96 06CMC1099 06CMCI099 06CMC 1106 06CMCl106
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E.T. Pelkey and J.S. Russel
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Five-rnernbered ring systems: systerns: pyrroles pyrroles and and benzo benzo analogs analogs Five-membered
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Five-membered ring systems: pyrroles and benzo analogs
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E.T. Pelkey and 1.S. J.S. Russel
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Five-membered ring ring systems: pyrroles and benzo analogs
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06T 10130 06Tl0130 06T10182 06T10182 06T11531 06Tl1740 06T11740 06T12375 06TA 107 06TA107 06TA3135 06THC53 06THC77 06THC93 06THC255 06TLl59 06TL 159 06TL743 06TL753 06TL799 06TL943 06TLl071 06TL 1071 06TLl469 06TL 1469 06TL 1881 06TLl881 06TL2151 06TL2409 06TL2435 06TL2517 06TL2605 06TL3521 06TL3535 06TL3693 06TL3755 06TL3893 06TL4113 06TL4631 06TL4683
E.T. Pelkey and J.S. Russel
R. Pathak, J.M. Nhlapo, Nh1apo, S. Govender, lP. J.P. Michael, W.A.L. van Otterlo, e.B. C.B. de Koning, Tetrahedron 2006, 62, 2820. A.M.e. Fonseca, G. Kirsch, Tetrahedron 2006, 62, 3493. M.M.M. Raposo, A.M.R.C. Sousa, A.M.C. KV. Srinivasan, Tetrahedron 2006, 62, 5109. S.S. Palimkar, P.H. Kumar, R.J. R.I. Lahoti, K.V. J.A. May, B. Stoltz, Tetrahedron 2006, 62, 5262. T.M. Lipinska, Tetrahedron 2006, 62, 5736. B. Metten, M. Kostermans, G. Van Vaelen, M. Smet, W. Dehaen, Tetrahedron 2006, 62, 6018. J. Ruiz, E. Lete, N. Sotomayor, Tetrahedron 2006, 62, 6182. T.D. Wahyuningsih, Wahyuningsih, K. K Pchalek, N. Kumar, D.S. Black, Tetrahedron 2006, 62, 6343. T. Kitawaki, Y. Hayashi, A. Ueno, N. Chida, Tetrahedron 2006, 62, 6792. F. Bellina, R. Rossi, Tetrahedron 2006, 62, 7213. P. Ciminiello, Dell' Aversano, E. Fattorusso, M. Forino, S. Magno, F.U. Santelia, V.I. Ciminiello, C. Dell'Aversano, Moutsos, E.N. Pitsinos, E.A. Couladoouros, Couladoouros, Tetrahedron 2006, 62, 7738. J.E. J.T. Gupton, E.J. E.I. Banner, A.B. Scharf, B.K. Norwood, R.P.F. Kanters, R.N. Dominey, lE. Hempel, A. Khar1amova, B1uhn-Chertudi, e.R. Hickenboth, B.A. Little, M.D. Sartin, M.B. Kharlamova, I. Bluhn-Chertudi, C.R. Hickenboth, K.E. Krumpe, B.S.Bumham, K'x. Du, K.M. KM. Keertikar, A. Diebes, S. Coppock, K.E. B.S.Burnham, H. Holt, K.X. Ghassemi, lA. J.A. Sikorski, Tetrahedron 2006, 62, 8243. Y. Aoyagi, T. Mizusaki, M. Shishikura, T. Komine, T. Yoshinaga, H. Inaga, A. Ohta, K K. Takeya, Tetrahedron 2006, 62, 8533. B. Temelli, C. Unaleroglu, Unaleroglu, Tetrahedron 2006, 62, 10130. I. Kawasaki, N. Sakaguchi, A. Khadeer, M. Yamashita, S. Ohta, Tetrahedron 2006, 62, 10182. B. Jolicoeur, E.E. Chapman, A. Thompson, W.D. Lubell, Tetrahedron 2006, 62, 11531. H. Chochois, M. Sauthier, E. Maerten, Y. Castanet, A. Mortreux, Tetrahedron 2006, 62, 11740. C. Biaggi, M. Beaglia, L. Raimondi, F. Cozzi, Tetrahedron 2006, 62, 12375. Hedenstrom, Tetrahedron Asymmetry 2006, 17, 107. P. Breistein, S. Karlsson, E. Hedenstr6m, B.F. Bonini, E. Capito, Capit6, M. Comes-Franchini, Comes-Franchini, M. Fochi, A. Ricci, B. Zwanenburg, Tetrahedron Asymmetry Asymmetry 2006,17,3135. 2006, 17, 3135. J.T. Gupton, Top. Top. Hetercycl. Chern. Chem. 2006, 2, 53. Chem. Rep. 2006, 6, 77. Published online. M. Somei, Top Heterocycl Chern. 2006,6,77. B.E. Love, Top. 2006,2,93. Top. Heterocycl. Chern. Chem. 2006, 2, 93. A. Nishida, T. Nagata, M. Nakagawa, Top. Heterocycl. Chern. Chem. 2006,5,255. 2006, 5, 255. M. Belley, E. Sauer, D. Beaudoin, P. Duspara, L.A. Trimble, P. Dube, Dubd, Tetrahedron Lett. 2006,47, 2006, 4 7, 159. E. Yasui, M. Wada, N. Takamura, Tetrahedron Lett. 2006,47,743. 2006, 47, 743. C. Wu, K 2006,47,753. K. Kawasaki, S. Ohgiya, Y. Ohmiya, Tetrahedron Lett. 2006, 47, 753. 2006,47,799. B.S. Gourlay, P.P. Molesworth, J.H. Ryan, J.A. Smith, Tetrahedron Lett. 2006, 47, 799. C. Jin, J.P. Burgess, M.B. Gopinatha, G.A. Brine, Tetrahedron Lett. 2006,47,943. 2006, 47, 943. D. Mal, B. Senapati, P. Pahari, Tetrahedron Lett. 2006, 2006,47, 47, 1071. K Kondo, T. Aoyama, Tetrahedron Lett. 2006,47, M. Kobayashi, M. Tanabe, K. 2006, 47, 1469. S. Akai, N. Kawashita, Y. Wada, H. Satoh, A.H. Alinejad, K K. Kakiguchi, I. Kuriwaka, Y. Kita, Tetrahedron Lett. 2006, 47, 1881. E. Bellur, P. Langer, Tetrahedron Lett. 2006,47,2151. 2006, 47, 2151. Hong, X.; J.M. Mejia-Oneto, Mejfa-Oneto, S. France, A. Padwa, Tetrahedron Lett. 2006,47,2409. 2006, 47, 2409. Y.R. Jorapur, J.M. Jeong, D.Y. Chi, Chi, Tetrahedron Lett. 2006,47,2435. 2006, 47, 2435. M.A. Guerrero, L.D. Miranda, Tetrahedron Lett. 2006,47,2517. 2006, 47, 2517. K. Dairi, S. Tripathy, G. Attardo, J.-F. Lavallee, Lavall6e, Tetrahedron Lett. 2006,47,2605. 2006, 47, 2605. K. Zong, L.B. Groenendaa1, Groenendaal, J.R. Reynolds, Tetrahedron Lett. 2006,47,3521. 2006, 47, 3521. D. Prajapati, M. Goahin, B.I. B.J. Gogoi, Tetrahedron Lett. 2006,47,3535. 2006, 47, 3535. A.I. Mikhaleva, A.B. Zaitsev, A.V. Ivanov, E.Y. Schmidt, A.M. Vasil'tsov, B.A. Trofimov, Tetrahedron Lett. 2006,47,3693. 2006, 47, 3693. T. Yamaguchi, T. Fukuda, F. Ishibashi, M. Iwao, Tetrahedron Lett. 2006,47,3755. 2006, 47, 3755. Q. Yang, X.-Y. Li, H. Wu, W.-J. Xiao, Tetrahedron Lett. 2006,47,3893. 2006, 47, 3893. 2006,47,4113. A.V. Butin, Tetrahedron Lett. 2006, 47, 4113. T.K. Chakraborty, Chakraborty, S.P. S.P. Udawant, S. Roy, B.K. Mohan, K.S. T.K KS. Rao, S.K. Duta, A.C. Kunwar, Tetrahedron Lett. 2006,47,4631. 2006, 47, 4631. C. Kalinski, M. Umkehrer, J. Schmidt, G. Ross, J. Kobl, C. Burdack, W. Hiller, S.D. 2006,47,4683. Hoffmann, Tetrahedron Lett. 2006, 47, 4683.
Five-membered ring systems: systems." pyrroles and benzo analogs
06TL4839 06TL534I 06TL5341 06TL5379 06TL5383 06TL5475 06TL548I 06TL5481 06TL556I 06TL5561 06TL5653 06TL5737 06TL5793 06TL6425 06TL6895 06TL7323 06TL7541 06TL754I 06TL7819
06TL8579
175
Danishefsky, Tetrahedron Lett. 2006, 2006,47,4839. C. Chan, C. Li, F. Zhang, SJ. S.J. Danishefsky, 47, 4839. A. Bhattacharya, R.E. Plata, M. Peddicord, Q. Ye, L. Parlanti, V.A. Palaniswamy, Palaniswamy, Bhattacharya, N.C. Patel, R.E. J.A. Grosso, Tetrahedron Lett. 2006,47,5341. 2006, 47, 5341. T. Kawasaki, W. Takamiya, N. Okamoto, M. Nagaoka, T. Hirayama, Tetrahedron Lett. 2006, 47,5379. J. Chen, H. Wu, Z. Zeng, C. Jin, X. Zhang, W. Su, Tetrahedron Lett. 2006,47,5383. 2006, 47, 5383. PJ.S. Gomes, C.M. Nunes, A.A.C.C. Pais, T.M.V.D. Pinho e Melo, L.G. Arnaut, Amaut, Tetrahedron P.J.S. Lett. 2006,47,5475. 2006, 47, 5475. Bhattacharya, S. Cherukuri, R.E. Plata, N. Patel, V. Tamez, Jr., J.A. Grosso, M. Peddicord, A. Bhattacharya, 2006,47,5481. Palaniswamy, Tetrahedron Lett. 2006, V.A. Palaniswamy, 47, 5481. J. Patel, N. Pelloux-Leon, Vallee, Tetrahedron Lett. 2006,47,5561. Pelloux-L6on, F. Minassian, Y. Vall6e, 2006, 47, 5561. J. Zhu, H. Wong, Z. Zhang, Z. Yin, N.A. Meanwell, J.P. J.F. Kadow, T. Wang, Tetrahedron Lett. 2006,47,5653. 2006, 47, 5653. Witherington, M.R.J. 47, 5737. S.M. Allin, J.S. Khera, J. Witherington, M.RJ. Elsegood, Tetrahedron Lett. 2006, 2006,47,5737. H. Sato, K. Hiroi, Tetrahedron Lett. 2006, 47, 5793. Blacklock, Tetrahedron Lett. 2006, 47, J.S. Bajwa, G.-P. Chen, Chert, K. Prasad, O. Repic, TJ. T.J. Blacklock, 6425. S.K. Chattopadhyay, Chattopadhyay, S.P. Roy, D. Ghosh, G. Biswas, Tetrahedron Lett. 2006,47,6895. 2006, 47, 6895. R.S. Kusurkar, S.K. Nayak, N.L. Chavan, Tetrahedron Lett. 2006,47,7323. 2006, 47, 7323. J.-i. Setsune, M. Toda, K. Watanabe, P.K. Panda, T. Yoshida, Tetrahedron Lett. 2006,47, 2006, 47, 7541. 2006, 47, O.S. Radchenko, N.N. Balaneva, V.A. Denisenko, V.L. Novikov, Tetrahedron Lett. 2006,47, 7819. E.M. Ferreira, B.M. Stoltz, Tetrahedron Lett. 2006, 47, 8579. 2006,47,
176
Chapter 5.3 Five-membered ring systems: furans and benzofurans Xue-Long Hou Shanghai-Hong Kong Kong Joint Laboratory Laboratory in Chemical Laboratory of Chemical Synthesis Synthesis and State State Key Laboratory Organometallic Institute ofOrganic Organometallic Chemistry, Chemistry, Shanghai Shanghai Institute of Organic Chemistry, Chemistry, The Chinese Chinese Academy of Sciences, 354 Feng Shanghai 200032, 200032, China. China. Sciences, Feng Lin Road, Road, Shanghai [email protected] xlhou @mail.sioc.ac, cn Zhen Yang Yang Key Laboratory of Bioorganic Chemistry Chemistry and Molecular Engineering ofMinistry of Ministry of Education, Biology, College Peking University, I0087/, Department of Chemical Chemical Biology, College of Chemistry, Chemistry, Peking University, Beijing 100871, China. [email protected]
Kap-Sun Kap-Sun Yeung Research Institute, Institute, 5 Research Parkway, Parkway, P.O.Box 5100, Bristol-Myers Squibb Squibb Pharmaceutical Research Wallingford, Wallingford, Connecticut 06492, 06492, USA. USA. [email protected] kapsun,yeung @bms.com Henry N.C. Wong
Molecules, Institute Institute of Chinese Medicine Department of Chemistry, Chemistry, Center Center ofNovel of Novel Functional Molecules, and Central Laboratory of the Institute Institute of Molecular Technology Central Laboratory Technology for Drug Discovery and Synthesis, t The Chinese Kong, Shatin, Kong SAR, Chinese University University ofHong of Hong Kong, Shatin, New Territories, Territories, Hong Kong SAR, China. China. [email protected] hncwon g @cuhk.edu.hk and Shanghai-Hong Kong Kong Joint Laboratory Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemical Synthesis, Shanghai Institute Chemistry, Feng Lin Road, Road, Shanghai Chemistry, The The Chinese Chinese Academy of Sciences, Sciences, 354 Feng Shanghai 200032, 200032, China. China. [email protected] hncwong @mail.sioc.ac, cn t An Area of Excellence of the University Grants Committee (Hong Kong).
5.3.1 INTRODUCTION This article aims to review papers that were published in 2006 on reactions and syntheses of furans, benzofurans and their derivatives. Two reviews have summarized the syntheses of furans <060BC1627> <06OBC1627> and tetrahydrofurans <06EJ01627>. <06EJO1627>. Another review <06CJ01613> <06CJO1613> records the progress of transition metal-catalyzed asymmetric ring opening of oxabenzonorbomadienes. oxabenzonorbornadienes. Like 2005, many new naturally occurring molecules containing tetrahydrofuran and tings were identified in 2006. References on compounds whose biological dihydrofuran rings activities were not mentioned are: <06HCA64; 06HCA73; 06JA3l48; 06JA3148; 06JNP1098; 06JNPl72l; 06JNP 1721; 06JNPl728; 06JNP 1728; 060L3613; 06OL3613; 06P735; 06P759; 06P965; 06T4743; 06TL4623>. Articles on those naturally occurring compounds containing tetrahydrofuran or <06CJO1667; dihydrofuran skeletons whose biological activities were assessed are: <06CJ01667; 06JAl1916; 06JNP274; 06JNP295; 06JNP67l; 06JNP671; 06JNP957; 06JNP1077; 06JA1l9l6; 06JNPlO77; 06JNP1249; 06OL991; 060L45 06OL4513>. 06JNP1271; 06JNP1289; 06JNP1543; 060L991; 13>.
177
Five-membered ring Five-membered ring systems: furans and benzofurans
References on those furan-containing compounds whose biological activities were not mentioned are: <06JNPI083; <06JNP1083; 06JNP1086; 06JNP131O; 06JNP1310; 06JNP1734; 06JNP1782; 06P965; 06T4988>. Naturally occurring compounds containing furan skeletons whose biological activities were assessed were mentioned in the following papers: <06JNP68; 06JNP113; 06JNPll3; 06JNP1749; 060L701;060L4935;06P452;06PI957;06P2288;06TL4007>. 06OL701; 06OL4935; 06P452; 06P1957; 06P2288; 06TL4007>. References of those benzo[b]furan- or dihydrobenzo[b]furan-containing compounds whose biological activities were not mentioned are: <06HCAll7; 06HCA1000; 06HCA1062; <06HCA117; 06HCAlOOO; 06H(68)93; 06H(68) 159; 06JNP876; 060L2269; 06H(68)159; 06OL2269; 06P459; 06P743; 06P2146>. References on those naturally occurring compounds containing benzo[b]furan or <06HCA127; dihydrobenzo[b]furan skeletons whose biological activities were assessed are: <06HCAI27; 06JNP121; 06JNP138; 06JNP229; 06JNP261; 06JNP299; 06JNP397; 06JNP1209; 06JNP1826; 06P307; 06TL1505; 06TL3685>.
5.3.2 REACTIONS REACTIONS 5.3.2.1 Furans Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. As illustrated in the scheme below, the reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization, which proceeded irrespective of the length of the <060L27>. carbon linker, was employed to construct the ABC tricyclic core of manzamine A <06OL27>.
tBuMe2SiO O ~ N ~ Bs NBoc ~NBoC
HOAc HOAc
_-.
PhMe PhMe r.t., r.t., 72 72 hh 80~ 80%
tBuMe2SiO ~.. . O . ~ O .,H BsNl v,,- _ ~ ,,~,.\s
Spirocyclization was also the reaction pathway under radical conditions if furan was tethered to a radical precursor at the 2-position, as shown below <06CC665>.
O o
EtOSCS~ EtOSCS~
NtBu NIBu
.j ~_,~ or
Lauroylperoxide peroxide Lauroyl CICH2CH2CI CICH 2 CH 2 CI MeOH MeOH 76% 76%
=
~,O
~_~ MeO
NtBu
When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions <06CC 194>, as exemplified <06CC194>, below. The formation of the kinetic products is the result of the higher nucleophilicity of the furan C2-position. carbon carbonanode anode LiCI0 LiCIO4 4 2,6-lutidine 2,6-1utidine
MeOH-PrOH MeOH-PrOH
H H
rn I[~U~opr o
+
Pr
62% 62%
H H
~ 23% 23%
OPr O~r
178
X.-L. Hou, Yang, K.-S. Yeung, and H.N.C. x.-L. Hou, Z. Yang, K.-S. Yeung, H.N.e. Wong
The scope of the ring-opening/recyclization of furan-containing substrates via the trapping of the transient oxonium ions, generated by the protonation of furan nucleus under strongly acidic conditions, by pendent nucleophiles was expanded <06TL4113; 06TL4117; 06JHC623; 06JHCl195>. 06JHC1195>. A new example is illustrated below <06SL3431>. 0
0 \N-N~r , / p-TsOH
Cl CI
~
CI Cl
CeH 06H6e reflux, 10 min reflux,
0 ":
0 ":
35%
2-Trimethylsilyloxyfurans were employed as C5-dianion equivalents in the spiroannulation with bi-functional ortho-esters to provide spirobutenolide derivatives <06OL3705>. When the second step was performed under radical conditions, instead of using <060L3705>. bicyclo[3.n.0]lactones were formed <06CC1200>. An interesting example is base, cis-fused bicyclo[3.n.O]lactones illustrated below.
Me3SiV\+O~ M',sJO~
EtC
Br Br
j
X_
EtO
OEt
\ (Me3Si)3SiH ~ (Me3SibSiH
ZnCI 2
Br
-.;;:
CH,cI,
.0
OsH,
-78°C to r.t -78~ 80~176 80%
EtO
OEt
s H H S ~
AIBN
reflux 90~176 90%
0
G O E Et t H . OEt
2-Triisopropylsilyloxyfurans were effective nucleophiles for the vinylogous Mannich addition to iminium ions that were formed by Rh2(cap)4-catalyzed oxidation of N-alkyl groups by THYDRO <06JA5648>. A stereoselective addition of 2-trimethylsilyloxyfurans to aryl aldehydes-derived aldimines employing a chiral phosphine/Ag complex as catalyst was developed <06AG(I)7230>. The prototypical example is shown below.
CC
tg tBuu
H
~ ~Jy~~
q ~.Q ' ~ P PPPh h 2 (1 0 O _~ q ~ ' ~ O MMe e 2 (1 mol%) mol%) AgOAc(1 AgOAc (1 mol%) /PrOH (1.1 (1.1 equiv.) equiv.) PrOH
ph~,.H
Me3SiO
THF -78°C, -78 ~ 18 h under air
82% 82~
Meo~
HN~ HN
Ph~ o O
ee > 98% de, 96% ee
A Lewis acid-catalyzed vinylogous Mukaiyama aldol reaction between 2-trialkylsi1yloxyfurans diastereoselectively 2-trialkylsilyloxyfurans and a-substituted s-substituted ketones proceeded <06OL2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran <060L2909>. 2-trimethylsi1y10xyfuran to aldehydes using 10 of 1,3-bis(3-(trifluoromethy1)phenyl)urea provided adducts mol% 1,3-bis(3-(trifluoromethyl)phenyl)urea with modest threo selectivity <06TL8507>. A syn-selective, enantiose1ective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran 2-trimethylsily10xyfuran to (£)-3(E)-3trimethylsilyl-acryla1dehyde trimethylsilyl-acrylaldehyde using MacMillan's chiral amine catalyst was adopted to prepare a key butenolide intermediate in one formal total synthesis of
179
Five-membered ring ring systems: Five-membered systems:furans and benzofurans
campactin <060L597>. <06OL597>. A diastereoselective aldol addition of 2-trimethylsilyloxyfuran to an (J.achiral aldehyde, a key transformation in a total synthesis of (-)-rasfonin, was obtained by using a chiral oxazaborolidine as illustrated below <06JAl1032>. <06JA11032>.
.. H H Ph(3,5-Me:e) Ph(3,5-Me2)
~"Ph(3,5-Me2) ~___N'N~"Ph(3,5-Me2)
oO
-~~,~) TfOH"I"B"
TIO H
_~
~ HJl_............... Me3SiO
I- I- T -
+ H
B0 OH OH 2-tol ( 4mol%) 8 m 0o l :: % 2-t61 (48 _ )_ ~
CH2C12 CH2CI2
--:-
p~ § § I
-78 cC, 18 -78 ~ 18 hh ~ 81% 81% lhreo : erythro erythro= = 20:1 20:1 threo: > 20:1 threodr > 20:1 threo
Furan that was loaded on a soluble dendritic polyglycerol support could be efficiently oxidized electrochemically to a 2,5-dihydro-2,5-dimethoxyfuran, 2,5-dihydro-2,5-dimethoxyfuran, which served as an intermediate in the synthesis of a pyrrole library <060L403>. <06OL403>. 2,5-Diphenylfurans were found to oxidize to cis-enediones cis-enediones by Selectfluor in aqueous THF, presumably through the action of in situ-generated situ-generated HOF <06TL6849>. 2-(5-Methoxyfuranyl)ruthenium complexes were readily oxidized by air to enediesters <06EJI649>. As shown below, the marine diterpene bipinnatin J was converted to intricarene by a biomimetic approach that involved an Achmatowicz-type oxidation of its 2-hydroxymethylfuran moiety to form an oxidopyrylium ion intermediate, which then participated in a transannular [5+2] cycloaddition with the butenolide ring <060L5901,06TL640l>. <06OL5901, 06TL6401>.
.~~,
o ~>O<
OH
"'< ~
1. 1. m-CPBA m-CPBA ....
2. 2. AC20 Ac20
C5H5N CsHsN DMAP DMAP
,.\(
,
DMSO 150 DC sealed sea1~6dtube o/~Ueb 26%
O~o
81% 81%
o
o
o
o
The oxidation of 2,5-disubstuted furans by singlet oxygen was exploited for the synthesis of [5,5,5] and [6,5,6] bis-spiroketals <060Ll945>. <06OL1945>. An unusual regioselective photooxidation of 3-bromofuran to 2- and 3-bromo-y-hydroxybutenolides, 3-bromo-7-hydroxybutenolides, as depicted below, was reported. The mechanism for the observed base-dependent regioselective deprotonation of the <06OL4831>. 1>. endoperoxide intermediate was not determined <060L483
Br Br
b 0
O 02, 2 , hv base base ,
Br Br
CH CH2CI 2 2CI 2
-78 cC ~
4.3 to to 5.3 5.3hh 4.3
Br Br
HO~O +HO~O . ~
b
. ~
.~.
HO
O
HO
O
100 DBU 78% 78% 0: 0:100 DBU Phosphaxene 70% 70% 80:20 Phosphaxene
-bipyrazole by reaction with two molecules of A 2-aminofuran was converted into 4,4' 4,4'-bipyrazole hydrazine <06TL8965>. Hydrogenation of 2-amylfuran under 5 atm of H, H 2 as catalyzed by 10% Rh/Cat80 Rh/C at 80 °C ~ in water provided 2-amyltetrahydrofuran in 90% yield <06SLl440>. <06SL 1440>. An advance in the area ofenantioselective of enantioselective hydrogenation of furans, as reported by Pfaltz, is the hydrogenation of offurans,
180
x.-L. Hou, Z. Yang, K.-S. Yeung, H.N.e. Wong X.-L. Hou, Yang, K.-S. Yeung, and H.N.C. Wong
2-substituted furans using chiral iridium/pyridine-phosphinite complexes as catalysts, achieving ee of up to 93% <06AG(I)5194>. Another notable example is the Rh/butiphane-catalyzed cis-hydrogenation of a furanylnucleoside as shown below <060L4133>. <06OL4133>. enantioselective cis-hydrogenation
O
H N
MeO2C~N
H H22 (80 (80 bar) bar) R, R)Jpr-buliphane)Rh(COD) SF4 ((R' ~iP rbutiphane)Rh(COD)BF4
«
e
H
O N ,_ Me O 2 C ~ N ' ~ ~
THF THF
O e
80~ 80°C 98% 98% 99% 99% de, de, 72:% 72% ee ee
2-Methoxyfurans reacted with ruthenium and platinum carbenoids, derived from tertiary propargyl carboxylates, regioselectively, leading to interesting triene systems, as <060Ll741>. represented by the example below <06OL1741>.
,Ru0,2,00,2,2,25 m~ I " oAc ]I
2(_C_O_)2_b_(2_.5_m_OI_%_).. [!",>:=
pow. OAc
89% 89% 50: 50 50"50
+
"V " - t"==r Ru]
O..,,~OMe
+
RUJ
+
n
l(oY'-OMe OMe
OAc OAc
~~e
The presence of a halogen substituent at the 5-position of N-alkenyl substituted 2furanyl amides markedly enhanced the rate of intramolecular Diels-Alder reaction and the yield of cycloadduct. This phenomenon, as determined by CBS-QB3 calculations, was attributed to the decreased activation energy and a greater stabilization of the cycloadduct imparted by the halogen substitution. The computation also suggested that a 5-methoxy group has the same favorable effect, and that substitution at the 5-position has a greater effect than that at the 3-position <06AG(I)1442; 06JOC5432>. The facile cycloaddition between furan SnC14 was determined by density functional and a 3,3-difluoro-2-propenoate as catalyzed by SnCl 4 theory calculations to have arisen from the high-energy barrier of cycloreversion. The <06JAI3130>. transition state of this reaction was characterized as zwitterionic in nature <06JA13130>. The gold-catalyzed cycloisomerization of furans tethered to alkynes was adopted to the synthesis of interesting spiroannulated dihydrobenzo[c]furans containing pentofuranosides, hexofuranosides and hexopyranosides <06TL3307>. It was found that this type of cycloisomerization could occur even with furans bearing sterically demanding substituents at the 5-position, and that an ortho-methoxy group on the phenyl substituents had a strongly accelerating effect on the reaction rate <06CEJ6991>. An example is shown below.
Y\
~ ~
N
I ...-:;;
°
O~NTS Ts
//
AuCI AuCI33 (5 (5 mol%) mol%)
CD3C N CD 3 CN 50 50 min. min. 88% 88%
" : Ji?=
NTs
. ~ "::~ OOH h-
I ~
o II
NTs
OH
The cyclopropanation of furan with methyl 4-bromophenyldizoacetate using the chiral dirhodium tetraprolinate was further studied, showing the initial bond formation occurred at the
181
Five-membered ring systems: furans and benzofurans Five-membered ring systems: benzofurans
furan 2-position <06JOC5349>. <06JOC5349>. 1,3-Dipo1ar 1,3-Dipolar cycloaddition of furanyltungsten complexes, in which furan function as a carbonyl ylide, was investigated <060M435>. <06OM435>. Furan participated in [4+3] and [3+2] cycloaddition reactions with 1-alkylidene-2-trimethylsilyloxyallyl and 1alkylidene-2-methoxyallyl cations respectively <060L4113>. <06OL4113>. A [4+4] intramolecular photocycloaddition between a furan tethered to a pyran-2-one was used to construct the fused <06OL4075>. A similar tricyclic [5-8-5] ring system of the fusicoccin diterpenoid traversianal <060L4075>. cycloaddition of a furan tethered to a 2-pyridone was examined for the synthesis of the tetraquinane crinipellin <06OL3367>. <060L3367>. 5.3.2.2 Di- and Tetrahydrofurans
The stereoselectivity of the Biichi-Paterno Btichi-Patern6 reaction between 3-hydroxy-2,3dihydrofuran and benzophenone benzophenone was found to be influenced by solvent, temperature and steric Di:itz benzannulation involving a dihydrofuran chromium carbene effect <06TL2527>. A D6tz complex and an alkyne was employed to form the aflatoxin B B,2 skeleton, providing the annulated product as the only regioisomer <06TL2299>. Cycloaddition involving 2,3dihydrofuran, l-aminoanthraquinone and salicyaldehyde was catalyzed by 1-aminoanthraquinone triphenylphosphonium perchlorate to form cis-fused furanochromenylaminoanthraquinone <06TL9291>. New catalytic conditions for the cyclization between 2,3-dihydrofuran and imines using Me3SiC1 Me 3SiCl <06SLl399>, <06SL1399>, phosphomolybdic acid <06TL4409>, SbC1 SbC133 <06TL5733> and iodine <06TL4509> <06TL4509> to form furanotetrahydroquinolines were developed. A diastereoselective and enantioselective variant of this reaction was achieved by using a (R)BINOL derived phosphoric acid as illustrated below <06JA13030>. <06JA13030>.
~
Arr
~ ~
O" \OH A
r
N/J/,,, ph + OH
~ ~ 9\
(Ar = = 9-anthryl) 9-anlhryl) :Ar (Ar (10 mol%) PhMe PhMe -10°C -10 ~
86o/o 86% cis :1 cis : trans trans = = 99 99:1 90% 90%00
(Y'j""
",p lr'~"""""Ph OH H OH
2-Benzoyl-4,5-dihydrofuran was readily oxidized by air, m-CPBA or DMDO to give a mixture of butyrolactone and tricyclic bis-acetal <06TL6285>. 2,3-Dihydrofurans were converted to butenolides by photo-oxygenation followed by dehydration of the intermediate hydroperoxides at room temperature <06T10688>. 2,3-Dihydrofuran underwent a radical group transfer reaction with xanthate to give an intermediate in which the anomeric xanthate further reacted with nucleophiles to provide 2,3-trans-disubstituted 2,3-trans-disubstituted tetrahydrofurans <06JOC2352>. Group transfer reaction also occurred photo-chemically between 2,3<06JOC2352>. dihydrofuran and difluoro(phenylseleno)acetate and phosphonate to provide 3-difluoromethyl substituted 2,3-dihydrofurans <06T3761>. In the absence of acetonitrile as an additive, the diastereoselective three-component coupling involving 2,3-dihydrofuran, N-tosyl imino ester and a nucleophile, as reported in 2005, provided trisubstituted pyrrolidines, as exemplified <06OL4509>. below <060L4509>.
182
X.-L. Yang, K.-S. Yeung, and H.N.C. Wong x.-L. Hou, Hou, Z. Yang, K.-S. Yeung, H.N.e. Wong
~
~
.i.;. . . . . + Me3Si. Me3Si Ph""O-P + TsHN'" 'C0 2 Et + 'V' Ph TsHN "~"'CO2Et
""
K: q
TiCI44
TiCI ------~ CH 0H2CI2 2CI 2 P h ~ N /N" ' C"'C0 O 2 E2 Et t -78 OCto Ph -78 ~ to 23°C 23 ~ Ts 72% Ts 99:1 99:1 dr
An interesting example of a triple electrophilic aromatic substitution between an oxonium ion, generated from a trisubstituted dihydrofuran, and phloroglucinol was exploited for the total synthesis of the CFsymmetric C~-symmetric xyloketal A, as depicted in the scheme below <060Ll427; <06OL 1427; 06JOC1620>. 06JOC 1620>.
.o yo. +
HOyyOH
Y
H HO
+
OH
)d a
BF3.Et20 MgSO4
O
O O
Et20 -78°C, -78 ~ 20 min 79% 80:20 dr 80: 20dr
As exemplified below, an interesting rearrangement of fused 2,5-dihydrofurans to tricyclic lactones under strongly acidic conditions was observed <06JOC9544>.
NHPh o
,,.o
O
85% H3PO4
85-100 ~ 2 h 88% ~;6H4_P_Me
HN
~
~[I~
~C6H4-P-Me
O Upon treatment with Me]SiOTf, Me3SiOTf, the 2,5-dihydrofuran-containing 2,5-dihydrofuran-containing l4-membered 14-membered marine cembranoid sarcophytoxide was converted to a 10-membered lO-membered ring product as shown below <06OL2957>. Presumably, the Lewis acid promoted the cleavage of the dihydrofuran ring to <060L2957>. provide a transient allylic cation, leading to a transannular cyclization.
~ -
Me Me3SiOTf (0.5 equiv.) equiv.) 3 SiOTf (0.5
:: ,0
0'\\
'"
,,,,
C C6H6 6 H6
r.t., 30 min min r.t., 15%
An 1,5-oxygen migration of a cyclohexene-fused 7intermolecular oxabenzonorbomadiene oxabenzonorbornadiene was induced by bromination <06Tl23l8>. <06T12318>. Double bond isomerization was minimized in a rhodium-catalyzed hydroformylation of 2,5-dihyfrofuran by using a <06CEJ6931>. phosphabarrelene ligand to produce 3-formytetrahydrofuran in 79% yield <06CEJ693 I>. The Pd(OAc)2-catalyzed hydrophenylation of 7-oxabenzonorbomadiene 7-oxabenzonorbornadiene was affected by the use of Pd(OAc),-catalyzed a triphenylphosphine-functionalized triphenylphosphine-functionalized imidazolium carbene as a ligand <06SLl193>. <06SL1193>. The ringopening reaction of 7-oxabenzonorbomadienes 7-oxabenzonorbornadienes was coupled to the ring-forming reaction of 2-
183
ring systems: Five-membered ring systems:furans and benzofurans benzofurans
iodoaryloxyallenes in a one-pot palladium-catalyzed process to provide interesting cis-2substituted-l-naphthalenols substituted-l-naphthalenols <060L621>. <06OL621>. Another example of a palladium-catalyzed reaction 7-oxabenzonorbornadiene involved a three-component coupling with aryl iodides and of 7-oxabenzonorbomadiene benzynes, as illustrated below <060L5581>. <06OL5581>. The regioisomer obtained is consistent with the insertion of the bicyclic alkene into the Pd-aryl bond before the benzyne.
oO
OMe TfO\ /SiMe3
ob
OMe OMe
Pd(dba)2 Pd(dba)2 P(2-furyl)3 P(2-furyl)s CsF
Mc:~N MecN
Lt, r.t, 10 10hh
83% 83%
The isomerization of 7-oxabenzonorbomadienes 7-oxabenzonorbornadienes to I-naphthols 1-naphthols could be interrupted to obtain 1,2-naphthalene oxides by using Cp*Ru(cod)CI Cp*Ru(cod)C1 as a catalyst and by careful work-up using neutral alumina, as shown below <06JA3514>. <06JA3514>. The regioselectivity of this reaction was consistent with the insertion of ruthenium into the more electron rich C-O C-O bond. The Cl C 1 ester group of 7-oxa- and 7-oxabenzo-norbomadienes 7-oxabenzo-norbornadienes also induced a high regioselectivity in the ruthenium-catalyzed [2+2] cycloaddition with disubstituted alkynes <06TL7185>. However, the ruthenium-catalyzed reaction between 7-oxabenzonorbomadienes 7-oxabenzonorbornadienes and propargylic alcohols in MeOH provided isochromenes <06EJ05449>. <06EJO5449>. 7-0xa7-Oxa- and 7-oxabenzo-norbomadienes 7-oxabenzo-norbornadienes could also be cyclopropanated by ruthenium carbenoids that were derived from tertiary \ <06JOC3569>. propargyl carboxylates using a catalytic amount of CpRuCI(PPh CpRuCI(PPh3) 3 4 <06JOC3569>. O
Cp*Ru(cod)CI Cp*Ru(cod)CI(5 (5 mol%) mol%)
Z ~ ~
CICH CICH2CH2CI 2 CH2 CI 60 cC, ~ 15 15 min min 60 neutral alumina alumina neutral 81% 81%
CO2Me
~ O MeO2C
2-Alkylidenetetrahydrofurans underwent a cyclo-condensation with amidines to give 4(3-hydroxyalkyl)pyrimidines, as can be seen below <06T5426>. (3-hydroxyalkyl)pyrimidines, Ph
o
Br~ Br O o
Ph
Ph
+ + HN.J..-NH2 HN'~NH2
et3N EtOH EtOH reflux, 12 12 hh reflux, 91% 91%
NAN "
Br OH
The formation of tetrahydrofuranyl ether from tetrahydrofuran and an alcohol via a tetrahydrofuran a-radical could be performed by using manganese(0) manganese(O) powder and CCI. CC14 <06TL511l>. <06TL5111>. These conditions provided a high yield of the hindered tertiary alcohol, dimethylphenylcarbinol. Upon oxidation with cerium ammonium nitrate, 2tetrahydrofuranylstannanes generated transient tetrahydrofuranyl oxonium ions, which were captured intramolecularly by hydroxyl groups to provide furo[2,3-b]pyrans <06TL3607>, as illustrated below.
184
X.-L. Hou, Yang, K.-S. Yeung, and H.N.e. H.N.C. Wong Wong x.-L. Hou, Z. Yang, K.-S. Yeung,
Ph
M e O ~
O H
Mas MeO2C Ph
CAN CAN (2 (2 equiv.) equiv.) MeCN MeCN 20 ~ 20°C 54% 54%
"O/ ~'SnnBu3
H HO
5.3.3 SYNTHESIS 5.3.3.1 Furans
3-Aryl furans were prepared in moderate yields by Rh-catalyzed regioselective hydroformylation of substituted propargylic alcohols followed by cyclization, and an example is shown below <06ASC545>.
j
-
Rh(OAc},z Rh(OAc)2 (5 (5 mol%) mol%) PPh PPh33 (20 (20 mol%) mol%) 700 700 psi psi COiH COM2 (1:1) 2 (1:1)
C>/-
..
A M S , 65°C 65 ~ 44 AMS,
57% 57% Negishi coupling of 2-furylzinc chloride with vinyl telluride provided 2-substituted furan with (Z)-double bond in a stereoselective manner, which was used in the total synthesis of 1-(Z)-atractylodinol, l-(Z)-atractylodinol, a biologically active natural product as depicted in the following scheme <06TL8l83> <06TL8183>
o O o
1. n-BuLi, n-BuLi, THF, THF, -78°C -78 ~ 1. -2-.-Z-n-:"C':"'1 -,T -F.....,--7 .....8 -t-o-2-5-oC--... • 2. ZnC12, T.....HHF, -78 to 25 ~ 2
3. 3. PdCI PdCI22,, Cui, Cul, THF, THF, 25°C, 25 ~ 30 30 hh
BUTe~ BuTe78o~A~ 78%
V
JMS
f;
h_ .
~
.
~
~
,k~
OH OH
1-(Z)-Atractylodinol 1-(Z)-Atractylodinol
TMS TMS
As can be seen below, a retro-Diels-Alder strategy was used to prepare 2,3- and 2,4disubstituted furans with a SF, SF5 group as one of the substituents, which was introduced into <06OL5573>. furan ring for the first time <060L5573>.
F5~CN 150-1600C ~ F5~ F5~CN 150-160 ---.... r~ 78%
a
Gold as an efficient catalyst has widely been used in furan synthesis. One example is shown below, in which the double hydroarylation of unactivated alkyne using 2-methylfuran afforded a difuranylmethane derivative in a moderate yield <06EJOC4340>. [(Mes3PAu}.zCI]BF4 [(Mes3PAu)2CI]BF4(2.5 (2.5 mol%) mol%)
---- C5Hll + ~ " ~
~
50°C, 50 ~ 77 dd 42% 42%
185
Five-membered ring ring systems: Five-membered systems:furans and benzofurans benzofurans
1,4-diketones, which were prepared 2,5-Disubstituted furans were synthesized from l,4-diketones, from the reaction of methyl vinyl ketones with arylboronic acids in the presence of CO using rhodium catalyst as illustrated below <06Tl1740>. <06T11740>.
\ %
H)2 1.1. RhH(CO)(PPh RhH(CO)(PPh3)3(0.5 mol%) 3h (0.5 mol%) CO, MeOH MeOH CO, o I 2. 2. IfTsOH, p-TsOH,PhMe PhMe .~O~oM 66% 66% OMe
O
~ .0
OMee
Diastereoselective Friedel-Crafts reaction of a 2-substituted furan with chiral glyoxylate regiospecifically gave chiral 2,5-disubstituted furans in high yields, and an example is shown in the scheme below <060L5045>. <06OL5045>.
--0 +~
2~ BnOCH BnOCH2
aO a + Y~CHO _ O~CHO
SnC,4 ,.~ + CH CH2CI 2 CI 22 -78°C -78~ 87%,>98 >98de de 87%,
" Ph'/' Ph"T"
~
_ = Ph'~ ~
. OH OH
CH2OBn
Functionalized hexanofuran shown below was provided as a 5.1:1 mixture of the desired diastereomer and its epimer by Pd-catalyzed cyclization of 3-iodo-4-substituted furan prepared from 3,4-diiodofuran through I-Li exchange, and was followed by trapping of the lithiated furan with an aldehyde. The modification of this procedure to produce diiodofuran using l-methyl-2-pyrrolidinone 1-methyl-2-pyrrolidinone as co-solvent was also reported <06JA17057>.
HO'"
g II
\\
HO'"ff~l ~ \ a
Pd(OAc)2 Pd(OAch
......
n_-B_u_4_N_B_r- - - - '••
I
Mecn_BE3tNU4NBrN_H20 ~'
"~~
Et 3N MeCN-H 2 0 75°C 75 ~ 75% 75%
Addition of acyl anions generated from acylsilanes to a,~-unsaturated ~,[~-unsaturated ketones using Nheterocyclic carbenes (NHCs) derived from thiazolium salts as catalyst produced 1,4diketones, which cyclized to form the corresponding furans in good yields under an acidic <06JOC5715>. 15>. condition <06JOC57 1. 1. NHC NHC(20 (20mol%) mol%)
O o
II ,,~SiMe3 + Ph~Ph phv,~.yp h ~ SiMe3 + . II
oO
DBU DBU iprOH, THF, 70°C
~ ~r_j P ~Ph h )
'PrOH,THF,70~ :. .~ 2. HOAc P 2. HOAc P 74% 74%
~ \
0
A three-component, one-pot reaction of acyl chloride, propargylic alcohol derivatives and NaI using palladium as catalyst provided trisubstituted furans as depicted in the following <06EJOC2991>. 3-Chloro-4-iodofurans can also be produced when IC1 scheme <06EJOC299l>. ICI and NaC1 NaCI are used in the second step.
186
X.-L. Hou, Yang, K.-S. Yeung, and H.N.e. H.N.C. Wong Wong Hou, Z. Yang, K.-S. Yeung,
1. Pd(PPh Pd(PPh3)2CI2 (2 mol%) mol%) 3 l:zCl z (2 Cui Cul (4 mol%) mol%)
°O
n'
.
I
I
0THP _ _E_t ~ ~/OTHP Et3_N_, 3N, _TH_F_,_rt_2_h_ THF, rt, 2h _~.. ~P =---I h.JJ,. +PhACI+ L 2. Pt!ZO~ P CI 2. Nal Nal
p-TSA ,rTSA MeOH MeOH rt, rt, 22hh
72% 72% As can be seen in the scheme below, the catalytic activity of gold species was also shown in a multi-substituted multi-substituted furan synthesis. Cyclization of allenones in the presence of Au(III)-porphyrin Au(III)-porphyrin gave rise to the corresponding corresponding substituted substituted furan in good to high yields. The catalyst can be recycled several times and still maintain the same catalytic activity <06OL325>. <060L325>. [Au(TPP)]CI (1 mol%) [Au(TPP)]CI(1 mol%) CF CO zH (10 mol%) CF33CO2H mol%)
O ~/J~~-~C4
.1~ H 9 ---------1.. acetone, acetone, 60°C 60 ~ 90%
C5Hll
C 5 ~ /
"O" "C4H9
Another example of Au-catalyzed was reported using alkynyl cyclopropyl ketones as a starting material. Trisubstituted Trisubstituted furans were given in high yields under mild condition condition via a domino reaction process and an example is given below <06AG(I)6704>. <06AG(I)6704>.
nBu
n U
[(PPh3)Au]OTf (1 mol%) MeOH CH2CI2 86%
OMe
APt-catalyzed A Pt-catalyzed cyclization of an enynone enynone as illustrated in the following scheme using a nucleophilic solvent afforded substituted furans in good to high yields. In this reaction, the [3-position of the double bond <06TL5307>. <06TL5307>. The nucleophile to attack the ~-position solvent serves as a nucleophile same reaction can also be catalyzed by Bu4N[AuC14] Bu 4 N[AuCI 4 ] in [bmim]BF [bmim]BF 44.• It is noteworthy that the catalyst can be recycled several time and keep the catalytic activity unchanged unchanged <06SLl962>. <06SL 1962>.
~ npr-PtCl PtC 12 (5 mol%) z (5mol%) - - - - -....
V o
I
MeOH 40°C 40 ~ 82% 82%
& npr
:::,...
OMe Me
Iodonium Iodonium ylides reacted with electron-deficient electron-deficient alkynes or conjugated alkynes using trisubstituted furans in moderate yields as depicted in the scheme below Rh-catalyst to form trisubstituted <06SC 1941 >. <06SCI941>.
'Ph
O
V
~O
O m
+ ~
.
fro \
~ Rh2,Oov,443. 43%
187 187
Five-membered ring ring systems: systems."furans furans and benzofurans
Reaction of a tungsten carbene complex with alkynyllithium followed by treatment of aldehyde in the presence of Et AI afforded trisubstituted furans in good to excellent yields Et3A1 3 Et3A1. <06AG(I)6874>. Dienes were the products without Et 3Al. M%
W(CO)5 nHex
PhMe2Si
fiMe ~ OC)5W
~
Li
THF,-78 ~
]e nile ~ nHex Li e PhCHO Et3AI SiMe2Ph 89% P
SiMe2Ph
(2,4-dioxobutylidene)-phosphoranes with aFeist-Benary cyclo-condensation of (2,4-dioxobutylidene)-phosphoranes chloroacetone gave rise to substituted furfuryl phosphonium salts, which underwent subsequent Wittig reactions to afford alkenylfurans in good yields as can be seen below <06JOC8045>. <06JOC804S>.
O:;2
1.BuLi, BuLi,THF, THF,00 °c ~ 1. oO ~?O2E: 2. nprcHO, THF, ~CO2E~ 2. nprCHO, THF, Ett CI~ ~Et Cl'v~ 0 ~ ---> 20 ~ o°c ---120 °c ----~ ~ ~ PPh - - - - -... ~ ~ E t O ~ v/PPh Ph3 80~ t4"O"P''JPPh3 70% \0a/ v/npr EtO 3 800C 0 3 70% npr 49% C,6 49% CIe E:Z=4:1 =4:1 E:Z
U
Fully substituted furan as depicted below was prepared from a Baylis-Hillman adduct in the presence of sulfuric acid in a moderate yield. Intermolecular Friedel-Crafts reaction is one of steps to give rise to the final tetrasubstituted furan <06T8798>.
OR ~ 1 /CO2Et 1~~
H2SO4 06H6
70-80~ 43%
Allenes as starting materials are still being explored. One example shown below is that the reaction of bromoallene with a 1,3-diketone under PTC condition provided a trisubstituted furan in high yield <060LS06l>. <06OL5061>.
~
c:: I ~ Ch I CI CI
oyo__
+~
~
K2003 K2C03 n-Bu4NBr .~. n_-B_l4_N_B_r---; acetone acetone 65% 65%
O
Br
CI
CI
O
The usefulness of allene derivatives has also been revealed in other examples. Thus, the tetrasubstituted furan illustrated in the following scheme was delivered in a annulated tetrasubstituted moderate yield using the diazoallene as precursor by a two-step reaction in the presence of Rhcatalyst <06S3605>. <06S360S>.
OEt
y
MeO M eO~
I
""
~ //
OMe O~
;C
R~(OAc)4
OE: 1. (3 mol%) mol%) N@O 1 Rh2(OAc)4(3 CH2 CI2, 23 ~ .OEt 2 2 0 __C_H_C_I_,_2_3_OC __ M M eQ*~ O Et e ~ 73% 73% ~ ~ • ~ _" ~ 2. PhMe PhMe ~_ 2. 120°C 120 ~ i M% ~O 88% MeO
188
x.-L. Hou, Hou, Z. Yang, K.-S. Yeung, X.-L. Yang, K.-S. Yeung, and H.N.c. H.N.C. Wong Wong
Propargylic dithioacetals have been shown to be good starting materials for the synthesis of trisubstituted furans. Recently, a modification appeared, which demonstrated that these compounds could also be used to prepare tetrasubstituted furans in good yields <06SL1209>. <06SLl209>.
1.nBuLi, nBuLiTHF, THF, , -78°C -78 ~ 1. 2.iPrCHO,-78~ nB nB~
~
2. iPrCHO, -78°C
3. Hg(OAc)z Hg(OAc)2
nB
4.1 4.12, CH2CI 2, KI, CH 2CI 2 56%
nBu
~
):J
iipr,,,p
I
~ ~ \ 0a/ nBu
56%
Tandem reaction of aromatic aldehydes with electron-deficient acetylenes and dialkyl acetylenedicarboxylates in the presence of EtJN Et3N led to the formation of fully substituted furans in moderate yields. One appropriate example is shown below <06EJOC5174>.
CHO [~~/~] iO2Me iO2Me + II
Et3N ~9 M e O 2 ~ 2 M e
+ II
CO2Me -10 ~ 55%
M eO2C'- ",0/
Three-component reaction of thiazolium salt, ketene precursor, and dimethyl iPr2Net as base gave rise to 1,4-thiazepine-fused acetylenedicarboxylate using 'Pr,Net l,4-thiazepine-fused furans in high yields, as can be seen in the following scheme <06AG(I)7793>.
I
.002 Me C~Me
~~/e ++ PA Ohm'++ ):~ Bre ~Et Et
P
Br 6
III[I]
/Pr2NEtoH2C,2 CO Me CO2Me 83% 2
As can be seen, the reaction between the anisyl derivative and the acetoacetate provided also tetrasubstituted furans. A subsequent demethylation cyclization delivered furo[3,4c]coumarins in a moderate yield <06JHC1699>.
.,,,,,,~,/0Me . ~ ~~ 0 piperidine piperidine ~# E tOM~02Et HBr HBr + A,)lOEt I ~ -H-O-Ac-· .,,~'V~OEt --M-eO-H-J~ MeOH HOAc
0 Me 0 OMe ~ 0
CX I
#
0
40%
50% 50%
0
0
'# 0)&~"':
o
5.3.3.2 Di- and Tetrahydrofurans Tetrahydrofurans Haloetherification remains one of the most popular approaches towards tetrahydrofuran skeletons. Yus reported a double iodoetherification reaction promoted by a silver salt, affording 1,7-dioxaspiro[4.5]decanes, and an example is shown in the scheme below <06T2264>. Kumar and Singh also reported an iodoetherification pathway to form 2,3-diphenyltetrahydrofurans <06T4018>. A bromoetherification converted 3-butenols into bromotetrahydrofurans <06TL5751>.
189
Five-membered ring Five-membered ring systems: furans and benzofurans
OH
OH
12 12
AgOTf AgOTf
Na2C03 Na2C03 THF THF
r.t., 12 12hh r.t., 99% Another general route from which tetrahydrofurans can be prepared is the Williamson ether synthesis. In this entry, many variations on leaving groups other than halides have been 06OL2831; 060L5477>; 06OL5477>; tosylates devised, e.g. mesylates <06AG(I)7072; 06JOC386; 060L2831; <06JOC836; 060L2635; 06OL2635; 06T5421; 06T8095; 06TL3401>; epoxides <06AG(I)81O; <06AG(I)810; 06CAJ894; 06CC3444; 06EJ02403; 06EJO2403; 06JA9561; 06JOC926; 06JOC1416; 060BC3220; 06OBC3220; 060L4375; 06OL4375; 06SLlI77; 06SLl177; 06SL2329> and water <06H(68)771; 06HCA3071; 06SL2035; 06T6107>. A bicyclic compound containing a tetrahydrofuran ring was synthesized, whose steps involved intermediate, as shown below <06JOC1139>. the opening of an epoxide intermediate, SiMe3
1. MsCI MsCI SiM83 u,,SiM e3 Et3N Et3N CH2CI2 :D~ CH2CI2 -40°C, aq. sat sat Ba(OH)2 Ba(OH)2 0~ u , aq. H~O~ -40 ~ 22 hh ( "'C0 2H 2R --5-0-0C-,-2-4-h-~ J 'C02Et 2. r"'' "C0 "C02R 50~ 24 h " (" I"'[. J'"C02 H 2. K2C03 K2C~ 100% HO HO 100% HO MeOH MeOH HO 25 °C, 30 min R 25~ R=EtandMe = Eland Me
~
99%
0d::~
cl::
4-Pentenols can be induced to undergo cyclization to form tetrahydrofurans under many conditions utilizing reagents such as mercury(II) mercury(I1) acetate <06T2857; 06TL5943> and cerium(III) chloride <06T7466>. Hex-2-ene-l,6-diols also led to the formation of tetrahydrofurans upon treatment with an acid <06S3621>. Mukaiyama's cobalt-catalyzed aerobic oxidative cyclization protocol has also been employed to from tetrahydrofurans from 4pentenols <060L4379>. OsO.-catalyzed <06OL4379>. Other approaches involving 4-pentenols are the OsO4-catalyzed oxidative etherification <06JA13704> as shown in the scheme below, as well as a similar Pd(TFA),-catalyzed oxidative version <06SL3533>. Pd(TFA):-catalyzed
H2~10 $ ~ ~ ~1 ~ j ~
/ ~
1% OX
080 4 (5 mol%) OS04 m~(5 0 Me3NO
TFA TFA
cinnamicacid acid cinnamic Me2CO-H20 Me2CO-H20 77% 77%
H21C10~ H2101~ 0 HO H
H OH
HO H
~O
1,5-Hexadienes 1,5-Hexadienes underwent an oxidative cyclization catalyzed by RRuO. u O 4 <060L3433> <06OL3433> as illustrated in the following scheme <06Tl 0989>. <06T10989>.
190
x.-L. Hou, Z. Yang, K.-S. Yeung, H.N.c. Wong X.-L. Hou, Yang, K.-S. Yeung, and H.N.C. Wong
H 2 1 C ~ O A c HOe "O" "O" 'OH + RuO2~ (20 mol%) /--OAc NalO4(4 equiv.) H 2 1 C ~ O A c H2101o
'~-'/
MeCN-EtOAc-H20 (3:3:1) 0 ~ 30 min
O
"
.o"
"o"
24%
"
OH
14%
"o"
b
9O/o
+
Palladium-catalyzed cyclization of bis-hydroxy-allyl bis-hydroxy-ally1 alcohols unexpectedly unexpectedly gave dioxabicyclo[2.2.2]octanes <06TL3271>, while the adjacent bis(tetrahydrofuran) cores of annonaceous acetogenins can be obtained via a stereoselective palladium-catalyzed double <06OL5637>. Palladium-catalyzed carboetherifications cyclization of bis(allylic acetate)diols <060L5637>. of substituted 4-pentenols in the presence of aryl bromides led to the formation of tetrahydrofurans bearing three stereocenters with moderate to good stereoselectivities <06TL2793>. A similar intramolecular version of this reaction gave also tetrahydrofurans in good stereo-control as shown below <06JA2893>. Pd2(dbab Pd2(dba)3
~Br ~
~or X_/ OH
h
oHBF4 PCY3oHBF4 PCY3 Na().fBu NaO-t-Bu
~ .-:: H
~ ;:
PhMe PhMe 105°C 105 ~ 40% 40%
dr 92:5:2:1 92:5:2:1
~O
,"Ph ,,Ph
H H
Major Diastereomer Diastereomer Major syn-addition syn-addition trans-THF
Other obvious methods for generating tetrahydrofuran frameworks are via chemical transformations of lactols <06AG(I)6904; 06JNP1531; 06JOC1251; 06JOC6287; 060L2039; 06OL2039; 06TA3; 06TL6433>; acetals <06JOCl172; <06JOCI172; 06TL3979> and lactol acetate <06CC2720; 06TL4561; 06TL5905>. Radical cyclizations have also been employed to the formation of tetrahydrofurans <06AG(I)8018; 06EJ0l547; 06EJO1547; 060L2209; 06OL2209; 060L4481; 06OL4481; 06SL1829>. Wender reported several rhodium-catalyzed cyclotrimerization of polyenes and dienecyclopropanes to lead to cyclic molecules embedded with tetrahydrofurans <06AG(I)2459; 06AG(I)3957; 06JA5354; 06JA6302>. In a study on the total synthesis of lactonamycin, the pivotal tetrahydrofuran ring was constructed via an intramolecular Michael addition reaction <06JOC2434>. Secosyrins 1 and 2 were also realized employing a Michael addition route <06SL3340>. An interesting transannular [2+2] photocycloaddition reaction of cyclic ether gave rise to the formation of a cyclobutane fused with two tetrahydrofuran rings <06TL733>. On the other hand, an approach to ophirin B Band and astrogorgin featured an intramolecular Diels-Alder cycloaddition as illustrated <06JA1371>. (-)-cladiella-6,11-dien-3-ol, in the following scheme <06JA 1371>. The total synthesis of (-)-cladiella-6, ll-dien-3-01, (+)polyanthellin A, (-)-cladiell-11-ene-3,6,7-triol and (-)-deacetoxyalcyonin acetate also made use of such intramolecular Diels-Alder strategy <06JA15851>.
os~Pr3
BnOv~~,osiipr3 1.06H625 ~ 2. hv PhSSPh PhSSPh
PrO2C/ Et3SiO Me
C6H6 C 6H6
,-
? ~.' MeHH Bn '" PrO2c Et3 "
191
Five-membered ring ring systems: furans and benzofurans
Au(III)-mediated ring contraction of C-glycoside scaffolds provided highly substituted tetrahydrofurans <060L5065>. <06OL5065>. Similarly, tetrahydrofuran-based y-azido ~,-azido esters were prepared <06T4110>. It was uncovered by Makosza that from 2-O-triflates 2-0-triflates of D-ribose and L-arabinose <06T411O>. enolates of y-chloropropyl ~,-chloropropyl ketones reacted with aldehydes in protic media to generate aldoltype products that would cyclize to form tetrahydrofuran tings rings <06Sl190>. <06S 1190>. Prins-type cyclization between homopropargylic alcohols containing terminal alkynes with aldehydes, forming tetrahydrofurans, was also observed by Cho <06OL3617>. <060L36 17>. Yadav developed an efficient synthetic method for highly substituted tetrahydrofurans via reactions of a vicinal tbutyldiphenylsilylmethyl-substituted cyclopropyl diester with aldehydes and ketones <06TL8043>. Lewis acid promoted rearrangement of 1,3-dioxolanyl-substituted 1,2-oxazines into novel molecules with 1,3,6-trioxa-7-azacyclopenta[cd]indene frameworks <06SL3498>. Lewis acid also mediated [3+2] [3+2] cycloaddition reactions of chiral allylsilanes with an a-keto ester <06H(67)369> or an aldehyde <06JAI5960> <06JA15960> to afford silyltetrahydrofurans in good to high stereoselectivities. Another thermally induced [2+3] [2+3] cycloaddition reaction between [60]fullerene and epoxides provided fullerenes fused with tetrahydrofurans <06JOC4346>. As [60]fullerene [5+2] approach towards the total synthesis of a naturally occurring can be seen below, a [5+2] molecule descurainin was reported by Snider <06T5171>.
n4
1. 1. Et3N Et3N CH2CI2 CH2Cl2 25 ~ 2 d 25°C, 31% 31%
oO
+
:~ AcO O
I""::
MeO MaO
.Q
OMe OMe
SiIBuMe2 OSitBuMe2
AcO
2. C5H5NoHF C5H5N,HF THF-C F-O5H5 N 5H5N 3. TH KOH 3.KOH MeOH-H MeOH-H20 20
H
O
MaO
MeOH ~ - ~ O M ~ Ac
87% 87%
Enantiomerically pure reactions of 1,3-bis-silyl enol Rhodium complexes as the triethylphosphine to afford <06JA9642>.
~ O
HO
OMe Descurainin
TiC14 mediated 2-alkylidenetetrahydrofurans were prepared by TiCI, ethers with enantiomerically pure epichlorohydrin <06TA892>. one shown below reacted in solution in the presence of 2,2-disubstituted-5-methylenetetrahydrofurans in good yield
Rh/,.,, O ~ Me (Et3P)2 Me
PEt PEt3 (10 equiv.) equiv.) 3 (10
~ M e e + (Et,3P)4RhH
C6D6 25 ~ 68%
3-Alkylidenetetrahydrofurans can be synthesized conveniently by many metal complex catalyzed cyclization procedures. In this connection, organometallic complexes of rhodium <06JAI1766; <06JAl1766; 06JOC91; 06S4053; 06TL6361>, nickel <06JA2609>, indium <06T3582>, palladium <06TL8905>, iridium <06TAI238>, <06TA1238>, ruthenium <06JA9262> and gold <06AG(I)7427> are all known to catalyze cyclizations of allyl propargyl ethers to form 3alkylidenetetrahydrofurans via various mechanisms involving organometallic intermediates. Highly enantioselective reductive cyclization of alkynyl aldehydes via rhodium-catalyzed hydrogenation also provided 3-alkylidenetetrahydrofurans containing a stereogenic 4-hydroxy group <06JA 10674>. A Rh(I)-catalyzed intramolecular [4+2] <06JA10674>. [4+2] cycloaddition led to the formation of a bicyclic product featuring an alkylidenetetrahydrofuran scaffold is shown below <06JA 12648>.
192
x.-L. Hou, Z. Yang, K.-S. Yeung, H.N.e. Wong X.-L. Hou, Yang, K.-S. Yeung, and H.N.C. Wong
[RhCI(diene*)h [RhCl(diene*)]2(5 (5 mol%) mol%) H (R,R)-Et-DUPHOS (11 4 -p-CF3 ~C6H4.P.CF3(R,R)-Et-DUPHOS (11 mOI%)q) mol%) ? 6H4"p'CF3 ~C6H4-P-CF3 AgSbF 17 ",Me AgSbF66 (20 (20 mol%) mol%) /......r..,,~,~,,,Me
oO N ~ M Mee ~
CH2012 CH 2 CI2
•
ID,
.#
r.t., r.t., 1.5 1.5 h
7
diene* = diene* = Me
H
97% 97% OO%H 98% ee
Me Me
M
3-Methylenetetrahydrofurans can also be realized by an intramolecular radical indium(l) iodide as a radical initiator <06TL28S9>. <06TL2859>. 3cyclization of bromoalkynes utilizing indium(I) Diiodomethylenetetrahydrofurans were also prepared from 1,o)-diiodo-l-alkynes l,ffi-diiodo-l-alkynes in the Diiodomethylenetetrahydrofurans presence of 1-hexynyllithium I-hexynyllithium <06CC638>. Takikawa achieved the total synthesis of brevione B <06T39> and decaturin D <06TL442S>,bothofwhichcontain <06TL4425>, both ofwhichcontain a spiro-fused 2,3-dihydrofuran ring. Their approach to these intriguingfunctionalities intriguing functionalities was by coupling a vinyl epoxide with a hydroxypyrone through a simple SN2'-type base-mediated SN2' -type epoxide opening, and was followed by a dehydrative O-alkylation step. A mild Ni(0)-catalyzed Ni(O)-catalyzed rearrangement of 1-acyl-2-vinylcyclopropanes l-acyl-2-vinylcyclopropanes was reported to <06OL573>. 2,3-Dihydrofuran rings were realized by allowing ~ 13give 2,3-dihydrofurans <060LS73>. diketones or ~-ketoesters -NaHC0 3-mediated 13-ketoesters to react with 2-bromo-2-cyclopentenone in K,C0 K2CO3-NaHCO3-mediated 3 <06S16S7> <06S1657> or Lewis acid catalyzed <06EJ0200S> <06EJO2005> conjugate-addition-initiated-ring-closure conjugate-addition-initiated-ring-closure 13-Keto-diphenylphosphine oxides were found tocyclize to form optically active (CAIRC) routes. ~-Keto-diphenylphosphineoxideswerefoundtocyclizeto <06OBC3108>, while flash vacuum pyrolysis of vinyl epoxides gave cis2,3-dihydrofurans <060BC3108>, <06OBC2912>. 2,3-dihydrofuran carboxylates as major products as illustrated in the scheme below <060BC29 12>.
ph~CO2
Et
180~"C 180 Sealed tube tube Sealed
EtO2C
PhMe PhMe
Ph~
80% 80%
Et02C.
+ Ph~ 10:1
A new domino lithium acetylide addition/rearrangement procedure on trans-l,2trans-l,2dibenzoyl-3,S-cYciohexadiene dibenzoyl-3,5-cyclohexadiene furnished 3-alkylidene-2,3-dihydrofurans via an intriguing mechanism involving three bond formations and two bond cleavages in one single operation <06SL1230>. The reaction of dimedone with meso-diacetoxycyclohexene meso-diacetoxycyclohexene in the presence of a <06SLl230>. <06S865>. palladium catalyst led to the formation of the tricyclic product as depicted below <06S86S>.
O
.4 o _
-
0
+ AcO. . . . . .
OAc
[Pd( Tj3_C3HS)CI]2 [Pd(rl3-C3H5)Cl]2 PPh3 PPh3 K2C0 3
THF THF r.t., 2.5 2.5 h h Lt., 67o/o 67%
-,-
m O O
H~
I
., -'""
Ii H
An obvious preparation of 2,S-dihydrofurans 2,5-dihydrofurans was by bis-allyl ether <06CC2489; 06JA1840> or by tandem allyl propargyl <06TS064> <06T5064> ring closing metathesis. Au(I) 06JA1840> <060Ll9S7>, <06OL 1957>, Au(III) <06EJ0l387> <06EJO 1387> and Pd(II) <06AG(l)4SOl> <06AG(I)4501 > catalyzed cyclization of allenyl 2,5-dihydrofurans were recorded. Reactions of allenyl carbinols with KO-t-Bu carbinols to form 2,S-dihydrofurans AgNO 33 were also shown to lead to the formation of 2,5-dihydrofurans 2,5-dihydrofurans <06SL2383>. Copperor AgN0 catalyzed rearrangement of vinyl oxiranes has been shown to lead to 2,S-dihydrofurans 2,5-dihydrofurans <06JA16054>. <06JA1 60S4>. In the total synthesis of salviasperanol, the vinyl epoxide embedded in a cycloheptane ring rearranged to a 2,S-dihydrofuran 2,5-dihydrofuran skeleton upon treatment with a catalytic <06OL2883>. Ga(III)-catalyzed cycloisomerization of enynes amount of trifluoroacetic acid <060L2883>. containing a cyclic alkene gave rise to the formation of eight-membered ring molecules fused with a 2,S-dihydrofuran 2,5-dihydrofuran <060LS42S>. <06OL5425>. As can be seen below, mercuric chloride mediated the
193
Five-membered ring Five-membered ring systems: systems:furans and benzofurans benzofurans
2,5-dihydrofuran frameworks cyclization of tethered alkynyl dithioacetals to form also 2,S-dihydrofuran <060L313>. <060L313>.
S~S /Pr~o M
HgCI HgCl2 (3 equiv.) equiv.) 2 (3 CaC0 3 (4 equiv.) ,. CaCO3(4equiv')
Ok,.Me OJ-Me Pr
pr>(J
°
MeCN-H MeCN-H20 (4:1) 20 (4:1) 25 25 °C,4 ~ h
L.~.~.
Me" "0" Me
32% 32%
Me 5.3.3.3 Benzo[b]furans and Related Compounds The formation of a diverse array of five-membered ring heterocycles via the cycloaddition of isocyanides with furan- or pyrrole-based enones was reported. The reaction <06OL3975>. mechanism is discussed and an example is shown below <060L397S>. O 2,6-Me2PhNC 2,,-Me2PhNC CaCI CaCI2 ~ 2
O
JJ~ D Me ~ . ~ " ~~~MN _~ H
PhMe PhMe 25 ~ 25°C 79% 79%
HN ~
Me/
Me" 4-Hydroxymethyl-4,8-dimethylfuro[2,3-h]chromen-2-one 4-Hydroxymethyl-4,8-dimethylfuro[2,3-h]chromen-2-one was realized in an efficient manner via a Claisen rearrangement of 4-(hydroxybut-2-ynyloxy)-4-methylchromen-2-one as depicted in the following scheme. Other examples with substitution of hydroxyl and with other substituents, such as chloro, amino, acetoxy were also reported <06JHC763>. A new approach for the synthesis of oxygenated benzo[b]furans was developed via epoxidation and cyclization 2'-hydroxystilbene <06T4214>. of 2' -hydroxystilbene <06T42 14>.
Microwaveirradiation ~I Microw(~eO~)diatiOn M~ (540w) N,N-diethylaniline O II[ ~I N,N-diethYlaniiine" 0:::"" ° °O 20-30 min Me
OH
OH
Me
"=::
MI"'\A
°
° °
20-30 min 56% 56%
M Me
OH
The treatment of 2-fluorophenyl-2-iodophenyl ethers, amines, and thioethers with 3.3 equivalents of t-BuLi and further reaction with selected e1ectrophi1es electrophiles gave rise to functionalized carbazoles, dibenzofurans, and dibenzothiophenes in a direct and regioselective manner. A selected example is illustrated below <06JOC6291>. Benzyl 2-halophenyl ethers was treated with t-BuLi, and then reacted with carboxylic esters to give 2,3-disubstituted benzo[b]furans benzo[b]furans <06JOC4024>.
F I O
1. t-BuLi t-BuLi (3.3 (3.3 equiv) equiv) 1. TH F THF -78°C -78 ~ to to O°C 0~ 2. 2. Ph Ph2S ~ 2S 22 -78 ~ to to 20°C 20 -78°C 64% 64% for for two two steps steps
SPh SPh
6:0 ° r~
~
p-Quinone monoimide was able to react with various azadienes in the absence of a Lewis acid to give 2,3-dihydrobenzo[b]furans, 2,3-dihydrobenzo[b]furans, a motif that is present in numerous biologically active
194
X.-L. x.-L. Hou, Hou, Z. Yang, Yang, K.-S. Yeung, Yeung, and H.N.C. H.N.e. Wong Wong
products, in moderate to excellent yields <06OL3919>. <060L39 19>. Three Three interesting interesting and novel pentacyclic pentacyclic products, benzo[b]furan-based scaffolds scaffolds were generated generated during a direct platinum-anodic platinum-anodic oxidation oxidation of of 2,42,4benzo[b]furan-based <06EJ0241>. Regioselective formation of of benzo[b]furanbenzo[b]furandimethylphenol, albeit in low yields <06EJO241>. based spirocyclic compounds compounds was accomplished accomplished by tri-n-butyltin hydride hydride mediated aryl radical based 4-exo-trig cyclization <06OL4059>. <060L4059>. Synthesis Synthesis of of the racemic scaffold scaffold of of 8-fluoro8-fluoro4-exo-trig coupling as illustrated illustrated below <06TL5701>. <06TL5701>. galanthamine was achieved by an oxidative coupling ~ ('Y0H
H0XX'N~ 1
MeO U eO~
MeO PhMe, H20 PhMe, 50oc 50 °C 40%
I
F CHO
.0
Meo~oo
K3[Fe(CN)6] K3[Fe(CN) 6] K2CO3 K2C0 3
1.0
N 'CHO "CHO
I
F
of benzo[b]furans, benzo[b]furans, naphthalenes, naphthalenes, indoles and A versatile and regioselective synthesis of benzothiophenes was achieved by reaction of of o-alkynylarene and heteroarene carboxaldehyde carboxaldehyde benzothiophenes derivatives in the presence of iodonium ions. The reaction mechanism was also discussed <06CEJ5790>. <06CEJ5790>.
Ph_%
Ph~~ OHC
r
~
1. IPy2BF4,HBF4 0H2012 0 ~ rt ~ 2. PPhHC=CH hHC--C 2, r.t. r.t?
36% 36%
m Ph...O0 Ph
P h '-':: ~ Ph
H H
I
'1\
h
Several substituted benzo[b]furans benzo[b]furans were synthesized efficiently in one-pot procedures HBF4·Etp in high by reaction of salicyaldehydes and ethyl diazoacetate in the presence of HBF4~ yields as shown below. A plausible mechanism was also given <06S 1711>. Two types of <06S1711>. naphtha[2,3-b]furan derivatives were made respectively by Lewis acid and HCI HC1 catalyzed ring cyclizations <06T8045>. AuBrJ-catalyzed AuBr3-catalyzed [4+2] benzannulation between enynal units and enol ethers was also applied to prepare benzo[b]furans <06JOC5249>. <06JOC5249>.
CI,~CHO + N2CHCO2Et CI
"OH
CO2Et
HBF4"Et20 Ci ~ ~ o j ~,CH OH2 012 2 CI 2 Lt., r.t., 1lhh 99% 99% CI
)
2-Substituted 3-halobenzo[b]furans were afforded by the palladium-catalyzed CuC12 and EtJN·HCl Et3NoHC1 as depicted in the annulation of 2-alkynylphenols in the presence of CuCI, scheme below <060L30 17>. Iodine-induced oxidative cyclization reaction of 2<06OL3017>. hydroxystilbenes was utilized in the synthesis of benzofurans <06SLl657>. <06SL1657>. Benzo[b]furan related furo[2,3-b]pyridine-4(1H)-one was also made effectively via iodocyclization <060Llll3>. <06OLl113>. A one-pot synthesis of benzo[b]furans was also reported by the Zn(OTf),Zn(OTf) 2catalyzed cyclization of proparyl alcohols with phenols in high yield <06JOC4951 >. <06JOC4951>. PdCI2 PdCI2
~Ph _E_t~_~_~H_12C_1.. .1~,.~ ~
M MeMOH
Ph
CuCI2 DEC DEC r.t. r.t. 78% 78%
M
CI CI
Me Me~r
Ph
Ph
195
Five-membered ring systems: furans and benzofurans benzofurans Five-membered ring systems:
Asymmetric synthesis of the rocaglamides was accomplished by employing [3+2] Br¢nsted acids. The photo-cycloaddition mediated by functionalized TADDOL based chiral BrOnsted [3+2] dipolar cycloaddition, a base-mediated a-ketol ~-ketol rearrangement synthesis consisted of a [3+2] 1,2and a hydroxyl-directed reaction <06JA7754>. Asymmetric synthesis of 1,2dihydrobenzo[b]furans was achieved by adamantylglycine derived dirhodium tetracarboxylate catalyzed C-H insertion <060L3437>. <06OL3437>. OH QH
OMe O MeO
1 hv>350 hv 350nm 1. nm TADDOL, -70°C -70 ~ TADDOL, PhMe, CH2CI2 PhMe, CH2CI2 ~
OH~
MeO
+ ~OMe Ph. ~ Ph,,,e,',~cooa e "V 'COOMe
MeO
MeO"
. II u
(14%yield, (14% yield, 58%ee) 58%ee) bMe OMe exo-methyl exo-melhylrocaglamide rocaglamide
2. NaOH, NaOH, MeOH MeOH 2. 3. Me4NBH(OAch Me4NBH(OAc)3
OH OH MeO ",C0 2Me MeO OH:: OH/~,,,CO2Me
OXO
I~ MeO
TADDOL = = A A r K AAr TADDOL r r Ar OH
MeO
olf
Ar-OH O1~r
0
A'
(71% yield, 60% 60% eel ee) OMe OMe (71 % yield, endo-methylrocaglamide rocaglamide endo-methyl
Ar Ar = = phenanthren-9-yl phenanllqren-9-yl
Cationic palladium-catalyzed addition of arylboronic acids to nitriles for the formation of benzo[b]furans was reported <060L5987>, <06OL5987>, an example of which is illustrated in the following scheme. The palladium-catalyzed cross coupling of alkynes with appropriately substituted aryl iodides for the synthesis of substituted dibenzofurans in moderate to excellent yields was also achieved <06JOC5341>. The benzo[b]furan core of heliannuls G and H were rt-allyl cyclization reaction <06TL7353>. The palladiumconstructed by a palladium-catalyzed n-allyl catalyzed oxidative activation of arylcyclopropanes was applied to the synthesis of 2<06OL5829>. substituted benzo[b]furans benzo[b]furans <060L5829>. OMe OMe
D I
MeO MeO
A'
CN CN
PhB(OH)2 PhB(OH)2 [(bpy)Pd(gOH)]2(OTf)2 [(bpy)Pd().l-OH)k(OTf)2
-------.~
oJ-O"~ Me Me
-
MeN0 MeNO2 2 reflux, reflux, 9 h
"--
M
OMe OMe Ph Ph , ~ ~
MeO "MeO
I
A'
~
Me Me
0
82% 82% A metallative 5-endo-dig 5-endo-dig cyclization reaction of 2-ynylphenols generated by a sequential treatment of BuLi and ZnCl, ZnC12 produced 3-zinciobenzo[b]furans 3-zinciobenzo[b]furans in excellent yields. These intermediates were allowed to undergo a transmetallation route to form the corresponding cuprates, which reacted with electrophiles to produce a variety of 2,3disubstituted benzo[b]furans <060L2803>. <06OL2803>. A similar strategy was utilized by the same team to construct the conjugated structures containing multiple benzo[b]furan benzo[b)furan units <06AG(I)944>.
196
Hou, Z. Yang, K.-S. Yeung, H.N.e. Wong X.-L. Hou, Yang, K.-S. Yeung, and H.N.C. Wong
~ ~
Ph 1. 1. BuU BuU (1.0 (1.0eqiuv),PhMe, eqiuv),PhMe,00 DC ~ to to rtrt p'Ph
I":: ,0
OH
2. 120 DC 2" ZnCI2 ZnCI2(1.0 (1"0equiv), equiv)'120 ~
3. 3. CUCN2UCI, CuCN2UCI,PhMe, PhMe,-78 -78 DC ~
4b=o 4. I
.~
~ O ~~~'O~4~ ' Ph (90% (90%overall overallyield) yield)
O
A palladium-catalyzed one-step synthesis of dihydrobenzo[b]furan-based dihydrobenzo[b]furan-based fused aromatic heterocycles from bifunctional bromoenoates or bromoalkyl indoles and iodoarenes was reported, and an example is provided in the scheme below <060L360l>. <06OL3601>. 2-Alkyl- or 2aryl-substituted benzo[b]furans benzo[b]furans were synthesized by a copper-TMEDA copper-TMEDA catalyzed intramolecular annulation from the corresponding corresponding ketones <060Ll467>. <06OL 1467>.
I
Pd(OAcl2, Pd(OAc)2,PPh PPh33 CS 0s2003, norbomene 2C0 3, norbomene
+ Br ~
O.,",,,z,/~CO2Et
DME
O
•-.--
100 DC
O~Br
45% 45%
~OO'Et
CO2Et
2-Amino-2,3-dihydrobenzo[b]furans were obtained employing starting materials 2-Amino-2,3-dihydrobenzo[b]furans generated from Baylis-Hillman adducts <06TL3913>.
O2N,, ,~CO2Me ph,~CO2 Me
CF COOH CF33COOH
H2N.,CO2Me
H H2SO (3.0eqiev) eqiev) 2 S0 4 4 (3.0
Cell6 60-70 ~ 3 h
•
Gold(I)-catalyzed synthesis of dihydrobenzo[b]furans dihydrobenzo[b]furans from aryl allyl ethers was reported as depicted below <06SLl278>. <06SL1278>. Highly efficient AuCI/AgOTf-catalyzed AuC13/AgOTf-catalyzed atomeconomical annulation of phenols with dienes was developed. This annulation generated various dihydrobenzo[b]furans dihydrobenzo[b]furans under mild conditions <060L2397>. <06OL2397>.
~ 7 Ph3PAuCl(5 (5 mol%) mol%) M M eeOo~W Ph3PAuCI Meo~o~ MeO. O ~ AgOTf(5 mol%) Me
y
OMe OMe
I """
AgOTf (5 mol%) CH CH2CI 2 2CI2 40 DC ~ 55% 55%
•
4
Me
0
OMe OMe
As can be seen in the following scheme, substituted (benzo[b]furan-3-yl)acetic acid was obtained in a high yield by heating substituted 4-chloromethylchromen with 2N NaOH solution <06T9258>. A benzo[b]furan core was also realized by a direct cyclization of Nef reaction products through an intramolecular cyclo-condensation <06SL567>. A facile synthesis of benzo[b]furoisocoumarins benzo[b]furoisocoumarins was reported by reaction of substituted phenols with ninhydrin in the presence of acetic acid, followed by treatment with a catalytic amount of Et N in refluxing Et3N 3 ethylene glycol <06SL207>. Various benzo[b]furans benzo[b]furans were made by N-heterocyclic carbene (NHC) catalyzed intramolecular nucleophilic substitution reaction from the corresponding aromatic aldehydes <060L4637>. <06OL4637>.
197
Five-membered ring systems: furans and benzofurans Five-membered
~
1
MeO" ~
"O" "O
NaOH(2.0 NL 80~
92%
~CH2CO2H
M
eO" "
u
A D6tz Dotz benzannulation reaction reaction was utilized utilized in the synthesis ]furan synthesis of the furo[2,3-b furo[2,3-b]furan core of aflatoxin illustrated below aflatoxin B, B2 as illustrated below <06TL2299>. <06TL2299>. Synthesis Synthesis of polynuclear aromatic compounds was achieved achieved by using using [5+5] [5+5] cycloaddition of 2-alkynylarylcarbene complexes complexes and enyne-aldehyde derivatives <06TL5303>.
;sr
H '<:::: Cr(CO)s Cr(CO)5 n " ~ o Et + MeO MeO ~ OEt _
==
"H oO H
' " : : K¢=
, H OH o ~ O M eOMe
THF
THF
0, I H' .6e 2SiM62ISu H 0O ~ S i M tBu OEt
SiMe2tBu ---'l"~ SiMe2tsu 80°C 80~ 31% 31~0
A new triethylamine-catalyzed cascade cascade reaction of aromatic aromatic aldehydes aldehydes and propiolates was developed to prepare various benzo[b]furan-based polycyclic aromatics. Interestingly, the prepare various chemical outcome outcome of this this process process depended depended on the reaction temperature temperature and was selectively <06OL 1241>. tailored by an appropriate choice of experimental conditions <060Ll241>. CliO CHO
6 0
C_O2Me
=
+ H ~ +H
CO2Me Co,M.
O
~
....
CH2CI2 -40 ~ 3h MeO2C...~,~O
CO2Me
As depicted depicted in the following following scheme, scheme, in the presence of sodium sodium iodate iodate and pyridine, several 5,6-dihydroxylated benzofuran benzofuran derivatives derivatives were were synthesized synthesized via an oxidation-Michael addition of [3-dicarbonyl compounds to catechols catechols in a one-pot one-pot procedure addition ~-dicarbonyl compounds procedure <06TL2615; 06JHCI673>. reaction of 2-benzo[b]furan sulfilimines with 06JHC1673>. A novel additive additive Pummerer reaction with carbon nucleophiles derived from ~-dicarbonyl [3-dicarbonyl compounds was also also employed to the synthesis of 2,3disubstituted benzo[b]furans <06TL595>. HO~ HO~ HO HO~
O° e ~ i j0~
m: O
NalO3
NalOs pyridine pynd ine -..--. HO HO
+ + " ,,-----t~.. Me~Me M Me EtOH EtOH,H H20 o i 470/0 4 7% 2
HO HO
"::
O~M"-'e
.6
0
~
Mee
An unexpected dimerization product was obtained obtained in 30% yield during during the palladiumcatalyzed hydrogenation of 2-(2-pyridylmethylene)-3(2H)-benzo[b]furan-3-one. A couple couple of scope of the substrates was limited similar types of substrates were were investigated, indicating the scope <06T8425>. O
~0
MeO...... MeO -......::r-O
H2 Pd-C EtOH EtOH 30% 30%
MeO MeO/~"~,,,~
O
OMe ~.,,,),"~O Me
198
X.-L. Hou, Yang, K.-S. Yeung, and H.N.e. H.N.C. Wong Wong Hou. Z. Yang, K.-S. Yeung.
The benzo[b]furan-based core structure of galanthamine was constructed by a novel synthetic methodology making use of a NBS-initiated semi-pinacol rearrangement, leading to the desired products in high yields <060Ll823>. <06OL 1823>. MO9
NBS NBS
~
O
OSiMe2tBu CH2CI2 0~ 95%
OMe
A practical method for the synthesis, resolution and determination of the absolute configuration of 9,9' -binaphtha(2, lob)furanyl-8,8' -diol was reported as shown below 9,9'-binaphtha(2,1-b)furanyl-8,8'-diol <06TS1275>. A rearrangement of 4-acetoxy-9-furanylnaphtho[2,3-b]furans to tetracyclic <06TL4117>. naphthodifurans was achieved under acidic conditions <06TL4ll7>.
5Y
O
~
~
o
1~ ~
-
OH OH
I
FeCI3 H20
reflux 90%
OH
HO
The tetracyclic benzo[b]furan-based core structure of liphagal was efficiently assembled by an acid-initiated polyene cyclization reaction to form the pivotal fused 6,7 ring <06OL321>. The acid-catalyzed dimerization substructure as depicted in the following scheme <060L321>. of benzo[b]furans was also reported in the synthesis of a certain type of benzo[b]furan dimers <06SL1497>. A base-mediated condensation of benzo[b]furan-2-aldehyde with functionalized <06SLl497>. pyrans was applied to the synthesis of a new class of high-brightness red-light-emitting dopants for OLED <060L2632>. <06OL2632>.
CISO3H
~~..,~~OMe u
OMe " ~ "OMe Br Br
,
, ~
-78°C. -78 ~ 30 30 min min 43% 43%
/
~
Me
OMe OMe
Br
1,2-Bis(2-n-alkyl-l-benzo[b]furan-3-yl)perfluorocyclopentene derivatives were 1,2-Bis(2-n-alkyl- 1-benzo[b] furan-3-yl)perfluorocyclopentene synthesized, and their photochromic performance was studied in solutions as well as in their <06EJO3105>. single crystalline phases <06EJ03l05>. E F,
F F hv
•
hv #
5.3.3.4 Benzo[c]furans and Related Compounds
A quantitative study on local aromaticity based on n-center electron delocalization indices, where n is the number of atoms in the ring, was performed on benzo[c]furan and benzo[b]furan.
199
Five-membered ring systems: furans and benzofurans Five-membered ring systems: benzofurans
The results show that benzo[b]furan benzo[b]furan is more stable by 14.4 kcal/mol due to a large decrease of <06T12204>. aromaticity of the benzene ring in benzo[c]furan <06Tl2204>. A convenient one-step synthesis of various symmetrically substituted 1,31,3diarybenzo[c]furans was recorded, and an example is shown below <06SL2035>.
0~MgBrTHF
~o O[~
S
O
MgBr
~ O ~S
THF O°C 0~
OMe OMe
~~ S
85% 85%
Two oxadisilole-fused benzo[c]furans benzo[c]furans illustrated below were prepared making use of Warrener's tetrazine protocol <06JOC3512>. <06JOC35 12>. Their reactivities, photophysical, redox and thermal properties were all assessed. As shown below, an isocorannulenofuran isocorannulenofuran was also bromocorannulene synthesized, again by employing Warrener's route, from readily accessible bromocorannulene <060L5909>. <06OL5909>.
/ \ /
~ O"Si~
/S
~Si
b--Si-\ As can be seen in the scheme below, insertion reactions of aldehydes to the C-H C-H bond of aromatic ketimines by using a rhenium catalyst provided benzo[c]furans benzo[c]furans via a mechanism involving consecutive steps of C-H C-H bond activation, insertion of aldehyde, intramolecular nucleophilic cyclization, reductive elimination, and elimination of aniline <06JA12376>. <06JA12376>.
Ph Ph
~ ~
I
Oi
[ReBr(CO)3(thf)]2 (2.5 (2.5mol%) mol%) [ReBr(COb(thf)12 4AMS '7
,Ph
+ + p-CF3C6H
H
PhMe Ph Me 11593% ~ 24 24 hh 115°C, 93%
~
::::,...
Ph Ph
~
~ ""-
o O H -p-CF 66H4PCF3 4 3
A rhodium-catalyzed intermolecular [2+2+2] cycloaddition of dipropargyl ethers with trimethylsilylynamides using (S)-xyl-BINAP as ligand led to the formation of 1,31,3dihydrobenzo[c]furans dihydrobenzo[c]furans in high enantioselectivities, as depicted in the following scheme <06JA4586>. <06JA4586>. The same research team also prepared C, C2 symmetric and unsymmetric tetraartha-substituted ortho-substituted axially chiral bis(l,3-dihydrobenzo[c]furans) bis(1,3-dihydrobenzo[c]furans) employing a similar strategy <06OL3489>. It was found that when nitriles instead of alkynes were used, pyridine analogs of <060L3489>. benzo[c]furans benzo[c]furans were obtained <06EJ03917>. <06EJO3917>. 0O pPh)L"N,Ph h.,,,U,,,N,Ph cod)21BF4 (10%) ph.,,~N,Ph ph [Rh( [Rh(ood)2]BF4 (10%) Et~ ~ Ph)lW (S)-xyI-BINAP SiMe3 (S)-xyl-BINAP 0O
I/
O\ 0,
Et
Et
Et Et
+
+
IIII
SiM63 SiMe3
CH CH2CI2 2CI2 r.t. r.t. 62% 62% 96%ee 96%ee
6X~M~ ~::::,... 0O'J
Et "Et
200
x.-L. X.-L. Hou, Z. Yang, Yang, K.-S. Yeung, Yeung, and H.N.e. H.N.C. Wong
Yamamoto showed that Cp*RuCl(cod) was able to catalyze cyclotrimerization reactions between diynylboronateand diynylboronate and monoalkynesto monoalkynes to form 1,3-dihydrobenzo[c]furans 1,3-dihydrobenzo[c]furans as illustrated by an example below <06T4293>. By utilizing the same method, Yamamoto also prepared a number of <06T4293>.Byutilizing spirocyclic C-arylribosides <060L3565>. <06OL3565>. These organometallic-catalyzed [2+2+2] cycloaddition pathways were also used by Hocek <060L2051> <06OL2051> and Shibata <06TA614> in their quest for functionalized C-nucleosides and atropisomeric chiral o-diarylbenzene derivatives, respectively.
O
~<~
o (co
Acetylene Acetylene [~~'~ ~ O Cp*RuCl(cod)(10mol%) (10 mol%) Cp*RuCI(cod) CH CH2Cl 2CI22
r.t.,1 r.t., 1 h 82%
Florio achieved a general method for the synthesis of hydroxyalkyl 1,3dihydrobenzo[c]furans from o-lithiated aryloxiranes and carbonyl compounds, and an example is depicted in the following scheme <06JOC3984>.
1. "BuLi t-BuLi 1.
[~~ U
oO Me Me ~.\'" Brr
THF
-78 ~ -78°C
Me
OH
2. 2. M~CO Me2CO
3. 3. Heat Heat
4. 4.
H+ W
e
67% 67% = >9812 >98/2 dr = As can be seen below, another route for the preparation of spiroannulated 1,3supra) was reported by Hotha, who made use of an AuC13 AuCl] dihydrobenzo[c]furans (vide supra) promoted intramolecular Die1s-Alder Diels-Alder reaction <06TL3307>.
O / , , ~ O . ,,,OMe "
I
,nO
~,O v,~Me
AuCI AuCI33(3 mol%) mol%) MeCN MeCN 10 10 min min
78% 78%
O/~.,,.O. ,,,OMe ph i O , ~ , ~ ~) ~ O H Bn Me
Acknowledgements: HNCW wishes to thank the Areas of Excellence Scheme established under the University Grants Committee of the Hong Kong Special Administrative Region, AoE/P-10/01) and an anonymous donor for financial supports. XLH China (Project No. AoE/P-lO/Ol) acknowledges with thanks supports from the National Natural Science Foundation of China, National Outstanding Youth Fund, the Chinese Academy of Sciences, and Shanghai Committee of Science and Technology. KSY thanks Dr Nicholas A. Meanwell for support. 5.3.4 REFERENCES 06AG(I)81O 06AG(I)810 06AG(I)944 06AG(I) 06AG(I)1442 1442 06AG(I)2459 06AG(I)2459 06AG(I)3957 06AG(I)3957 06AG(I)4501 06AG(I)4501 06AG(I)5194 06AG(I)5194
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202 06JA5354 06JA5648 06JA6302 06JA7754 06JA9262 06JA9561 06JA9642 06JA10674 06JAII032 06JA11032 06JAI1766 06JA 11766 06JAl1916 06JA11916
06JAI2376 06JA12376 06JA 12648 I2648 06JA13030 06JA 13130 06JAI3130 06JA13704 06JA15851 06JAI5851 06JAI5960 06JA15960 06JAI6054 06JA 16054 06JA17057 06JHC623 06JHC763 06JHCI195 06JHC 1195 06JHCI673 06JHC1673 06JHC1699 06JHCI699 06JNP68 06JNP 113 06JNPI13 06JNPI21 06JNP121 06JNP138 06JNP 138 06JNP229 06JNP26I 06JNP261 06JNP274 06JNP295 06JNP299 06JNP397 06JNP67I 06JNP671 06JNP876 06JNP957 06JNPI077 06JNP1077 06JNPI083 06JNP1083 06JNP 1086 06JNP1086 06JNPI098 06JNP 1098 06JNP1209 06JNPI209 06JNP1249 06JNP I249
X-L. Hou, Z. Yang, K.-S. Yeung, and H.N.C. H.N.e. Wong X.-L.
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Five-membered ring systems: furans and benzofurans Five-membered benzofurans
06JNP1271 06JNP 1271 06JNP1289
06JNP 1310 06JNP1310 06JNP1531 06JNP 1531 06JNP1543
06JNP 1721 06JNPl721 06JNPl728 06JNP 1728 06JNP1734 06JNP1749 06JNP 1749 06JNP1782 06JNP 1782 06JNP1826 06JOC91 06JOC386 06JOC836 06JOC926 06JOCl139 06JOC1139 06JOCll72 06JOC 1172 06JOC1251 06JOC 1251 06JOC1416 06JOC 1416 06JOC1620 06JOC2352 06JOC2434 06JOC3512 06JOC3569 06JOC3984 06JOC4024 06JOC4346 06JOC4951 06JOC5249 06JOC5341 06JOC5349 06JOC5432 06JOC5715 06JOC6287 06JOC6291 06JOC8045 06JOC9544 06OBC2076 060BC2076 060BC2912 06OBC2912 060BC3108 06OBC3108 060BC3220 06OBC3220 06OL27 060L27 060L313 06OL313 060L321 06OL321
06OL325 060L325
203
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204 060L403 060L573 060L597 060L62I 060L621 060L701 060L99I 060L991 060Lll13 06OL1113 060Ll241 060L1241 060Ll427 060L1427 060Ll467 060L 1467 060Ll741 060L 1741 060L1823 060Ll823 060Ll945 060L 1945 060Ll957 060L1957 060L2039 060L2051 060L2209 060L2269 060L2397 060L2623 060L2635 060L2803 060L2831 060L283I 060L2883 060L2909 060L2957 060L3017 060L3367 060L3433 060L3437 060L3489 060L3565 060L3601 060L3613 060L3617 060L3705 060L3919 060L3975 060L4059 060L4075 060L4113 060L4133 060L4319 060L4375 060L4379 060L4481 060L448I 060L4509 060L4513 060L4637 060L4831 060L4935 060L5045 060L5061 060L5065 060L5425 060L5477
X.-L. Hou, Z. Yang, Yang, K.-S. Yeung, Yeung, and H.N.C. x.-L. H.N.e. Wong
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ring systems: furans and benzofurans Five-membered ring
060L5573 06OL5573 06OL5581 060L558I 06OL5637 060L5637 060L5829 06OL5829 06OL5901 060L5901 060L5909 06OL5909 060L5987 06OL5987 060M435 06OM435 06P307 06P452 06P459 06P735 06P743 06P759 06P965 06P1957 06P2146 06P2288 06S865 06Sl190 06S1I90 06S1657 17 I I 06S 06S1711 06S3605 06S362I 06S3621 06S4053 06SCI941 06SC 1941 06SL207 06SL567 06SL 1177 06SLlI77 06SLlI93 06SL 1193 06SLl209 06SL 1209 06SLl230 06SL1230 06SLl278 06SL1278 06SL1399 06SLl399 06SLl440 06SL 1440 06SLl497 06SL1497 06SLl657 06SL1657 06SL 1829 06SLl829 06SLl962 06SL1962 06SL2035 06SL2329 06SL3340 06SL3431 06SL3498 06SL3533 06SL2383 06T39 06T2264 06T2857 06T3582 06T376I 06T3761 06T4018 06T411O 06T4110 06T4214
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206 06T4294 06T4743 06T4988 06T5064 06T5171 06T5421 06T5426 06T6107 06T7466 06T8045 06T8095 06T8425 06T8798 06T9258 06Tl0688 06T 10688 06Tl0989 06T 10989 06TI1740 06Tl1740 06T12204 06Tl2318 06T12318 06TA3 06TA614 06TA892 06TA1238 06TA1275 06TL595 06TL733 06TL1505 06TL 1505 06TL2299 06TL2527 06TL2615 06TL2793 06TL2859 06TL3271 06TL3307 06TL3401 06TL3607 06TL3685 06TL3913 06TL3979 06TL4007 06TL4113 06TL4117 06TL4409 06TL4425 06TL4509 06TL4561 06TL4623 06TL5111 06TL5303 06TL5307 06TL5701 06TL5733
X-L. Hou, Hou. Z. Yang. X.-L. Yang, K.-S. Yeung. Yeung, and H.N.e. H.N.C. Wong
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Five-membered ring systems: furans and benzofurans
06TL575I 06TL5751 06TL5905 06TL5943 06TL6285 06TL636I 06TL6361 06TL6401 06TL6433 06TL6849 06TL7185 06TL7353 06TL8043 06TL8183 06TL8507 06TL8905 06TL8965 06TL929I 06TL9291
207
Mita, T. Nishizawa, Sano, M. Segi, Segi, T. Nakajima, 2006, 47, Nishizawa, T. Sano, Nakajima, Tetrahedron Lett. 2006, M. Honda, Honda, T. Mita, 5751. G. Jake, Franck, B. Seon-Meniel, HocquemilIer, B. Figadbre, Figadere, Tetrahedron Lett. 2006, Jalce, X. Franck, Seon-Meniel, R. Hocquemiller, 2006, 47, 5905. D.K. Mohapatra, 5. S. Mohapatra, M.K. Gurjar, Tetrahedron Lett. 2006,47,5943. 2006, 47, 5943. M.K. Gurjar, J. Robertson, AJ. A.J. TyrreII, Tyrrell, S. Skerratt, Skerratt, Tetrahedron Lett. 2006,47,6285. 2006, 47, 6285. K. Mikami, Mikami, S. Kataoka, K. Aikawa, Tetrahedron Lett. 2006, 47, 6361. Kataoka, K. Wakabayashi, K. 2006,47,6361. B. Tang, C.D. Bray, Bray, G. Pattenden, Tetrahedron Lett. 2006,47,6401. Tang, C.D. 2006, 47, 6401. J.-c. Moon, 0.-5. Park, Tetrahedron Lett. 2006,47,6433. J.-C. Jung, Jung, J.-c. J.-C. Kim, Kim, H.-I. H.-I. Moon, O.-S. Park, 2006, 47, 6433. S.J. Blank, Blank, C.E. C.E. Stephens, Tetrahedron Lett. 2006,47,6849. 2006, 47, 6849. 5J. R.R. Burton, Burton, W. Tam, 2006,47,7185. Tam, Tetrahedron Lett. 2006, 47, 7185. Shindo, M. Yoshida, K. Shishido, Tetrahedron Lett. 2006, 2006, 47, 7353. S. Morimoto, M. 5hindo, A. Gupta, Gupta, V.K. V.K. Yadav, Yadav, Tetrahedron Lett. 2006,47,8043. 2006, 47, 8043. 2006, 47, 8183. J.M. Oliverira, G. Zeni, Zeni, I. Malvestiti, R.H. R.H. Menezes, Tetrahedron Lett. 2006,47,8183. M. De Rosa, Rosa, L. Citro, Citro, A. Soriente, Soriente, Tetrahedron Lett. 2006,47,8507. 2006, 47, 8507. J.T. Metza, Metza, Jr., R.A. R.A. Terzian, Terzian, T. Minehan, Tetrahedron Lett. 2006,47,8905 2006, 47, 8905 47, 8965. M. Bakavoli, B. Feizyzadeh, M. Rahimizadeh, Tetrahedron Lett. 2006, 2006,47,8965. V. Gaddam, D.K. Sreenivas, R. Nagarajan, Tetrahedron Lett. 2006,47,9291. Gaddam, D.K. 2006, 47, 9291.
208
Chapter 5.4 Five membered membered ring ring systems: systems: with with more more than than one one N N atom atom Five Larry Yet Albany Molecular Research, Inc., Inc., Albany, Albany, NY USA [email protected] Larry. Yet @albmolecular.com
5.4.1
INTRODUCTION INTRODUCTION
The synthesis and chemistry of of pyrazoles, imidazoles, and 1,2,3-triazoles were actively pursued in 2006. A review on the cross-coupling reactions on azoles with two and more <06£J03283>. Publications heteroatoms for pyrazoles and imidazoles has been published <06EJO3283>. relating to 1,2,4-triazole and tetrazole chemistry were not particularly well represented this year. The solid-phase and combinatorial chemistry of of these ring systems have not been investigated compared to past years. No attempt has been made to incorporate all the exciting chemistry or biological applications that have been published this year.
5.4.2 5.4.2
PYRAZOLES AND AND RING-FUSED RING-FUSED DERIVATIVES DERIVATIVES PYRAZOLES
A short review has been published on the utilization of chiral enaminones and azomethine imines in the synthesis of functionalized pyrazoles <06ARK3S>. <06ARK35>. Addition of hydrazines to 1,3-difunctional compounds is one of the most common methods employed for the preparation of pyrazoles. 1,3-Diketones were synthesized directly from ketones and acid chlorides and were then converted in situ into pyrazoles by the addition of hydrazine <060L267S>. <06OL2675>. This method is extremely fast, general, and chemoselective, allowing for the synthesis of previously inaccessible pyrazoles and synthetically demanding pyrazolecontaining fused rings. A highly regioselective synthesis of l-aryl-3,4,S-substituted 1-aryl-3,4,5-substituted pyrazoles based on the condensation of fluorinated 1,3-diketones with arylhydrazines has been described where N,N-dimethylacetamide is used as the solvent <06SL3267>. New bis-pyrazole derivatives bis(]3-diketone)precursors with hydrazines were synthesized from aryl- and xylyl-linked bis(~-diketone)precursors 3-Amino-5-trifluoromethyl-lH-pyrazoles were synthesized by cyclocondensation <06SC707>. 3-Amino-S-trifluoromethyl-1H-pyrazoles 1, I-trifluorobut-3-en-2-ones with hydrazines <06SL148S>. reactions of 4-amino-4-ethoxy-l, 4-amino-4-ethoxy-l,l,l-trifluorobut-3-en-2-ones <06SL1485>. The application of microwave heating to a silica-assisted solution-phase synthesis technique has
209
than one N atom Five membered ring ring systems: with with more more than
been utilized to develop a rapid and efficient two-step protocol for the preparation of pyrazoles 5 from aryl methyl ketone 1 and ethyl trifluoroacetate 2 with aryl hydrazine 4 via trifluoroketo enol 3 <06TL2443>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic and sulfonyl hydrazines led to the synthesis of N-1 substituted 3-acyl-4-cyano-5aminopyrazoles, which became versatile intennediates intermediates for the synthesis of many biologically reacted 3-Arylhydrazono-4-polyfluoroalkyl-2,4-dioxobutanoates reacted active scaffolds <06TL5797>. 3-Arylhydrazono-4-polyfluoroalkyl-2,4-dioxobutanoates with hydrazines give ethyl hydrazines to give ethyl 4-aryldiazeno-3-polyfluoroalkyl-lH-pyrazole-5-carboxylates 4-aryldiazeno-3-polyfluoroalkyl-lH-pyrazole-5-carboxylates <06RJOC887>. <06RJOC887>. Microwave irradiation of substituted hydrazines and ~-ketonitriles ]3-ketonitriles furnished 5aminopyrazoles, which were transformed transfonned to their corresponding N-carbonyl derivatives by treatment with an isocyanate or a chlorofonnate chloroformate <060BC4158>. <06OBC4158>. CF3
o0
00
NaH 0 OH O .....U... + .ill... Nail,, DME DME,, 160°C 160 ~ • II .IOH )l+)l . Ar OEt Ar Me Me FF3C OEt microwave 3C mICrowave Ar Ar~ CF CF33 2 61-95% 3 1 61-95%
Me-Q-NHNH 2 M e - - @ NHNH2 4 Si-TsOH,EtOH EtOH Si-TsOH,
Ar~. N N
160 160 cC, ~ microwave microwave 48-95% 48-95%
Me Me
5
13-bromovinyl aldehydes 6 are cyclized with phenylhydrazine in toluene in the Cyclic ~-bromovinyl presence of a palladium(II) acetate and a phosphorus chelating ligand together with sodium tertl-aryl-1H-pyrazoles 7 in moderate to good yields <06T6388>. This method butoxide to give 1-aryl-lH-pyrazoles oThe reaction of 0also applied to other acyclic aldehydes and arylhydrazines. fluorobenzaldehydes 8 and their O-methyloximes 9 with hydrazine has been developed as a new practical synthesis of indazoles 10 <06JOC8166>.
~ n CHO \JCCHO Br Br
n
PhNHNH2, PhNHNH2, Pd(OAc)2 Pd(OAc)2 (5 (5 mol%) mol%) •D. PhMe, PhMe, 125 125 °C ~
I
CHO NH NH , DME 2 2
R~..,,,.~ I-r~'~CHO ~ . . D M NH2N E reflH2' uFx R~
88
F
reflux
29-82% 29-82%
7 7
OJ"
~ RR~ [ ~ ~ IN , NN ~
10 10
N
QGN n N\ Ph Ph
dppf dppf (7.5 (7.5 mol%), mol%), NaOt-Bu NaOt-Bu(2 (2 eq) eq)
66
a
~
,
n n
Yield Yield
1 1
20% 20% 79%
2
2
3 4 4
79%
65% 65%
77%
77%
,,OMe N NH 2NH 2 , DME
~ NH2NH2' uerlxfF DME I ~R--
N H H
H
reflux
69-94% 69-94%
9
R= = H, H, OMe, OMe, CI, CI, Sr, Br, FF R
(E)-N-methoxy-N-methyl-a-enaminoketoesters (E)-N-methoxy-N-methyl-~-enaminoketoesters were employed as synthetic precursors for the regioselective condensations with hydrazines in a microwave-assisted synthesis of ethyl 1,5N(l ')-substituted (S)disubstituted-4-pyrazole carboxylate derivatives <060L3219>. <06OL3219>. Protected N(l')-substituted (S)3-(4-methoxycarbonyl-IH-pyrazol-5-yl)alanines were prepared acid-catalyzed 3-(4-methoxycarbonyl- 1H-pyrazol-5-yl)alanines by cyclocondensations of chiral enaminone, available from L-aspartic acid, with hydrazine <06S2376>. hydrochlorides <0652376>.
210
1. L. Yet Yet
Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of Nmonosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. <06OL3505>. lH-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde 1H-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL258l>. <06SL2581>. A one-pot synthesis of 1-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring 3-aryl-2-benzoyl-l,l-cyclopropanedicarbonitriles 14 with hydrazine provided a new opening of 3-aryl-2-benzoyl-I,1-cyclopropanedicarbonitriles process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. 0 O
R11V N ~ ~ RR 3 3 R
t;J
R22 R
NH NH2NH2H20 2NH 2H20 (10 eq)
NHR 22 ~ _ R1 / ~ ~ R 3
R1~R3
KOH (2 eq), ethylene ~_ glycol, 100°C 100 ~ v glycol,
11
~ n
+
R1 R1
+
,N N H H 13 13
12
0-69% HH
1 = I-Bu, t-Bu, Ph, Ar, R1 CH CH2CH2CH=CH2 2CH 2CH=CH2 R22 = H, phthalamlde, phthalamide, R R3 3= = Me, Me, Ph, Ar R
8-58%
CN
yCN
R3
Ph
NH NH2NH 2,, DMF 2 NH 2 DME, reflux
COPh 14
Ar Ar
11
,N N H
55-75%
15 15
Various five-membered ring heterocycles have been utilized in the preparation of pyrazoles. 1,2,3-Triazoles 16 underwent a Diels-Alder cycloaddition with dimethyl acetylene dicarboxylate under solvent-free conditions and microwave irradiation to afford pyrazole-3,4-dicarboxylates 18 with extrusion of the substituent on position 4 of the triazole intermediate 17 as a nitrile in the presence of silica-bound aluminum chloride <06TL876l>. <06TL8761>. A series of 6-substituted fluorinated indazoles 20 has been obtained through an ANRORC-like rearrangement (Addition of Nucleophile, Ring-Opening and Ring-Closure) of 5-tetrafluorophenyl-l,2,4-oxadiazoles 5-tetrafluorophenyl-1,2,4-oxadiazoles 19 with hydrazine <06T8792>. Unexpected ring-opening of benzimidazoles with nitrilimines led to pyrazole derivatives <06TL8807>. 3-(p-Aryl)-4-cyanosydnone 21 underwent 1,3-dipolar cycloaddition with acrylic acid esters to give pyrazoloesters 22 and 23 in varying ratios
,N
R1
N
N / Ph
R2 16
DMAD, Si0 SiO2-AICI 3 2-AICI 3 microwave, 80-130 °C ~ ~. microwave, 20 min min 20
Ph 1 R2 Ph "~,1 CO2M e R~I~c02Me
N
r
1
MeO2C CO2Me Me02C)jC02Me
RI~N= - RL=N.
N" N " ~ N-N--\ C0 CO2Me 2Me 17 17
R1 1 = H, Ph, CHO, C0 CO2Me, 2Me, Et 2== H, Me, Et, (CH (CH2)3Me hMe R2 2
35-94% 35-94%
R2 R2
'I \
,N
J ~Ph
Ph 18 18
211 211
membered ring systems: with more than one N atom Five membered
<06SL90l>. <06SL901>. Reductive cleavage of 5-silyl, 3-, 4- and 5-silylmethylisoxazoles gave their [3-enaminones, which on reaction with hydrazines, provided regioselective corresponding silyl ~-enaminones, syntheses of 3- or 5-silylpyrazoles and 3-, 4- or 5-silylmethylpyrazoles, respectively <06T611>.
F\ ~F
NH2NH 2, DMF, 25°C NH2NH2'93-980/~ 25 ~ 93-98%
N/R~,.N
I
R=Me, Ph R =Me, Ph
0
,N N,N
::::-.-
X
X= = NHMe, NHMe, NMe2' NMe2, OMe OMe X
X F
2
X N ~i « FN-N F, F , NHH2 F :?' ~
H
F
F
20 20
19
~O
OR OR
PhCI, PhCl,reflux reflux
J!: 05 RO
'I \
NC NC .N NC | R = Et, t-Bu, ~~,/~ ,~O R=Et, t-Bu,Bn Bn . [~ 76-80%,57:43 EtO N 76-80%,57:43to to 78:22 78:22ratio raUo 'N-O R R== CHPh CHPh22 21 85%,100:0 100:0ratio ratio 85%, OEt OEt
O~OR O
0
O
\ NC 'I N.N
NC
Q Q +
+
OEt OEt
22
23
A one-pot process to form 1,3,4-substituted 1,3,4-substituted pyrazoles 25 by Suzuki coupling of arylboronic acids to chromone 24, followed by condensation with hydrazine has been reported <06JC0286>. <06JCO286>. The synthesis of 3 or 5-o-hydroxyphenol-4-benzylpyrazoles 5-o-hydroxyphenol-4-benzylpyrazoles has been accomplished by treatment of 3-benzylchromones, 3-benzylflavones and their 4-thiochromone 4-thiochromone analogs with hydrazine hydrate in hot pyridine <06EJ02825>. <06EJO2825>.
O A JJ... R~I R
I
U~J 24 24
°
1 ArB(OH)2' ArB(OH)2,Pd(PPh Pd(PPh3) (2 mol%), mol%), 1. 3)44 (2 "
OH N-NH I]11/~
K K2CO eq), THF, THF, H H20, reflux= 20, reflux. 2C0 33 (2 eq),
2. NH NH2NH 2 (1.5 (1.5 eq), eq), 25°C 25 ~ 2NH 2 R R == H, H, Me, Me, OMe, OMe, CI, Cl, N0 NO22
48-95% 48-95%
25
Other miscellaneous type of reactions have been used in the synthesis of pyrazoles. Domino coupling/hydroamidation of iodoenynes 26 with bis(Boc)hydrazine led to a copper-catalyzed coupling/hydroamidation highly efficient synthesis of 3,4,5-trisubstituted 3,4,5-trisubstituted pyrazoles 27 <06AG(E)7079>. <06AG(E)7079>. A novel one-pot synthesis of pyrazoles has been accomplished by the reaction of ~-formyl [3-formyl enamides with hydroxylamine hydrochloride catalyzed by potassium dihydrogenphosphate in acid medium 4-(3-aminopropyl)-5-amino-l-methylpyrazole <06TL43>. A new synthetic process approach to 4-(3-aminopropyl)-5-amino-l-methylpyrazole <06OPRD159>. Microwave-assisted starting from 3-cyanopyridine has been developed <060PRDI59>. Microwave-assisted preparation of a wide range of 5-ethoxycarbonylpyrazoles and 3-pyrazoles by 1,3-dipolar cycloaddition of diazo compound to acetylenes has been reported <2006H(68)1961>. <2006H(68)1961>. The regioselective, scaleable synthesis of three 4-(2-alkyl-5-methyl-2H-pyrazol-3-yl)piperidines has discussed <06TLl729>. <06TL1729>. Reaction of phenylhydrazine 28 with 1,3-dibromo-2-propanol 1,3-dibromo-2-propanol 29 afforded I-phenyl-lH-pyrazole 1,3-Dipolar cycloaddition of 1-phenyl- 1H-pyrazole 30 <06JOCI35>. <06JOC135>.
212
L. Yet
diphenylnitrilimine on olefins in the presence of porous calcium hydroxyapatite gave pyrazolines under solvent-free microwave irradiation <06SCl 1l>. <06SCl11>. An enantioselective 1,3-dipolar cydoaddition cycloaddition reaction between diazoacetates and R-substituted acroleins, which gave 2pyrazolines with an asymmetric tetrasubstituted carbon center with titanium BINOL catalyst has been published <06JA2l74>. <06JA2174>. Reaction of the Htiisgen zwitterion, derived from triphenylphosphine and dialkyl azodicarboxylates 31, with allenic esters 32 afforded highly functionalized pyrazoles 33 <060L22 13>. 1,3,5-Trisubstituted pyrazoles were synthesized from <06OL2213>. chalcones and hydrazines in the presence of iodine <06SC2l89>. <06SC2189>. R~ 1
19BocNHNHBoc, BocNHNHBoc, Cui Cul (5 (5 mol%), mol%), 1. N,N-dimethylethylenediamine N,N-dimethylethylenediamine(20 mol%), mol%),
R2-
~
Cs2CO 3 (1.5 equiv), equiv), THF, THF, 80 80 °C ~ CS 2C0 3
R3
26
2 " TFA, TFA, CH CH2CI 2,, 25 °C ~ 2. 2CI 2
2 3 RN___./R .-."~ ~N R1 N H 27
66-92%
~NHNH2
V [~t
N H NH 2 + +
Br~BroH Br~Br
R 33 = = Bn, Bn n-Bu, n-Bu, n-Hex, n-Hex R
' (CH2)nCl(or ' CH CH2COEt, 2 COEt, (CH 2 )nCI(or OBn)
K2 C0 3, H2 0, 120 °C •
OH
28 28
R1 = H, H, n-Pr, n-Pr, Ph, Ph, Bn Bn R1 R22 = = H, H, Et Et R
K2CO3' ~ mH20' i c r ~ 120 ~C
( ~ ~ ~ - - - ~ "N/~ N
microwave 81% 81%
29 29
30
R 1 0 2 C ~ O Et ,CO2R1 R1 ,c02 N=N
C
/ R10 O2C 2
31
+ +
R1 =Et, i-Pr
PPh 3 , DME, 25 °C
R2/
"
32
\ CO2Et
35-72%
~
R3
J
CO2 R1
R 22 ==Me, Me, Ph, Ph A R Arr
R3 =
R 3 = H, Ph Ph
33
A one-step heterocyclization of o-nitrobenzylamines to 3-alkoxy-2H-indazoles in the presence of 5% potassium hydroxide in alcoholic solvents has been reported <06JOC2687>. -disubstituted indazolone derivatives starting from methyl The synthesis of a series of N,N' N,N'-disubstituted anthranilates in the presence of [phenyliodine(III)bis-(trifluoroacetate)] via an N-acylnitrenium intermediate has been presented <06JOC350l, <06JOC3501, 06TlllOO>. 06TIll00>. The Schiff bases, prepared from several amines and 2-nitrobenzaldehydes, were reacted with triethyl phosphite under microwave irradiation to generate nitrenes that underwent insertion reactions to give indazoles <06TL6795>. Lewis-acid promoted "coarctate" cydization cyclization of ten 2-(phenylazo)benzonitrile derivatives <06JOC6619>. furnished the isoindazole ring system <06JOC66 19>. Several metal cross-coupling reactions have been applied to pyrazoles. C-H Arylation of aryl tosylates or chlorides could be achieved with a ruthenium catalyst at the C-2 phenyl position of 1-phenyl 1-(p-tolyl)pyrazole 34 to give pyrazole 35 <06AG(I)26l9>. <06AG(I)2619>. Copper-catalyzed NI-phenyl or l-(p-tolyl)pyrazole arylation of pyrazole can be accomplished using air-stable copper(I) iodide as a copper source and 1,lO-phenanthroline 1,10-phenanthroline in the presence of potassium fluoride/alumina as a base <06SL2l24; <06SL2124; 1-Benzyl-4-bromo-lH-pyrazole can be cross-coupled with 3-pyridine-boronic acid 06TL5203>. l-Benzyl-4-bromo-lH-pyrazole in excellent yield <06AG(I)1282>. Heck cross-coupling reaction of 3-iodoindazoles with methyl 2-(acetylamino)acrylate provided a general route to new dehydro 2-azatryptophans and protected amino acid derivatives after catalytic hydrogenation <06S3506>.
213
N atom Five membered membered ring systems: systems: with more more than one N atom
o
~ N
(Me)H (Me) H
~
34 34
n
I.( ,N
ArOTs or ArCI ArCI N ArOTs or [(RuCl2)(p-cymene)2 (2.5 mol%) mol%) •~. ~ JAvrA r [(RuCI 2)(p-eymene)2]] (2.5 phosphoramide ligand ligand (10 (10 mol%) mol%) phosphoramide (Me)H K2CO NMP (Me) H K 2C0 33,, NMP 35 51-81% 51-81%
A)
N-Methylation at the pyrazole ring by sequential treatment of S-tributylstannyl-45-tributylstannyl-4trifluoromethylpyrazole 36 with LDA and iodomethane regioselectively provided the N5-1ithiated-4-trifluoromethylpyrazole methylpyrazole 37 <06T6332>. The addition reaction of S-lithiated-4-trifluoromethylpyrazole with a wide range of aldehydes or ketones allowed easy and high-yielding introduction of substituents on position S 5 to give pyrazoles 38. Efficient preparation of 3-aryl-1H-pyrazoles 3-aryl-lH-pyrazoles 41 by reaction of l-protected-S-(4,4,S,S-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazoles 40, 1-protected-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazoles prepared from pyrazole 39 with usual conditions, with (het)aryl halides has been described <06TL4655>. The SEM protecting group was difficult to remove in the presence of the <06TL46SS>. carboxylate derivatives and often required drastic refluxing conditions and excess tetrabutylammonium fluoride. The choice of THP protecting group was found to alleviate these shortcomings. The C-3 position of isoindazoles is readily functionalized by metalation with lithium diisopropylamide followed by reaction with a variety of electrophiles <06SC28S>. <06SC285>. Indazole 42 can be regioselectively protected at N-2 by a SEM group using novel conditions (Scheme 12) <06JOCS392>. <06JOC5392>. The SEM group of 43 efficiently directed regioselective C-3 lithiation and the resulting nucleophile reacted with a wide range of electrophiles to generate novel indazole derivatives 44 after the SEM group was removed by treatment with tetrabutylammonium fluoride in tetrahydrofuran or by aqueous hydrochloric acid in ethanol. 1(p-Methoxybenzyl)pyrazole, when treated with either n-butyllithium or lithium diisopropylamide, underwent metalation at the exocyclic -position but mutated to the S-lithio 5-1ithio species in the course of few minutes or hours <06EJ024l7>. <06EJO2417>. Trapping the intermediates with a rapidly reacting electrophile such as chlorotrimethysilane or carbon dioxide offered selective 3,5-disubstituted-pyrazoles access to either of the two possible regioisomers. N-Arylation of 3,S-disubstituted-pyrazoles with 4-fluoro and 2-fluoronitrobenzene under microwave irradiation conditions with and without solvent compared to the classical heating afforded N-arylation regioisomers in yields depending on the method used <06ARK138>.
F3C
F3C
~ N Bu3Sn H 36
1. LOA, THF, -78 °C
1. LDA, THF, 78 ~ _ 2. Mel Mel 93% 93%
~~N.N Bu3Sn Me 37
F3C1. -78 °C 1. n-BuLi, n-BuLi, THF, THF,-78 ~ ,,.
2 RCHO RCHOor or RCOR RCOR 2. 46-96% 46-96% R = H, H, alkyl, alkyl, aryl aryl R
•
IRReg. N HO
Me 38
214
L. Yet
NaH, SEMCI, THF 1. Nail, n-BuLi, THF THF 2. n-BuLi, 3. B(Oi-Prb
----'------'-''------
N
44. pinacol 9 pinacol 5. HOAc, HOAc, THF THF 75%
H 39
n ~'B--<'N ~N
Cyhex2NMe Cyhex2NMe SEMCI --T-H-F-THF
H 42
Pd(PPh 3)44 (5 mol%). mol%). 1. ArX, Pd(PPh3)
~/7---~N
°
NaHCO NaHC0 33 (2 eq), DME,
I
"
H 20, reflux reflux (40-93%) (40-93%) H20,
N SEM SEM
Ar Ar
~~'//~N ~N N' N H
TBAF, THF, THF, reflux reflux (60-95%) (60-95%) 2. TBAF,
40
41
0::
::--- N-SEM N-SEM
~
94%
1. n-BuLi, THF,-78 ~ THF, -78°C
"'N''
43
E
2. E<±>(72-98%) 3. TBAF, THF, reflux or HCI, EtOH, reflux
D,
cd ~
l
"N
,N N
44 H
>94%
of a pyrazolyl disulfide 45 Substitution reactions on pyrazoles have been reported. Reaction of of sodium dithionite at room with bromotrifluoromethane and ethyl bromide in the presence of temperature afforded pyrazolyl sulfides 46, followed by oxidation with hydrogen peroxide in <06JFC94S>. ~ trifluoroacetic acid afforded sulfenylpyrazoles 47 in excellent yields <06JFC948>. [3Chloropyrazole-4-carbaldehyde 48 has been utilized in the efficient synthesis of thiopyrano[S,6thiopyrano[5,6c]coumarin/[6,5-c]chromones c]coumarin/[6,S-c]chromones through intramolecular domino Knoevenagel Knoevenage1 hetero Diels-Alder Diels-Alder reactions with 4-hydroxy coumarin and its benzo analogs <06TL226S> <06TL2265> and a rapid synthesis of bis-tetrahydropyrazolo[4' ,3':S,6]thiopyrano[4,3-b]quinolines via imino Diels-Alder mono- and bis-tetrahydropyrazolo[4',3':5,6]thiopyrano[4,3-b]quinolines 3-Methylindazole 49 was Boc-protected followed by radical reactions <06TL7S71>. <06TL7571>. bromination with N-bromosuccinimide to give bromoindazole 50, which then underwent nucleophilic substitution by the carbanion of diethyl acetamidomalonate followed by decarboxylation and hydrochloride salt formation to yield a synthesis of 2-azatryptophan 51 <06T7772>. A simple and efficient protocol for the synthesis of 3-methoxy-4-arylmethyleneand 3-methoxyheteroarylmethylenepyrazoles 3-methoxyheteroarylmethylenepyrazoles 53 have been reported from the reaction of 4pyrazolomethyl alcohols alcohols 52 with either alcohols, alcohols, thiols, thiols, aryl and heterocyclic (furanyl, indolyl and pyrrolyl) compounds in the presence of camphorsulfonic acid (CSA) <06TLSI7>. <06TL817>. These reactions are believed to proceed via a Friedel-Crafts-type Friedel-Crafts-type carbocation type mechanism. m
m
S
CN
RS. CN ~N.N
CF CF3Br 3 Br or EtBr
H 2 N ~ N -N
Na2S204, Na2S204, Na Na2HPO4 2HP04 •
CI~CI
y
DMF, DMF, H H20, ~ 2 0, 25 °C
Et (95%) Et(95%)
R R =CF = CF33 (51%), (51%), Et(96%) Et (96%)
-
CF3 45
- 22
RS H 20 2, TFA H202, TFA •~ R =CF 3 (96%),
H2N
CF3 46
CN
H2N"\-'"~N CI
/CI
CF3 47
215 215
Five membered membered ring systems: with more than one N atom
R R
CHO .CHO
e
"1;-(
¥e
N/N~S~Me N.N~S.--"~/eMe II
Ph
48 C0 CO2Et 2Et
Me 1. 1. BoezO, Boc20, DMAP, DMAP, Me
C.:...: N....I.(9.::..:7-,-%:.L) ~NN _C.::..:H..:..>3c CH3CN (97%)
~N,
~N'
H
2. 2. NBS, NBS, MCPBA, MCPBA,
49 49 H
~~/IB
c6
__ c:?' .... "
~ \ <...N ,N ~ N Me
1. AcNHCH(C0 2Eth, Na, 1. AcNHCH(CO2Et)2, Na,
EtOH, 70 ~
I",N
EtOH, 70 'C
N
50 Boc Boc
2. NaOH, EtOH, EtOH, H H20, reflux2. NaOH, 20, reflux , 3. 3. HCI, HCI reflux reflux (70%) (70%)
Condition A: ROH ROH or or RSH, RSH, Condition
CSA (0.1 (0.1 eq), eq), 25 'C ~
o{
~14'. _ ~
---~-------
I
CCI 4 , 85 CCI4, 85 'C ~ (61%) (61%)
HO~'~OMe H01iOMe
Br
I
NH20HCI
NH2"HCI
"N :::,... , ~['~~N'N N H H 51 c:?'
51
R-~',~OMe R~OMe •
------'---"-'---Condition B: B ArH ArH or HetH, HetH, CSA
'<. .N ~:~
R R
= OR, OR, SR SR (50-100%) =
~ Me
R R
= Ar, Het Net (50-85%) (50-85%) =
(0.1 (0.1 eq), eq), CH CH2CI ~ 2, 25 'C 2CI 2,
52 52
53 53
Alkylation on the nitrogen of pyrazoles has been investigated. Microwave-assisted organic (SIC) as chemically synthesis in nonpolar solvents utilizing cylinders of sintered silicon carbide (SiC) inert and strongly microwave absorbing materials as passive heating elements (PHEs) was demonstrated for the alkylation of pyrazole 39 with phenylethylbromide to give pyrazole 54 <06JOC4651>. The synthesis of 2,2-dichlorotritluoromethyl 2,2-dichlorotrifluoromethyl pyrazole derivatives 56 from Freon-l 13 has been carried out in the pyrazoles 55 by the interaction of N-sodium salts with Freon-ll3 presence oftetrabutylammonium of tetrabutylammonium iodide (TBAl) (TBAI) as the catalyst <06SCI967>. <06SC1967>. 1,1'-Di(4-nitro or 2-nitrophenyl)-5,5'-disubstituted-3,3' -bipyrazoles have been prepared in one step by N,N2-nitrophenyl)-5,5'-disubstituted-3,3'-bipyrazoles N,Narylation of 5,5' -disubstituted-3,3'-bipyrazoles with 4-tluoro 5,5'-disubstituted-3,3'-bipyrazoles 4-fluoro and 2-tluoronitrobenzene 2-fluoronitrobenzene under microwave irradiation and classical heating <06ARK46>. phenylethylbromide, phenylethylbromide, SiC
~.N N H 39
heating heatingelement, element' NaHC0 NaHCO33
~.N
I.!... ,N N N
~~Ph /Ph
88% 88%
54
R R
r1,'N
~N.N
R~ R
n
=
PhMe, PhMe, microwave, microwave, 250 'C ~
N H H
55 55
R
/
1. 1. NaH, Nail, DMF, DMF, 25 25 'C ~ 2. CIF CIF2CCFCI 2,, TBAI 2CCFCI 2
R= =H H (72%), (72%), Me Me (70%) R
,,..-
ff-~.. R~N R N II
CF CF2CFCI2 2CFCI2 56 56
216
L. Yet
Fused pyrazole compounds have been prepared from N-alkyl substituted pyrazoles. For palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an example, a palladium-catalyzedlnorbomene-mediated spa C-H functionalization as the key step has been described, in which an alkyl-aryl aromatic sp' <06OL2043>. A variety of highly bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from N-bromoalkyl pyrazoles 57 and aryl iodides 58.
/~ N~ N N
+ + I +
Br ~Br
57 57
R R
Pd(OAc)2(10 (10 mol%) mol%) Pd(OAc)2
R
''6
tri-2-furylphosphine (22 mol%) mol%) tri-2-furylphosphine (22
_ CS C0 (2 eq), norbornene (2 eq) Cs2CO 3 (2 eq), norbornene (2 eq) 2 3
~I 58 58
MeCN, MeCN, 90°C 90 ~
r-tP N-N
R R == Me Me (54%) (54%) = = FF (49%) (49%) = CF 3 (42%) = CF 3 (42%)
59
1-Ethylpyrazole-4Some electrophilic reactions on pyrazoles have been reported. l-Ethylpyrazole-4carbaldehyde 61 was prepared from l-ethylpyrazole 1-ethylpyrazole 60 by the Vilsmeier reaction <06RJOC550>. Bromination of 3-(3-arylpyrazol-4-yl)acrylic acids 62 led to the formation of 2bromo-3-(3-arylpyrazol-4yl)acrylic bromo-3-(3-arylpyrazol-4yl)acrylic acids 63 which were converted to 3-(3-arylpyrazol-4yl)propionic acids 64 by treatment of of potassium hydroxide with an alcoholic solution <06RJOC701>. 3-Aryl-l-phenyl-4-mercaptomethylpyrazoles reacted with monochloroacetic acid to give 3-aryl-l-phenyl-4-pyrazolylmethylsulfanylacetic acids whose oxidation with hydrogen peroxide in acetone or acetic acid solution led to 3-aryl-l-phenyl-4pyrazolylmethylsulfinyl- and sulfonylacetic acids, respectively <06RJOC703>. The nitration of 100% nitric acid and 65% oleum or a mixture of 60% 5-chloropyrazoles 65 with a mixture of 100% nitric acid and polyphosphoric acid gave substituted 5-chloro-4-nitropyrazoles 66 <06RJOC901>. 4-Acyl-5-hydroxy-l-phenyl-3-trif1uoromethylpyrazoles 4-Acyl-5-hydroxy-l-phenyl-3-trifluoromethylpyrazoles 69 were prepared by reaction of 1-phenyl-3-trifluoromethyl-lH-pyrazol-5-ol l-phenyl-3-trif1uoromethyl-1H-pyrazol-5-o1 67 with trimethyl orthoacetate, triethyl orthopropionate and triethyl orthobenzoate, respectively, followed by hydrolytic cleavage of the primarily fomled formed condensation products 68 <06H(68)1825>. R R
19 POCI POCI33 1.
r1,'N ~~'N.N
R--<
R
OHC R OH)1C R
2. H 20
2Ha O ,,. R = HH (77%) (77%) R = Me Me (69%) (69%) =
~i
Et Et
60 60
HO2CHC=HC. Ar H02CHC=HC'pjAr
y \
,N N ~i Ph Ph 62 62
Y \
~~'N.,NN R R
~i Et Et
61 61
HO2CBrC=HC. Ar H02CBrC=HC'pjAr B~
CHCI3 CHC~
•
Y \ ,N N ~ i Ph Ph 63 63
HO2CC-C. Ar H02CC=C'pjAr KOH KOH
----=-:..=..:....:._.=. EtOH EtOH
47-66%
~'II . N,\ N Ni ~ Ph Ph 64 64
217 217
Five membered membered ring ring systems: systems: with with more more than than one one NN atom atom Five
R
or HNO3/PPA 45-91%
CI R1 65
HO
n
022NN ~ O
HNO3/SO3-H2SO4 =
2
R ,R2
Ji
CI..---".L .N CI
t';J
R1 R1 66 66
R1 = Me, Et, n-CFH15, R2 = Me, n-Pr, i-Pr, Ar OR2 RI~CF3
CF 3 ,CF3
~.N N N'
,O R I ~
1 2 R1C(OR2)3, 110-140 ~
R C(OR
h
I
O~N. N I
1= R1 =Me, Et, Ph 2 R2==Me, Et
Ph 67
HCI, H20 -_ HOJ'L.N.N EtOH
110-140 °C
46-96% 46-96%·D.
CF3
I
Ph 68
Ph 69
provided a general methodology for the generation of o0Microwave irradiation provided of excess sodium iodide in quinodimethanes derived from dibromopyrazole 70 in the presence of DMF <06SL579>. The cycloaddition reactions with electron-deficient dienophiles such as Nmethylmaleimide afforded the corresponding corresponding heteropolycyclic adduct 71. Dimethyl p-benzoquinone were other successful acetylenedicarboxylate, diethyl azodicarboxylate and p-benzoquinone dienophiles employed in this reaction. N-Acetyl-styrylpyrazoles underwent Diels-Alder cycloaddition reactions with N-methylmaleimide under solvent-free conditions to give the <06SLl369>. corresponding tetrahydroindazoles in good yields and high selectivity <06SL1369>.
oO
N./~
oo
rN-Me
~' oO
r
~Br
Br ~~ ~Br N
"Me (2eq) (2 eq) ~
Nal (3 eq), eq), DMF
I
I
Ph Ph
N,
N-Me
/
Ph Ph
microwave
70 70
~~N-M' 71 71
0O
80% 80%
An efficient route to 4-aryloxy pyrazoles 74 bearing a trifluoromethyl group has been developed from 4-hydroxypyrazole 72 under basic conditions with 3,5-dicyanofluorobenzene 73 with concomitant removal of the silyl group to give pyrazoles 75 <06SLl404>. <06SL 1404>. Fries-type oN
N
)
N NC
~CN
CN
HO
F F3C 72
OTBS K2CO3,DMF, 90 ~ 85%
O
1. MsCI, MsCI, Et EtaN, CH2CI2 1. 3 N, CH 2CI 2 • OH 2. 2. NaCN, NaCN, DMF, DMF,70°C 70 ~
F3C
65% 65%
74
CN
F~5:t Q
F3C
N
75 75
218
L. Yet Yet
rearrangement of 3-acyloxypyrazoles led to 1-acyl-I,2-dihydro-3H-pyrazol-3-ones 1-acyl-l,2-dihydro-3H-pyrazol-3-ones in the presence of titanium(IV) chloride or tin(IV) chloride <06JHC859>. A series of 2-(5-aryl-3-styryl-4,5-dihydro-1H-pyrazol-l-yl)-4-(trifluoromethyl)-pyrimidines 2-(5-aryl-3-styryl-4,5-dihydro-lH-pyrazol-l-yl)-4-(trifluoromethyl)-pyrimidines 78 was synthesized by the cyclocondensation of 5-aryl-l-carboxamidino-3-styryl-4,5-dihydro5-aryl-l-carboxamidino-3-styryl-4,5-dihydro1H-pyrazoles 76 with 4-alkoxy-l,1,l-trifluoroalk-3-en-2-ones 4-alkoxy-l,l,l-trifluoroalk-3-en-2-ones 77 <06S2349>. Ar Ar
d
'~ \N A r ~ N . N + Ar ,+ N
L
H2NANH'HCI H2N/'~NH.HCI 76
~
AF Ar Ti(Oi-Pr)4 Ti(Oi-Pr)4 or BF BF3"OEt 3 'OEt 22 (cat)
U , ~ ~M /Me e F F3C 3C
~
77
R
EtOH,25°C EtOH, 25o c
------
60-90%
R= = H, Me, Ph, Ph, Ar, 2-furyl, 2-furyl, 2-thienyl, 2-thienyl,
N
dNJ<-N N
N~N II ~I
R~CF3 RI,,,-J~'~CF3 78 78
1,3,5-Trisubstituted pyrazolines were converted to the corresponding pyrazoles efficiently by the treatment of a catalytic amount of HI0 HIO 33 or 1,0, I205 in water <06TL9283>. 1,3,5-Trisubstituted pyrazolones were oxidized to the corresponding pyrazoles in high yields by molecular oxygen in the presence of catalytic amount of N-hydroxyphthalimide and Co(OAc), Co(OAc) 2 in acetonitrile at room temperature <06T2492>. Many pyrazole fused ring systems have been reported. N-Substituted 5-pryazolones underwent thermal condensation with esters of -keto acids, losing water and alcohol molecules, to form N-substituted pyrano[2,3-c]pyrazol-6-ones 79 <06CHE326>. Ethyl 5-amino-3trifluoromethyl-lH-pyrazole-4-carboxylate was utilized as an useful reactant for the synthesis of pyrazolo[I,5-a]pyrimidine 80 <06JFC409>. Regioisomeric syntheses of trifluoromethylated pyrazolo[1,5-a]pyrimidine polyfluoroalkylpyrazolo[1,5-a]pyrimidines 81 and 82 was accomplished from 3-amino-5methylpyrazole <06RJOC142>. Simple methods for the preparation of phosphorus-containing fused pyrimidine analogues such as pyrazolo[3,4-c][1,5,2]diazaphosphinine systems 83 and 84 <06S 1613>. A series of substituted from amidine derivatives of pyrazoles have been reported <06S1613>. IH,6H-pyrano[2,3-c]pyrazol-6-ones 8S 1H,6H-pyrano[2,3-c]pyrazol-6-ones 85 were synthesized from one-pot cyclocondensation of ]3-keto esters under solventhydrazine derivatives or 1H-pyrazol-5-one derivatives with various ~-keto free conditions using microwave irradiation <06SC51>. l-Chloro-2-formyl-3,41-Chloro-2-formyl-3,4dihydronaphthalene reacted with various aminopyrazoles to deliver 6,7-dihydro-pyrazolo[2,3a]benzo[h]quinazolines 86 <2006SC160l>. A one-pot and convenient synthesis of <2006SC1601>. pyrazolo[3,4Cb]pyridines multisubstituted pyrazolo[3,4~b ]pyridines 89 has been achieved by a two-step reaction of 5azido-1-phenylpyrazole-4-carboxaldehydes azido-l-phenylpyrazole-4-carboxaldehydes 87 to ketones 88 in ethanolic potassium hydroxide pyrazolo[1,5-a]pyrimidine <06SC1549>. A convenient regioselective one-pot approach to pyrazolo[I,5-a]pyrimidine (~,~-unsaturated imines generated in situ with amino heterocycles has been derivatives from a,~-unsaturated I I>. One-step intermolecular aza-Wittig synthesis of pyrazolo[1,5reported <06TL26 <06TL2611>. a]pyrimidine and imidazo[I,2-b]pyrazole derivatives from 5imidazo[ 1,2-b]pyrazole (triphenylphosphoranylideneamino)-3-phenylpyrazoles and a-chloroketones o~-chloroketones has been reported <06JHC523>. Pyrazolo [3,4-b]pyridines were prepared from 2-tosyloxy-3-acylpyridines in the presence of hydrazine <06CC726>. 1,3-Dipolar cycloaddition of dimethylacetylene dicarboxylate to sydnones was exploited in the synthesis of 1-aryl-4,5-dihydro-lH-pyrazolo[3,4djpyridazine-3,6-diones d]pyridazine-3,6-diones <06JHC827>.
219 219
Five membered membered ring systems: with more than one N atom
Me
F30 RF
Me
Me
N~.j.,." Me
EtO2C N1
,N N~
80
79
F 3 C ~ R F F3C~RF
NyN'1
N H..O
Me
Me
82
81 R 11
Me
Me
O~ ,,OH
R R
R1
R 22
~R
R2
N: Jl
~..~ /P~ .Me
N
!N'~NLAr Ph 83
Ph
0
~NHH
oY
R3 84
~
85 85
86
OHC
R11
OH)jCR
N3
OV
'I ,N \ + R3..L/R2 N
Ph Ph
88
R11= = Me, Ph Ph R
KOH, KOH,EtOH EtOH
~
reflux reflux
[
87 87
R1
=
R22 = H, H, Ac Ac R
R
65-92% 65-92%
89
Ph
(66) (66)
=
R33 = Me, Me, Ph, Ph, Ar, -(CH2) nR Ar, -(CH 2ln-
A convenient one-step transformation transfonnation of primary and secondary amines into the corresponding unprotected guanidines 4-benzyl-3,S-dimethyl-lH-pyrazole-lusing 4-benzyl-3,5-dimethyl1H-pyrazole- 1carboxamidine carboxamidine 90 and its polymer-bound variant were described <06S461>. 1,3-Dipolar polymer-bound alkynes to azomethine imines generated in situ situ from Ncycloaddition of polymer-bound aminopyridine iodides followed by aromatization aromatization of the cycloadducts gave polymer-bound pyrazolopyridines that were released from the resin as carboxylic pyrazolopyridines carboxylic acids with trifluoroacetic acid or as methyl esters with sodium methoxide <06JC0344>. <06JCO344>.
R~e Me
__ )It\{N
RMe N ~ ~N NH
R== Ph, P h ,\~) R
/=:::NH
CIH-H CIH.H2N 2N
90 90
5.4.3
IMIDAZOLES AND RING-FUSED RING-FUSED DERIVATIVES IMIDAZOLES DERIVATIVES
Trisubstituted imidazoles have been synthesized from 1,2-diketones 1,2-diketones or a-hydroxyketones t~-hydroxyketones Trisubstituted with ammonium acetate in very short reaction times with excellent yields in the presence of 1,l,3,3-N,N,N',N' 1 , 1 , 3 , 3 - N , N , N ' , N ' --tetramethylguanidinium t e t r a m e t h y l g u a n i d i n i u m trifluoroacetate as an ionic liquid <06SC6S>. <06SC65>. Iodine acted as an efficient catalyst in the synthesis of 1,2,4,S-tetraarylimidazoles 1,2,4,5-tetraarylimidazoles 93 using benzoin 91,
220
L. Yet
aromatic aldehydes 92 and benzylamine in the presence of ammonium acetate <06TL5029>. A variety of aromatic, aliphatic, and terpenoidal aldehydes underwent condensation with ammonium acetate or amines to give 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles in high yields using zirconium(IV) chloride as an efficient catalyst at room temperature l-substituted-I,2<06SC299l>. <06SC2991>. A highly versatile method for the preparation of enantiopure 1-substituted-l,2disubstituted and 1,4,5-trisubstituted imidazoles was developed by using the cyclocondensation reaction of a 1,2-dicarbonyl compound, an aldehyde, a 1,2-amino alcohol and ammonium acetate <06T8199>.
Ph/~OH Ph
O
+ +
ArCHO ArCHO 92 92
BnNH 2 BnNH 2,, NH NH4OAc 4 0Ac (2 eq) 12 (10 mol%), EtOH, reflux reflux 12 (10 mol%), EtOH, • 94-98% 94-98%
XNI
Ph Ph
x,[~ N~_Ar
)--Ar
ph/ Ph
t'N o\
93 Ph Ph
91
2-Imidazolines 96, prepared from the reaction of aldehydes 94 and ethylenediamine 9S 95 with molecular iodine in the presence of potassium carbonate, were smoothly oxidized to the corresponding imidazoles 97 in good yields using (diacetoxyiodo)benzene at room temperature <06SL227>. Similarly, the preparation of 2-imidazolines 96 was performed by cyclization of nitriles 98 with ethylenediamine 9S 95 under microwave irradiation in solvent-free conditions followed by aromatization to imidazoles 97 under microwave irradiation in toluene and using manganese oxide or Magtrieve™ Magtrieve TM as the oxidant <06S5868>. The system, I2/KI/K2CO3Prt20, I/KVK,C0 31H,o, oxidized carbon-nitrogen bonds for the synthesis of imidazolines and benzimidazoles from 90 ~ has also been reported aldehydes and diamines under anaerobic conditions in water at 90°C <06TL79>. Rapid and efficient preparation of 2-imidazolines and bis-imidazolines by reaction of ethylenediamine with nitriles in the presence of catalytic amounts of sulfur under ultrasonic irradiation has been reported <06TL2129>.
~NH2 95 ~NH2
RCHO 94
H H2N 2N K2CO (3 eq) eq) 112, 2, K 2C033 (3 t-BuOH, t-BuOH, 70°C 70 ~
98
R~J
N DMSO, "~l....J DMSO,25°C 25 ~ 50-100% 96 38-83% 38-83% = Ar, cyclohexyl, cyclohexyl, 2-furyl R=
H2N~ NH2 95 H2N~NH2 RCN RCN
H H H N R.~x{N'--~ Phl(OAc}z, PhI(OAc)2,K K2CO~ R~NJ 2C0 3• R__.~N'-~
microwave
solvent-free 74-98% 74-98% pyrazolyl-type R= =pyrazolyl-type
=
H H N R~.~\N~
R~J N
96
N
97 97
™ ~" Mn02 MnO2or Magtrieve MagtrieveTM
PhMe, PhMe, microwave microwave 56-64% 56-64%
•
H H N R"~xN~
R~J N
97 97
A microwave-assisted, one-pot, two-step protocol was developed for the construction of imidazo[I,2polysubstituted 2-aminoimidazoles 101 via the sequential formation of imidazo[1,2~-bromocarbonyl a]pyrimidinium salts from readily available 2-aminopyrimidines 99 and a-bromocarbonyl pyfimidine ring with hydrazine <060L5781>. <06OL5781>. A compounds 100, followed by opening of the pyrimidine
Five membered membered ring systems: atom systems: with more than one N atom
221
single-pot novel synthesis of varied substituted 4-hydroxyimidazoles 103 by SeO,-mediated SeO2-mediated amino-4-N,N-dimethylamino-4-methyl-l,3oxidation of 1-aryl-2-phenyl/thiomethyl/secondary l-aryl-2-phenyUthiomethyl/secondary amino-4-N,N-dimethylamino-4-methyl-I,3diazabuta-l,3-dienes 102 has been reported <06SL2199>. Reaction of tetracyanoethylene, ammonium acetate and carbonyl compounds afforded 2-[S-amino-2,3-dihydro-4H-imidazol-42-[5-amino-2,3-dihydro-4H-imidazol-4<06TLl44S>. ylidene]malononitriles <06TL1445>. 2-Aminoimidazol-4-carbaldehyde derivatives were prepared by the reaction of tert-butoxycarbonylguanidines tert-butoxycarbonylguanidines with 3-bromo-l,l3-bromo-l,1dimethoxymethylpropan-2-one <06SL2836>. Addition of lithiated methoxyallene to imines provided allenyl amines, which upon reaction with iodine and nitriles furnished <06SLl683>. Addition of allyl amines to isocyanates afforded Ndihydroimidazole derivatives <06SL1683>. allylureas, which are converted to imidazolidin-2-ones with generation of two bonds and up to two stereocenters when treated with aryl bromides and catalytic amounts of Pd,(dba)/Xantphos Pd2(dba)3/Xantphos in the presence of sodium tert-butoxide <060L2S31>. An efficient route to 4-aryl-Stert-butoxide <06OL2531>. 4-aryl-5pyrimidinylimidazoles via sequential functionalization of 2,4-dichloropyrimidine has been <06OL269>. published <060L269>. 1. 1. MeCN, MeCN, 130-150 130-150 °C, ~
I~N/TL....N NHR1 99
~ [ ] / R3 +
microwave
microwave
R_ ~ N _ _
2. 60% NH2NH2 2.60% NH2NH2 (5 eq),
R2
O 100
MeCN, MeCN, 100 °C, ~
~
microwave microwave
R3 101
38-96%
N R1
NH2
Et,l l ,Bn, R R11 = n -Me, C5H = n-CSH11 , cyclopropyl, cyclopentyl cyclopentyl cyciopropyl, R22 = = H, Me, Bn, Ar R R33 = = H, H, Ar
Ar AF [ i
RyN
R'~~M e Ny-Me NMe2 NMe2 102
SeO2 Se02 dioxane, H H20 20 50-55 °C ~
Ar
= R "-~,kN ~--'-OH
R = Ph, piperidinyi, piperidinyl, pyrrolidinyl, thiomethyl
51-69% 51-69% 103
Metal-mediated approaches to the synthesis of imidazoles have been reported. The palladium-catalyzed coupling of imines and acid chloride was used to provide a new, one-step method to synthesize imidazoles <06JA60S0>. <06JA6050>. A new efficient copper-catalyzed preparation for 1,4-disubstituted imidazoles 106 via the cross-cycloaddition between isocyanides 104 and 105 has been published <06JA10662>. [3+2]-Cycloaddition of aziridines 107 with various nitriles in the absence of organic solvent catalyzed by SC(OTf)3 Sc(OTf)3 afforded the corresponding imidazolines 108 in good to excellent yields under extremely mild reaction conditions <06TLlS09>. <06TL1509>. Cu(OTf), Cu(OTf) 2 or Zn(OTf), Zn(OTf) 2 mediated [3+2] [3+2] cycloaddition reactions of various a-alkyl or a-aryl ~-aryl substituted N-tosylaziridines with nitriles has also been described for the syntheses of substituted <06TL5399>. imidazolines <06TLS399>.
222 222
L. Yet Yet L.
Cup Cu20(10 (10 mol%) mol%) ArNC ArNC
++
NC/'-.EWG NC/~EWG
104 104
Ark Ar\
1,10-phenanthroline 1,10-phenanthroline ~
/N~ "'~ % ,>~-.. 4:.NN>--EWG EWG
(20 (20 mol%) mol%)
105 105
THF, 80 °C ~ THF,80
106 106
88-98% 88-98%
RCN, Sc(OTfh Sc(OTf)3 (25 (25 mol%) mol%) RCN,
TsTs N N Ar-----ZJ Ar ~
solvent-free, 25°C, 25 ~ air air solvent-free,
I~ =
51-94% 51-94%
107 107
=
N~ N ITs \ / Ar
R = Me, Me, n-Pr, n-Pr, Ar R
11)8
Multicomponent reactions have been described for several syntheses of imidazoles. Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted microwave-assisted threecomponent one-pot sequential reactions or one-pot domino reactions have been described <06JOC3137>. Multicomponent reactions between 2-aminopyrimidine, aldehydes and <06JOC3137>. imidazo[1,2-a]pyrimidines <06TL947>. Two novel one-step microwave isonitriles afforded imidazo[I,2-a]pyrimidines imidazo[ 1,2-a]pyridyn,2-a]pyridines and imidazo[l ,2-a]pyridynmediated syntheses of arrays of 3-iminoaryl-imidazo[ 11,2-a]pyridines 3-ylamino-2-acetonitriles were synthesized by multicomponent reactions under microwave ~-aminopyridines, aldehydes, and trimethylsilylcyanide trimethylsilylcyanide condition in methanol by simply mixing a-aminopyridines, catalyzed by polymer-bound scandium triflate <06TL2989>. 3-Aminoimidazo[1,2-a]pyridines have been synthesized via the multicomponent reaction of aldehydes, isocyanides and 21-butyl-3-methylimidazolium bromide aminopyridines in the presence of the ionic liquid I-butyl-3-methylimidazolium [bmim]Br <06TL3031>. A radical phosphination reaction of organic halides and alkyl imidazole-l-carbothioate has been reported <06JA4240>. 4-Arylsulfonylmethyl-5-nitroimidazoles were prepared by reacting four chloromethylaryl sulfones with 5-nitroimidazole derivatives via a vicarious nucleophilic substitution (VNS) of hydrogen reaction <06SC3639>. substitution <06SC3639>. Application of palladium-catalyzed rc]tallyl chemistry to 4-allylimidazoles 109 provided entry to substituted substituted imidazoles 110 without allylic transposition <06T10555>. <06Tl0555>. The multi-gram scale polybromination of variously substituted imidazoles was performed using a stoichiometric amount of the bromine-DMF <06TLl949>. substitution reactions of 2-cyano-3complex <06TL1949>. In some nucleophilic substitution nitroimidazo[I,2-a]pyridine, nitrogen and oxygen nucleophiles underwent substitution of the 2nitroimidazo[1,2-a]pyridine, of the 3-nitro group <06JHC565>. cyano group, while sulfur nucleophiles underwent substitution of
L
«(',,/'oJlx O
N f'J PG
X
Pd 2 (dbah PPh3 PPh 3 Pd2(dba)3,
Null NuH or Nuc, solvent solvent = 62-98%
109
PG PG = =Bn, Bn, MOM MOM
= Me, OEt, Ot-Bu X=
Nuc t~NuC
~
N
f'J
PG
110
223
more than one N atom Five membered membered ring systems: with more atom
A new reaction of the efficient difluorocarbene-generating reagent trimethylsilyl fluorosulfonyldifluoroacetate (TFDA) is reported in which molecules containing an Nalkylimidazole 111 or benzimidazole structure underwent an unexpected one-pot conversion to N-difluoromethylthioureas 112 <060L5549>. <06OL5549>. Thermolysis of 1,2-dialkynylimidazoles 113 in benzene solution afforded 7-phenyl-5H-cyclopentapyrazines 114, which presumably formed by solvent trapping of cyclopentapyrazine carbene intermediates <06TL353>.
,R ~~/~
R /
TFDA (4 (4 eq), eq), NaF NaF (cat) (cat) TFDA DME, DME' 105°C 105 ~ R
= Bn (63%), Me (52%) =
111
112
CF2H
a2
Phil, 80-100 °C ~ PhH,
Ph
38-88%
N/~\
R11 = H, H, Ph Ph R
N ~"'~"'R1 113
= H, Ph, Ph, n-Pr, n-Pr, = H,
RZ2 = R
114
R1
Ar, CHzOMe CH2OMe
A basic ionic liquid, 1-methyl-3-butylimidazolium l-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and I-butyl-31-butyl-3), has been introduced as a catalyst and methyl-methylimidazolium tetrafluoroborate ([bmim]BF ([bmim]BF4), 4 reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC399I <06JOC3991;; 06TLl555>. 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the a,~-unsaturated c~,[3-unsaturated ester <06S3859>.
,H(NO2) H(NO z)
O
R/~O ~ 115 115
+ +
~---~ ~i . N H H
116
[bmim]BF44 or or [bmimlBF [bmimlOH, 50~ 50°C
8 -98O/o 81-98%
R= = Me, i-Pr, n-C n-C4H9, 4H g,
Ph Ph
~.___~H (NO2) =
O R
N
;.. Me O 117
Several reports of the synthesis and chemistry of benzimidazoles have been published. The most common methods involved the condensation of 1,2-phenylenediamine with a carbonyl group. 2-Substituted benzimidazoles were prepared from 1,2-phenylenediamine and esters under microwave conditions <06SC2597>. A highly selective synthesis of 2-aryl-l-arylmethyl-lH1,3-benzimidazoles from the reaction of 1,2-phenylenediamines and aromatic aldehydes in the presence of silica sulfuric acid in ethanol or water has been reported <06TL2557>. Microwaveassisted one-step high-throughput synthesis of benzimidazoles from phenylenediamine and carboxylic acids in the presence of triphenyl phosphite has been disclosed <06TL2883>. A
224
L. Yet
simple and environmentally friendly synthesis of 2-substituted benzimidazoles was developed Condensation of aldehydes with 1,2using a small-pore-size zeolite <06SC3625>. 1,2phenylenediamine and catalytic iodine in water provided a convenient synthesis of benzimidazoles <06JHC773>. 2-Substituted benzimidazoles 119 were prepared by reaction of 2-azidoaminobenzenes 118 with aldehydes under thermal conditions <06SC3425>. The reaction probably proceeded via a sequential imine formation, azide decomposition forming a nitrene, and electrocyclization. The treatment of benzylidene(2-nitroaryl)amines 120, prepared by the reaction of o-nitroaniline and benzaldehydes, with carbon monoxide in the presence of a catalytic amount of selenium under basic conditions, afforded 2-aryl-1H-benzimidazoles 2-aryl-lH-benzimidazoles 121 <06SLl09>. <06SL109>. Hydrogenation of Nsubstituted 2-nitroanilines with palladium on carbon as catalyst in the presence of trimethyl orthoformate and catalytic pyridinium p-toluenesulfonate at room temperature provided the corresponding disubstituted benzimidazoles <06TL5359>. A liquid phase PEG-ester resin, derived from the commercially available 4-fluoro-3-nitrobenzoic acid, was used in the multistep synthesis of specifically functionalized bis-benzimidazoles where microwave irradiation through ten steps involved ipso-SNAr reaction, neutral reduction and acid cyclization <06TL2601>. Using carbodiimide reagents [1,3-diisopropylcarbodiimide or N-(3-dimethylaminopropyl)-N'ethylcarbodiimide hydrochloride (EDC)], a mild, generalized, one-pot method that delivered N2-arylaminobenzimidazole esters from commercially available aryl isothiocyanates and 1,2<06JCO907>. Homonuclear Diels-Alder Diels-Alder dimerization phenylenediamines has been developed <06JC0907>. of various 5-ethenyl-2-phenylsulfanyl-1H-imidazoles 5-ethenyl-2-phenylsulfanyl-lH-imidazoles provided a novel highly regio- and stereoselective route to the preparation of multifunctionalized 4,5,6,7-tetrahydrobenzimidazoles <06T10l82>. <06T 10182>. 2CHO R2CHO R
HOAc, HOAc, EtOH EtOH _reflux
al 118
Na
44-96% 44-96%
r " / , ' h / N ~v A r NO2 120
R1
R2
~ N 119
H
= =
R11 = H, CI, C I, Me, OMe R n-C6H13, Ph, Ar R22 = i-Pr, n-CsHn.
(XI
r ' ~ ' ~ ' r ~N , ~ ~" L~ I ~ }-Ar ~2--Ar DBU, 1A-dioxane, 1,4-dioxane, 120°C 120 ~ "q-/ -N ~ N H H 76-99% 76-99% 121 121
CO, Se (10 mol%), 3A MS
Imidazoles and fused-derivatives have participated in a myriad of cross-coupling reactions. The reaction of protected 4,5-diiodoimidazoles with (PhMe,CCH,),CuLi (PhMe2CCH2)2CuLi regioselectively provided 5-cuprated imidazoles, which readily reacted with various electrophiles furnishing functionalized imidazoles in good yields <06CC2170>. Remarkably, these resulting monoiodoimidazoles underwent again an iodine-copper iodine-copper exchange reaction in the presence of sensitive functional groups like an aldehyde or a ketone. In the presence of copper(I) bromide, 2aminopyrimidine-4,6-diol, and tetrabutylammonium fluoride, a variety of imidazoles underwent the N-arylation reaction with aryl and heteroaryl halides <06JOC8324>. 4,7-Dimethoxy-l,1O4,7-Dimethoxy-l,10phenanthroline was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazole with aryl iodides and bromides under mild conditions <060L2779>. <06OL2779>. Copper-
225
more than one N atom Five membered membered ring systems: with more
catalyzed N-arylation of imidazole and benzimidazole can be accomplished using air-stable 1,10-phenanthroline in the presence of potassium copper(I) iodide as a copper source and 1,1O-phenanthroline fluoride/alumina as a base <06SL2124; 06TL5203>. By using copper(I) iodide as the catalyst and L-Proline as the ligand, the Ullmann-type coupling reactions of aryl/heteroaryl bromides and imidazoles in [Bmim]BF44 at 105-115 °C ~ gave the corresponding NN-arylimidazoles/N-arylimidazoles/Nheteroarylimidazoles in good yields <06T4756>. A general and efficient method for the copper6-halogenoimidazo[1,2-a]pyridines has catalyzed cross-coupling of amides and thiophenols with 6-halogenoimidazo[l,2-a]pyridines been reported <06T6042>. C-H Arylation of imidazoles and benzimidazoles has appeared recently in the literature. The first palladium- and copper-mediated C-2 arylations of imidazole 122 with aryl iodides under ligandless and base-free conditions to give 2-arylimidazoles 123 has been described <06EJ01379>. <06EJO1379>. This system worked for benzimidazole also and no N-arylation products were observed for both imidazole and benzimidazole. Efficient palladium-catalyzed microwaveimidazo[1,2-a]pyrimidines has been disclosed <06JC0659>. <06JCO659>. assisted arylation of 2-substituted imidazo[l,2-a]pyrimidines The sterically-hindered imidazolyl carbene ligand complex 125 catalyzed the efficient C-H arylation of imidazo[1,2-a]pyridines 124 to give 126 <060L1979>. <06OL1979>. Palladium-catalyzed direct arylation and heteroarylation of imidazo[I,2-a]pyridines imidazo[1,2-a]pyridines at the 3-position where comparisons between classical heating and microwave irradiation has been described <06SL3237>. N
~N [,; N H H 122
Arl, (5 mol%) Ari, Pd(OAc}z Pd(OAc)2(5mol%) Cui Cul (2 (2 eq), eq), DMF DMF 140°C 140~
53-89% 53-89%
N ~" ~N)~Ar [ r-Ar ~N N H H
123
CsOAc(2 CsOAc(2 eq) eq)
~~N~/~_ CO2Et 124
~--N/""I
125 125 (2.5 (2.5mol%) moI%) • ArX, ArX, DMA, DMA,125°C 125 ~ 51-98% 51-98%
=
~'~N~~CO2Et 126 Ar
N? N--..<.Me Me O Pd(I)2PPh3 125
Many ring-fused imidazole derivatives have been synthesized by various methods. 3Bromoimidazo[1,2-a]pyridine derivatives have been directly synthesized from reaction of 2aminopyridines with a-haloketone ~-haloketone derivatives followed by DMSO oxidation <06CL270>. The synthesis of dipyrido[ 11,2-a:2',3'-d]imidazole ,2-a:2',3' -djimidazole and hitherto unknown benzo and aza analogues has been described <06JOC260>. An efficient new route for the synthesis of benzimidazo[1,2a]quinolines has been developed via the palladium catalyzed intramolecular Buchwald-Harwtig aryl amination of newly synthesized 2-(2'-bromoanilino)quinolines <06JOCI280>. <06JOC1280>. Iodinemediated, oxidative desulfurization promoted cyclization of N-2-pyridylmethyl thioamides served as an efficient and versatile method for the preparation of imidazo[1,5-a]pyridines imidazo[l,5-a]pyridines <06OL5621>. Methyl 2-trimethylsiloxycyclopropanecarboxylates, 2-aminopyridine and <060L562l>. isonitriles were combined in a one-pot reaction to provide a series of novel o-amino 8-amino acids incorporating an imidazo[I,2-a]pyridine imidazo[1,2-a]pyridine backbone <06S2677>. A highly efficient one-pot methodology has been developed to synthesize a class of substituted 1-pyridylimidazo[1,5I-pyridylimidazo[1,5a]pyridines, using Br6nsted Bronsted acidic ionic liquid I-butylimidazolium 1-butylimidazolium tetrafluoroborate, [Hbim]BF44 <06S2849>. 5H-imidazo[5,I-a]isoindoles 5H-imidazo[5,1-a]isoindoles were prepared from intramolecular C-H arylation
226
L. Yet Yet
Thermolysis of 1,2-dia1kynylimidazoles palladium-catalyzed reactions <06SL3170>. 1,2-dialkynylimidazoles in chlorinated solvents led to 5-chloroimidazo[I,2-a]pyridine 5-chloroimidazo[1,2-a]pyridine products <06T3798>. The synthesis of polyfunctional imidazo[l,5-a]pyridines imidazo[1,5-a]pyridines via the reactive species generated in situ from Nsubstituted lactams and Viehe's salt has been reported <06TL1395>. <06TLl395>. A series of 5,7,8polysubstituted imidazo[ imidazo[I,2-a]pyridines 1,2-a]pyridines were synthesized regioselectively from in situ generated o~,[3-unsaturated a,~-unsaturated imines and dianions derived from methyl azolyl acetates in a one-pot procedure <06TL2941>. Fused imidazo-pyridine and -azepine derivatives were synthesized using a sequential van Leusen/intramolecular Heck protocol <06TL3225>. A concise route to access fused imidazole rings employing the van Leusen three-component reaction followed by a palladium/copper catalyzed intramolecular C-arylation has been reported <06TL8873>. Synthesis of some 4,5-dihydro-2H-benzo[g]indazoles and 8,9-dihydro-2H-benzo[e]indazoles via the Vilsmeier-Haack reaction under thermal and microwave irradiation conditions has been reported <06JHC389>.
5.4.4
1,2,3-TRIAZOLES RING-FUSED DERIVATIVES 1,2,3-TRIAZOLES AND RING-FUSED
A microreview on the copper(I)-catalyzed alkyne-azide "click" cycloadditions from a <06EJO51>. mechanistic and synthetic perspective has been written <06EJ051>. 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 1,2,3triazoles is known as the "cream of the crop" of all click reactions. [3-Tosylethylazide ~-Tosylethylazide (TSE-N ), (TSE-N3), 3 which could be prepared in one step from p-tolyl vinyl sulfone and sodium azide/sulfuric acid, underwent copper(I)-catalyzed 1,3-dipolar cycloadditions with alkynes in the presence of sodium ascorbate to produce TSE-protected 1,2,3-triazoles 1,2,3-triazoles where the protecting group could be removed tert-butoxide <06TL3035>. Primary, secondary, and aromatic azides underwent using potassium tert-butoxide 1,3 dipolar cycloaddition-coupling with an excess of alkyne in the presence of Cu(CH3CN)4PF, Cu(CH3CN)4PF~ as catalyst, N,N,N'-trimethylethylenediamine N,N,N'-trimethylethylenediamine as ligand, molecular oxygen, and 4I,4,5-trisubstituted-1 ,2,3-triazoles methoxymorpholine N-oxide (NMO) as co-oxidant to afford 1,4,5-trisubstituted-l,2,3-triazoles <06T6405>. Copper(II) acetate-promoted regioselective synthesis of 1,4-disubstituted-l,2,3I,4-disubstituted-1 ,2,3triazoles in water has been reported <06SL957>. The use of methylene chloride as a co-solvent with water in the copper(I)-catalyzed 1,3-dipolar cycloaddition of organic azides and alkynes increased reaction rates and provided the corresponding 1,2,3-triazoles 1,2,3-triazoles in excellent yields compared to other organic co-solvent systems <06TL51 05>. A series of orthogonally protected <06TL5105>. 1,4-disubstituted-1,2,3-triazoles were prepared from the corresponding alkynols and trialkylsilyl1,4-disubstituted-I,2,3-triazoles propargyl azides via 1,3-dipolar cycloaddition <06TL6971>. <06TL697 I>. A polymer-supported Htfisgen' s [3+2] [3+2] cycloaddition reaction between azides and benzyldimethylamino catalyst for the Htiisgen's alkynes to give I,4-disubstituted-1 ,2,3-triazoles was prepared from copper(I) iodide and 1,4-disubstituted-l,2,3-triazoles Amberlyst A-21 <060Ll689>. <06OL1689>. A three-step solid-phase-supported sequence involving reductive amination by N-phenylpiperazinyl-substituted alkylamines, N-acylation by alkynoic acids, and azide-alkyne [3 + 2] cycloaddition parallel synthesis of 1,2,3-triazole 1,2,3-triazole carboxamides has been <06JCO252>. reported <06JC0252>. A three-component coupling was used to prepare a series of 1,4-disubstituted-1,2,3-triazoles I,4-disubstituted-1 ,2,3-triazoles 129 from the corresponding acetylated Baylis-Hillman adducts 127, sodium azide and terminal alkynes 128 <06TL3059>. This same reaction was also carried out in either water or in
227
Five membered membered ring systems: with more than one N atom
polyethylene glycol as a solvent in the presence of copper(I) iodide <06TL30SS>. <06TL3055>. A copper(I) catalyst in a mixture of the ionic liquid [bmim][BF44]] and water effected three-component reaction of halides, sodium azide and alkynes to form 1,4-disubstituted 1,2,3-triazoles <06TL1545>. <06TLlS4S>. R1/~ QAc RI..~.~./EWG
+
~
R2
NaN 3, Cu, CuSO 4 ~ EtOH, 80 ~
128
127
EWG
k,,.
72-92%
= Ph, Ar, 3-furyl, n-C n-C5Hll R 11 = 5 H 11
..N N,,l~l ~_~'--129
R22 = = Ph, n-C n-C5Hll, CH2CH2OH 2 CH 2 0H 5H 11 , CH
EWG = = CO CO2Me, CO2Et, 2 Me, C0 2 Et, CN
R2
Tandem azidination- and hydroazidination-Htiisgen [3 +2] cycloadditions of ynamides are regioselective and chemoselective, leading to the synthesis of chiral amide-substituted 1,2,3triazoles <060BC2679>. I-substituted-4-amino-I,2,3-triazoles 132 were <06OBC2679>. A series of diversely 1-substituted-4-amino-l,2,3-triazoles synthesized by the copper-catalyzed [3+2] cycloaddition between azides 130 and ynamides 131 <06T3837>. Cu(OAc)2, sodium ascorbate Cu(OAch, R-N 3 +
~ 131
130
,Bn N, Bz
,N=N /~~
t-BuOH, H H20 20
38-96% 38-96%
~
RIN
R= =alkyl, Bn, carbohydrate carbohydrate
N"Bn Bz
132
[3+2]-Cycloadditions of alkyl azides 134 with various unsymmetrical internal alkynes 133 in ,2,3the presence of Cp*RuCl(PPh,), Cp*RuCI(PPh3) 2 as catalyst in refluxing benzene led to 1,4,S-trisubstituted-l 1,4,5-trisubstituted-l,2,3triazoles 135 and 136, whereas alkyl phenyl and dialkyl acetylenes underwent cycloadditions to afford mixtures of regioisomeric 1,2,3-triazoles and acyl-substituted internal alkynes reacted with complete regioselectivity <06JOC8680>. In addition, propargyl alcohols and propargyl amines were found to react with azides to afford single regioisomeric products. Coppercatalyzed [3+2] cycloaddition of azides to mono- and disubstituted alkynes with N-heterocyclic carbene ligands have been found to be a versatile and highly efficient reaction in which an internal alkyne was successfully shown to work for the first time <06CEJ7558>. <06CEJ7558>. 3
,R3 •R R 11 R
== ~
133
R 22 R
+ +
3 R3N3 R N3
134 134
Cp*RuCl(Peh3) 2_ Cp·RuCI(PPh 3h. PhH, 80°C 80~ PhH, 10-100%
-
,R33 .R
N-N ,N-N
N'~R2 N~R2
N-N ,N-N + +
N'/~R1 1 N'I'-R
R 11 R
R 22 R
135
136 136
"Click" chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various ppseudo-oligosacchardies s e u d o - o l i g o s a c c h a r d i e s and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed
228
L. Yet
cycloaddition between an ethynyl a-C-mannoside cz-C-mannoside and alkyl 6-azido-a-C-mannoside 6-azido-o~-C-mannoside derivatives was suited to the (l,6)-ligation (1,6)-ligation between a-D-mannose ~-D-mannose units through 1,4-disubstituted triazole bridges, thus resulting in the formation of linear oligomers with alternating triazole and mannose fragments up to a triazolo-pentamannose derivative <060BC322S>. <06OBC3225>. Cu(I)-catalyzed 1,3-dipolar cycloaddition between azido-2' -deoxyribose and terminal alkynes. azido-2'-deoxyribose alkynes, afforded quantitatively 4substituted 1,2,3-triazolyl-nucleosides under solvent-free microwave irradiation <06TL4807>. Click chemistry in the area of peptide and protein chemistry has also been seen. A small library of protein tyrosine phosphatase (PTP) inhibitors was synthesized by the Cu(I)-catalyzed 1,3-dipolar alkyne-azide cycloaddition reactions <060L713>. A panel of 1,2,3-triazole <06OL713>. metalloprotease inhibitors was assembled by reacting eight zinc-binding hydroxamate alkynyl warheads with 12 azide building blocks <060L3821>. <06OL3821>. Similar cycloadditions of azidoalkynes having ester, furanoside and peptidic tethers led to the formation of monomeric triazolophanes of higher ring sizes. Peptidotriazoles, unnatural oligomers with alternating amide and triazole linkages, were synthesized efficiently on solid support <06TL66S>. <06TL665>. A practical approach toward proline derived triazolopeptides employing [3+2] azide-alkyne cycloadditions as the key reaction step and the analysis of their cis/trans cis/trans prolyl ratios has been reported <06T8919>. Cu(I)-catalyzed 1,3-dipolar cycloaddition 'click chemistry' was used to prepare 18F-radiolabeled '8F-radiolabeled peptides <06TL6681>. "Click" cyclization was employed in the efficient route to well-defined macrocylic polymers <06JA4238>. a-Isocyano ~-Isocyano acetamide-based three-component reaction followed by a coppercatalyzed intramolecular [3+2] cycloaddition of alkyne and azide afforded complex macrocycles <06OL4145>. A strained monomeric 12-membered triazolophane was formed by the Cu(I)<060L414S>. catalyzed intramolecular cycloaddition of an azide to an alkyne having a constrained tether incorporating an aromatic ring and a furanoside ring <06TL277S>. <06TL2775>. Novel fluconazole/bile acid conjugates were designed and their regioselective synthesis was achieved in very high yield via Cu(I)-catalyzed intermolecular 1,3-dipolar cycloaddition <06TllI78>. <06Tl1178>. A new fluorous F F~717 CLICK-TEMPO catalyst for the oxidation of alcohols to aldehydes was prepared by a facile approach using the copper-catalyzed azide-alkyne cycloaddition as the ligation method <06SL2767>. Conjugated tetra-I,2,3-triazoles tetra-l,2,3-triazoles were synthesized by the coupling reaction of terminal alkynes <06SL64S>. <06SL645>. New nonlinear compounds containing 1,4-diaryl-[1,2,3]-triazole were prepared using a straightforward and efficient method for the regioselective synthesis of [1,2,3]-triazoles <06SC9S1>. <06SC951>. Potassium azidoalkyltrifluoroborates reacted with various alkynes in a copper(I)-catalyzed reaction to give l,4-disubstituted 1,4-disubstituted organo-[1,2,3]-triazol-l-yl<06OL2767>. 1,2,3-Triazoles with 1-position trifluoroborates <060L2767>. I-position substituents, derived from tocopherol (vitamin E), were synthesized by 1,3-dipolar cycloaddition reactions of Sa-azido5o~-azido- <06EJO2081>. The reaction of benzyl azide with terminal di-, tocopheryl acetate with alkynes <06EJ02081>. tri-, and tetraynes appended with a range of functional groups proceeded regioselectively to give terminal I,2,3-triazole 1,2,3-triazole products <060L603S>. <06OL6035>. The addition of azide or diazo reagents to activated substrates is also another method of 1H-triazoles 138 from alkenyl preparing 1,2,3-triazoles. Palladium-catalyzed synthesis of IH-triazoles halides 137 and sodium azide in the presence of xantphos ligand has been reported <06AG(I)6893>. A regiospecific 1,3-dipolar cycloaddition of 2-diazopropane to iminoethers afforded in two steps the corresponding 4-aryl-S,S-dimethyl-SH-I,2,3-triazoles 4-aryl-5,5-dimethyl-5H-1,2,3-triazoles <06TL668S>. <06TL6685>. 4,S-Dihydro-lH-I,2,3-triazoles 4,5-Dihydro-lH-1,2,3-triazoles can also be prepared from the 1,3-dipolar cycloaddition of 2diazopropane to imidates <06JHC499>. An efficient and regioselective procedure for the
Five membered membered ring systems: with more than one N atom
229
synthesis of 1,2,3-triazoles via a [3+2] [3+2] cycloaddition of polymer-bound vinyl sulfone and sodium azide under microwave irradiation has been described <060L3283>. <06OL3283>. NaN NAN3, Pd2(dba)3 3 , Pd 2 (dbab
R ~Br
R~Br/~
xantphos, dioxane . xantphos, dioxane ----------DMso, 90-110 9o-1lo °C oc " or DMSO,
137 137
R:: R = Ph, Ph, Ar, Ar, 2-furyl, 2-furyl, CH CH2OBn 2 0Bn
N=N N=N
R@ H R~NH
138 138
45-94% 45-94%
Other non-traditional preparations of 1,2,3-triazoles 1,2,3-triazoles have been reported. The rearrangement in dioxane/water of (Z)-arylhydrazones of 5-amino-3-benzoyl-1,2,4-oxadiazole 5-amino-3-benzoyl-l,2,4-oxadiazole into (2-aryl-5phenyl-2H-1,2,3-triazol-4-yl)ureas was investigated mechanistically in terms of substituents on different pathways <06JOC5616>. A general and efficient method for the preparation of 2,4diaryl-l,2,3-triazoles 140 from a-hydroxyacetophenones ct-hydroxyacetophenones 139 and arylhydrazines is reported diaryl-1,2,3-triazoles <06SC2461>. 5-Alkylamino-1H-1,2,3-triazoles 5-Alkylamino-lH-1,2,3-triazoles were obtained by base-mediated cleavage of <06S1943>. cycloadducts of azides to cyclic ketene N,N-acetals <06S 1943>. Oxidation of N(alkylamino)pyrazolones is a good and general strategy for the preparation of monocyclic 1,2,3triazin-4-ones, which upon photochemical reaction resulted in the loss of carbon monoxide and <06EJO3021>. A new simple and efficient rearrangement to a 2-alkyl-2H-1,2,3-triazole <06EJ03021>. approach to 2,4-disubstituted-I,2,3-triazoles-5-amines from 2,4-disubstituted-l,2,3-triazoles-5-amines the reaction of 2arylhydrazononitriles and hydroxylamine has been described <06ARK53>. Reaction of Nfluoropyridinium fluoride generated in situ situ with a series of isonitriles and diazo compounds led to the formation of the corresponding (pyridine-2-yl)-IH-I,2,3-triazoles (pyridine-2-yl)-lH-1,2,3-triazoles in good yields <06TL2631>. <06TL263l>.
O Ar2"J~1 OH R
2 NHNH , CuCI Ar Ar2NHNH2, 2 CuCI22
139
A~ N ~N R -ikl"Ar2
AcOH, AcOH, reflux reflux 52-86% 52-86%
R:: H, Ph R=H, Ph
140
A variety of triazole-based monophosphines (ClickPhos) 141 have been prepared via efficient 1,3-dipolar cycloaddition of readily available azides and acetylenes and their palladium complexes provided excellent yields in the amination reactions and Suzuki-Miyaura coupling reactions of unactivated aryl chlorides <06JOC3928>. A novel P,N-type ligand family (ClickPhine) is easily accessible using the Cu(I)-catalyzed azide-alkyne cycloaddition reaction <06OL3227>. Novel chiral and was tested in palladium-catalyzed allylic alkylation reactions <060L3227>. ,2,3-triazoles 142, ligands, (S)-(+)-l-substituted (S)-(+)- 1-substituted aryl-4-(l-phenyl) aryl-4-(1-phenyl) ethylformamido-5-amino-l ethylformamido-5-amino- 1,2,3-triazoles
R2P, k/.~Ar 2P)=(Ar R N,.N.N.ph N'N,NPh 141 R R ::= Ph, Ph, t-Bu, t-Bu, Cy Cy
Me~,, Ph
O
HN~
NH2
N.-N .N
142
~Ar
230
L. Yet
were prepared were used as catalytic chiral ligands in the silver (I)-promoted enantioselective allylation reaction of aldehydes with allyltributyltin <06SC1063>. <06SC 1063>. Benzotriazole-related methodology publications appeared in 2006. Reaction of 1formylbenzotriazole with triphenylphosphine/carbon tetrachloride afforded 1-(2,21-(2,2dichloroviny1)benzotriazole, dichlorovinyl)benzotriazole, where lithiation followed addition of electrophiles gave a variety of functionalized N-(ethynyl)benzotriazoles <06T3794>. Novel mono- and symmetrical di-Nhydroxy- and N-aminoguanidines were readily prepared from the reaction of diverse hydroxylamines or hydrazines with reagent classes di(benzotriazol-l-yl)methanimine, (bisbenzotriazol-I-yl-methylene)amines, benzotriazole-l-carboxamidines, benzotriazole-lbenzotriazol1-yl-methylene)amines, benzotriazole1-carboxamidines, benzotriazole1-hydroxy-IH-I ,2,3-benzotriazole-I-carboximidamide carboximidamides, and N' N'-hydroxy1H- 1,2,3-benzotriazole1-carboximidamide <06JOC6753>. c~-Carbolines were prepared from benzotriazoles and azines bearing beating a leaving group at the C2 a-Carbolines position through the modified Graebe-Ullmann reaction under microwave irradiation l-chlorobenzotriazole has <060L415>. A one-pot synthesis of unsymmetrical disulfides from 1-chlorobenzotriazole <06OL415>. been described <06JOC8268>. Michael addition of benzotriazole or 1,2,3-triazole to nitroolefins, promoted by a cinchona alkaloid, gave Michael adducts in moderate to high <06OL1391>. Stable and easily accessible N-acylbenzotriazoles, derived enantioselectivities <060Ll391>. from a variety of aliphatic, unsaturated, (hetero)aromatic, and N-protected-R-amino carboxylic acids, were reacted with Grignard and heteroaryllithium reagents to afford the corresponding ketones <06JOC9861>. Some interesting fused 1,2,3-triazole ring systems have been reported. A series of 5piperidyl-substituted 7-hydroxy-3H-l,2,3-triazolo[4,5-d]pyrimidines 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines 143 has been synthesized from pipecolinate esters, benzylazides, and cyanoacetamide <06CHE246>. 4-Alkylidene-5,6dihydro-4H-pyrrolo-[1,2-c][l,2,3]triazoles dihydro-4H-pyrrolo-[1,2-c][1,2,3]triazoles 144 were prepared from alkylidenecyclopropanes via diiodogenation/Cu(I)-catalyzed 1,3-dipolar cycloaddition/intra-molecular Heck reaction sequence <06SLl446>. <06SL1446>. 6,6-Dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-benzotriazol-4-one 145 N-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine and were prepared from N-(5,5-dimethyl-3-oxocyclohexenyl)-S,S-diphenylsulfilimine A tandem aza-Wittig reaction of an benzenediazonium chloride <06SC2087>. ,2,3-triazolo[4,5-d]-11,2,4,2,4iminophosphorane with acyl chlorides afforded 3,5-dihydro-l 3,5-dihydro-l,2,3-triazolo[4,5-d]triazolo[1,5-a]pyrimidin-9-ones 146 <060BC130>. <06OBC130>. N-Acyl and N-alkoxycarbony derivatives 147 of 1H-1,2,3-triazolo[4,5-c]pyridine IH-I,2,3-triazolo[4,5-c]pyridine have been prepared and applied in the protection of amines and amino acids <06JHC417>. Two series of compounds, 3-aryl- and 3-methyl-7aryl[l,2,3]triazolo[l,5-a]pyridines aryl[1,2,3]triazolo[1,5-a]pyridines have been synthesized by Suzuki cross-coupling reactions, with a triazolopyridine halide and an aryl or heteroaryl boronic acid in moderate to good yields <06TL81Ol>. <06TL8101 >. OH OH
cf):j" r""~/~h N//~'N" k NNJ Ar Ar ,,~ H H 143
00
"R R R33
144
,~,..R11 R R22 R
0
0
MeD>-Ph
NIN-Ph
Me
145
N N" I W ')--RR N'"N £ 'N N "N IN, Pi~ Ar Ph Ar
.J--
146
aN
R--I(N-N N~N
N
147
231
Five membered ring systems: with more than one N atom
5.4.5
1,2,4-TRIAZOLES AND RING-FUSED DERIVATIVES DERIVATIVES 1,2,4-TRIAZOLES AND RING-FUSED
A comprehensive review on the chemistry of mercapto- and thione-substituted 1,2,41,2,4triazoles and their utility in heterocyclic synthesis has been published <06ARK59>. The thermodynamic parameters, MH" Z~H # and MS", AAS#, were determined for the interception of an intermediate, with the structural characteristics of an aziridinium imide, by nucleophilic solvents during the reaction of2-methyl-2-butene of 2-methyl-2-butene with N-phenyltriazolinedione <06TL2961>. <06TL2961 >. Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of N-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[1,2,4]triazoles <06SC2217>. ~-lithiation and <06SC22 17>. 5-Methyl triazoles could be further functionalized through (X-lithiation subsequent reaction with electrophiles. (E)-N' -(Ethoxymethylene)hydrazinecarboxylie acid (E)-N'-(Ethoxymethylene)hydrazinecarboxylic methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3H-I,2,44-substituted-2,4-dihydro-3H-1,2,4triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. HOAc, microwave
[~N'
N N'
R1/~'N R2
O
+
~ R3149N HN H2
151
n 3
R22 = = pp-ToI, 4-OMeC6H R Tal, 4-0MeC 6 H44
•=
R2,,/N.~,,,m
=
R33 = Me, Ph, Ph, p-tol p-tol R
R 1-~N" N
77-100%
148
RNH 2 +
R 11== Me, Bn, p-Tol
EtO'/% N " NHCO2Me
152
EtOH,50 EtOH, 50 °C ~ then
NaOMe, MeOH, MeOH, 75°C 75 ~ NaOMe, 34_94% 34-94%
150
ID,
N-NH N-NH
If~ ~, -~ 0 N I
I
R
153
The methyl ester of N-tert-butoxycarbonyl-(Z)N-tert-butoxycarbonyl-(Z)- -bromo- -(1,2,4-triazol-l-yl)dehydroalanine -(1,2,4-triazol- 1-yl)dehydroalanine was prepared by treatment of the methyl ester of N-tert-butoxycarbonyl-(E)N-tert-butoxycarbonyl-(E)- -(1,2,4-triazol-l-(1,2,4-triazol-1<06EJO3226>. A yl)dehydroalanine with N-bromosuccinimide, followed by triethylamine <06EJ03226>. convenient approach to 4,5-disubstituted-3-hydroxymethyl-I,2,4-triazoles 4,5-disubstituted-3-hydroxymethyl-l,2,4-triazoles as well as to the corresponding 3-chloromethyl and 3-carboxaldehyde derivatives was developed starting from 3mercapto-l,2,4-triazoles which can, in turn, tum, were readily obtained from acyl hydrazines and N-l of the base were isothiocyanates <06S 156>. 156>. 1,2,4-Triazole nucleoside analogues bonded at N-1 synthesized by addition of N-halo-3,5-dibromo-l,2,4-triazoles N-halo-3,5-dibromo-I,2,4-triazoles to 1,2-unsaturated carbohydrate derivatives <06S496>. N,N,N' (TBBDA) or N , N , N ' ,,N'N ' - TTetrabromobenzene-I e t r a b r o m o b e n z e n e - l , 3,3-disulfonylamide -disulfonylamide trichloromelamine (TCM) were used as effective oxidizing agents for the oxidation of urazoles and bisurazoles to their corresponding 1,2,4-triazolinediones under mild and heterogeneous conditions <06S1631>. IH-l,2,4-triazole <06S 1631>. The first cross-coupling reactions on halogenated 1H-1,2,4-triazole nucleosides has been described <06T330l>. <06T3301 >. Bromination of 2-aryl-l-[1,2,4]triazol-l-ylalk-32-aryl- 1-[1,2,4]triazol- 1-ylalk-3-
232
L. Yet
yn-2-0Is afforded 6-bromo-7-hydroxy-5-alkyl-7-ary1-7,S-dihydro-[ I,2,4]triazolo[ 1,2-a]pyridazinI ,2-a]pyridazinyn-2-ols 6-bromo-7-hydroxy-5-alkyl-7-aryl-7,8-dihydro-[ 1,2,4]triazolo[ 4-ylium salts, which were converted to 3-alkyl-5-arylpyridazines on treatment with strong alkali <06T8966>. The reactions of urocanic acid methyl esters with singlet oxygen and 4-methyl<06TS966>. 1,2,4-triazoline-3,5-dione were explored <06Tl0700>. <06T10700>. Aryltriazole nucleosides with various aromatic groups in the 5-position on the 1,2,4-triazole ring were synthesized via a Suzuki reaction starting with bromotriazole nucleoside under microwave irradiation <06TL6727>. A facile method for the synthesis of 3-allyl-4-(1,2,4-triazolo-3,5-dione)cyclopentenes 156 from bicyclic 1,2,4-triazolo-3,5-diones 154 by the PdlLewis Pd/Lewis acid catalyzed reaction of allyltributyltin 1-Methyl-l,2,4-triazole underwent direct 155 in ionic liquid has been described <06TL3997>. I-Methyl-I,2,4-triazole silylation at the C-5 position with bromotrimethylsilane in the presence of triethylamine <06S 1279>. <06S1279>. ~ " . . . . j Sn Bu3 ~SnBU3 /~.,N...~
O
R
155 155
[Pd(allyl)CI12 dppe (10 mol%) [Pd(allyl)CI]2 (5 mol%), m~176176 m~ 112 [bmim]PF 66,, 60°C 60 ~ 2 (2 mol%), [bmim]pF
N)~ N"R O 154
D.
O - ~ N ~/~-O ~,,,N-NH
76-95% 76-95% R
= = Ph, Bn, Cy, CH CH2Ar 2Ar
156
\\
N-Phenyl-l,2,4-triazole-3,5-dione 157 has been found to be an efficient and chemoselective reagent for the oxidation of thiols to their corresponding symmetrical disulfides <06TL9211>. N-4-(p-Chloro)phenyl-I,2,4-triazole-3,5-dione 158 has been used as an effective oxidizing agent N-4-(p-Chloro)phenyl-l,2,4-triazole-3,5-dione for the oxidation of 1,3,5-trisubstituted pyrazolines to their corresponding pyrazoles under mild <06TL833>. The asymmetric synthesis of hydrobenzofuranones conditions at room temperature <06TLS33>. via desymmetrization of cyclohexadienones using the intramolecular Stetter reaction has been accomplished with 1,2,4-triazolium salt catalyst 159 <06JA2552>. 1,2,4-Triazolium salt catalysts 160 and 161 were employed in the highly enantioselective azadiene Diels-Alder reactions <06JAS41S>. Dimethyl-2-(3-nitro-l ,2,4-triazol-l-yl)-2-pyrrolidin-I-yl-l ,3,2<06JA8418>. Dimethyl-2-(3-nitro- 1,2,4-triazol1-yl)-2-pyrrolidin- 1-yl- 1,3,2diazaphospholidinium hexafluorophosphate hexafluorophosphate (MNTP) has been developed as a powerful condensing reagent for phosphate and phosphonate esters <06T3667>. N=N N=N
H
~
Iv'e\
)
~N
o~~o ~
R 157 R = Ph 158 158 R R= = 4-CIC 4-CIC6H 6 H 44
159
160 R = 4-OMeC6H4, BF4 161 R = 2,4,6-MeC6H 2, CI
Q O
Several interesting 1,2,4-triazole fused-ring systems have been reported. A facile synthesis of 3,5-dihydro-6H-imidazo[ I ,2-b]-11,2,4-triazol-6-ones ,2,4-triazol-6-ones 162 obtained by an 3,5-dihydro-6H-imidazo [ 1,2-b]was iminophosphorane-mediated annulation <06EJ04 I70>. S-TrifluoromethylI,2,4-triazolo[4,3<06EJO4170>. 8-Trifluoromethyl-l,2,4-triazolo[4,3b]pyridazines 163 has been prepared from 4-trifluoromethyl-4,5-dihydropyridazin-3-one
233
Five membered membered ring systems: with more than one N atom
<06S 103>. <06S103>. Arene carbaldehyde-3-methylquinoxalin-2-yl hydrazones, obtained by the condensation of 2-hydrazino-3-methylquinoxaline with various aromatic aldehydes, on treatment with iodobenzene diacetate in dichloromethane, underwent oxidative cyclization to exclusively afford l-aryl-4-methyl-I,2,4-triazolo[4,3-a]quinoxalines 1-aryl-4-methyl-l,2,4-triazolo[4,3-a]quinoxalines 164 <06SC1873>. 2-Aminofuran-3carbonitriles reacted were converted to 2-amino-furo[3,2-e][1,2,4]triazolo[I,5-c]pyrimidines 2-amino-furo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidines in three steps <06ARK68>. The synthesis of fused [5,5]-1,2,4-triazoles [5,5]-l,2,4-triazoles via a tandem cyclopropane rearrangement-cyclization sequence has been described <06SC3377>. A convenient two-step preparation of [1,2,4]triazolo[4,3-a]pyridines 165 from 2-hydrazinopyridine and carboxylic acids has been reported <06TL7591>. The Groebke-type multi-component reaction between 3-amino1,2,4-triazole, aromatic aldehydes and benzylic isonitriles has been studied from the viewpoint of 1,2,4-triazole, convenient generation of combinatorial arrays of imidazo[1,2-b][1,2,4]triazoles imidazo[I,2-b][1,2,4]triazoles 166 <06TL6891>. 2,3-dihydro-l,3<06TL689 1>. One-pot three-component synthesis of highly functionalized 2,3-dihydro-I,3dioxo- 1H,5H-pyrazolo[ 1,2-a][ <06HCA1176>. dioxo-IH,5H-pyrazolo[l ,2-a][ 1,2,4]triazoles I,2,4]triazoles has been reported <06HCA 1176>.
~>~
Me~N-N Me N=( N>-Me
NHR Nk/~"~NHR \
Ph Ph 162
n
A rr' == ~ N Ar' -N,
CF3
R R22 \::N
N
N
erN,'N N ~ _N_tN OCNX ~ [ /. Ar Ar N N Me Me ~ Ni N NH NH22 R R 163
164
165
R1--~N...~_ _/ R1-f-J:N~ N H H
N
166
A solution-phase synthesis for the preparation of substituted 2-(l,2,4-triazol-32-(1,2,4-triazol-3yl)benzimidazoles from 1,2,4-triazole-3-carbaldehydes and ortho-phenylenediamines o r t h o - p h e n y l e n e d i a m i n e s has been developed for the purpose of producing diverse lead generation libraries <06TL8025>. The syntheses of metabolites of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-( 1,2,4-triazol-14-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1ylmethyl)quinoline-3-carboxylate (TAK-603), a disease-modifying antirheumatic drug, has been 1-(1H-indol-l-yl)-2-phenyl-3disclosed <06T8707>. Efficient microwave-assisted synthesis of 1-(lH-indol-l-y1)-2-phenyl-3(lH-l ,2,4-triazol-I-yl)-propan-2-0Is (1H-1,2,4-triazol1-yl)-propan-2-ols as antifungal agents has been reported <06T6479>.
5.4.6 5.4.6
TETRAZOLES RING-FUSED DERIVATIVES T E T R A Z O L E S AND AND RING-FUSED DERIVATIVES
A review has been published on the methods of functionalization of tetrazoles for the period 2001 to mid 2005 <06RJOC469>. The search for new radical structures having both low 2001 selectivity and high reactivity toward the addition reaction onto alkenes has led to a new tetrazole-derived thiyl radical <06JOC9723>. A series of 1-substituted I-substituted IH-l,2,3,4-tetrazoles 1H-1,2,3,4-tetrazoles 168 have been synthesized in good yields from amines 167, triethyl orthoformate, and sodium azide through the catalyzed reaction with Yb(OTf)3 <06E102723>. Yb(OTf)3 <06EJO2723>. Zinc hydroxyapatite (ZnHAP) is an effective heterogeneous catalyst for the [2 + 3]-cycloaddition of sodium azide with nitriles 169 to afford 5-substituted IH1H1809>. A practical synthesis of 5-(4'-methylbiphenyl-2-yl)-lH-tetrazole tetrazoles 170 <06SC <06SC1809>. from 2-tluorobenzonitrile 2-fluorobenzonitrile has been described as a key intermediate in the synthesis of several <06JHC1353>. angiotensin II receptor antagonists <06JHC 1353>. Sterically hindered 2,4-disubstituted 3-(5tetrazolyl)pyridines were synthesized from corresponding nicotinonitriles using microwave
234
L. L.
Yet
technology <06Tl849>. <06T1849>. 1-Isocyanomethylbenzotriazole and 2,2,4,4-tetramethyIbutylisocyanide 2,2,4,4-tetramethylbutylisocyanide smoothly underwent Ugi type reaction to afford 1,5-disubstituted aminomethyl tetrazoles, which could cleaved under acidic conditions to yield substituted a-aminomethyl ~-aminomethyl tetrazoles <06TL4289>. HC(OEth, HC(OEt)3, NaN NaN33
Yb(OTf) (20 mol%) RNH22 167 167
MeOCH2Ch2OH MeOCH 2 Ch 20H
•
100°C 100 ~ R = Ph, Ar, phenylethyl
71-91%
NaN 33,, ZnHAP
N-N
,,
N.
N
ArCN
R
169 169
I
168
120 ~ DMF, 120°C
71-86%
N-N N" N H 170
r
Photolysis of 4-allyl-tetrazolones resulted in molecular nitrogen elimination with formation of 3,4-dihydropyrimidinones <06JOC3583>. The reactions of 1,4-bis[2-(tributylstannyl)tetrazol~,0>dibromoalkanes were carried out in order to synthesize pendant alkyl 5-yl]benzene with a,O)-dibromoalkanes halide derivatives of the parent bis-tetrazole <06T9577>. A range of 5-amino-l-aryltetrazoles was obtained directly from the corresponding 1-aryltetrazoles l-aryltetrazoles in one pot by consecutive ringopening, azidation and intramolecular cyclization <06S1307>. The synthesis and characterization of 5-( 1-(2-( IH-tetrazole-5-yloxy)naphthalen-l-yl)naphthalen-2-yloxy )-lH5-(1-(2-(1H-tetrazole-5-yloxy)naphthalen-l-yl)naphthalen-2-yloxy)-lHtetrazole (BIZOL) as the first bis-tetrazole BINOL-type ligands has been described <06TL3929>. Alkylation of l-aryl-4,5-dihydro-lH-tetrazol-5-ones I-phenyl-4,5-dihydro1-aryl-4,5-dihydro-lH-tetrazol-5-ones and 1-phenyl-4,5-dihydroIH-tetrazole-5-thione 1H-tetrazole-5-thione with tetrakis(2-chloroacetoxymethyl)methane in refluxing acetonitrile in the presence of potassium bromide and triethylamine gave tetrakis[2-(4-aryl-5-oxo-4,5-dihydro1H-tetrazol1-yl)acetoxymethyl]methanes tetrakis [2-(1-phenyl1H-tetrazol-5IH-tetrazol-I-yl)acetoxymethyl]methanes and tetrakis[2-( l-phenyl-IH-tetrazol-5ylsulfanyl)acetoxymethyl]methane, respectively <06RJOC 1056>. A practical, safe, high-yielding and efficient synthesis of (S)-pyrrolidin-2-yl-lH-tetrazole (S)-pyrrolidin-2-yl-1H-tetrazole 171 has been developed, which avoided the generation of ammonium azide in the cyclisation step and the use of a 9: 9:11 acetic acid-water mixture as the solvent in the hydrogenation <06SL889>. (S)-5-Pyrrolidin-2-yltetrazole 171 has been employed in the sequential, organocatalyzed asymmetric reaction to give chiral 1,2-oxazines 1,2-oxazines from achiral ketone starting materials <06CC32I 1>, in the asymmetric addition of malonates to a range of enones <06CC66>, in the <06CC3211>, asymmetric conjugate addition of nitroalkanes to enones <060BC2039>. <06OBC2039>.
n N, "N~ ,l'l
N••*N:N H H
HN-N HN-N
171 171 Pyridine N-oxides were converted to tetrazolo[ I1,5-a]pyridines ,5-a ]pyridines 172 by heating in the presence sulfonyl or phosphoryl azides and pyridine in the absence of solvent <06JOC9540>. 3-R-5Trinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-ones Trinitromethyltetrazolo[1,5-a]-l,3,5-triazin-7-ones 173 have been prepared from the alkylation of 5-trinitromethyltetrazolo[l ,5-a]-1 ,3,5-triazin-7-one silver salt with different alkylation agents 5-trinitromethyltetrazolo[ 1,5-a]-1,3,5-triazin-7-one <06CHE417>. The use of 2-fluorophenylisocyanide in the combinatorial Ugi-tetrazole reaction followed by a nucleophilic aromatic substitution afforded tricylic tetrazolo[1,5-a]quinoxaline 174 in good yields and with high diversity <06TL2041>.
235
Five membered ring systems: with more than one N atom
Q"'-.:
R~
N\ "N , N""N
N~N
172 172
O
N'J~N-N (O2N)3C'~N/~" N"N 173 R
RLNR~N;N RLNR~N 174
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Five membered ring systems: with more than one N atom
06SL2124 06SL2199 06SL2199 06SL2581 06SL258I 06SL2767 06SL2836 06SL2836 06SL3170 06SL3170 06SL3237 06SL3267 06T611
06T 1849 06TI849 06T2492 06T3301 06T3667 06T3794 06T3798 06T3837 06T4756 06T5868 06T6042 06T6332 06T6332 06T6405 06T7772 06T7772 06T6388 06T8199 06T8707 06T8792 06T8919 06T8966 06T8966 06T9577 06Tl0182 06T10182
06T10555 06Tl0555 06Tl0700 06T10700 06TI1100 06T 11100 06TlI178 06Tl1178 06TL43 06TL79 06TL255 06TL353 06TL655 06TL817 06TL833
239
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240 240 06TL947
06TL 1395 06TLl395 06TL 1445 06TLl445 06TL 1509 06TLl509 06TLl545 06TL 1545 06TLl555 06TL1555 06TL1729 06TLl729 06TL 1949 06TLl949 06TL2041 06TL2129 06TL2265 06TL2443 06TL2557 06TL2557 06TL2601 06TL26 1I 06TL2611 06TL2631 06TL2775 06TL2883 06TL2941 06TL2961 06TL2989 06TL3031 06TL3035 06TL3055 06TL3059 06TL3225 06TL3929 06TL3997 06TL4289 06TL4655 06TL4807 06TL5029 06TL5105 06TL5203 06TL5359 06TL5399 06TL5451 06TL5797 06TL6201 06TL6479 06TL6479 06TL6681 06TL6685
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Five membered ring systems: with more than one N atom
06TL6727 06TL6743 06TL6795 06TL689I 06TL6891
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242 242
Chapter 5.5 Five-membered ring ring systems" systems: with with N Nand (Se) atoms atoms Five-membered and SS (Se) a Yong-Jin W Wu and Bingwei Bingwei V. Yang Yangbb Yong-Jin u a and Research Parkway, Wallingford, Wallingford, CT 06492-7660, USA aBristol Myers Squibb Company, 5 Research bBristol Myers Squibb Company, PO PO Box Box 4000, Princeton, Princeton, NJ NJ 08543-4000, USA bBristol yong-j [email protected] and and [email protected] [email protected] [email protected]
5.5.1
INTRODUCTION INTRODUCTION
chapter focuses on the syntheses syntheses and reactions of of these 5-membered 5-membered This review chapter heterocyclic ring systems containing nitrogen and sulfur (or selenium) (reported during of these 1t-rich 2006). The importance of re-rich heterocycles in medicinal chemistry and natural products is also covered.
5.5.2 5.5.2
THIAZOLES THIAZOLES
5.5.2.1 Synthesis Synthesis of of ThiazoIes Thiazoles
The Hantzsch reaction discovered in 1889 1889 remains one of the most reliable routes to thiazoles and numerous applications of of this reaction appeared during the past year <06BMCL2773; 06BMCL5317; 06JA2995; 06JMCAC235; 06JOC5031; 06JOC8302; 06T66; 06Tl 110; 06T11592; 06TL239; 060L3057>. 06T1110; 06OL3057>. For example, the Hantzsch reaction of a-bromomethyl ~-bromomethyl ketone 1 with thioamide 2 is utilized to construct one of the two thiazole rings in a recent total synthesis ofmyxothiazols of myxothiazols <060BC2906>. <06OBC2906>.
Me °tO
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S/
3
Another frequently used method for construction of thiazoles consists of cyclization of compounds containing C(=S)-NH-CH-C(=O) or C(=S)-NH-CH-C(=S) fragment (with loss of water or hydrogen sulfide). The requisite thioamides are prepared from their corresponding amides using phosphorus pentasulfide, Belleau's reagent, Lawesson's reagent or the recently developed fluorous Lawesson's reagent, which can be easily removed by a simple filtration through fluorous fluorous reverse phase silica silica <060Ll625>. <06OL1625>. For example, example, 2-N-acylglycinamides 4 undergo dithionation dithionation followed followed by trifluoroacetic acid acid anhydride anhydride (TFAA)-mediated (TFAA)-mediated cyclization cyclization to furnish furnish aa series series of of trifluoroacetamides 66 in in moderate yields <06TL2361>. <06TL2361>. Interestingly, the analogous reaction of of the corresponding corresponding monothionated acetamide acetamide 77 results in an an approximately approximately equal equal mixture ofthiazole of thiazole 88 and and oxazole oxazole 9. 9.
243
Five-membered ring systems: Nand Five-membered systems." with N and S (Se) atoms
O
Ph
Lawesson's Lawesson's reagent reagent or or Belleau's Belleau's reagent reagent
R == alkyl, alkyl, aryl aryl R
O
4
Ph S Ph Ph N-{ 0~ . . . L L . N ~ NH2 TFAA TFAA .~s~~N.. " R = CF33 W)LCF 21-46% R 5 S 21-46% R 6S H
--z J-6
Lawesson's reagent: reagent: Y Y= = Me Me Lawesson's Fluorous Lawesson's reagent: Fluorous Lawesson's reagent: Y = = (CH (CH2)4(CF2)5CF 3 2 l4(CF 2 )sCF 3 Belleau's reagent: reagent: YY == Ph Ph Belleau's S
Ph Ph N N-{ 0O
Ph TFAA TFAA
--Z_'P-S ~
ph...~S~~ N...~CF )LCF33 Ph
O
Ph +
+
N 0 Ph~o~~N~--CF3
8
7
9
The thionation of 1,4-dicarbonyl compounds and their subsequent cyclization can be carried out in two steps as described above, but frequently the two-step sequence can be combined in one single operation. Thus, treatment of N,N-diformylaminomethyl aryl ketones 11 with phosphorus pentasulfide and triethylamine gives arylthiazoles 12 directly <06SL460>. It is unclear whether the formyl group is lost before or after thiazole formation. The thiazole-based dipeptides 14 are also obtained from p-ketoamides I]-ketoamides 13 via cyclization upon treatment with the Lawesson's reagent on solid phase <06OL2417>. <060L24 I 7>. Similar transformations (15 to 16) have been carried out using the fluorous Lawesson's reagent as described above <060L1625>. <06OL 1625>. 2SS,, Et 3N Arj(' CHO P NaN(CHO)2 Ar~/~N..CHO P2S5 Et3N ArS.~S N Br -NaN(CHOh ~' N' ..• Ar~ ---+-. I 'i IN 61-83% s--.lJ 50-95% CHO 61-83% 50-95% 0O CHO
Ar,, ~ O 10
Bn Bn
0O
/ ~ NH__~L. RHN~N0o-{.) RHN O~ 13 13
12
11
0 Me O o~LMe 0
Lawesson's Lawesson's reagent
reagent
Bn Bn
0O
. RHN~Nro-{.) RHN O--~ ~ N / ~
H H N N
R11 R
8 1R2
1s 15 O 0
1
R2
Fluorous Fluorous 1 Lawessons' Lawessons' 48-82% 48-82% reagent reagent
-( R= = CBZ, CBZ, Fmoe, Fmoc, Boe, Boc, Alloe AIIoc
14 14
Me Me
2-Aminothiazoles are frequently synthesized by the reaction of aromatic or aliphatic amines with a-thiocyanatoketones, t~-thiocyanatoketones, which are prepared from a-haloketones t~-haloketones by treatment with potassium thiocyanate. These two operations can be performed in one pot using a supported reagents system, KSCN/Si0 KSCN/SiOz-RNH3OAc/AI203 2-RNH 30Ac/AIz0 3 <06T3201>. This method provides a direct synthesis of 2-aminothiazoles 20 from a-haloketones t~-haloketones 17 and amines, thus obviating the isolation of intermediate a-thiocyanatoketones t~-thiocyanatoketones 18.
O
KSCN/SiO2,3
RI@X
R NH3OAc/AI203 =
Ia.~O SCN R2
1
R2 17
18
OH 1 RI~N R1-...Li N / \ ~ ~ f-"~H2 N-R3 j 39-99%-H20 ,~.. _
19
s
21)
Oxidation of thiazolines represents another approach to thiazoles. This method has been applied to the synthesis of N-Boc-L-thiazole methyl ester 22 <06JA10513>. Conversion of resin-bound thiazolines 23 to thiazoles 24 is also reported <06OL2417>. <060L24 17>.
244
Y-J. Y.-J. Wu Wu and BY. B. V. Yang
Me ..Et Me~Et
HN H~ Boc Boc
J. _y
Me. Et 0 Bn 0 Bn 0 Me~EtN 0 "~/N,~ BrC(~.3 HN ~ N ~N,)lO ~ o HN~N,~o HN' "f O 87% = HNI ~Y98i% J! I ~IR SS~-/ 0
S-~J S 21
DBU DBU, BrCCI 3
Me
l~oc S"~/ Boc 22
l~le Me
23 23
J._y
DBU, Bn DBU, Bn BrCCI 3 HN/~/N/~ BrCCI3 0 HN' I
0 O
0 (~ ~
"f // 87% ~Ri ~ SS----(/ ~ 87% II R R = Cbz, Cbz, Fmoc Fmoc 24 24
0
A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of of isonitrile 25, Bocprotected L-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives 3 : 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of of the a 3: initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the of tubulysin U and V. synthesis oftubulysin
R
BF3
MeO2C. N~ e "~ ~"'C 2 HS~
9
25''NMe
BF3.Et20 MeO2C
i
O
[
i-Pr i-Pr
R= R=
Ti 0o H
N~
BF3e
Me NS~~O Me Me 27
R
N
O
~ S e ~AMe,NNS MMe O ,0
---~
Me [ Me Me
j~It
R
OAc Me02C~~OAC
BOCHN~\ BooHN-~-.v/~
MeO2C 2C Me0
..__~? MeO2C
. 40%
Me 2 NH --Me2NH
,
40%
30 30
28 28 R
MeO2C N ~ MeO'C{r[>N0oAO ~ OAc
r
~" l(~SH ~.~. SH \,.N,
I Me L~MeMe
Me
29 29
A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with N,N-dimethyl-4-N',N'bis(trimethylsilyl)aminobut-2-yne amide 3Ia 31a and ethyl 4-N,N-bis(trimethylsilyl)aminobut-2ynoate 3Ib, I>. Presumably, the initial adducts 33a/b undergo 31b, respectively <06TL866 <06TL8661>. intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. C(O)X c(o)x
~1
TMSJ
s S
qo~ III)
7
c(o)x
Bt32 32 R.-A-. Bt R"~ II
,11I)
SJJ S
]
qO)X C(O)X
S--P S~.)
|/ 40-93% 40-93%
C(O)X
[~
N
C(O)X
R-<~I
THF, TMS-N THF, MeOH; MeOH; [ R~N R R R -R-{J1. [, Et3N Et3N +MS N H TMS TMS TMS33a/b 34a/b 33a/b 34a/b 31a: 31a: X = NMe2 NMe2 N 31b: X X= = OEt OEt 31b: R R = aryl, aryl, alkyl, alkyl, alkoxy, alkoxy, phenoxy, phenoxy,Bt Bt Bt = 'IN
S
N
35a/b 35a/b
245 245
Five-membered ring systems: with N Nand Five-membered and SS (Se) atoms
A novel synthesis of of iodothiazole iodothiazole 38 38 takes advantage advantage of of Wiemer's Wiemer's protocol protocol for the A of vinyl iodides iodides from ketones <06JOC5031 <06JOC5031>. phosphate 37, 37, prepared prepared synthesis of >. The thiazolyl phosphate converted to the desired iodothiazole iodothiazole 38 upon 2-isopropylaminothiazoline-4-one 36, 36, is converted from 2-isopropylaminothiazoline-4-one in situ situ generated generated trimethylsilyl iodide. This iodide iodide is a key intermediate intermediate in the treatment with with in treatment ofthe quinolone substructure substructure of of the protease protease inhibitor inhibitor BILN BILN 2061. 2061. synthesis of the quinolone
H KHMDS, H Nal, H H KHMDS, H Nal, N N i_pr/NyN (PhOhPOCI i-Pr/N i_pr/NYfO,p~OPh TMSCI ,. i_Pr ~ . ~ yo "'~N~"O" ~'OPh"OPh TMSCl i_Pr/N O (PhO)2POCI= ~S~/ i-Pr'~ N-.~~/_~-I yyl S-.l S O iO l OPh 55% S 83% 55% 83% 36 36
38 38
37 37
5.5.2.2 Synthesis Synthesis of of Fused Fused Thiazoles Thiazoles 5.5.2.2
of 2-arylbenzothiazoles 41 has been synthesized via microwave irradiation of of 1I : A series of of ortho-aminothiophenols ortho-aminothiophenols 39 and alkyl or aryl acylacetonitriles <06JHC1609>. <06JHC I609>. 1I mixture of of ortho-aminothiophenols ortho-aminothiophenols with [3~ efficient than that of This reaction appears to be more efficient benzothiazoles reported previously <05H(65)2119>. <05H(65)2119>. ketoesters to form substituted benzothiazoles O
H
;:NH2 R oN I
R1- v
39
"SH
-MeCN
1 --...-. 77-98O, o. O=N I r RI=HC 77-98%
RI.~Z~.J-..SHR 40
-H 20 -H20
R11
,:;
S S
R
R1 = H, CI R= alkyl R = aryl, aryl, alkyl
41
Benzothiazoles can be obtained from ortho-haloanilides ortho-haloanilides under strong basic conditions as exemplified by the formation of of 5-bromo-2-(3,4-dimethoxyphenyl)benzothiazole 5-bromo-2-(3,4-dimethoxyphenyl)benzothiazole 43 from <06JMC179>. A Cu(I)-catalyzed version of dibromide 42 <06JMC179>. of this transformation has been of ortho-haloanilides ortho-haloanilides 44 with cesium carbonate in the developed <06JOC1802>. Treatment of presence of copper(I) iodide and a ligand furnishes fumishes benzothiazoles 45 in good yields. This cyc1ization cyclization involves an intramolecular C-S cross-coupling of the ortho-haloanilides ortho-haloanilides and presumably proceeds via an oxidative insertion/reductive elimination pathway through a Cu(I)/Cu(lII) Cu(I)/Cu(III) manifold. Both 1,1O-phenanthroline 1,10-phenanthroline (l,lO-phen) (1,10-phen) and N,N'-dimethylethylene10-phen shows greater substrate tolerance. diamine provide ligand acceleration, but 1, 1,10-phen
~
B C~ [ ~ r/~"h/Br S Cui Cul (5 (5 mol%), mol%), CS Cs22003 sS.__.Ar Nail / ~~S)-Ar ~/~_._ 1,10-Phen (10% (10% mol) mol) ~ Brr SS ~ ~Br S 1,10-Phen Ar I )-Ar N ~ )(A 51% A)l-N ~)( ~_v~N..- ~ >99% >990/0(Ar= (Ar = Ph) Ph) " ::::--. Br 43 44 ~ = 4-0Me-Ph) Br Br 42 ~N ~ Ar r 51%=Br H Ar Ar 93% (Ar (Ar=4-OMe-Ph) 45 45 Ar Ar == 3,4-di-OMe-Ph 3,4-di-OMe-Ph
(Jc
The Jacobson thioanilide radical cyc1ization cyclization chemistry has been extensively used for the synthesis of benzothiazoles as shown by the preparation of 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole 47 <06JMC179>. The harsh reaction conditions (K (K3Fe(CN)6, 3Fe(CN)6, NaOH,
246
Y.-J. ~.-J. Wu and B. V. V. Yang
nYNAy s
QI
R-
/LJ...y
46 46
F
~
H
48
H
K3Fe(CN)6 550;; II K 3 Fe(CN)6 55% NaOH NaOH
0. ('yS
~
Ar ---~ R-+ R JrAr
N
49
~S
OA'' c DMP
.
N N
~ 85-95% [ 85-95%
Ar _.,, R-~~~Ar
Y = 3,4-dl-OMe-Ph 3,4-di-OMe-Ph
//~Ar JrAr
~
50
O
y~~y
47 FF 47
R R-+
O-S·
HS
[~
s
N II r N~Ar
__•S r;::=:yS
R /~---Ar R~~~Ar N
52
51
H H20, 90~ can be overcome by using the Dess-Martin periodinane (DMP) (CH2CIz, (CH2C12, 20, EtOH, 90°C) 25°C) <06JOC8261>. The reaction probably proceeds via thiyl radical 50, which undergoes 25~ 1,5-homolytic radical cyclization followed by aromatization of radical 51 to give 2arylthiazole 52. A modified Pictet-Spengler reaction has been applied to the synthesis of thiazoloquinolines 58 <06T3228>. Condensation of anilines 53 with aryl aldehydes 54 followed by endo cyclization results in the formation of thiazoloquinolines 58 under a variety of of endo traditional Pictet-Spengler protocols such as 2% trifluoroacetic acid in dichloromethane.
i6
Ar s N1HN~/~ "a,
ArCHO
NH2
TFA TFA 53
s:<3
[
-
1 HN--{ ~ = R R1HN---<,,~N
N
57
I
:;/1 ~
RHN~~ 1@
-
H
N:;/
~I
56
55
Ar
Ar /S L-~/L~NH H
JJs R1HN==s
S .). ~NH NH
S
R'",,-,-
54
H Ar
S(@
Ar ]
75-85% 75-85%
•"
S R1HN__/%N
N
=
R11 = phenyl, phenyl, benzyl benzyl
58
A novel series of5H-thiazolo[3,2-a]pyridine-5-ones of 5H-thiazolo[3,2-a]pyridine-5-ones 64 is prepared by addition of malonic esters 59 to 2-alkynylthiazoles 60 <06H(67)523>. A plausible reaction mechanism involves an intramolecular cyclization of the initial adduct 61 to give the cyclobutenoxide intermediate 62. Ring-opening of this intermediate and subsequent cyclization lead to 5H-thiazolo[3,25H-thiazolo [3 ,2a]pyridine-5-one 64.
247 247
Five-membered ring systems: with N Nand Five-membered and SS (Se) atoms
R2
R~I/CO2Me
~'-~
CO2Me 59
N/~
Nail NaH
MeO2C"~ ,,~OMe
60
61
R1oe MeO2C--.~ /o~ 2 _/~"y--:-OMe
S.....Y 62 S ~
O ~OMe RI~eN ~
lfM
O 48-83o/o 48-83%
CO2Me 63
N
1 = Me, allyl R allyl R1 2 R R2 = = Ph, Ph, n-Bu n-Bu
CO2Me 64
5.5.2.3 Synthesis Synthesis of of Thiazolines Thiazolines 5.5.2.3
Cyclodehydration of of the compounds bearing C(=O)-S-C-C-NHz C(=O)-S-C-C-NH2 moiety is a common approach to thiazolines. This method has been used repetitively to form the thiazoline moiety <06CC1757>. Exposure ofthioester in a recent synthesis of of chiral cyclic oligothiazolines <06CC1757>. of thioester 65 to trifluoroacetic acid results in cyclodehydration to give thiazoline 66, a doubly protected dimer unit. This dimer is converted to carboxylic acid 67 via basic hydrolysis and thiol 68 by thiazolidinone ring with a Boc group and subsequent base-induced ring the activation of of the thiazolidinone opening. Acid 67 is coupled with thiol 68, and the resulting thioester is treated with trifluoroacetic acid to furnish tetramer 69, which undergoes double deprotection to provide thiocarboxylic acid 70. Di- and tri-merization of this acid in a head-to-tail fashion produce a 1.8 : 1 mixture of of 71a of macrocyclic thioesters 71a and 71b in 63% yield. Boc deprotection of and 71b and subsequent cyclodehydration give cyclic octathiazoline 72a and dodecathiazoline 72b, respectively.
Y.-Z
248 248
Wuand andB. B.V.V. Yang Yang Y-J Wu
Boc Boc I HN Me H ~ HN". ~Me Me HfZMe
° fco
N a=< S O==/NSJ 65S" S 65
M e Me
j-co ~
Me N ~
NHf s
TFA HyMe __ N 96% a=< S 960/00::~, SSI
2
j-
Me Me
R CO2R 2
Boc,. bl,= N-~--CO2Me C0 2Me
Me N HN~S - Bo?
• Boc20,91%; Boc20, 91%; NaOMe,81% NaOMe, 81%
j
HS HSI
68 68
NaOH I ~ 66 R=Me N7~~~ ~~67 ~R ~= ~e 78% C ~ H Me Me Me /IN N + OtO 2M e 2Me yMe C0 Me N I N ~ s . . . SJ Me
67,BOPCI,
67,BOPCI, Et3N ' 77o/o; EI 3 N, 77%; TFA, 93% 93O/o• TFA,
~
H Me N " J k ~ S ' ~
H U J~ N_'i'~J./ O=
jJ
S
NaoH,8,%
~~~ :t ° [~~HBOC Mo MO~] ):s S
S '\ s--'~,
L~z N r- J ~ M e
63%
Boc Me N - ~ S ' ~
HH~~'T~ S"~7'0
69
Me
S S
Me_ S
C" ' - ~L---N
BOPCI, BOPCI, Et3N Et 3N
Me -4 S9
_
BOC20,90%; Boc20, 90%; NaOH,81%
S
- ~
Me
Me Nq-- CO2H
O%..S Me,,,J.S
79% 79% (a) 77% (b)
Me
nn = 1; 1" b: b: n = =2 a: n =
Me S
71a/b 71a/b
~
~SeN~
[MO ~Me
TFA
N
S~
S
'-~--N N~,~e s~n~o S~N K~
N~.NiMe NN e BocHN gocHNf"q
__N
Me Me
S S" "N \'N
MO]
]
N N~ "~ /
M7
Jn
Compounds bearing C(=S)-NH-C-C-OH C(-S)-NH-C-C-OH fragment (~-hydroxy (J3-hydroxy thioamide) can also undergo cyclodehydration to form thiazoline derivatives. The utility of of this strategy has been demonstrated in the synthesis of halipeptins A and D <06JA4460>. Exposure of of 73a/b with (diethylamino)sulfur trifluoride (DAST) brings about intramolecular cyclization to provide thiazolines 74a/b, which are advanced precursors to halipeptins A and D. Me Me
Me R H Me o ~_yR N~
°
N
.-. U
°
Me S )/---Me Me
L /
~
C0 2 Me N CO2Me Me ,~-DAST IVlU OH 85%85%
OMe OMe i ~ / 0 n-Pr v _ ~"'-ffv n-Pr~ w ~ N IVle _.'~r~ 33 Me 73a/b Me 73a/b
° °YN
Me Me
Me R
N
~
/'
M S>" e g OMe '" y--Me Me =.. ~ o n-Pr/ v %., //n-Pr w - u--"" N 3 a: R ==(CH2)2OTBDPS I~le __'~ 3 (CH2hOTBDPS b: R R = Et Et b: 74a/b 74a/b Me
°
~e
°/ N~_X
Me Me/
NI CO2Me C02Me ,,Me IVl~
° °YN
Kelly's biomimetic biomimetic methodology, methodology, first first reported reported in in 2003 2003 <03AG(E)83>, <03AG(E)83>, has has become become one one of of Kelly's the the most most reliable reliable routes routes to to thiazolines. thiazolines. In In this this approach, approach, the the phosphorus-activated phosphorus-activated amide amide carbonyl group group undergoes undergoes nucleophilic nucleophilic attack attack by by the the cysteine cysteine thiol thiol group group to to provide provide the the carbonyl thiazoline moiety moiety (see (see 76). 76). Kelly's Kelly's thiazoline thiazoline formation formation has has been been applied applied to to the the total total thiazoline syntheses of three three complex complex natural natural products: products: halipeptin halipeptin A A (75 (75 to to 77) 77) <06TL <06TLl1081>, 081>, apratoxin apratoxin syntheses of in Kelly's Kelly's A (78 (78 to to 79) 79) <06OL531> <060L531> and and (R)-telomestatin (R)-telomestatin <06OL4165>. <060L4165>. The The typical typical protocol protocol in A
249 249
Nand Five-membered ring systems: with N and S (Se) (Se) atoms
methodology involves triphenylphosphine oxide and triflic anhydride, but the cyclodehydration and deprotection of S-t-Bu group in 80 is carried out with addition of anisole, which drives the reaction to completion. Kelly's approach is also utilized in the solid-phase synthesis of thiazoline-based peptides 82 from resin-bound dipeptides 81 <060L2417>. <06OL2417>.
1
Me Ph3P(O), I N~NH ,,CO2allylTf20 /Fm~
Fmoc O
Me .~ ~N..,CO2allyll ~ Me >.N ,CO2allyl 75% HNAyN'X,cozaIlYI (O~" ""~"Me " = HN~/"~/~ I SJ "Me Fmoc C (TfO)Ph3P,-~d7 6 J Fmoc S7~~7Me Tr 76 77
Me FmocHNfyN;"coZaIlYI (0 ~ Me [ (TfO)Ph P'" 3
Me STr
75
CO2AIlyl Me,,~,, Troc Me~ poc .... /NH NH QO- /Me Me t-Bu t-Bu° OII [" I S T r o ~ o . . , ~ N , STr ~ COzAllyl
° Me:
°Ac)'
78 78
IVle
CO2AIlyl Ph3P(O), Me~. Troc Ph poc 3 P(O), Me~ Bu ° Fmo," Tf20 N QO Me Me t-t-Bu O Fmoc Fmoc Fmoc ..'- N , " TfzO ) - _ I~_ ~\ , S ~ o I-I~~ - I1~ COzAllyl
-
Me Me
~
~ O °-<;St-Bu i - - St-Bu O/__~~kN~ o.:)--{ ~)-<~IR O ~NN HN HN //--O Ph Ph3P(O), 3 P(O), ;=( ~o ;=( TfzO, N! ' ~ T~sOole O~N N~_.~.Me anisole N t Me 0yN N t Me Me " 0yN
79 79
Bn 0 RHN ' ~ N~ O
°
~N
NYO
20%
o-\r~ N~Mee
~"O~~_oNk~o~OvI
20%
~N
telomestatin
telomestatin
80 80
81 OTrs/ 6 / Ph3P(O),
NYO
~"O~~_oNk~o~Ov! O-\_N N~Mee
[o~o
[o~o
°Ac)'
Bn ' Tf2Oo RHN~/N~o 82
S~-
R= CBZ,Fmoc
5.5.2.4 Reactions Fused Derivatives Derivatives 5.5.2.4 Reactions of of Thiazoles Thiazoles and Fused
The first practical, large-scale synthesis of 2-amino-5-fluorothiazole 84 employs the reaction of dilithiated 2-butoxycarbonylaminothiazole 83 with N-fluorobenzenesulfonimide (NFSi) <06OPRD346>. <060PRD346>. This reaction generates a 70 : 15 mixture of the desired fluorinated thiazole 84 and the sulphone 85, and after three consecutive recrystallizations thiazole 84 is isolated in 35-40% yield. This procedure has been utilized to prepare multikilogram quantities of 84, which is a heterocyclic amine component of a series of glucokinase inhibitors.
BocHN~N_~
BOCHN--<)
N 83 83
t-BuLi"NFSi BOCHN1IF BocHN..../S.~...F
t-BuLi; NFSi
BocHN..../S~.JSO2Ph
+ BOCHN1ISOzPh
36% (84)
84 84
85 85
A regioselective generation of thiazol-2-yl and benzo[d]thiazol-2-yl magnesium chlorides (87 and 89) uses 2,2,6,6-tetramethylpiperidyl MgCleLiCI MgCI*LiC1 (TMPMgCleLiCI), (TMPMgC1.LiC1), readily iso-propyl MgCleLiC1 available by reacting iso-propyl MgCleLiCl with 2,2,6,6-tetramethylpiperidine
Y-J. Y.-J. Wu Wu and BY. B. V. Yang Yang
250
<06AG(E)2958; 06CC583>. This mixed Mg/Li amide, which has excellent solubility in THF (1.2 M) and is stable for more than six months as THF solution at 25~ 25°C, allows the regioselective functionalization of various aromatic and heteroaromatic compounds. Thus, TMPMgC1.LiC1 at both thiazole and benzothiazole undergo smooth C-2 magnesiation with TMPMgCleLiCl 25~ and the resulting magnesium chlorides are trapped with benzaldehyde and iodine, 25°C, respectively, to furnish adducts 88 and 90.
(j flS /~N ~
q
Me. Me Me Me PhCHO PhCHO THF ++ ~____N THF,' 25°C 25o2• ~ S N-MgCI-LiCI -MgCI,LiCI /~N/,~MgCI 94% 94% Me Me M/ -Me 87 86 86 TMPMgCI-LiCI TMPMgCI,LiCI
~/,~ Q~
/•N/• 88
Ph
OH
TMPMgCI-LiCI TMPMgCI*LiCI
THF, 25~ THF,25°C
N
• ~NN/,~
MgCI
98%
I 90
89
A new methodology for direct phosphonation of thiazoles has been developed <060L529 I>. Reaction of substituted thiazoles 91 with dimethyl or diethyl phosphates in <06OL5291>. the presence of manganese (III) acetate dihydrate provides 5-dimethyl or diethylphosphonothiazoles 95. The high C-5 regioselectivity is rationalized by comparing the two of phosphonyl radical 92 to the thiazole intermediates 93 and 94, which result from the attack ofphosphonyl ring at the C-4 and C-5 position, respectively. The radical in intermediate 94 is next to an imine as opposed to a sulphur as in the case of 93, and therefore, 94 is more stable than 93. As a result, the C-5 phosphonation involving 94 is favored. In the case of unsubstituted thiazole, the C-2 and C-5 phosphonations proceed in a ratio of 78 : 10, indicating that the C-2 position of thiazole is most reactive for phosphonation, followed by the C-5, and the C-4 is the least.
R2 Mn(OAch ~~S% Mn(OAc)3 5 R1 HP(O)(OR)z HP(O)(OR)2 91
I
I R1 = =H
t
1
R22==H H R
•
O (RO)21~' R~S2k~ N R1
~P(O)(OR)z
93
92 92
/
s
97 97 (78%) (78%)
94
)~ R2 H =
N\\ ~ Oii oO fiNN //7--N (~_q.))__P(OMe) ~P(OMe)z2 ++ (Meo)zp-Z '" /]-- '\\;> (MeO)2P---~,.S,~ S 98 98 (10%) (10%)
R h --N 1 80-92%. 80-920/0=
j
O Ii ~o (MeO)zp'r,-N (MeO)2P\ R1 1l.._~R1
R)c2 N
N
(RO)z~\
o O
'I \\
S~
R1
95
R11 = Me, Me, Et, Et, OMe, OMe, R OEt, OEt, H, H, acetyl acetyl
R22 R
Me, Ph, Ph, H H =Me,
R = Me, Et R=Me,
S 96
~-heteroarylation of simple esters and amides via nucleophilic A mild and efficient a-heteroarylation aromatic substitution has been described <060Ll447>. Treatment of 2-chloro<06OL1447>. benzo[d]thiazole 99 with tert-butyl tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl tert-butyl 2-(benzo[d]thiazol-2-yl)propanoate 100. 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 10! is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed a-arylation ~-arylation reactions. First, heteroaryl chlorides
251
Nand Five-membered ring systems: systems." with N and S S (Se) atoms
may be used; Second, the reactions can be conducted at ambient temperature as opposed to the elevated temperature usually required by palladium-catalyzed a-arylation ~-arylation reactions.
r~'~---Ss ,CO2t-Bu C02t-Bu //k~__O I J-+OHH ~ N Me N Me 101 101
(X
NaHMDS, NaHMDS, NaHMDS, [ . ~ ~ sS~. NaHMDS, .,EtC0 EtCO2t-Bu, EtC0 2t-Bu, ,2t-Bu, EtCO2t-Bu, CI I }-CI N air, air, 84% 84% ~~ -" N N N22,,91% 91% 99 99
.
(X
~ S > ~ Cs
C02t-Bu
~
Me
O2t-Bu (X1M N Me N
100 100
The palladium- and copper-mediated C-2 arylation of thiazole with 4-iodoanisole under ligandless and base-free conditions provides 2-(4-methoxyphenyl)thiazole in good yield <06EJOCI379>. <06EJOC1379>. However, the scope of this selective C-2 arylation has not been disclosed.
N..
MeO
fJ SI
I ++ C ~
Me0-o-I
S
Pd(OAc)2(5 (5 mol%) mol%) Pd(OAch Cui equiv) •. Cul (2 (2equiv) 84% 84%
MeO
~N '/ ~ /; S
J
of thiazoles have been reported. For example, Several palladium-catalyzed C-5 arylations ofthiazoles 2,5-diarylthiazole 104 is prepared via arylation of thiazole 102 at C-5 with aryl iodide 103 using PdCIz(PPh3)2 PdCb(PPh3)2 as a catalyst and silver(I) fluoride as an activator <06T9548>. The selectivity in the arylation of 4-methylthiazole with biphenyl triflate 105 depends on the choice of base: cesium carbonate favors the C-2 arylation, while the C-5 arylation dominates <06H(68) 1>. The C-2 selectivity issue is overcome by using 2with potassium carbonate <06H(68)1>. trimethylsilylthiazoles, which serve as efficient counterparts for palladium-catalyzed crosscoupling reactions with aromatic triflates (without any fluoride anion source) to afford 2-aryl thiazoles. For example, mono-thiazoles 1l0a/b ll0a/b are obtained from triflate 108 using 2trimethylsilylthiazoles 109a/b.
S
PdCI PdCI2(PPh3)2 2(PPh 3h (3 mol%), AgF (3mol%),AgF = 21103 Ar21 103 Ar
102 102
104 Ar1= 4-0Me-Ph; 4-OMe-Ph Ar 4-CO2Et-Ph Ar Ar22 = 4-C0 2Et-Ph 104
()
1
Ar 11
Ar
=
.
Ar11 Ar
Ar2--fJ
S
=
46% 46%
Pd(OAch, PPh 3 , K2C0 3 , LiCI
PJ(gOA3'c)I~PichP3' I= - ~ 7
~ O T f OTf
OH
OH
109a 109a (R = = H) 109b 109b (R = = Me) Me)
~OTf
Ph
105 Pd(OAc)2, I ~N PPh3, r~//~--Me base S-....(/ [ ~ ~ / / ~ _~N _
R
N----( R TMS.~s---~ TMS--L(S"
108 108
Ar2 ,, ,,
~
O c?'H
~ ~I 110a (71%) (71%) 110a 110b (73%) (73%) 110b
Ph S . . j 106
+ ~ l e Me
Ph
S-..~'N
1.61 (Cs2CO3) 107
1 93.5 (K2003)
A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 <030L3607>. <03OL3607>. According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAch/IMes] [Co(OAc)z/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication <060L2899>. <06OL2899>.
252 252
Y.-J. Wu Wu and B. V. V. Yang Y-J
/~S.~ [J
Ph-I, IMes (10 mol%) ,,Ph-I'lMes(10m~ X Co(OAc)2(5 (5 mol%), mol%), Co(OAch CS 0s2003, 64% 2C0 3,64%
~S ~ Ph
S
Ph-I, (10 mOI%)... Ph-I, IMe~ IMes(10mol%)x
(J-/~S.~
Co(OAc)2(5 (5 mol%), mol%), Co(OAch Cui, Cul, CS Cs2CO 3,, 84% 84% 2C0 3
S
Ph Ph
A parallel synthesis of a library of of 2-aryl-6-chlorobenzothiazoles 112 involves a regioselective palladium-catalyzed Suzuki coupling reaction of 2,6-dichlorobenzothiazole 111 with arylboronic acids (1.1 (1.1 equiv) under microwave irradiation <06TL3091>. When excess phenylboronic acid is used, Pd(PPh Pd(PPh3)4 3)4 still provides 2-phenyl-6-chlorobenzothiazole exclusively, 113 generates 2,6while 2-dicyclohexylphosphinobiphenyl diphenylbenzothiazole as the major product. ArB(OHh, CI ArB(OH)2'Pd(PPh Pd(PPh3)4' CI 3)4, "--~ S~)~ Na2C03, Na2CO3,dioxane/H dioxane/H20 ~S/~_ C1D=S C1D=S 20 CI =_ Ar I J-CI I J-Ar ~ N N 57-79% 57-79% ~ ~ -~N 112 111 112 111
.
/:~
Me2N /,~'~ PCy2 113
The synthesis of 4-bromo-2'-chloro-2,5'-bis(thiazole) 117 from 2-chlorothiazole via palladium-catalyzed cross-coupling reactions has been reported <06JOC3754>. Among the three coupling methods (Negishi, Suzuki and Stille), the Stille coupling route proves to be the best. Lithiation of 2-chlorothiazole with LDA and subsequent quenching with tributyltin chloride give 2-chloro-5-tributylstannylthiazole 114, which is coupled with 2,4-dibromo117. This compound can also be prepared by the Suzuki thiazole 116 to give bis(thiazole) 117. coupling reaction of 2,4-dibromothiazole with the first known thiazoleboronic acid ester 115, but the yield is much lower. The Negishi coupling protocol suffers from substantial side reactions and results in an inseparable mixture of of products. The transition-metal-catalyzed cross-coupling reactions on various azole systems including thiazoles and benzothiazoles have been summarized in a recent review <06EJOC3283>.
~~/~ riS
CI
tLN'>-CI
LDA, BU3SnCI Bu3SnCI LDA,
,-Bu3Sn~s~ --CI
95% 95%
LOA, LDA, pinacolB(O-iPrh; B(O-i ; HOAc Pr)3; pinacol; HOAc 95% 95%
Stille (81%) (81%) Stille
N
..
N=~,.
Br--.~ NxN.....Br Br~NyBr
Ls
Me
q Me L-c~ Met Me ,B S Me-~-o'B~s-Me ~[~N/J-CI ~y--cl Me 115 N 115
°t
117
116
116 Suzuki(12%) (12%) Suzuki
A synthesis of the eastern fragment of the thiazole peptide GE2270 relies on a regioslective bromine-lithium exchange reaction of thiazoles and Negishi cross-coupling reaction <06JOC4599>. 2,4-Dibromothiazole 116 undergoes the known regioselective bromine-lithium exchange to give 4-bromo-2-thiazolyl lithium 118, the TBS protected (S)mandelate 119 is added, and the resulting adduct is reduced stereoselectively to provide threo threo alcohol 120. 120. This alcohol is converted the Boc protected amine 121 in a four step sequence. Bromine-lithium exchange of 121 and subsequent transmetalation to zinc are followed by a regioselective Negishi cross-coupling with 2,4-dibromothiazole 116 to furnish bis(thiazole) 122. 122. This compound could serve as a building block for the synthesis of of thiazolyl peptide GE2270.
253
Five-membered ring systems: with N Nand and S (Se) atoms
Br
)-N
Br n-BuLi n-BuLi ~_ /~SSL L i
/(s?---Br Br
118
116
Ph Br 1. /J, 119 119 Br,'kfi__N 1. N Et0 C 'OTBS 92% 2 EtO2C "'OTBS92%,. (~Y' S\~
f
J','OTBSPh sy"OTBS
2. 2. L-selectride, L-selectride, 86% 86%
(1·
OH 120 120 OH 4 steps! steps / 4
Br Br~ '~~N N
Ph
1. 1. t-BuLi, t-BuLi, ZnCI ZnCI22 Br Br 2.116, 2. 116, [PdCI [PdCI2(PPh3)2] 'k,~N 2 (PPh 3 hl N
N Ph .kr--N Ph ., Y \ ~_\L J,, S/ v__ "OTBS sY"OTBS 122 I~HBoc 122 NHBoc
44% 440/0
Ph Ph
(Y \ , ~SsY"OTBS ~.~~'"OTBS 121 121
NHBoc I'TH 'l B~
The cycloaddition of of 2-aminothiazoles with dimethyl acetylenedicarboxylate (DMAD) has been thoroughly investigated <06JOC5328>. <06JOC5328>. Treatment of thiazoles 123 with DMAD in acetonitrile leads unexpectedly to 6-(dimethylamino)-3,3-pyridinedicarboxylates 128. According to the proposed mechanism, nucleophilic attack of the thiazole at C-5 to DMAD gives the zwitterionic intermediate 124, which cyclizes to the fused cyclobutene 125, the formal [2 + 2] adduct. Thermal disrotatory opening of 125 leads to all-cis all-cis 1,3-thiazepine 126, 6rt-electrocyclic ring closure to give 7-thiawhich undergoes a symmetry-allowed disrotatory 6n-electrocyclic Alternatively, the 2-azanorcaradiene 127. Desulfurization of 127 gives rise to pyridine 128. 128. Altematively, zwitterionic intermediate 124 could lead to 7-thia-2-azabicyclo[2.2.l]hepta-2,5-diene 7-thia-2-azabicyclo[2.2.1 ]hepta-2,5-diene 129, the formal [4 + 2] cycloadduct, through the attack of of its carbanionic center to the C-2 of of thiazole moiety. Further sulphur extrusion in 129 would provide the regioisomeric pyridine 130. This pathway proves to be operative, although in low extension, only in rare instances. The zwitterionic intermediates can be trapped when the reactions are carried out in methanol instead of acetonitrile. For example, exposure of thiazole 131 to I1 equiv of of DMAD in methanol gives a 24 24:: 76 mixture of(E)of (E)- and (Z)-isomer 132 and 133. 133. In the case ofthiazole of thiazole 134, the fused cyclobutene intermediate 135 is isolated in 52% yield, and it cleanly transforms into pyridine 136 under thermal conditions.
254
Y.-J. Y.-J. Wu Wu and B. B. V.K Yang Yang
r ~}:-S Ef)
kN.Me2
~Mez ftS Ny
N~
E E
I ~Mez ,~ME2
123 123__
R'\)
==
~ ......,
/ NvYE
[2+2] [2+2]
\,"'."
solid solid arrow arrow
," N ~ R ~ E
E E
f\l EE
~ _ _ ~
'------124 124
~aShed
M::N~Ej Ny 129 129
E
Me'N---<~1JC E
E
_
;;\N~E Me~ Ny
Me,,
,S~
E
M/ Me/
N: N RR 125
E E
N:--..
128 128
E E
'rt s
DMAD DMAD
N~
90%
90%
131 R R 131
R= = 4-Tol
'N---{ Jl_
M M/
N 132
Me2N MezN
/~S ItS
N~ N
Me 134 134 Me
DMAD DMAD 52% 52%
Ni={
l
R
/
!
E
E 126 E126
E
N:--..
E
R
R
127
E E
.S~E S~E
Me Me,,
--
I-Me S., 70-91 % /M Me\Nf;rHE N N ~ ~ E 70-91~176 e ~ N ~ ~ [ "E Me' Me~\N-ycE Me' I -,•
130 130 R
Me2N MezN
Me/NN~8 ~ Me'N1(S,,-
Me .e
R
R R
i
I
E E == COzMe; CO2Me;RR == CH=CH-Ar, CH=CH-Ar,Ar Ar
[4+2] [4+2] /dashed arrow arrow
Me E MegN~
Me Me
H H
+
R
Me,, . S ~ E Me'N---<~0 NJl-R ~E M/ / N Me
H E Ij Me .S1J( S~ E Me 'N---{ I NMe// N ~e E Me : E Me 135
133
Me Me ~
90% 90%"
'NN ~ ~ E 'N-ycE Me' N:--.. E E
I
136 Me
Oxidation of of thiazoles 137 with HOF.MeCN HOFoMeCN provides easy access to the family of of thiazole N-oxides 138 <06CC2262>. <06CC2262>. The readily made HOFeMeCN HOF.MeCN complex, considered to be one of of the best oxygen transfer agents in chemistry, transfers an oxygen atom directly to thiazole-containing compounds of the thiazole moiety. A compounds without affecting the double bonds of small amount of N,S,S-trioxide 139 is also formed in this oxidation. of N,S,S-trioxide R2
~S,~ HOF-MeCN N HOF,,MeCN: R3 R1 137
R2Z
8 ~
Ef) 0 R~, ~,,O ~S% R3 S R1
R3)f~R1
138 (78-91%) (78-91%) 138
2
+
R~ ~,,O ~/~S\~ R3 R1 O O 139 (3-10%)
R = H, Me R1I=H,Me R2 I Me, Me, = ary RZ = aryl a33 == H, H, Me, Me, Ac, R Ac, (CHz)zOAc (CH2)2OAc
5.5.2.5 5.5.2.5 Thiazole Thiazole Intermediates Intermediates in Synthesis Synthesis An enantioselective enantioselective synthesis of of both (R)- and (S)-a-alkylcysteines 144 and 147 is based based on the phase-transfer of tert-butyl tert-butyl esters of of 2-phenyl-2-thiazoline-42-phenyl-2-thiazoline-4phase-transfer catalytic alkylation of carboxylic acid and 2-ortho-biphenyl-2-thiazoline-4-carboxylic 2-ortho-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of of 142 and 145 with alkyl halides and potassium potassium hydroxide in the <06JOC8276>. presence presence of of chiral catalysts 140 and 141 gives the alkylated products, products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This of chiral ~-alkylcysteines. a-alkylcysteines. method may have potential for the practical synthesis of
255
Nand Five-membered ring systems: with N and S (Se) (Se) atoms
e
allyt
X 140 X = 3',4',5'-trlfluorophenyl 3',4',5'-trifluorophenyl X
141
NrC02t-Bu N /CO2t-Bu 140 (1 (1 mol%), mol%), Ph~ RX,KOH Ph~/f 7 RX, KOH ,.
-----
S S"
42-99% yield 42-99% yield 67-99% ee ee 67-99%
142 142
N ,,'CO2t-Bu N~,C02t-BU
Ph--~~R Ph~.J S
R
~ ~NsT 'I
S
Ph Ph 145 145
H2N...~,CO2H
=-
143 143 R= = alkyl, alkyl, aiiyl, allyl, benzyl, benzyl, propargyl propargyl
/CO2t-Bu 141 141 (1 (1 mol%), mol%), /7~k NrC02t-Bu
If ~ -
He) H(J) ---
HSj~"R 144
.N~,,. CO2t-Bu
CO2H H2N--(:C02H ) 'R HS 147 147
RX, CsOH cso.
77-99% 77-99% yield yield 68-88% ee ee 68-88%
Ph
146
of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply The utility of demonstrated in a recent enantioselective synthesis of of FD-891, a 16-membered macrolide <06JA3128>. thiazolidinethione propionate aldol reactions for <06JA3128>. This synthesis features four thiazolidinethione of 12 stereogenic centers. For example, addition of controlling the configuration of 8 of aldehyde 149 to the enolate solution of N-propionyl thiazolidinethione 148 produces aldol syn isomer. Compound 148 product 150 with excellent selectivity (dr > 20:1) for the Evans syn also undergoes diastereoselective aldol addition with 3-butenal to give the non-Evans syn syn aldol product 152 under different conditions (dr > 15: 1). Both aldol products are 15:1). incorporated into FD-891. Asymmetric aldol reactions using thiazolidinethione chiral auxiliaries are also applied to the synthesis of bistramide <06JA4936>, (+)-SCH 351448 <060L2887> and salinomycin <060L527>. <06OL2887> <06OL527>. Bn Bn
C:'" sy.
OTBS OTBS
I~ r(Y 0 OH
- ~.[fJ
II S S
¥e
O OH 150 150
TICI TiCl4, 4, (-)-sparteine, (-)-sparteine, 2 2 NMP' ~ 0H2012' 78% _C_H_C_1_,
_~_~_:_' -o.c OHC
Bn Bn
~ S 0O N__OTBS S
149 149
OTBS
TICI TiCI4, Bn 4, "Bn ~le (-)-sparteine' $ ~ ' N Me tyle CH2C12, 730/0 -
r~, ye _~_~_~_ta_12~_~_i~_~o.'. y / ( 1/ ~ S~" ~
148 148
OHC~ 151 151
n
S/(N~ S S
0O
OH OH
152
The stereoselective addition of the titanium enolate of N-acetyl-4-phenyl-l,3-thiazolidineN-acetyl-4-phenyl-l ,3-thiazolidine2-thione 153 to the cyclic N-acyl iminium ion 154 is utilized in the synthesis of of (-)stemoamide, a tricyclic alkaloid <06JOC3287>. The iminium ion addition product 155 undergoes magnesium bromide-catalyzed anti-aldol anti-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide.
256
/-~
Y.-J. WuandB.V Wu and B. V. Yang Y-i.
Ph
Me~---~
153
/Me MgBr,Et20' ~.~ TMSCl, S h ___~0 M et3N; HCl N~/~/ e ~ H
tiCl4, .--J' Ph DIPEA 0 "~ / x
154
155
74% CHO
S
O
OH
157
N-(Alkoxy)thiazole-2(3H)-thiones 158 are precursors to alkoxyl radicals which can participate additions, ~-fragmentations 13>. For ]3-fragmentations and remote functionalizations <060BC23 <06OBC2313>. example, microwave irradiation of 158 in the presence of tributytin hydride or bromotrichloromethane affords tetrahydrofurans 162a and 162b, respectively. Conceivably, the alkoxyl radical 160, 160, generated under microwave conditions, undergoes 5-exo-trig 5-exo-trig cyclization to give a cyclized radical 161. 161. Hydrogen (Bu3SnH) or bromine atom transfer (BrCCb) (BrCC13) onto radical 161 leads to tetrahydrofuran derivatives 162a/b.
Ar AF ""is
Me%S
Me--LL.N~s
!-tx~ F Ar"is Ar/ S X-y JlW
[
•
oO
158
]~
159
II
Ph~
Me--LL.N~s
" k Ar X -y = H-SnBu 3. Br-CCI }""is ~--, X-Y H-SnBu3, Br-CCI33 Me"~r Ar = 4-0Me-Ph 4-OMe-Ph Me--LL.tf).-.SY Ar =
X-Y
[
163
O~ _5-_ex_o-_tri 5-exo9__-trg iP~;_ ~Y ~ Ph~ ] I1,
Ph
Ph'
160
161
~_.~1 pjY xX
64% (X= (X = H) H) 64% 68%(X=Br) (X Br) 68%
=
I1,
Ph'
162a 162a (X (X = = H) H) 162b (X (X = = Br) Br) 162b
The synthesis of a series of piperidine imino-C-glycosides 169 involves a stereoselective addition of 2-thiazolylmagnesium bromide 165 to a N-glycosylhydroxylamine N-glycosylhydroxylamine 163, a hidden open-chain sugar nitrone 164 <06JOC7574>. The resulting N-thiazolylalkylhydroxylamine 166 is reduced to a secondary amine, which, upon mesylation, transforms into a substituted piperidine 167 via a SN2 SN2 intramolecular cyclization. Cleavage of the thiazole ring to formyl group is carried out by a one-pot, three-step reaction sequence consisting of microwaveassisted N-methylation of the thiazole ring by methyl iodide, reduction of the Nmethylthiazolium salt with sodium borohydride, and mercury chloride-promoted hydrolysis of the resulting thiazolines. The crude piperidine aldehyde is further reduced to the primary alcohol 168, and removal of the O-Bn and N-Bn groups in 168 affords a pair of 2,6-dideoxy2,6-iminoheptitol hydrochlorides 169.
257
Five-membered ring systems." systems: with N Nand Five-membered and SS (Se) atoms
0oe OH eL,., oH ~NBn /~.,.,, ~,/I,,IIJn Y BnO
OH II
Bno NBn ---)0 )0 NBn
BnO
BnO"' BnO'" "~ "'OBn "'OBn OBn
BnO'" ' ~ '"OBn "'OBn BnO"' OBn
163
N ~N OH OH HO Th i ( )-MgBr L,~ ~-- MgBr NBn n O ~ , , T;r 6~,.NBn S 165 _-.. BBno~O
(ThMgBr) (ThMgBr) 80%
164
Bno,,'y"'oBn BnO'" "]~ "'OBn OBn = 166 1. Cu(OAc)2.H20, 1. Cu(OAclz-H 20, Zn, HOAc (74%) MsCI, Et3N Et3 N (80%) 2. MsCI, 6 S / 6 R = 3/1 6S/6R 3/1
@ e CI CI H2 H2 Pd(OHlz/C, Pd(OH)2/C, Bn Mel Mel; NaBH4; NaBH 4 : HCI . ~ , N, , ~ . HgCI2. NaBH44 '""' ./NN, ...r"-.. HCI,. H2 H2 = 2_:_Na_B_H_ Bno~NToH .H_9_C_1 BnO -''~, .~ " h ~ O H BnO OH., BnO r" 'f' OH _ - - C)
92% 92%
,~" y BnO" BnO""'J OBn OBn 169
Bno,"y"'oBn BnO'" "1/ '"OBn
56%
I
Bn Bn BnO/,,, Bno/""(Ni",,,Th ' N ~Th Bno"'y"'oBn BnO. . . . . . OBn
OBn
OBn
168
167
0-Nitro-2-benzothiazoiyi o-Nitro-2-benzothiazoiyi a-manniside c~,-manniside 170 has been identified as an efficient mannosyl ~-seleclivl: =v,~nosylation li1:1nnosylation of <06BCSJ479>. donor in the direct [3-selective of glucosamine derivatives <06BCSJ479>. H 8( C6 F5)4 as a promoter proceeds smoothly to give a 4 Mannosylation of of 171 with 170 using H[3((J6Fs)4 t~-mannosides 172. 172. This Tl~is represents the first example of of direct [3of 13~- and a-mannosides ~ : 1I mixture of selective mannosylation with the chitobiose acceptor 171. 171. The ~-trisaccharide 172 serves as a key building block for the synthesis of of the pentasaccharide core commonly present in the Nlinked glycans.
OAIlyl OAII~Bn
~ L OBn
OBn -0 OBn~--~]-O AllylO AIIylO--~~ +
OBn
HO~=~
N
--
O~I~
S~ NO NO2 170 2 OBn
AIlYIO~O~:::O' AllylO-~O1-'~~O PhthN PhthN
BnO~N3 BnO~-~..~N3 PhthN 171 PhthN 171
OAIlyl OAII~Bn L, OBn OBn O B n ~ l - O -0 A l l y l O ~ k - - ~ ~ ~OBn ~..OBn AllylO ,. O - - ~ - ~ O0 ~-OBn o OBn • AllylO O~:uO' AllylO---~O O HB(CsF5)4 PhthN B ~ N 3 HB(C PhthN BnO~N 6 Fs )4 tool%) PhthN (20 mol%) 172 PhthN 3 5A~ MS 172 5NMS 95% (a!~ (odl3== 1/4) 1/4) 95%
~
The Julia olefination reaction involving alkylsulfonyl benzothiazoles remains one of the most effective methods for the stereoselective formation of olefins. The power of Julia olefination is demonstrated in the total synthesis of cystothiazole A <06TlI592> <06Tl1592> and FR901464 <06Tl378>. <06T1378>. Coupling of sulfone 173 with aldehyde 174 using LHMDS proceeds stereoselectively to give a 14 : 1 mixture of cystothiazole A and its Z-isomer in 64% yield. Epoxyaldehyde 175 also undergoes E-selective Julia olefination with sulfone 176 to give the desired diene 177, which is converted to FR901464 in four steps. The Julia olefination reaction involving alkylsulfonyl benzothiazoles is also applied to the synthesis of phorboxazole A <060L6043>, <06OL6043>, iejimalide B <06AG(E)5832>, (-)-codonopsinine <06TA1380>, myxothiazols <060BC2906>. <06OBC2906>.
258
Y-J. Y.-J. Wu Wu and and B. B. V. K Yang Yang
O
o~ S~
--'~-/N\ /N<.7/i_Pr ~..N "<.S/"~~ S +
Me,,, O. ,,CHO /% '-_ OTBS OTBS
175 0---" O"-'~" 175
+
64% 64%
~CHO CliO
R R
173 Mev'" 0 ",CHO MeO~_~~ MeO
LiHMDS LiHMDS
OMe OMe OMe OMe Me Me
174 174
E/Z== 14/1 14/1 Ell
OMe OMe OMe OMe ~NN
~ ~e
R=C0 2 Me R = CO2Me
N~ /-Pr N~i-pr
l S~S
'
cystothiazoleA cystothiazole
"'" 0=
~ [ ~ S S\ q,sp O,, ,~O ~e, Me ..O.. ,MeoMe...OTBS MeUOTBS 0 , M .& N 1 / ~""O' 0 " .& 176 Me" 'N 176 Me...." H H
LiHMDS LiHMDS 68% 68%
Me 0 -~e, O M Me Me Me OTBS OTBS Me'o/O. .... ~ ....r" ""1" o Y Me", 0 ""~""O" eq-y Me01-'r Me"" "'N~ MeO'~..~~ Me,,,,Lv.J,,, N..JJ..~ /% OTBS )('OTBS H 0----"'177 O" 177 There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[d]thiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide 178, prepared in two steps 2-(benzo[dlthiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide from 2-chloro-N-methoxy-N-methylacetamide, reacts with a variety of aldehydes in the o~,13-unsaturated Weinreb amides 179 presence of sodium hydride to furnish the a,~-unsaturated <06EJOC2851 >. An efficient synthesis of fluorinated olefins 182 features the Julia <06EJOC2851>. o~-fluoro 1,3-benzothiazol-2-yl sulfones 181, readily olefination of aldehydes or ketones with a-fluoro available from 1,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro ~-fluoro acrylates 185 <060L1553>. <06OL4457>. <060L4457>.
o=
o NaH, 00 O ] ~ S Ns/ ~ 0\ zO O Nail RCHO RCHO O [ ~8" II ,Me Me ' ,. R . ~ ~ N MII e Me R~N \ S ~ N ' 44-72% 44-72% .& N ~N, 179 178 OMe R "OMe R == alkyl, alkyl, aryl, sugar 179 'OMe "OMe aryl, sugar
O=~~S)
r;/'~-'h~S\ O\ .//(3 LDA, LDA,NFSi NFSi. N/,)--S~ 90% 180 180 Ar NaH, Nail, Selectfluor [~S, O\//O Selectfluor X , , S/ M//~-730/0 = 73% t_BuO2 t- Bu0 2C
O=~~S) 183
o
O=S 0 0 [ ~S/ ''..~" N .& - N '~IFF
181 181
LHMDS, LHMDS, 1 2 R1R2C(O) R R C(0) 62-98% 62-98%
Ar
~ ~ [ ~ S~_~/O O=S;8"0 N ~F F .& N t_BuO2 C t- Bu0 2C 184 184
r-
RCHO, RCHO, DBU 70-99% 70-99%
Ar =~ R1 "
>=
F F
182 182
R2
t_BuO2C t-Bu02C
R R
FF
H
l==
5.5.2.6 5.5.2.6 Thiazolium-Catalyzed Thiazolium-Catalyzed and-Mediated and -Mediated Reactions Reactions
of an aldehyde-derived acyl anion with a Michael The thiazolium-catalyzed addition of acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence presence of of a fluoride anion, carbinol 186 is not cleaved to an aldehyde <06JA4932>.
259
Five-membered ring systems: Nand Five-membered systems." with N and S (Se) atoms
and thiazolium zwitterion, but instead, it acts as nucleophlic acyl reagent, thereby selectively accessing carbonyl anion 189 presumably via a 1,2-hydrogen 1,2-hydrogen shift of the initial adduct 188. Treatment of carbinol 186 with tetramethylammonium fluoride (TMAF) and thiocarbanilide in the presence of nitroalkenes 187 provides p-nitroketones 13-nitroketones 190. In the absence of the thiourea additive, the yield is significantly lower. The incorporation of chiral thiourea 193, derived from quinine, into the reaction with (E)-(2-nitrovinyl)cyclohexane 191 produces p13nitro ketone 192 in 74% ee. This fluoride-activated acyl anion strategy is divergent from the typical combinations ofheteroazolium of heteroazolium salts and bases, and therefore reactive nitroalkenes can be used as substrates substrates (nitroalkenes decompose rapidly upon exposure to amine bases).
e
OTES OTES
o 0e
Y " " ~ NO2187 Ar A r J.. / ~ , SS Me4NoF ~_ 'Me/li~ }-Me IeMe/NII/~ Me (PhNH)2C=S (PhNH)20:S Ie Me 186 Me Ar = 4-CI-Ph 4-CI-Ph 186 Y == alkyl, aikyl, aryl aryl Y
r
'X' \
1R~
TMAF TMAF I RJ"~'NO22 193 191 193 191 N0
R'~ RX'. 0 , N 2 NO2 Ar Ar"
0 "O
67% yield yield 67% 74% 74% ee ee R R == cyclohexyl cyclohexyl
11
Ar , . l 1S- t Me Ar 0 Me -
'H Me/N'~ Me®
12-H shift shift
OH
/[•F3
OH e NoMe
ue, Me
189 Me Me 189
/ /
56-80% 1 56-80%
~
/ o~
O ~ O M e
A o2 Ar r y Y NNO 2 Y 190 190
H N..,JJ-,~. f l ~ 193
192
1
Ar~-tS
,- Ar
188 Me Me 188
F3C
1
The conjugate addition of acylsilanes to unsaturated esters and ketones utilizing Nheterocyclic carbenes derived from thiazolium salt 200 (Sila-Stetter reaction), first communicated in 2004 <04JA23 14>, has been described in full detail <06JOC5715>. The <04JA2314>, proposed reaction pathway starts with the deprotonation of the thiazolium salt 200 with DBU to yield thiazol-2-ylidene 201, a nucleophilic carbene. Addition of this carbene to acylsilane 194 generates intermediate 196, 196, which undergoes a 1,2-silyl group migration from carbon to
O ph--~TMS-194
1995 ~.. ~ 195 0 Ar" ~ "Ar' Ar '""'" Ar' 200 200 (30 (30 mol%) mol%) DBU DBU (30 (30 mol%) mol%)
r
200 (30 mol%) 200 (30 DBU DBU (30 (30 mol%) mol%) 77-94% 77-94%
~
,.• l
OTMS
TMS;l p h ~ SliS Ph'
k
1 -]
Ph OTMS Y Brook Brook Ph" -liS 50-82% 0 0 0 Y -= Peh~NI/'~YI NO Y N/M~e Ar"r D v A"Ar' E( A r' Et/ Et/ 9 \ | Me 197 198 197 Me Me _J 196 196 I Rt;lH2, RNH2, Y acyl y = (CH (CH2)2OH acyl anion anion 2hOH aCid acid
E(~-t
®-t
1
N..P(O)Ph2 Ar.~ H 202
@
ITMS~
HN"P(O)Ph2 .~ Ar
.Ph O 203
NI/~--.~--Y DBU= Et" 9 \ Be Me 200
eII~N~ Y Et/ Bre Me 201
R R I
Ph~Ar' Ph\(NJrAr'
)-J
Ar Ar
199 199
to oxygen (Brook rearrangement). This thermodynamically driven migration results in acyl 195. This carbonyl anion anion equivalent 197, 197, which adds to the a,p-unsaturated o~,[3-unsaturated ketones 195. methodology provides easy access to various l,4-diketones 1,4-diketones 198, 198, which are well known additions of precursors to polysubstituted furans and pyrroles. The thiazolium-catalyzed additions
260
Y-J. x-J. Wu Wu and B. B. V.V. Yang Yang
acylsilanes have also been extended to N-phosphinoylimines 202 to give a-aminoketones o~-aminoketones 203. The N-heterocyclic carbene (NHC) catalyzed carbonyl anion addition reactions have been extensively investigated, but in contrast, the corresponding nucleophilic substitution reactions have received considerably less attention. Recently, NHCs generated in situ from thiazolium salts 205 have been applied to intramolecular nucleophilic substitution reactions <06OL4637>. For example, treatment of aldehydes 204 with 205 (25 mol%) and DBU (70 <060L4637>. mol%) at 160°C 160~ provides benzopyrones 208. In the case of aldehydes 209, benzofuranones 212 are obtained exclusively. Presumably, the reaction involving aldehyde 204 proceeds via SN2 SN2 pathway, while aldehyde 209 undergoes SNI SN1 reaction, where the initial carbon cation 210 rearranges to give the more stable intermediate 211, thus leading to benzofuranones 212. yY e~~ S Me--/{(fj) Me 205 ~ ,. 205 1I e Me IVle
'ys
a
~ C H O CHO R...!I
Y~)__~/Me S,,,,/,,.N_Me r//~-'~,.4 X
~ O~X DBU 204 48-76% Y= = (CH (CH2)2OH; X= = I,I, OTs OTs Y 2 hOH; X
a
CHO 205 cHo 20, ;/ R...!" ~o O~OTS Ots DBU O,U
206
Y, Me S~e 1 =- ~ O HR " ~ N " M/ e l =
[_
@/t.~ R-I~
207
A S, N-.e =a
sI
o
oo O
Ar
OAr
,,.,N..Me
R[ [
45-86% / R 45-86%
209
0
0
208
I
Ar Ar
"cD '"
~~d 0
Me Me
212
~~ "O" Ar 211
210
Benzotetramisole 213 has been identified as an effective catalyst for kinetic resolution of of sec-benzylic and propargylic alcohols 214 to give 215 in excellent enantioselectivity sec-benzylic
<06OL1351; <06011351; 06OL4859>. 060L4859>. The benzotetramisole-catalyzed kinetic resolution has been extended to 2-oxazolidinone 217 via enantioselective N-acylation <06JA6536>. OH OH
(RCOhO (RCO)2ODIPEA, DIPEA,
R1~R2 R1LR2
OH --OH O_C(O)R QC(O)R =. R1A.R2 /I,... + 1+ R /'-"R2 213 (4 mol%) mol%) R1 R2 R1/~R2 213 (4
214
215
0 O HNAO
ph)__/
Ph~ 217
216
(EtCO)20 (EtCOhO,'
0 O
DIPEA, _-
213 (4-10 mol%) 213(4-~Omo1~ 15-50%
15-50%
)LNAO
Et Et
LJ
Ph"" Ph"" 218 218 (92-99% (92-99% ee) eel
R11 = = phenyl, phenyl, propargyl propargyl R R22 = = alkyl R alkyl R =/-Pr, Et R =i-Pr, Et 0 O
+
+
h)/ P
HNAO
Ph)--l 219 (17-99% ee) eel
O=S~.. I~
\oN
N~",
213 213
"Ph Ph
of trisubstituted aryl alkenes and aryl alkene esters using Asymmetric hydrogenation of iridium-phosphine thiazole complexes 220 have been reported <06JA2995>. The tetrahydrobenzo[d]thiazole complex (220b) delivers higher enantioselectivity than the 220c), and cyclopenta[d]thiazole and cyclohepta[d]thiazole counterparts (220a and 220e), ofthiazole replacement of thiazole moiety with oxazole dramatically reduces the enantioselectivity. The
Five-membered ring ring systems: systems: with with N Nand (Se) atoms atoms Five-membered andSS (Se)
261
carbene-tetrahydrobenzo[d]thiazo1e complex complex 221 is also synthesized, synthesized, iridium-N-heterocyclic carbene-tetrahydrobenzo[d]thiazole but only moderate enantioselectivity enantioselectivity is obtained obtained <06TL7477>. <06TL7477>. but 9 BArF
Ph ,Ph
e
_.." - - ) l r - - . ( ~
:
/
O:r -
[ 220a/b/c 220alb/c n=O;b: n=1;c: n=2 a: n=O; b: n=l; c: n=2
R R22
ee
("N' , , , ~ BArF/~N~!I e@ BArF )D~\ ] _/ wJ,'Ir--j Ir--./,,~
R R3
'>=98% ee(220) 1 ~2~~0 or 221 34-90% ee (221) 34-90% ee (221) (0.5 mol%)
-\
N R11
>98% ee(220)
I
(0.5 mol%)
Ph
R R R22 R3 HIIHI1H H, , ' ~ , 'H
221
R R11
BArF = tetrakis(3,5-di-trifluoromethylphenyl)borate
H H
bifunctional tridentate bis(thiazoline) bis(thiazoline) 222 has been shown to promote The C2-symmetric bifunctional of nitroalkanes to nitroalkenes in high the zinc(II)-catalyzed asymmetric Michael addition of enantioselectivity <06JA7418>. <06JA7418>. The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of of indoles, but the enantioselectivity is moderate <060L2l15>. <06OL2115>.
r Y
'-':::~I N :::,.., ~
N
ph....~/NO 2
Ph~N02 223
EtNO 22 EtN0 222 (25 mol%) =
Ph Ph
Me....~NO2 Me~No2
Et Et2Zn 2Zn (25 mol%) Ti(Oi-Pr)4 Ti(O/-Pr)4
N0 NO22 224
synlanti = 11.7/1 syn/anti ee 54% yield, 95% ee
S "N H NY S
)_---l
Ph Ph P'h Ph 222 222
Zn(OTf)2 (5mol%) (5 mol%) 222 (5 mol%)
Ph Ph
H -"
I ~ _ lJ-)
~'-'::: 1l ~. NO2 99% yield
~~'N
H
N02 99% yield 78% ee 78%ee 225
5.5.2.7 5.5.2.7 Thiazole-Containing Thiazole-Containing Natural Natural Products Products
of thiazoleDuring the past year, there have been numerous reports on the synthesis of containing natural products, including halipeptin A <06JA4460; 06TLl081>, 06TL1081>, halipeptin D <06JA4460>, obyanamide <06T9966>, tubulysin D <06JA16018>, <06JA16018>, tubulysin U and V <06AG(E)7235>, apratoxin A <060BC2906>, <06OBC2906>, cystothiazole <06Tl1592; 06H(69)231>, myxothiazol A and Z <060BC2906>, <06OBC2906>, bistratamide <06TL239>, (R)-telomestatin <060L4165; <06OL4165; 06Sl289> 06S1289> and GE 2270 <06JOC4599>. The relative and absolute stereochemistry of antimitotic macrolide archazolid A and B, originally isolated in the early nineties, has been determined on the basis of extensive highfield NMR studies, molecular modelling and chemical derivatization <060L4751>. <06OL4751>. The proposed structures have yet to be confirmed by total synthesis. The E stereochemistry at ~14,15 A14'15of (-)-mycothiazole has been revised to Z, and a closely related analog, mycothiazole-4,19-diol, has also been isolated from Cacospongia Cacospongia mycofzjiensis mycofijiensis <06JNP145>. Studies on a recent collection of the Red Sea sponge Negombata Negombata magnifica magnifica have led to the discovery of latrunculin T, a new member of the latrunculin family <06JNP219>.
262 262
r. -J. Wu Wu and BY. B. V. Yang Y-J.
Me'"
OMe n-Pr
Ar~
O---. Q.,,._ _ --<~N\O o.~'NH2 S/,__~~N . ~ ) N )"q NH2 r=r ,,~N "J~ N~ S..-:N
Ar/yMe N1 Me N Me HN HI~" T NyMe y}::,
Me e O..~MeMe~.../S
0
~J Me~N~, ,,,Me i1~'%N _ Me~OM~_NHMe ~"N ~
O
/''''(~
S/ N N~
Sr
.
~
:
,---S !IS
N,
_'Et
.0
O--~Nj.kEt
~
'~)
\
N"" S
OH OH
Y"N/\. J~ O Phh
--b
,\ S
'
Hr--(O
0H~N~H ) .Me""~b Me ... ~ O ~ ~ O~ ==~S O 0 OH Me i-Bu 0 NH y 0 ,H N~r-NH Me t-Bu O NH_ \\ N,H N---~. halipeptin halipeptinAA (R (R=OH) OH) apratoxin II / 'l'N -N'----""~--N~ - ~/ ,j\. // apratoxin ~"I halipeptin halipeptinDD(R (a == H) H) (Ar== 4-MeO-Ph) 4-MeO-Ph) MeHN MeHN~ ....~'(~/ "~ \o-.~,_CH OMe (Ar ' ( IIi ,S i-Pr o CH2OMe SS--~Me Me /-Pr 2
Me'' '(C ~--N'"~O H2)2R
(1 0O i-Pr Bn ~e~O, i-Pr OR OR2 Bn '-~"'1r~JN~N HN~Mee ~.-~-~E IR N~sN/~~'--~~ 2
GE GE2270 2270
o~s,
s~o
.L_R
1
C0 2H O 2t H M 6 tubulysinD (R1= CH2OC(O)i-Bu,RR22== Ac) Ac) tubulysin :tCH20C(O)i_BU, 0 Me 1 tubulysinUU(R (R1== H, H, RR22== Ac) Ac) BnN ~Jl Oi .--l Me tubulysin Bn~ 1 2 tubulysin V (R =H, R =H) I' 'N' tubu'ysin H )VO(R1 OMe M:e H' R2= MeSH ot-~__,.,.~/N. N, H N;/ Me
0
~~R1
OMe OMe
-;:/ ~ S
X
II{S
~N ~~
O~~N--~ 6_..~ //l O ,,~N N,,~Me-[ °IN N ::'t Me z.,.. .,1.. -7 y ~N ~N0 f0O ~ o N k ~ o ~ O
Me
N
Mee
N_
[N, N,Me HN 0 I O~O L;/'~v~sN -MeO~O.~7 ~N ,0 ~ / ~)-Et Et telomestatin....c... ~--
MeO2~ Mle-/
N.:::/ i- Pr i-Pr
r
I
s
I
rO
5.5.2.8 Thiazole-Containing Thiazole-Containing Drug Candidates important thiazole analogs have been disclosed, disclosed, including including SSRA number of biologically important 125543 (CRF1 (CRF j antagonist antagonist as antidepressant, antidepressant, phase I) <06DF282>, <06DF282>, tebipenem and its 125543 prodrug, tebipenem tebipenem pivoxil (broad-spectrum (broad-spectrum antibacterial antibacterial agents, agents, phase phase II) <06DF676>, BMS-605541 (antitumor (antitumor agent) agent) <06JMC3766>, <06JMC3766>, GW610 GW6IO (antitumor agent) agent) <06JMC179>, BMS-605541 (antifungal agent, agent, phase I) <06DF187>, <06DFI87>, and AF267B AF267B (M1 (M j muscarinic receptor BAL-4815 (antifungal
263
Five-membered ring systems: with N Nand and S (Se) (Se) atoms
agonist for Alzheimer's disease, phase I) <06N671>. <06N671 >. The discovery of of the second generation epothilones as antitumor agents, including fludelone (preclinical), has been reviewed <06JOC8329>. S
~ ~~1/~"~
Me_~S N~~---"L~'O'~/OMe ~]I Me Me~
Me F . ~ ~
OMe OIk~e
N
JeSirN:=c:;e Fv=)-6-0Me
N
O",OH ,,OH Me l S N ~ F OMe e ~ , , "Me O,Me ~ ~ / ~ N -~ ~ ~ S GW610 M k--~l ~'~'O'Me Me ~~7 GW610 Me~\ /~--CI H o Me ~ ~ /; CI SSR-125543 0 H SSR-125543 fludelone O'~N/N~NM e O H " OH MeO N.I~ Et /N---~ Me H~ / Et~'-'S ~--/ /~\\ HO )L AF267B '\ ,N I H H jMe ]__? S ~'~JN AF267B \N-'NMe N Me M~e S
F3C/-~
Me
MeQ
H~:}--Q--CN
P-F
0
~__Fs---(/
F F
5.5.3
N)
p Me"o ~ N ~ S / - e
~
OJ-N~S
CO2R 2R C0 tebipenem(R (R == H) H) tebipenem tebipenempivoxil pivoxil tebipenem (R== OCH OCH2OC(O)t-Bu) (R 2 0C(O)t-Bu)
-
BAL-4815 BAL-4815
X:OMe
n
:t
F .,<,,,. g
N
S
FyyF
Y
\\rN~NH \~N--~/ "N N H / ~'%/'~NH 0 0 BMS-605541 BM8-605541
ISOTHIAZOLES ISOTHIAZOLES
of Isothiazoles Isothiazoles 5.5.3.1 Synthesis of A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium t~-cyanoketene a-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide <06SC825>. Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates isothiazole-3,5-dithiolates 229. The formation of229 of 229 is assumed to arise from the addition of of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230.
Ar Ar [
I
HN~"-CN HNI('CN O 226 226 0
NaOEt, NaOEt, CS C822
NaS SNa piperidine, piperidine, HOAc " HOAc ,...~ CN 95% Ar/ Ar/ CN sulfur sulfur 95% 0 O 227 227
)c
H I " ] I/
H N
S& n N~as iSe 1 ~8 ~I s~"-" NaS
Ar/ Ar
r
N
o
S8
228
-S~ ~
RS"'/S"N R = alkyl, aryl R alkyl, aryl
=
Ar/N'~ O
~SR 230
~
R-X
70-85% 70-85%
n
H H /N
75%
NaS"/S"N Na~S'N H ~! N Ar/N"~ Ar/ oO
~SNa SNa 229 229
A novel synthesis of isothiazolidines involves sulfonium ylides, formed by the reaction of thietanes and nitrenes <06TL 11 09>. Exposure of N-(p-tolylsulfonyl)imino)phenyliodinane <06TL1109>. of N-(p-tolylsulfonyl)imino)phenyliodinane 232 with excess of thietanes 231 (5 equiv) in the presence of of a catalytic amount of of Cu(II)
264
}1.-J. Wu and B. V. V. Yang Y.-J
acetylacetonate affords cis-isothiazolidines cis-isothiazolidines 234. One plausible explanation for the cis cis selectivity is that the cis isomer of the diastereomeric mixture of thietane 231 selectively reacts with 232 to form the sulfimide intermediate 233, which undergoes [1,2]-sigmatropic rearrangement to give the cis cis product 234.
R111 g R1 Ph'-NtslI JCf ~S
R11 R
Phl=NTs
R1
232
R2 RZ
56-75% 56-75%
~R' RZ~~NTS R "k.._eNTs
Cu(acac)z Cu(acac)2
231 231
R11 == aryl, aryl, alkyl R R 2 == aryl, aryl, H H RZ
RzJ:5S N R2
9
I
Ts 234 234
233 233
A series of benzisothiazolone derivatives 238 has been prepared from I I>. The key cyclization step features the formation of a methylthiosalicylate 235 <060L48 <06OL4811>. N-acylnitrenium the iodine ion 237, generated by hypervalent reagent, phenyliodine(III)bis(trifluoroacetate) (PIFA). This ion cyclizes to benzisothiazol-3-one 238 upon intramolecular trapping of the thiol moiety.
o 0
OMe ~OMe
llA"SH v
SH
R rJ~-R ~ r cit 1 llA 0
AIMe3, AIMe3, RNH RNH2 z
~ N
=
63-95% 63-950/0
235 235
v
PIFA I ~ N e _ _ I S _ HR = )~ ~ "SH
-R
"SH SH
236 236
o
0
R == aryl, aryl, benzyl, benzyl, Me Me R
60-78% 60-78%
,-
~N-R ~s ~~S N-R
238 238
237 237
Radical cyclization of acyclic sulfinamides 239 provides easy access to cyclic sulfinamides 241 <06AG(E)633>. Conceivably, the reaction pathway involves thiophilic attack by the aryl radical with a concomitant or successive expulsion of the p-tolyl or lerltertbutyl radical.
[1_{):"::
BU3SnH, AIBN -----_> R
N-RZ]
I
~.
\
'-.-(~S=O
239
Y
86O . o.
31-86%
>
-y
1:)" 240 Y 240 Y OMe, F, F, H; RZ2 = H, H, Me; X = Br, I;I; Y = Ts, t-Bu t-Bu R 11 = OMe,
241
O
A practical synthesis of the bicyclic dienyl sultam 246 has been reported <06JOC6573>. The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps.
o,~p
~o 4ste0s= CI
v
RCM ReM
~
Cl
98% 980/o 242
243
H
d'5 244
Et3N
=
F , ~ ste~-~
9~o/o 245
246
An efficient synthesis of N-alkylated-4-substituted isothiazolidine-dioxides (sultams) 251 has been developed utilizing epoxides 248 <06TL4245>. Addition of a secondary lA-dioxane affords the amino alcohol 249, which is sulphonamide 247 to epoxide 248 in hot 1,4-dioxane
265
Nand (Se) atoms Five-membered ring systems: with N and SS (Se)
converted to the benzensulfonate benzensulfonate 250. 250. Treatment of of 250 with with n-BuLi leads to the formation converted of N-alkylated-4-substituted N-alkylated-4-substituted sultam 251. 251. Chiral Chiral 4-substituted 4-substituted sultams are easily accessed accessed of translated to the product product through through the using the chiral epoxide. The chirality is faithfully translated inversion at the sulfonate-bearing sulfonate-bearing carbon carbon as a result of of cyclization occurring occurring exclusively via a inversion SN2 pathway. 00
OL/O \S/ 247 Me/S\NHR Me/'+ ......NHR2
4-
O 0 R l-j--~ R1?
K2C0 3 , K2003, E4NCI Et4NCl
Me ~O Me OH ~g S~.O
..]..~,.,~ I • RR1~N'R2 1 N'R2
86-97% 86-97%" 248 248
PhS0 2CI PhSO2Cl pyridine pyridine
Me,, Me tO0 's:s0 S~.c~
. R1~N'R2 BsO
= R1/~
I v N'R2 250 249 R11 = Ph, alkyl; R22 = Bn, Ph; Bs = PhSO2 PhS0 2
n-BuLi
0 O O~I / - - ~ ~::::O
-CN-
~
R1 72-83% 72-83%D. R1 (2 steps) steps)
N"R2 R2
251
of chiral 3-substituted 3-substituted sultams suitams 256 makes use of of a An asymmetric synthesis of diastereoselective nucleophilic addition reaction <06EJOC1271>. <06EJOCI271>. The nucleophilic nucleophilic 1,2diastereoselective of various organo-cerium organo-cerium reagents to the C=N double bond of of ~SAMP-hydraznoco-SAMP-hydraznoaddition of of the sulfonate 252 gives hydrazines 253 in good to excellent diastereoselectivity. Removal of chiral auxiliary by reductive N,N-bond cleavage and Cbz protection of the primary amine leads to aminosulfonates aminosulfonates 254. After ester hydrolysis and chlorination, the resulting aminosulfonyl chlorides 255 are cyclized under basic conditions to afford 3-substituted 3-substituted sultams 256. MeOJ",,/~x~ N--N~
78-99% 78-990/0"
YO)s+...~-~~ H O O
RMgBr RLi or RLi CeCl3 CeCI 3
MeO/"',,/~k, Meo"--""o H N -N .N~
Htr
BH BH3oTHF; 3·THF; CbzCI,K2CO3 CbzCI,K 2C0 3
YO.~s/--....../~ R YO'S~R
0' '0 O"O
252
50-99% 50-990/0
253 253
COCI 2 2 72-83%
NHCbz _NHCbz
Cl \ S . . ~ v / : - . . R CI"S~R 0"0 O' ~O 255 ee = 78-93%
HBr, HBr, HOAc; HOAc; Et Et3N 3N ,.
YO'S~R YOoS~,o~R
0"'0
254 ee = 78-93%
de = = 78->96% 78->96% EtOH, H H20; 20; NaOAc; NaOAc; =
NHCbz _NHCbz_
o
1[/0 HN-EO~' O-;5
HN-S/
J \ R~ R~''.//
Y = cyclohexyl alkyl, Ph R = alkyl,
256 ee = 78-93%
Chiral N-substituted benzisothiazole-3-one-l, I-dioxide (saccharin) derivatives 258 are benzisothiazole-3-one-l,l-dioxide synthesized via the direct ortho-lithiation ortho-lithiation of 3-N-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA <06TL6405>. Compounds 257 are readily prepared from (L)-amino acids.
o,,o _R
%/o LOA, HMPA
62-71%
R1 R2
Me,/-Pr, R = Me, i-Pr, s-Bu, Bn OH
R1 R2
257
O 258
R1, R R22== H, H, H; H; R\ or CH=CH-CH=CH
Various saccharin derivatives 260 have been prepared by chromium (VI) oxide catalyzed H H5IO6 ortho-toluenesulfonamides 259 <06T7902>. The reaction sI06 oxidation of substituted ortho-toluenesulfonamides presumably proceeds through a benzylic radical intermediate 261 generated from the
266 266
Y.-J. Y.-J. Wu Wuand andB. B.V.V. Yang Yang
abstraction abstraction of of aa benzylic benzylic hydrogen hydrogen by by chromium chromium oxo oxo and and peroxo peroxo species. species. Subsequent Subsequent intramolecular hydrogen hydrogen transfer transfer leads leads to to the the formation formation of of the the N-centered N-centered radical radical intermediate intermediate intramolecular 262. 262. This This radical radical is is easily easily oxidized oxidized to to the the carbonyl carbonyl diradical diradical 263 263 which which cyclizes cyclizes to to afford afford the the saccharin skeleton skeleton 260. 260. Alternatively, Alternatively, radical radical 262 262 can can undergo undergo aa second second hydrogen hydrogen atom atom saccharin abstraction to to give give an an alkyl alkyl diradical diradical 264, 264, which which undergoes undergoes intramolecular intramolecular coupling coupling to to give give abstraction sultam sultam intermediate 265. This intermediate can can be readily readily oxidized oxidized to 260. The excess excess H H5IO6 is to regenerate the high-valence chromium chromium species species to to force force the reaction to to sI06 used is completion. Further development development of of this methodology methodology culminates culminates in the direct direct synthesis synthesis of of completion. substituted substituted N-tert-butyl saccharin saccharin analogs analogs 267 from from their corresponding corresponding substituted substituted toluene derivatives 266 via aa one-pot, one-pot, three-step sequence: sequence: chlorosulfonation chlorosulfonation with chlorosulfonic chlorosulfonic acid, acid, trapping the sulfonyl sulfonyl chloride with tert-butyl tert-butyl amine amine and and the oxidative oxidative cyclization cyclization of of the resulting ortho-toluenesulfonamide. ortho-toluenesulfonamide.
°°
3 I (cr(n) Q"O~r/0 ~\)s~O (Cr(n) V ~ HI0 HIO3 "'i \J\~ '" S~NHR2 H-atom H-atom R1 ~--..~S\NR2 1QS'NHR 1 RI~-~ .I NHR22 Cr(n-1) Cr(n-1) HsIO~ H5106 RRl~fi"~~ S\ NHR2 transfer R transfer=_ Lt~_fl~CH3 [ Q~'...-:::: H++,,-e ~<"~CH3 -H -e : ' ~ C HCH 22 259 CH 3 259
261 261
H5106(8 (8 equiv), equiv), 1Cr03 HsI0 CrO3(10 (10 mol%) mol%)
12-92% 12-92% o
6
. ----
262
R1= = H, H, halogen, halogen,CF CF3, NO2 etc. R 2 etc. 3 N0 R22= = H, H, alkyl alkyl R ' 1
-H+, -e
o,, o RI~N-R 260
t
~S"NR2
2 ~ O
265
264
CIS0 t-BuNH 2, Et CISO3H; Et3N; 3H; t-BuNH2, 3N; H equiv), Cr03 H510 (7 equiv), CrO3 (10 (10 mol%), mol%), sI06 6 (7
R3~
R3 ,f~__. .. .v O//o \~ ~~N-t-Bu
AC20 (7 equiv), equiv), 38-79% Me Ac20 38-79%
266
267
1[Ol o,,/o
I~1--
S\NR2 O
263
3 =H, halogen, R3=H, halogen, R CF3, t-Bu , t-Bu CF 3
O
5.5.3.2 5.5.3.2 Reactions Reactions of of Isothiazoles Isothiazoles
of the J-substituted ~-substituted J-amino ~-amino sulfone 271 involves the A highly stereoselective synthesis of addition of of a sulfonyl anion, derived from N-PMB sultam 268 upon treatment with <060L789>. Removal of of the N-sulfinyl NaHMDS, to chiral N-sulfinyl imine (S)-269 <06OL789>. followed by basic workup affords amine 271. The stereochemical outcome of of the adduct 270 was established via proton NMR analysis of of the Mosher's Mosher's amide derived from 271.
PMB_N./~ PMB-NC) 3.(~, //~\,~ 268 268
°°
t-Bu....//N..s.. Ar t-Bu,-?-N'S,Ar TFA; PPMB-N~~'S,Ar MB-N~ H FA; 3 PMBN ~ (5)-269 O 0" NaHC0 (S)-269 N Ar TNaHCO3 NH2 PMB-N~NH2 's i-Bu : S II NaHMDS NaHMDS " (~' '~) t-Bu"S" " (~S~3 d'o i-Bu '0 i-Bu O 91% 91% 271 Ar 270 271 Ar == p-tolyl p-tolyl 270 dr dr >99:1 >99:1
c/
°
Diels-Alder reaction reaction between between isothiazole-dioxides isothiazole-dioxides and various dienes dienes represents represents an The Diels-Alder attractive attractive approach approach toward toward aa range range of of bibi- and and tricyclic tricyclic derivatives derivatives containing containing the the fused fused
267
ring systems: with Nand N and SS (Se) (Se) atoms Five-membered ring
Sc(OTf)3 appears heterocyclic nucleus <06EJOC4285>. In all the cycloadditions evaluated, Sc(OTf)3 to be the most effective catalyst which affords high yields under mild conditions. The two endo/exo selectivity in reactions with dienophiles 272a and 272b exhibit different endo/exo cyclopentadiene and furan. The 4-aryl substituted isothiazole-dioxide 272b gives a mixture of exo and endo adducts in all cases, with the latter being preferred (endo/exo: 5/1 5/1 with furan and 8/1 with cyclopentadiene, reaction not shown). However, a major selectivity is found with isothiazole-dioxide 272a, and the selectivity depends on the nature of the diene: -- CH CH2) cyclopentadiene delivers the endo adduct 273 (X = 2 ) exclusively, whereas the exo O) is the sole product from furan. addition product 274 (X == 0)
OX ~ h
o 'S'l0 u~O~'SON
r:'N
X
~ Sc(OTf.3.. 70% (X = CH2) CH2) "{ 70% (X = NHBn NHBn 88% 88% (X (X = = 0) O)
X Ox,.,//O X q,p CI~S'N ~H NHBn
H0
X
Sc(OTfh
J\__£~"o ~~Oo.. /
~H
~
+ +
272a
A r ~ Ng~O
I!-J--.-.H AH NHBn N
1 ",,#.N "'iN BnHN BnHN 273
NEt2
274
272b
endo/exo: 99/1 99/1 (X (X = CH CH2); 0/100(X = 0) O) endolexo: 2 ); 0/100(X
Ar = p-MeO-C6H4
The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, <06JHC1045>. The adducts from 4-bromoisothiazole (R 11= = Br) are labile and respectively <06JHCI045>. undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278 and isoxazolo-isothiazoles 281.
' 2~ " ~O' 0O R R2 2 R2CH2N2 R CH 2N2
~,,~O O~
276 J{N
R11 R
275 275
90% 90%
~
N;t 'N "
(B
e
85-90%
"
-HBr -HBr
. 74% (from (from 275) 275) 74%
'N ;;z
1 R2 = C0 H R NHBn HBn R2 CO2Et 2Et 277 277
NHBn NHBn
Ar-C=N-Oe Ar_C----N~_O 279 279
R2 R ~2 O "+30O
1 = Br RI=Br R
1 R =Br RI=Br
A~ ;;z N N'0 A~,,~O N;t
-HBr -HBr
'N
1
R
HBn NHBn
~ ~S
N;t 'N
I
'N ;;
NHBn H NHBn 278 R11= Br R =H. H, Br R22= CO2Et. Ph R =C0 2Et, Ph
O~O
Ar Ar~,.~O
Ar Ph. 22,6-diMe-Ph 6-diMe-Ph Ar = =Ph,
I ;;'NN N N;t'0oa4
87% (from 275) 275) 87% (from Ar =2,6-diMe-Ph Ar = 2,6-diMe-Ph
NHBn NHBn
281 281
280
The regioselective ozonation of of alkylidene-sultams 282 followed by reaction with diazomethane leads to the formation of of highly reactive bicyclic trioxo-isothiazolidine 284 <06HCA971>. <06HCA97 1>.
MeOx~CO2Me /'-
R
N
~SO2
MeO MeO.
C0 C O2Me 2Me
0):Js02
03 = O~N/S 02
57-75%
,\
MeO~CO2Me MeO\t~,~p02Me
CH2N2 = O ~ N ~SO2 0~N,~02 88%
R ==H. H, Me Me
t\
Me
Me
Me Me
282
283 283
284 284
3,5-Dichloro- and 3,5-dibromoisothiazole-4-carbonitriles 3,5-dibromoisothiazole-4-carbonitriles 285a/b 285a/b undergo regioselective 3,5-DichloroStille, Negishi, Sonogashira coupling reactions at C-5 to provide 3-halo-5-substituted 3-halo-5-substituted
268
Y.-J. WuandB.V Wu and B. V. Yang Y.-J.
isothiazoles <060BC3681>. <06OBC3681>. However, the analogous couplings with 3-chloro- or 3-bromo5-phenylisothiazoles 286a/b at C-3 fail to yield any desired products. To this end, the first 3iodo-5-phenylisothiazole-4-carbonitrile iodo-5-phenylisothiazole-4-carbonitrile 291 is prepared via Sandmeyer iodination of of the 33,5-dichloroisothiazole-4-carbonitrile 286a in two steps. amino analog 290, available from 3,5-dichloroisothiazole-4-carbonitrile palladium-catalyzed coupling reactions, and the This iodide shows sufficient reactivity in the palladium-catalyzed C-3 coupling products 287 and 292 are obtained in good yields. The cross-coupling reactions on azoles with two and more heteroatoms including isothiazoles have been reviewed <06EJOC3283>.
NC NC
X Suzuki NC XX NC X Suzuki or Stille ~s~N ~ = ~s~N X X S,N or or Negishi Negishi Ph Ph S/N
)j
)j
a:X= a: X = CI CI b: X = Br b:X=Br
285a/b 285a/b
Sonogashira 1Sonogashira 69-91% 69-91% NC NC
X X
~
~ .--::;N R R::;:;'---
,N S
288a/b
NC NC Ph Ph Suzuki ^)( v =_ ~s~N or or Stille Stille Ph Ph S/N Suzuki
)j
286a/b
287
80% or 80% or Stille Stille 90% 90%
Br2, NHBn Br2, NHBn AIBN
)j
Ph
S/N
289
P h ~ s S/N "N 292 Ph
Suzuki SUZUki~
BnNH2 j BnNH2 90% (X == CI) Cl) Yo (X 90 o
NC NC
XI
NC NC
NH22 NH
)j
AIBN" ~s~N 90% Ph 90% Ph S/N 290 290
R R
NC 'S 'I \;
i-amyl /-amyl nitrite, 12
T Sonogashira
~
70-100% 70-100%
NC NC
)j
II
nitrite,85%12D" • P h ~ s ~N 85%
Ph
S/N
291
5.5.3.3 5.5.3.3 Isothiazoles Isothiazoles as Auxiliaries Auxiliaries in Organic Organic Syntheses Syntheses Oppolzer's camphor sultam, a well known chiral auxiliary, has been utilized in the asymmetric [2,3]-sigmatropic rearrangement of of glycine-derived allyl ammonium ylides. These reactions are known to be highly selective in terms of relative and absolute <05JA1066>. For example, the stereocontrol with substrates bearing acyclic alkene moiety <05JAI066>. [2,3]-rearrangement of of N'N'N'-allyldialkyl N'N' N' -allyldialkyl glycinoyl (2S)-sultam salts 293 gives the allyl [2,3]-rearrangement glycine derivatives 295 with a high level of diastereoselectivity, in favour of of the (2'R)-isomer (dr > 96 : 4). However, when the chiral camphorsultams of of the ylides derived from Nmethyltetrahydropyridine (NMTP) undergo rearrangement, the reactions proceed with exclusive cis-stereoselectivity cis-stereoselectivity but no absolute stereocontrol as exemplified by the formation of of 1 : 1 diastereomers of of pyrrolidine carboxylates 297 and 298 from the NMTP (2S)camphorsultam salt 296 <06Tl1506>. <06Tl1506>. The lack of of diastereoselectivity in the cyclic series suggests that the sigmatropic rearrangements of N-chiral ammonium ylides are controlled by nitrogen stereogenicity.
269
Five-membered ring ring systems: with with N and S (Se) (Se) atoms Nand
Jv ~" ~Me -
'77 Xo~KT'\e \i
XS~ O.-~I ~ H HJ 64-99% 64-99~
Me NaH Nail=
RLN R{ e
N"""s
I
R1-~'R2
10
(f '0
H XS + R~H(xs R~"H " R ~ ~N "[~~N~ +
2 R
294
Br 293 0 + \~3
2'
0Me
0O
~
R
~
NaH
o
53O/o 53%
N"""
296 296
=
2'R/2'S = 96/4 96/4 to to >99/1 >99/1 2'R/2'S
Me Me
N~ N
Me e B~ Br
O
0
(2'S)-295
(2'R)-295
2= R11,, R2 = allyl, allyl, Bn, Me; XsS = = (2S)-camphor sultam Me
R2 2 R
0
Xs xs
S c:f O+ \'\(3 0
R
+ +
N\
XS Xs
O'~ ''s'' Xs
Me
297
(45:55) (45: 55)
Me
298
The camphor sultam auxiliary has been applied to the asymmetric aziridine synthesis via aza-Darzens reaction of N-diphenylphosphinylimines. Reaction of the chiral enolates derived from N-bromoacetyl (2R)-camphorsultam 299 with N-diphenylphosphinyl aryl and tertbutylimines 300 generates (2' (2'R,3'R)-cis-N-diphenylphosphinyl R,3' R)-cis-N-diphenylphosphinyl aziridinoyl sultams 301 in high diastereoselectivity <06T368l>. <06T3681 >. However, the stereoselectivity of this reaction depends on the structure of the imine substituents: arylimines substituted substituted in the ortho-position ortho-position usually give mixtures of cis- and trans-aziridines, trans-aziridines, and exclusively trans-configured trans-configured products 306 are obtained from ortho-bromo, ortho-bromo, iodo, and trifluoromethylphenylimines <06T3694>. Me.
Me
P(0)Ph P(O)Ph22
R R.. N
C~O 299
Br
+
+
il17NP(0)Ph NP(O)Ph2
Me
B'IrN~ •
or;
+ ~ l
o
H N H H NH XR
~RR
If O o
301 exclusive XRR = = (2R)-camphor sultam; R = = aryl, aryl, heteroaryl, vinyl, t-Bu Me
Br~o
40_78oo " 2 40-78% dr > 95: 95 955 dr>
300
O
[
NaHMDS
N
O+ \(3 0/\0 303
R
NP(0)Ph NP(O)Ph22
P(0)Ph P(O)Ph22 [I
H N H
LiHMDS
69-72% 69-72%
304
XSs = = (2S)-camphor sultam
P(0)Ph P(O)Ph22 [
XRrR
H N H H NH R
xR
oO
302 none P(0)Ph P(O)Ph22
[I H H N NH H
x'l)) o R/~
~{)O
305 exclusive for R = H, N0 NO22
306 306 exclusive for R= = Br, I, CF CF33
XS.. ~
R
An elegant application of Oppolzer's sultam in the asymmetric [C+NC+CC] coupling reaction provides convenient access to a variety of pyrrolidines 312 in a single step <06OL3647>. Simply mixing aldehyde 307, chiral amine derived from glycyl (2R)(2R)<060L3647>. camphorsultam 308, and electron-deficient alkene 309 in THF in the presence of a catalytic amount of silver acetate results in the clean production of highly functionalized pyrrolidines 312. The reaction proceeds through imine 310 formed from aldehyde 307 and amine 308. The subsequent [3+2] [3+2] cycloaddition with alkene 309 leads to 2,S-cis 2,5-cis disubstituted pyrrolidines, presumably via the intermediacy of a metalated (E, E)-azomethine ylide 311. The Oppolzer's chiral glycyl sultam serves several important roles: (1) it reduces the nucleophilicity of the amine component, thus preventing unwanted Michael addition; (2) it
270
Y-J BY. r.-J. Wu and B. V. Yang Yang
facilitates azomethine ylide formation by enhancing the a-acidity or-acidity of the imine; (3) it controls the diastereofacial diastereofacial selectivity of the 1,3-dipolar 1,3-dipolar cycloaddtion in a predicable maner, i.e. alkene approaching from the endo-Re e n d o - R e face of the (E,E)-azomethine ylide as depicted by 311. m
R~)(~H0307 RI" ~CHO ~, ".R2
+ +
AgOAc (5 mol%) R (5 mol%) H2N N ..COX COX R H zy.... •
r<
H~"I-I 308
H H 308 + + H H
>=< )-~ Z
Y Y
Z
°
307
309
end~Re Mi:¥e Me
X
R
O~ '''XR
Y
H4, R 2
y
R
1( H
~H
H
xR
H~~~R N 11 >
V
H N)rH ,O~N' N " =..O.,,,y~N~s,~ H-'-"';: S R~" jJ Kg, Elle/L.. 0/ R2../[[. Ag, 0 ''0 0 -H R1l . l r 'H z2 'Ni8 H Nfe ~H H H 310 310 RR;" R I ~1\Hv 311 311 1
63-94% 63-94%~R dr: 7:1 7:1 to 19:1 19:1
~
O
R H'')_-{O Z Y
312
312
H R1~= = Bn, BnO, alkyl; RZ2 = H, NHBoc; Y = COzMe, NHBoc; Y CO2Me, SOzPh; SO2Ph; Z = H, COzMe CO2Me Y, Z = CON(Ph)C(O); CON(Ph)C(O); XRR=(2R)-camphor =(2R)-carnphorsultam sultam or Y,
Other applications applications of Oppolzer's sultams include diastereoselective allylation of glyoxylic oxime ethers <06TL611>, asymmetric aldol reactions in the syntheses of macrolide FD-891 <060L2695> and antitumor antibiotic <06OL2695> antibiotic belactosin and its analogs <06JOC337>, silver (1) (I) promoted asymmetric halomethoxylation of a, ct, p-unsaturated [3-unsaturated carboxylic acid derivatives <06TA21 0>, Lewis acid-catalyzed [4+2] <06TA210>, [4+2] cycloaddition of a, t~, p-unsaturated ~-unsaturated carboxylic acid derivatives to cyclopentadiene and cyclohexadiene <06TA822>, dialkylboron triflatepromoted anti anti addition of acylated Oppolzer's sultam to aldehydes <06TA1152>, <06TA1152>, and Baylis>. Hillman reaction with Oppolzer sultam derived acrylamide <06EJOC4731 <06EJOC473 1>. 5.5.3.4 Pharmaceutically Pharmaceutically interesting isothiazoles Several biologically active isothiazoles isothiazoles and their saturated and/or oxygenated analogs have been reported in 2006. Isothiazoles have been incorporated into TrkA kinase inhibitor 313 <06BMCL3444> and the allosteric allosteric MEKI MEK1 (MAP kinase/ERK kinase) inhibitor 314 sultams into the selective selective TACE (TNFa (TNF~ converting enzyme) inhibitor 315 <06BMCL5561>, suItams (ICso: MMP-l, 2, 9, 13 > 2128 nM) <06BMCLl028> (ICs0: TACE 5.9 nM, MMP-1, <06BMCL1028> and human melanocortin subtype-4 receptor (MC4R) selective agonists 316 <06BMCLll30>. <06BMCLl130>. Compounds containing isothiazole isothiazole moiety that are currently in clinical development include STA-5312 (rosabulin), (rosabulin), a tubulin binder for the treatment of drug-resistant cancers (Phase 1) I) <06BMCL5164>, and CP-547632, a potent, selective and orally bioavailable vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor inhibitor for cancer therapy endothelial (phase II) <03CR7301 <03CR7301> >
271 271
Five-membered ring systems: systems." with Nand N and S (Se) (Se) atoms atoms
OH OHHN~Me , ~ ~~.Me r W"
~
s Ii
OH H~
NH OH
/-~S.~O
O
o
NH
9 9
s
o
313 313
o
CI
CII C
C'"S ~ ' sd-'o ~ ~.j
Me 314 314
316 R - H, Me
315
N.~o H
CN
~
H
O o 5.5.4
S,,
~~S~~
~Me Me STA-5312 STA-5312
CP-547632
THIADIAZOLES THIADIAZOLES
A practical a-heteroarylation c~-heteroarylation of simple esters or amides has been developed via nucleophilic aromatic substitution. Exposure of chlorothiadiazoles 317 and 319 to NaHMDS ,N-dimethylacetamide leads to the formation of functionalized and tert-butyl tert-butyl acetate or N N,N-dimethylacetamide 1,3,4-thiadiazole 1,3,4-thiadiazole 318 and 1,2,4-thiadiazoles 320, respectively <060Ll447>. <06OL1447>. t-Bu, N = ~ rC02t-Bu N___(CI CI MeC0 MeCO2t-Bu, cO2t-Bu 2 NaHMDS -NaHMDS f'J9 NyS N yI S 79o/o "• NyS N yI S 79% Ph Ph Ph Ph
f'J={ ~7 317
~8 318
CI /--C(O)R N-----~ NaHMDS MeC(O)R NaHMDS f'N---------[ IN={ J="\ CI MeC(O)R
Sv N S,,,~N
rC(O)R
Ph Ph
•.. SvN 69-87% S,~N 69-87% I Ph Ph
~9 319
~o 320
t
R =Ot-Bu,'Bu' NMe2R=Ot NMe2
Direct electrophilic electrophilic silylation of of thiadiazole 321 with bromotrimethylsilane (TMSBr) under basic conditions provides easy access to C-silyl thiadiazole 322, which can serve as a synthetic equivalent of <06Sl279>. of an organometallic intermediate or a silyl-protected azole <06S 1279>.
N-N
Ph~s ,~ 321
TMSBr, TMSBr, Et Et33 N N pyridine-toluene pyridine-toluene
720/0 72%
.--
N-N N-N Ph--ZS>--TMS PhJZ'S'h"TMS
322
Reaction of of N,N-dimethylsulfamoyl aziridines 323 and 325 with primary amines furnishes substituted 1,2,5-thiadiazolidine 1,2,5-thiadiazolidine 1,1-dioxides l,l-dioxides 324 and 326, respectively, in a regioselective manner <06SL833>. Aziridine Z)-bicyclo[4.2.1]non(lR,6S,Z)-bicyclo[4.2.l]nonAziridine 325 is made from (1R,6S, dimethylsulfamide 3-en-9-one in two steps: N,N-dimethylsulfamoyl imine formation using dimethylsulfamide 3-en-9-one and subsequent reaction with trimethylsulfoxonium ylide. The product from the reaction with 4-methoxy-benzyl amine can be subsequently manipulated (debenzylation and derivatization) to give the alternative alternative nitrogen substitution pattern in a controlled manner. derivatization)
272 272
Y-J. Wu and and B. V. Yang Y.-J.
sulfamides 326 326 serve as key intermediates intermediates in the synthesis synthesis of of a series series of of potent potent and Cyclic sulfamides selective 7-secretase y-secretase inhibitors inhibitors with with potential potential for the the treatment of of Alzheimer's Alzheimer's disease. selective O 0 IIII
0 O iiII R\ MezN-S=O " MezNSOzNH z, I Ti(OEt)4' 50% RNH z
O oo 0 \\11
MezN-S=O RNH Me2N--S=OI O 0 S z I RNH2 HN' 'N-R N = HN.S..N_R ~ N 64-87% , . ~ Bn. -C-& 64-87% n/~ ~-/ Sn "..
.
9
324 Sn 324 B
323
alkyl, ARCH2 ArCH z R ==alkyl,
O 0
II
Me2NSO2NH2,Me2N--S=O N'SII=O I ti(oet)4,50% ~ RNH2 ~ H .. = _ ";,,_..... 60-87% Me3S(O)l, 60-87% Me3S(O)I, Nail NaH 87%
8/
9
87%
; ....
325 325
......
326 326
5.5.5 1,3-SELENAZOLES, 1,3-SELENAZOLES, 1,3-SELENAZOLIDINES 1,3-SELENAZOLIDINES AND AND 1,2,3-SELENADIAZOLES 1,2,3-SELENADIAZOLES 5.5.5 A A series of of 5-acyl-2-amino-l,3-selenazoles 5-acyl-2-amino-l,3-selenazoles 331 are prepared prepared from selenazadienes selenazadienes 327 327 upon treatment with ~-haloketones a-haloketones 328 328 in hot methanol or acetonitrile. In the presence presence of of upon triethylamine, reaction of of selenoazadienes 332 with 1,3-dichloro-propan-2-one 1,3-dichloro-propan-2-one (5 equiv) affords the bis(selenazoyl) ketones 333 in high yields, whereas the same reaction without base produces CH2C1) produces the corresponding corresponding selenazoles 331 (R 33 = CH <06831>. 2Cl) preferentially <06S31>.
R1 R2-N.,~Se
O X-~R3
R1 R2-N- Se
1 R1 t R-N. SSe
I
I
R2-N
/ 1}cOR 1 3
R
x =Sr, Br, CI Cl 327N~NMe2 X=
329 ~r
330 NMez NMe2 _]
330
-Me2NH Rt 11 R R2-N Se R2-N Se COR3 N~/.~/k~COR3
1 68-100% -MezNH 168-100%
R1
O O R2-N"~ se Cl.~..../Cl R1, Se ~ - S e R1 N~, Et3N -" R2.N~NZ " ~ ! ~ - N'.R2 NMe2 82-91% 332 333
lr 331
Reaction of N,N-unsubstituted selenoureas 332 with methyl vinyl ketone in the presence of ferric chloride in refluxing ethanol gives 2-amino-5-(1-ethoxy)-1,3-selenazoles 2-amino-5-(1-ethoxy)-l,3-selenazoles 335 <06H(68)2145>. <06H(68)2145>. This approach obviates the use of lachrymatory halo carbonyl compounds frequently utilized in the synthesis of 1,3-selenazoles. 1 R R1 I
R2- N
~x~_~/l~' e
~x~ ~Me o
R2-1(I'ySe ~SeNH2-FeC.3, " --> FeCI 3, NHz EtOH EtOH 332
R1
R1
i [ 2_R1
R2-N~se
N NI ~ ~
N~
L
333
I
Me
R11
i R1
R2-N~se
]
S~HH - -"~R2-N"~''N 1,,'-..,. N~
.I. . '1
334 Me
OEt
2 Ri
liD Et
77-89% R2- N'Y,-se
-N'_FeC.2= R SNI~/~O -77-89~176 -FeClz -HCI
-HCI
N)
OEt
Me 335
A novel synthesis of 1,2,3-selenadiazoles 338 starts with the Michael addition of 2nitropropane to a,~-unsaturated ~,13-unsaturated ketones 336 under basic conditions <06JHCI49>. <06JHC149>. The resulting adducts are treated with semicarbazide hydrochloride to give semicarbazones 337, which are converted to 1,2,3-selenadiazoles 338 by reaction with selenium dioxide in THF (the choice of the solvent appears to be important in this case).
273
Nand Five-membered ring systems: systems." with N and S (Se) atoms
H / NNH H22
oO
Ar~Ar' A r / ~ k - - Ar'
NI N
%0
h - ,N0
-
Se02 SeO2 2
Ar ..)-f-Me /'---~M e Ar' Ar' Me 337
336
N-.N.-se N~"N'se NO //~.~ NO2
N ,N-{
1. 1. Me2CHN02, Me2CHNO2, NaOMe NaOMe 2. 2. NH NH2NHC(O)NH2 2NHC(0)NH2
•
2
62-73%" Ar Ar 62-73%
Me )----('Me Ar' Me 338
Alkylisoselenocyanates 339 are versatile starting materials for the synthesis of of various N-aUylselenoureas selenium-containing heterocycles. Reaction of of 339 with allylamine yields N-allylselenoureas 340 which undergo intramolecular cyclization in the presence of of hydrogen chloride to afford imino-selenazolidines 341 <06CL626>. When propargylamines 342 are used 5-methyl imino-selenazolidines instead of allylamine, 5-methylidene-selenazolidines 5-methylidene-selenazolidines 343 are obtained directly <06H(68)1607>. Addition of 339 with sodium hydroselenide generates the intermediate Nalkyldiselenocarbamates 344, which react with bromoacetylbromide 345 to provide oxoselenazolidines 346 <06S2738>.
Se Se
H2N~ R-N=C=Se R-N=C=Se 339 339
342
H2N~,. R'N.Jl.N~ R-N~IJ-.N~HCl, EtOAc
---_I
.
81-100%
H H 340
89-97%
XNHRI65-97%
R = aryl, Bn, R : ary,, Bn, cycloalkyl cycloalkyl 1 H, Me RI= R = H, Me
H . L I %N
I )=NN Me7 ~Se R R M~se 341 341
R = aryl, aryl, cycloalkyl cycloalkyl
~ ~ , , ~NaHSe
Rq ~~bN,R
HCI, EtOAc
[ se ] R'N H
..~
Sg
344
343
R2 0
Se
R3"~Br Br 345
R.N4 .
10-37% 10-37%
R2 346
Alkylisoselenocyanates 339 are also used in the synthesis of 2-methylidene-l,3selenazolidine derivatives <0613344>. <06T3344>. Nucleophilic addition of of the carbanion derived from malononitrile malononitrile 347 to 339 leads to an intermediate keten-N, Se-acetal 348, which reacts with 2haloacetate ester and 1,2-dibromoethane 1,2-dibromoethane to provide 1,3-selenazolidin-4-ones 1,3-selenazolidin-4-ones 350 and 1,3selenazolidines selenazolidines 352, respectively. 1 R CH 2CN RICH2CN 2CH(X)C0 R3 , R R R Br(CH2)2Br 347 R2CH(X)CO2R3' Br(CH 2 2l2Br,, 347 O~-.v tq CN Et J NN CN Et Et33 N ++ Et33N CN 0XN CN /
>=<
"
R11 CrR 352
T
t
31-62% 31-62% R = aryl, aryl, cycloalkyl cycloalkyl 1 = CN, C0 Et R RI= ON' CO2Et 2
[(BbNR ON] [(~~F
Br(CH Br(CH2)2Br 2l2Br
R1
351 351
5.5.6
R-N=C=Se R-N=C=Se
339 339
34-86% 34-86% R2 == H, H, Me Me R
1I EtEt3NN
X = CI, Br X=CI, Br R33 == Me, Me, Et Et R
3
]
[HN ON [eH~ _ CN] R
Se>=
2CH(X)C0 3 (X)CO2R3 R 2R ,. R2CH
1
R 2 L SSe e ' ~ R R1 R2 350
t
[1:~e o "-.-/ >=
I|
R1
Se
349 349
ACKNOWLEDGMENT ACKNOWLEDGMENT
of this review. We thank Dr. Richard Hartz of Bristol-Myers Squibb for critical reading ofthis
274
5.5.7
y.-1. Wu and B. V. Y.-J. V. Yang
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06JA2995 06JA3128 06JA4460 06JA4932 06JA4936 06JA6536 06JA7418 06JA10513 06JAI0513 06JAI6018 06JA 16018 06JHCI49 06JHC149 06JHC 1045 06JHCI045 06JHC1609 06JHCI609 06JMCI79 06JMC 179 06JMC3766
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2276 76
Y.-J. Wu Wu and B. V. V. Yang Y.-I.
06TL6405
Org. Lett. 2006, 8, 2695. lJ. Garcia-Fortanet, J. Murga, J.A. Marco, Org. M.T. Crimmins, G.S. G.S. Vanier, Org. Org. Lett. 2006, 8, 2887. B. Sezen, D. Sames, Org. Org. Lett. 2006, 8, 2899. Org. Lett. 2006, 8, 3057. D.e. Myles, Org. 2006,8,3057. B.R. Hearn, D. Zhang, Y. Li, D.C. Garner; H.U. H.U. Kaniskan; lJ. Hu, J. Wiley; M. Panzner, Org. Org. Lett. 2006,8,3647. 2006, 8, 3647. P. Gamer; T. Doi, M. Yoshida, K. Shin-Ya, T. Takahashi, Org. 2006,8,4165. Org. Lett. 2006, 8, 4165. B. Zajc,.s. Zajc,.S. Kake, Org. Org. Lett. 2006, 8, 4457. lJ. He, lJ. Zheng, lJ. Liu, X. She, She, X. Pan, Org. Org. Lett. 2006, 8, 4637. lJ. Hassfeld, e. C. Fares, H. Steinmetz, T. CarIomagno, Carlomagno, D. Menche, Org. Org. Lett. 2006, 8,4751. 8, 4751. A. Correa, I. Tellitu, E. Dominguez, R. SanMartin, Org. Org. Lett. 2006, 8, 4811. V.B. Birman, L. Guo, Org. Org. Lett. 2006, 8, 4859. X. Mu, lJ. Zou, Q. Qian, W. Zhang, Org. Org. Lett. 2006, 8, 5291. J.D. White, T.H. T.H. Lee, P. Kuntiyong, Org. Org. Lett. 2006, 8, 6043. 2006,8,6043. M.e.T. Fyfe, P. Martin, PJ. P.H. Briner, M.C.T. P.J. Murray, F. Naud, MJ. M.J. procter, Org. Org. Process Res. Dev. 2006, 10, 346. H.lshihara, M. Koketsu, M. Kogami, H. Ando, H. Ishihara, Synthesis 2006, 31. I.I. Pervak, A.S. Merkulov, A.A. Yurchenko, A.A. Tolmachev, A.M. E.V. Zarudnitskii, I.I. Pinchuk, Synthesis 2006, 8, 1279. 1279. B.K. Pal, Pal, Synthesis 2006, 1289. S.K. Chattopadhyay, S. Biswas, B.K. 1289. M. Koketsu, Y. Yamamura, H. Ishihara, Synthesis 2006, 2738. S.A. Ahmed, Synth. Commun. 2006, 36, G.H. Elgemeie, A.M. Elzanaty, A.H. Elghandour, EIghandour, SA 825. P.W. Sheldrake, M. Matteucci, E. McDonald, Synlett 2006, 460. lJ. Hannam, T. Harrison, F. Heath, A. Madin; Madin; K. Merchant, Synlett 2006,6,833. 2006, 6, 833. M.e. M.C. Bagley, C. Glover, Tetrahedron 2006, 62, 66. M. Zhao, lJ. Yin, M.A. Huffman, Huffman, J.M. J.M. McNamara, Tetrahedron 2006,62,1110. 2006, 62, 1110. H. Motoyoshi, M. Horigome, H. Watanabe, T. Kitahara, Tetrahedron 2006, 62, 1378. 1378. T. Aoyama, S. Murata, I. Arai, T. Takido, Y. Suzuki, M. Kodomari, Tetrahedron 2006, 62, 3201. Sawant, B. Saha, Saha, B. Kundu, Tetrahedron 2006, 62, 3228. S. Duggineni, D. Sawant, G.L. Sommen, A. Linden, H. Heimgartner, Tetrahedron 2006, 62, 3344. J.B. Sweeney, A. Tavassoli, A.B. McLaren, S. Thobhani, Tetrahedron 2006, 62, 3681. J.B. Sweeney, A.A. Cantrill, M.G.B. Drew, A.B. McLaren, S. Thobhani, Tetrahedron 2006, 62, 3694. 62,3694. L. Xu; H. Shu, Shu, Y. Liu, S. Zhang, M.L. Trudell, Tetrahedron 2006, 62, 7902. K. Kobayashi, M.S. Mohamed, A. Mori, Tetrahedron 2006, 62, 9548. W. Zhang, Z. Ma, D. Mei, C. Li, X. Zhang, Y. Li, Tetrahedron 2006,62,9966. 2006, 62, 9966. J.B. Sweeney, A. Tavassoli, lA. J.A. Workman, Tetrahedron 2006, 62,11506. 62, 11506. H. Akita, N. Sutou, T. Sasaki, K. Kato, Tetrahedron 2006,62,11592. 2006, 62, 11592. 17, 210. S. Hajra, A. Karmakar, M. Bhowmick, Tetrahedron Asymmetry 2006, 2006,17, A. Chojnacka, A. M. Piatek, e. C. Chapuis, J. Jurczak, Tetrahedron Asymmetry 2006, 17, 822. B.H. Fraser, D.M. D.M. Gelman, P. Perlmutter, F. Vounatsos, Tetrahedron Asymmetry 2006, 17, 1152. S. Chandrasekhar, B. Saritha, V. Jagadeshwar, SJ. S.J. Prakash, Tetrahedron Asymmetry 2006, 17, 1380. Y. Nakamura, K. Okumura, M. Kojima, S. Takeuchi, Tetrahedron Lett. 2006,47,239. 2006, 47, 239. N.A. Kulkarni, K. Chen, Tetrahedron Lett. 2006,47,611. 2006, 47, 611. 2006, 47, 1081. S. Hara, K. Makino, Y. Hamada, Tetrahedron Lett. 2006,47,1081. V. Nair, S.M. S.M. Nair, S. Devipriya, D. Sethumadhavan, Tetrahedron Lett. 2006,47,1109. 2006, 4 7, 1109. MJ. M.J. Thompson, W. Heal, B. Chen, Tetrahedron Lett. 2006,47,2361. 2006, 47, 2361. B.T. Kim, l-N. J.-N. Heo, Tetrahedron Lett. 2006,47,3091. 2006, 47, 3091. Y. Heo, Y.S. Y.S. Song, B.T. E. Cleator, F.J. FJ. Sheen, M.M. Bio, K.M.J. K.MJ. Brands, AJ. A.J. Davies, U.-H. Dolling, Tetrahedron Lett. 2006, 47, 4245. A. Ould Aliyenne, J. E. Khiari, lJ. Kraiem, Y. Kacem, B. Ben Hassine, Tetrahedron Lett.
06TL7477 06TL866I 06TL8661
2006,47,6405. 2006, 47, 6405. 2006,47,7477. K. Kallstrom, P.G. P.G. Andersson, Tetrahedron Lett. 2006, 47, 7477. P.K. Sasmal, S. Sridhar, 2006,47,8661. Sridhar, J. Iqbal, Tetrahedron Lett. 2006, 4 7, 8661.
060L2695 06OL2695 06OL2887 060L2887 06OL2899 060L2899 060L3057 06OL3057 06OL3647 060L3647 060L4165 06OL4165 060L4457 06OL4457 06OL4637 060L4637 06OL4751 060L475I 060L48 II 06OL4811 06OL4859 060L4859 06OL5291 060L5291 06OL6043 060L6043 06OPRD346 060PRD346 06S31 06SI279 06S1279 06S1289 06S2738 06SC825 06SL460 06SL833 06T66 06Tl110 06TIII0 06T1378 06T3201 06T3228 06T3344 06T3681 06T368I 06T3694 06T7902 06T9548 06T9966 06T 11506 06T11506 06T11592 06TA210 06TA822 06TAI152 06TA1152 06TA1380 06TL239 06TL611 06TL 1081 06TLl081 06TL 1109 06TLlI09 06TL2361 06TL236I 06TL3091 06TL4245
o
277
Chapter 5.6 Five-membered ring systems: with 0O & S (Se, Te) atoms
R. Alan Aitken* and Lynn A. Power University ofSt. of St. Andrews, UK (e-mail: [email protected]) raa@ st-and.ac.uk)
5.6.1
1,3-DIOXOLES DIOXOLANES 1,3-DIOXOLES AND AND DIOXOLANES
The conversion of 1,2-diols into the corresponding 2,2-dimethyl-I,3-dioxolanes has been corresponding 2,2-dimethyl-1,3-dioxolanes PII,2 <06SL305>, while highly achieved by reaction with acetone and polymer-supported Ph Ph3P/I 3 stereoselective conversion of trans epoxides 1 into the cis dioxolanes 2 has been reported <06EJO3007> or photocatalytically with a using acetone with either a Lewis Acid <06EJ03007> pyridinium salt catalyst <06H(68)1861>. <06H(68)1861>. Conversion of non-enolisable aldehydes and ketones, RIR'C=O, R'R2C=O, into dioxolanes 3 can be carried out in excellent yield by slow addition of l DMF <060L3745>. <06OL3745>. An 2-chloroethanol in DMF KOBu t to a mixture of the compound and 2-chloroethanol interesting dioxolane to dioxolane rearrangement is involved in the conversion of 4 into 5 upon acid-catalysed treatment with ethanediol <060BC22l8> <06OBC2218> and the stereospecific <06JOC1537>. Palladium-catalysed rearrangement of 6 to give 7 has also been described <06JOCI537>. coupling of aryl halides with 2-hydroxyethyl vinyl ether gives either of the isomeric dioxolanes 8 or 9 depending on the catalyst and ligands used <06EJ0765>. <06EJO765>.
.o
O
RI~--~,,,R2
RI~R 2
O.
TsOH
2
3
~
68%"
4 ~
O2N
z
5
O/~Ph BF3,Et20 O2N
6
R~ ~ O ~ c o 2 M e
O 7
8
~O R1
002
=
_
|0
CO2Me
11
R2
12
R
9
~~O O 13
278
Aitken and and L.A. L.A. Power Power R.A. Aitken
of substituted catechols catechols with DMAD DMAD and 0.1 equiv. DABCO DABCO directly gives the Reaction of <06S2286> and photochemical addition of of 1,3-dioxolan-2-yl radicals to benzodioxoles 10 <06S2286> benzodioxoles products 11 <06CC4300>. <06CC4300>. New studies on the industrially alkynes in acetonitrile affords products of epoxides 12 to give dioxolan-2-ones dioxolan-2-ones 13 include include catalysis by important carboxylation of phosphonium salts <06CC1664>, <06CC1664>, quaternary ammonium saltsilica-supported quaternary phosphonium <06TLl27l> and tris(dibutylamino)bromomethane with terminated polyethyleneglycol <06TL1271> of 1,3-dioxolan-2-ones 1,3-dioxolan-2-ones from 1,2-diols and ZnBr,2 <06JMOC(250)30. <06JMOC(250)30. The formation of ZnBr diphosgene is efficiently promoted by activated charcoal <06S885>. of routes to dioxolanones involving metal-promoted cyclisation of of alkenyl and A variety of alkynyl carbonates and other esters has been described and these include copper triflatecatalysed reaction of of t~-allyloxy a-allyloxy acids to give dioxolan-4-ones <06EJO3554>, <06EJ03554>, palladiumof hexa-2,4-diene-l,6-diol monocarbonates to give mediated rearrangement and cyclisation of <06Tl1218>, and cyclisation of propargyl carbonates and esters to afford 4dioxolan-2-ones <06T11218>, alkylidenedioxolan-2-ones using mercuric triflate <06TL8369, <06TL8369, a gold(I) complex <06OL515> <060L515> or a palladium catalyst <06T2545>. More unusual methods leading to dioxoles of the Meldrum's acid diazirine 14 to give 15 and dioxolanones include Wolff rearrangement of <06RJOCI213>, <06RJOC1213>, reaction of succinimide with methyl 2-diazoacetoacetate to give 16 SnCl 4-promoted reaction of the fluorinated carbamate 17 with furan to give <06TL2643> and SnC14-promoted 18 among the products after hydrolytic work-up <06JA13130>.
O
N :>
14
3 19
o0
>tx
O hv MeOH. ..L~, o.~CO2Me _O , ~O~ O O~'/-N O~ ~ F~== O NEt2 O C0 CO2Me H F CO2Et 2 Me
_hV_,_M_eO_H__
°
15
O
o
o}\-. o Bu'CHO utc o R--< R~/-" 0 =R o--4.. 0Me O~OM e 20 20
16
17
~ 1 [ SnCl4 Q
O
21
SnCI 4
But
HO'"F ~ O ~ HO"'QO FF F
~_ o~o0
Et02C EtO2C
18 18 A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047l29> <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of <06Tl864> the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with 15>. pivalaldehyde <06S39 <06S3915>. Newly reported conditions for hydrolysis of 2,2-disubstituted dioxolanes to give the corresponding aldehydes or ketones include treatment with I, 12formed in situ from CuS0 CuSO 44 and Nal NaI in acetone <06SL215>. Electrochemical fluorination of 1,3-dioxolan-2-one to give 22 has been reported <06MI2477> while loss of SPh and either radical addition or substitution results <06SL 1015>. 015>. Both cis when 23 is photolysed in the presence of alkenes or arenes respectively <06SLl and trans divinyldioxolanones 24 have been prepared by reductive coupling of acrolein followed by cyclisation with diethyl carbonate, and used for palladium-catalysed asymmetric 1>. A Barbier-type allylation in water results when 2-aryl-I,3-dioxolanes alkylation <06JA393 <06JA3931>. 2-aryl-1,3-dioxolanes [3-cyclodextrin are treated with allyl bromide, zinc and ammonium chloride in the presence of p-cyclodextrin to give ArCH(OH)CH,CH=CH, ArCH(OH)CH2CH=CH 2<06TL2133>. Treatment of the ferrocenyl dioxolane 25 with
279
Five-membered ring systems: with 0 & & S (Se, (Se, Te) atoms
alkyllithiums, RLi, gave not the expected ortho-metallation but the two products 26 and 27 <06T9038>. A review of silylated heterocycles as formyl anion equivalents includes mention of compounds such as 28 <06CC4881>. <06CC4881>. F. F
FLO o >=0 0
PhS~O>=O
22 22
23
"O 0
",,/OMe
Fe
RLi
~
o
28
24
O~OMe ~ . . ~ O M e RLi
\Q!
C00>-TMS
o
:):0 o /=0
o
OH
,.
25
OH \Q!<:=C \Q!
Fe
Fe
27 27
26
Various new studies on the asymmetric reactions of chiral hydroxy acid-derived dioxolan4-ones 21 have appeared, including Michael addition of their anions to ethyl crotonate and <06ARK(vii)292>, to enones <06T9174> and 2-benzylidene-1,3-diones 2-benzylidene-l,3-diones butenolide <06ARK(vii)292>, <06JOC6785>. Addition of <06T8069> and to sugar-containing chiral N-sulfinylimines <06JOC6785>. <06OL5729>. The [2+2] achiral dioxole anions to chiral N-sulfinylimines was also described <060L5729>. cycloaddition of chiral 5-alkylidene-I,3-dioxolan-4-ones 5-alkylidene-l,3-dioxolan-4-ones to dichloroketene has also been reported <06T4153>. New applications of dioxolane compounds include the formation of polymers containing spiro-2,2-bis dioxolane units <06MI2875>, <06MI2875>, and a variety of polymers with different uses containing fluorinated dioxole and dioxolane monomer units <06MM7591, <06MM7591, 06JPS(A)1613, 06JPS(A)1613, 06MIl017, 06MI 1017, 06MIl703, 06MI 1703, 06MIl873, 06MI 1873, 06JPS(B)1385>. 06JPS(B) 1385>. New TADDOL TADDOL derivatives 29 have been made <06S2159>, and used as catalysts both as such <06JOC1359> <06JOC1359> and in the form of derivatives like 30 which acts as a ligand for Pd-catalysed coupling of aryl chlorides <06CC1419>. The behaviour behaviour of bicyclic dioxolanes such as 31 <06S3122> and 32 <06SL331> as peptidomimetics has been reviewed. A variety of bicyclic dioxolane compounds 33 have been useful for treating conditions associated with blood platelet <06WOP105529> and the tricyclic dioxolane 34 has been patented aggregation or activation <06WOPI05529> <06USP128604>. as a fragrance ingredient <06USPI28604>.
R rR o A~,~.~ oH ><0 OH
~
o
OH
OAr~R Ar R OH 29
o0
Ph Ph Ph Ph
P'H >
\ o ~ % - q ~o Ph Ph
R11 R
/~-- o
HO2C~31 32
30
:
~=Gx
R2
33 X = = 0, O, S, NH, CH z 2
R3
o
34
280 5.6.2
R.A. Aitken Aitken and and L.A. LA Power Power R.A.
1,3-DITHIOLES AND AND DITHIOLANES DITHIOLANES 1,3-DITHIOLES
conditions for the reaction of of carbonyl compounds compounds with ethanedithiol ethanedithiol to New catalysts and conditions 1,3-dithiolanes include HHClO. <06S2497, 06S2767>, 06S2767>, a 1:3 give 2-substituted 1,3-dithiolanes C 1 0 4 oon n silica <06S2497, mixture of of SiO SiO,2 and P205 P,Os without solvent <06PS(181)387>, <06PS(l81)387>, anhydrous CuSO CuSO.4 in CH2C12 CH,CI, or or solvent-free <06PS(181) 1445>, SnC12 <06PS(l81)1445>, SnCI, under solvent-free microwave conditions <06TL5155> <06TL5155> ZnCI" NiC12 NiCI, or CuC12 CuCI, supported on natural phosphate rock <06ARK(ii)31>. and catalytic ZnC12, New synthetic approaches to dithioles include cycloaddition of thiiranethione 35 with DMAD to form 36 and with benzyne to give the corresponding corresponding benzodithiole <06CEJ7742>, <06CEJ7742>, Phl to give 37 benzoyl isothiocyanate, PhC(=O)NCS, PhC(=O)NCS, with DMAD in the presence of Ph3P of 38 with SSg8 and its subsequent reaction <06TL2953>, and formation of 39 by treatment of <06H(68)2243>. Further results on the generation of of thiocarbonyl DMAD to give 40 <06H(68)2243>. with DMAD compounds and their cycloaddition with ylides by reaction of thioketones with diazo compounds 06HCAI910>. thiocarbonyls to afford 1,3-dithiolanes have appeared <06T7776, 06HCA1910>.
S B ut,~~ Butxf But But', "SS
DMAD DMAD
But
O, ~\
MeO2C Me02C
,;~CO2Me
r Ph
-~s
Ph-(,Jl )=N
35
N H H
36
$8 S
..~~S " ___~ ,,S
S
3'7 37
DMAD
S'
38
39
.O012H25
cS~../CN
40
.s.
s
012H25
41
"
Li.>(,'S'"] /'v~ MeO2C" "S..~ + 44
N 42
s
R ~'
"Ar 43
O "
MeO2C~s '10]
L.__/ 45
A 1,3-dithiol-2-thione 41 bearing lactic acid-derived long chain chiral groups has been 2-cyanomethylene-l,3-dithiolane with aldehydes or prepared <06T3370>, and reaction of 2-cyanomethylene-I,3-dithiolane to give products 42 has been reported <06S3009>. A new synthetic route ketones and TiCI TiC14 4 to the propargylic dithioacetals 43 has appeared <06SL3173> and, while the dithiolane anion 44 undergoes straightforward Michael addition to an enone, use of an excess in the presence of the non-deprotonated dithiolane gives adducts such as 45 <06TLl961>. <06TL1961>. Work on electroactive TTF-type compounds has continued at a high level and synthesis of such compounds based upon 1,3-dithiolane-2,4,5-trithione oligomer has been reviewed <06CHE423>. TTF derivatives with pendant mercaptoalkyl chains have been prepared and their electrochemistry as monolayers on a gold surface examined <06T4419>. New dithiole <06Tl1106>, 47 <06S2815> and 48 and TTF-type donors prepared and studied include 46 <06Tlll06>, <06H(67)655> while the calculated and experimental Raman spectra of 49 and its Z-isomer have been compared <06SM(l56)75>. <06SM(156)75>. Salts of formula (50),1 (50)2I33 have been studied
281
Five-membered ring systems: with 0 & & S (Se, (Se, Te) atoms
<06MCLC(455)65> and superconducting and metallic materials based upon donors such as 51 <06JAI456>, <06JA1456>, 52 <06CCI592>, <06CC1592>, and 53 <06IC3275> have been reported.
:x S=c s
HN
..-0:
S
~S "1"
u
riSe seo >==< NH II >===< I S S::--.. Se Se S
47 47
-c.
as S
I
S
S
>==<sID S
48 48
49 49
~Se Se_/O~ ~ Se Se-/O- ~: ~Se/~Se[~0J ~ ~~=:~SS~ I~S"] ..~Se/~Se~oJ \S/ 50 51 ~S~s e Se_~S~ N~Se Se~l S Se52 Se./Br/I S.~ Se/~Se)[~S~ ~N-~Se/~SeLi ~s~Se/~Se ~i..Br/i
Ls'-~
S 46
(
53
54
(~~S~Se--, ~==:~Se./' ~
55
~S~Se S Se/~SeL Se./',
Ls.~Se/e~S [ Br ~/S~Se
57
58
56
A series of papers describing detailed studies on dibromo- and diiododithiadiselenafulvalene and tetraselenafulvalene derivatives has appeared including examples <06JMAC3381>, 56 and 57 <06JMACI62> <06JMAC162> and 58 58 such as 54 <06JMAC4110>, 55 <06JMAC338l>, <06T8152>. Further studies on extended and dimeric or trimeric TTF derivatives with a variety of spacer groups have appeared <06JA10484, 06CEJ2709, 06SM(156)127l> 06SM(156)1271> and these include methylantimony-linked compounds such as 59 and 60 <06TL8937>, TTF-containing molecular wires <06TL5059>, and a field-effect transistor based on benzodi-TTFs 61 <06CC2750>. Trimeric donor-acceptor systems based on quinoxalino-TTFs have been examined <06CCI878> <06CC1878> as have hybrid structures containing a TTF in conjunction with a cyclodextrin <06T970l>, <06T9701>, a crown ether <06TL3431, 06H(67)665, 06Tl998>, 06T1998>, a porphyrin <06JA2444> or a phthalocyanin <06T3545>. New materials showing conductivity and superconductivity based on non-aromatic TTF analogues such as 62 and 63 have been described <06CCI331, <06CC 1331, 06SM(l56)991, 06SM(156)991, 06SM(l56)1043>. 06SM(156) 1043>. [
[I
I S S~ S S~ se riSe se[(Sb se] S'[(SbI i ~===~ SJ~ I~se/~se-sb~sel~ 1~~~~TSb"~ ..~/~S ~se- ~~~~~S~S li >===<Se >===<SeeI II S>==<S J II SS>==<SS~I II Se Se Se-lSb SbJ- Se Se
ri S
S
II
59 59
RSXS RS
I
SJC[S
>==<S S
62 60 60
I
.&
61
SJ(SR
>==<S S
I
SR 63
Deprotection of 2,2-disubstituted-l,3-dithiolanes to give carbonyl compounds can be achieved using Oxone® Oxone | with KBr in aq. MeCN <06TL8559> and a review of silylated heterocycles as formyl anion equivalents includes reference to 64 <06CC488l>. <06CC4881>. A method for transformation of propargylic dithiolanes 43 into tetrasubstituted fmans furans has been reported <06SLl209> and Michael addition of enolates to the chiral dithiolane dioxide 65 takes place <06SL1209>
282
R.A. Aitken and L.A. Power
with variable diastereoselectivity <06SL2043>. A variety of carbonyl-containing alkylidenedithiolanes undergo rearrangements on treatment with simple amines as illustrated <06ASC1986>. Oxidation with by conversion of 66 into 67 <06JOC8006> and 68 into 69 <06ASCI986>. rearrangement of 70 to give 71 brought about by Cu(lI) Cu(II) and water has been reported for R === SCH2CH2CN or SeCH,CH,CN SeCH2CH2CN<06TL3123>. SCH,CH,CN
Cs.t s
o0
o0
8
•8
R
>--TM8
"=<~ J
8
64
8
6()
~ r o
0
Ar@~~ Ar'-'::::
8
8
68
-c~ C02H
8r 8=< [
8
72
NHR33
67 67
o Ph Ph ph EtNH2 EtNH~ [~" @ ~ Ph /
Y68
R1~NHR2
66 66
\S8 / -'S8 69
8S ~ / RR
I
NEt NEt
~
--r\
8
8
8~8'y-'8 ~
s-- \ s ~ S ~ N ~ ~
R
70 70
~ .)-J
73
V
Y'
8J(8~8/'-..8
8=< 8
~8rO
[~I s>=<s•X-
S ((8
~_JLC'H.
Ar/ Ar
00
8
0
-
o0
R3NH2
~ "---.J
65
oo
00
2 1~ R '-':::: j~_ NHR
"h
\d
--r8
8s
j
R R
8
CX[ >=<
JC 0
71 71
,pr i :-)" 'Pri
8 S
S 8
S ~'-~N ~'' 8 -N
8
8
8
I
R R
PPh 2
74
Self assembly of halogen adducts of carboxylic acid 72 and similar compounds in the solid state has been examined <06POL989> and the X-ray structure of compound 73 has been reported to show an interesting supramolecular stacking <06AX(E)o5469>. A chiral TTF 74 containing both oxazoline and phosphine groups has been found to be an effective ligand for Pd-catalysed asymmetric allylation of malonates <06TlI942>. <06T11942>. 5.6.3
1,3-OXATHIOLES AND OXATHIOLANES 1,3-0XATHIOLES AND OXATHIOLANES
New catalysts for the reaction of carbonyl compounds with 2-mercaptoethanol to give 2substituted-I,3-oxathiolanes HCIO. on silica <06S2497>, and either iodine substituted-l,3-oxathiolanes include HC104 <06CL542> or phosphotungstic acid <06JMOC(247)14> under solvent-free conditions. A new method for conversion of 2-hydroxyalkyl tert-butyl sulfides into 2-tert-butyl-I,32-tert-butyl-l,3oxathiolanes involving treatment with Bu'CHO, PhSH and BF3oEt20 BF3·Et,D has been described AI(OTf)33 <06T931>. 1,3-0xathiolan-5-ones 1,3-Oxathiolan-5-ones have been prepared by a new method using AI(OTf) <06EJ03554> and used to provide a -CH(SH)CO- unit in fused ring systems <06T5464>, <06EJO3554> while 1,3-oxathiolan-2-ones are formed directly from epoxides, sulfur and CO in a process NaH <06T5803>. Although generally not isolated, spiro 1,3-oxathiolanes are catalysed by Nail intermediates in the reaction of terpene-derived thiones with vinyloxirane postulated as key intermediates to give a variety of products <06HCA456>. Cleavage of 2-substituted 1,3-oxathiolanes back to the carbonyl compounds canbe ~-cyclodextrin in water <06SC3771>. A variety of reactions achieved with IBX and catalytic ]]-cyclodextrin between diazo esters and 1,3-oxathiolanes leading to ring-expanded products have been <06RCBI464, 06T361O>. Treatment of the simple oxathiolanone 75 with described <06RCB 1464, 06T829, 06T3610>. 1,2-dithietane 76 which underwent thermolytic ring Lawesson's reagent unexpectedly led to the 1,2-dithietane 850°C Electrochemical fluorination expansion to 77 under FVP conditions at 850 ~ <06HCA991>. Electrochemical 1,3-oxathiolan-2-one to give the 4-fluoro product has been reported <06MI2477>. of 1,3-oxathiolan-2-one
283
Five-membered ring systems: with 0 & & S (Se, (Se, Te) atoms
5.6.4
1,2-DIOXOLANES
A few new compounds of this type have been obtained by ozonolysis of suitable substrates and typical examples include 78 <06TL771> and 79 <06EJ02l74>. <06EJO2174>.
o
Ph
Jl 0
~hCH"
LR PhOHs_s \s\ _L ' - ~ s-s LR
/-
CHPh
5.6.5
08
~~ C)('i:) _
ID
75
~ O C )pH
CHPh
F W FVP
S 77
76
OOH
::/1
0 0-0
~
79
78
1,2-DITHIOLES AND DITHIOLANES
An important paper describing the properties of cyclic compounds containing silicon and tin includes many sulfur-, selenium- and tellurium-containing compounds and describes the preparation of both 80 and 81 from I-(CH2)3SAc 1,2I-(CH')3SAc <06JA14949>. The preparation of 1,2diselenolane 82 by a new route has also been described and its 13C '3C NMR spectrum reported <06RJGC229>. Further chemistry of substituted 1,2-dithiole-3-thiones 83 has been described including their preparation <06RCB <06RCB147>, 147>, and reaction with chromium carbenes <06JOC808> and Na2S Na,S <06JFC(127)774>. Reductive cleavage of the S-S bond in 84 using LiEt3BH followed by reaction with Cp'MC1, LiEt3BH Cp*MC12 gives rise to a series of metal derivatives 85 <06POL823>. Anti-inflammatory activity has been claimed for substances like 86 that H2S into biological tissues by virtue of the dithiolethione group <06WOPl <06WOP111791>. release H,S 11791>.
CS
/~'S /~'Se R2 Se ~j-+e ~..-~;e R~J N
80
81
82
.S
ff-~ .S
~
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S-S
;-S ~=S 83
84
85
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5.6.6
O'~1/O"1- O'o "~"'z'Br'I AcO'~'Meu 89
H S,'s
R'
2
R
87
0
or R r r O
or
~"~..";'~S" ~d 88 88 0 O
HS 90
1,2-0XATHIOLES 1,2-OXATHIOLES AND OXATHIOLANES OXATHIOLANES
The cyclic sulfinates 87 and 88 have been prepared by radical cyclisation of the tert-butylsulfinates as shown <06AG(E)633. corresponding haloalkyl tert-butylsulfinates 5.6.7
THREEHETEROATOMS THREE HETEROATOMS
The unusually stable cross-ozonide 89 has been reported <06TA1780>, and a range of 1,2,3-trithiolane 90 have been isomeric mono- and disulfoxides of the E-cyclooctene-derived I,2,3-trithiolane prepared <06T5441>. <06T5441 >.
284 5.6.8 5.6.8
Aitken and R.A. Aitken and L.A. Power
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06RCB1464 06RCB1464 06RJGC229
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286 06SM(156)75 06SM(156)75 06SM(156)99I 06SM(156)991 06SM(l56)1043 06SM(156)1043 06SM(l56)1271 06SM(156) 1271 06T829 06T93 06T931I 06T1864 06T 1864 06T1998 06T2545 06T3370 06T3545
06T3610 06T361O 06T4153 06T4419 06T544 06T5441I 06T5464 06T5803 06T7776 06T8069 06T8069 06T8152 06T9038 06T9174 06T9701 06T11106 06T11218 06T11942 06TI1942 06TA1780 06TL77 06TL771I
06TL1271 06TL127I 06TL1961 06TL 1961 06TL2133 06TL2643 06TL2953 06TL3123 06TL3431 06TL5069 06TL5155 06TL8369 06TL8559 06TL8937
R.A. Aitken and L.A. Power
A. Kowalska, R. Wojciechowski, J. Ulanski, M. Mas-Torrent, E. Laukhina, e. C. Rovira, K. Yakushi, Synth. Met. 2006, 156,75. 156, 75. E.1. Zhilyaeva, A.M. Flakina, R.N. Lyubovskaya, LV. E.I. I.V. Fedyanin, K.A. Lyssenko, M.Yu. Antipin, R.B. R.B. Lyubovskii, E.1. E.I. Yudanova, Yudanova, J. Yamada, Synth. Met. 2006, 156, 991. B. Barszcz, A. Lapinski, A. Graja, A. Flakina, E. Zhilyaeva, J. Yamada, R. Lyubovskaya, Synth. Met. 2006, 156,1043. 156, 1043. C. Carce1, Carcel, L. Kaboub, A.K. Gouasmia, J.M. Fabre, Synth. Met. 2006, 156,1271. 156, 1271. S. Zhu, e. C. Xing, S. Zhu, Tetrahedron 2006, 62, 829. M.J. MJ. Porter, F. Saez, A.K. Sandhu, Tetrahedron 2006, 62, 931. DJ. Cross, J.A. Kenny, I. Mann, I. Houson, L. Campbell, T. Walsgrove, M. P. Peach, D.J. Wills, Tetrahedron 2006, 62, 1864. M.e. Diaz, B.M. Illescas, N. Martin, J.F. Stoddart, M.A. Canales, J. Jimenez-Barbero, M.C. Dfaz, Jim6nez-Barbero, G. Sarova, D.M. GuIdi, Guldi, Tetrahedron 2006, 62,1998. 62, 1998. K. Kato, H. Nouchi, K. Ishikura, S. Takaishi, S. Motodate, H. Tanaka, K. Okudaira, Okudaira, T. Mochida, R. Nishigaki, K. Shigenobu, Shigenobu, H. Akita, Tetrahedron 2006, 62, 2545. E. Gomar-Nadal, C. Rovira, D.B. Amabilino, Tetrahedron 2006, 62, 3370. e.A. Descurtins, Tetrahedron C.A. Donders, S.-X. Liu, e. C. Loosli, L. Sanguinet, Sanguinet, A. Neels, S. Descurtins, 2006,62,3545. 2006, 62, 3545. A.V. Stepakov, A.P. Molchanov, Molchanov, J. Magull, D. Vidovic, G.L. Starova, J. Kopf, R.R. Kostikov, Tetrahedron 2006, 62,3610. 62, 3610. D.I. MaGee, T.e. T.C. Mallais, P.D.M. Mayo, G.M. Strunz, Tetrahedron 2006, 62, 4153. D.1. J. Lyskawa, M. Oc;afrain, Oqafrain, G. Trippe, Tripp6, F. LeDerf, M. Salle, Salld, P. Viel, S. Palacin, Tetrahedron 2006,62,4419. 2006, 62, 4419. A. Ishii, M. Suzuki, R. Yamashita, Yamashita, Tetrahedron 2006, 62, 5441. L.D.S. Yadav, V.K. Rai, S. Yadav, Tetrahedron 2006, 62, 5464. Y. Nishiyama, e. C. Katahira, N. Sonoda, Tetrahedron 2006, 62, 5803. S. Lesniak, G. Mloston, K. Urbaniak, Urbaniak, P. Wasiak, A. Linden, H. Heimgartner, Tetrahedron 2006, 62, 7776. Fernandez, E. Molina, M.C. Mufioz, Munoz, J.R. Pedro, e. G. Blay, I. Fem~indez, C. Vila, Tetrahedron 2006, 62, 8069. Garcfa, R.E. R.E. Howard, Tetrahedron 2006, 62,8152. 62, 8152. RJ. Collis, F. Garcia, A. Alberola, R.J. W. Zhang, F. Xie, H. Yoshinaga, Yoshinaga, T. Kida, Y. Nakatsuji, I. Ikeda, Tetrahedron, 2006, 2006, 62, 9038. M.C. Munoz, Mufioz, J.R. Pedro, C. Vila, Tetrahedron 2006, 62, Fernandez, B. Monje, M.e. G. Blay, I. Fem~indez, 9174. G.G. Surpateanu, Surpateanu, D. Landy, e.N. C.N. Lungu, S. Fourmentin, Fourmentin, G. Surpateanu, Surpateanu, C. Rethore, R6thor6, N. Avarvari, Tetrahedron 2006, 62, 9701. S. Dolder, S.-X. Liu, X. Guegano, Dau1, C. Leiggener, A. Hauser, A. Gu6gano, M. Atanasov, e.A. C.A. Daul, Neels, S. Decurtins, Tetrahedron 2006, 62, 11106. M. Yoshida, Y. Ohsawa, M. Ihara, Tetrahedron 2006, 62,11218. 62, 11218. C. R6thor6, e. Rethore, I. Suisse, F. Agbossou-Niedercorn, E. Guillam6n, R. Llusar, M. Fourmigu6, Fourrnigue, N. 62, 11942. Avarvari, Tetrahedron 2006, 62,11942. M.1. M.I. Mangione, S.A. Testero, A.G. Suarez, Smirez, R.A. Spanevello, J.-P. Tuchagues, Tetrahedron: Asymmetry 2006,17, Asymmetry 2006, 17, 1780. D.N. Kumar, N. Sudhakar, B.V. Rao, K.H. Kishore, U.S. Murty, Tetrahedron Lett. 2006, 47,771. 47, 771. Y. Du, J.-Q. Wang, J.-Y. Chen, F. Cai, J.-S. Tian, D.-L. Kong, L.-N. He, Tetrahedron Lett. 2006, 47, 1271. S.M. Allin, J.S. Khera, e.1. Witherington, K. Doyle, M.R.J. M.RJ. Elsegood, Eisegood, M. C.I. Thomas, J. Witherington, Edgar, Tetrahedron Lett. 2006,47,1961. 2006, 47, 1961. K. Surendra, N.S. Krishnaveni, K.R. Rao, Tetrahedron Lett. 2006,47,2133. 2006, 47, 2133. V. Nikolaev, L. Hennig, H. Heimgartner, B. Schutze, V. Nickolaev, Tetrahedron Lett. 2006,47, 2006, 47, 2643. I. Yavari, H. Djahaniani, Djahaniani, Tetrahedron Lett. 2006, 47, 2953. L. Boudiba, L. Ouahab, A. Gouasmia, Tetrahedron Lett. 2006,47, 2006, 47, 3123. 2006,47,3431. W. Liu, J.-H. Lu, Y. Ji, J.-L. Zuo, X.-Z. You, Tetrahedron Lett. 2006, 47, 3431. G. Chen, Y. Zhao, Tetrahedron Lett. 2006,47,5069. 2006, 47, 5069. 2006,47,5155. G. Bez, D. Gogoi, Tetrahedron Lett. 2006, 47, 5155. Nishizawa, Tetrahedron Lett. 2006, 478369. H. Yamamoto, M. Nishiyama, H. Imagawa, M. Nishizawa, 47 8369. U.V. Desai, D.M. Pore, B.V. Tamhankar, S.A. Jadhav, P.P. Wadgaonkar, Tetrahedron Lett. 2006, 47, 8559. 2006,47,8559. 2006, 47, 8937. M. Ashizawa, H.M. Yamamoto, A. Nakao, R. Kato, Tetrahedron Lett. 2006,47,8937.
Five-membered ring systems: with 0 & S (Se, Te) atoms
06USP047129 06USP047129 06USPI28604 06USP128604 06WOPI05529 06WOP105529 06WOPI I 1791 06WOP 111791
287
J.H. Simpson, EJ. E.J. Delaney, US Pat. 047 129 (2006) [Chern. [Chem. Abstr. W.A. Nugent, K. Zhu, J.H. 2006,144,274257]. 2006, 144, 274257]. A.T. Levorse Jr, B.D. Newirth, M. Pawlack, US Pat. 128604 128 604 (2006) [Chern. [Chem. Abstr. 2006, 145,69374]. 145, 69374]. P.S. Watson, J.G. Douglass III, B. Suchozak, S. Pandiaraju, C.E. C.E. Dixon, D. Levin, PCT Int. Appl. WO 105529 105 529 (2006) [Chern. [Chem. Abstr. 2006, 145, 397740]. I I I 791 (2006) [Chern. A. Sparatore, P. Del Soldato, PCT Int. Appl. WO 111 [Chem. Abstr. 2006, 145, 432197].
288
Chapter 5.7
Five-membered ring systems Five-membered systems with 0 & N atoms
Stefano Cicchi, Franca M. Cordero, Donatella Giomi Dipartimento di Chimica Organica 'Ugo Dipartimento 'Ugo Schiff', HeteroBioLab, Universita Universith di Firenze, Italy
[email protected]
5.7.1
ISOXAZOLES ISOXAZOLES
Isoxazoles are privileged aromatic heterocycles due to their wide spectrum of biological activities and their use as versatile building blocks in organic synthesis. Recent progress in the field of transition-metal-catalyzed cross-coupling reactions on isoxazole systems has been summarized and discussed <06EJ03283>. <06EJO3283>. Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl ~ ~lenaminones 2, useful synthons in the regioselective synthesis of silyl- and <06T611>. silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611 >. RZ 2 R
R11
R 11 R
)j ~~/o~NH2[Ni]. . R:~'~ rt
R3 R3
0
,N
1 1
RZ 2 R
R4NHN~z
R11
R 11 R
2 RZ
)jN ~~/N.
NH2 R4NHNH2 Hz [Nil R : t NHZ EtOH, rt R3 R3--~--O EtOH, rt rt~ R3 R3 EtOH, 0 EtOH, 2 3 2 3
,N NI 4 R4 R
3 R3
4 R4
2 Yield 3 Yield
Me H TMS Et Me H TMS Et Me CHzTMS Me CONH Me CH2TMS Me CONH z2 Me H CHzSiMePh CH2SiMePh2z Et CHzTBDPS Ph Ph CH2TBDPS H
91% 91% 89% 89%
91% 91% 78% 78%
90% 96%
93% 34%
The Pd/C assisted hydrogenolysis of of substituted 3-(2-nitrophenyl)isoxazoles 4 results in the formation of substituted 4-aminoquinolines 5 through reduction of the nitro to an amino group, followed by isoxazole ring cleavage and concomitant ring closure. In contrast, similar catalytic hydrogenation of 3-nitrophenyl-4,5-dihydroisoxazoles led to reduction of the nitro group with retention of the isoxazoline ring <06S <06S1995>. 1995>. N-O~
,.,2
NH2 R1
10% Pd/C, Pd/C, Hz H2
R-~-
II 4
~
MeOH, 40 psi 79-93%
-
R
R2
R= = H, CI, Cl, OMe OMe CF3, CH2OH R11= = H, Me, CF 3 CHzOH CliO, COzMe CO2Me RZ2= =H, CHO,
5
On the other hand, 4-alkoxycarbonyl- and 4-aminocarbonyl-substituted isoxazoles 6 undergo unusual conjugate reduction with sodium borohydride and sodium
289
Five-membered ring ring systems systems with 00 & N N atoms atoms Five-membered
trifluoroacetoxyborohydride, respectively, to give 4,5-dihydroisoxazoles 4,5-dihydroisoxazoles 7 and 8. They are trifluoroacetoxyborohydride, through sonication sonication with secondary and tertiary alkyl iodides, iodides, in the also alkylated at C-5 through of zinc dust and copper(I) copper(l) iodide, leading leading to compounds compounds 9. This behavior, behavior, analogous analogous presence of presence of acrylates and acrylamides, is characteristic characteristic of of 4-substituted 4-substituted isoxazoles isoxazoles but but not of of the to that of trans-4,5-disubstituted 5-substituted regioisomers. regioisomers. These processes processes generally afford trans-4,5-disubstituted 5-substituted incorporation of of chiral auxiliaries into the ester function allows one to isoxazolines and the incorporation of stereocontrol (86-88% yields, 93 to > 2: 98% de). This perform alkylations with a good level of cyc1oadditions to alkenes methodology provides a complementary approach to nitrile oxide cycloadditions of 4,5-dihydroisoxazoles 4,5-dihydroisoxazoles <06JOC3221>. <06JOC322 1>. for the asymmetric synthesis of
=
HOH2C,,,~(,R 1 Ar.-..-,,~N..O
R= R OMe
Ar~
NaBH44 (15 equiv) Ar EtOH, reflux
= OMe, OMe, NH NHZ] R= Ar = 2,4,62,4,6-Me3C6H2 R 2 Me3C6 HZ Ar = 1 1 CH2OH R1 = H R1 = H, Me, Ph, CHzOH R RZ ROC 2 = Et, t-Bu, i-Pr, c-C c-06Hll, ROC. 6 H11 , adamantyl adamantyl ~~N,
=
=
b
Zn, Cul, Cui, R21 RZI Zn, aq . M aq. MeOH e OH ~ -_ rt sonicate, 5 °C ,Rz ,R2
O
N/O
Ar
H 2 N O C , ~ R R11 HzNOC
R = NNH H 2z
NaBH44 (15 equiv) equiV) Arb Ar.J,~N,,O CF 3CO zH (15 equiv) N CF3CO2H THF, rt 8890-92% 90-92%
N 6
7 61-91%
=
R 11
ROC. ROC
925-100% 9 25-100%
Treatment of Baylis-Hillman (BH) derivatives 10, obtained from 3-(2-bromophenyl)-5methyl-4-isoxazolecarbaldehyde, with tributyltin hydride allowed a straightforward synthesis of isoxazolo-benzazulene systems 11 along with minor amounts of of isoxazolo-benzazulene of the debrominated products 12 <06TL7043>. BH adducts made from 5-isoxazolecarbaldehydes 5-isoxazolecarbaldehydes were converted in moderate yields into pyrrole derivatives by reaction with primary amines and then DBU <06S102l>. <06S1021>.
I-~
~ I
~ ~
R
Br Br 10 10
BU3SnH, Bu3SnH, AIBN AIBN
-----. toluene, reflux
~I-~ I~
+ R +
//
EWG G R= = H, OH, OAc EWG = COzR, CO2R, CN 11 11 40-50% EWG =
1-~
c0: I~
R
~
EWG 1211-33% 12 11-33% EWG
Catalytic enantioselective crossed aldehyde-ketone benzoin cyc1izations cyclizations of ketoaldehydes, such as 13, readily obtained from an aryl nitrile oxide and a 1,3-diketone, were studied in order to perform the synthesis of complex molecules. Significant asymmetric induction was observed with chiral triazolium salts such as 14, in the presence of DBU as base, leading to compound 15 in high yield and with 99% ee in favor ofthe of the R enantiomer <06AG(E)3492>. MOMO
MO«t~ ~;
N--O
MOMO
14(10mol%) DBU (10 (I0 mOI%~ mol%) DBU
O
THF, rtrt 13
NmO
Ph
[
~
0 OH O 15 87% 99% ee 1587%
I~,,, "~ 14
O
290
S. Cicchi, F.M Cordero, and D. Giomi CicchL F.M.
A one-pot synthesis synthesis of 3-methyl-5-aryl-4H-pyrrolo[2,3-d]isoxazoles 3-methyl-5-aryl-4H-pyrrolo[2,3-d]isoxazoles was performed in high yields by Sharpless Sharpless epoxidation of 4-amino-3-methyl-5-styrylisoxazoles 4-amino-3-methyl-5-styrylisoxazoles <06TL4957>. 1,2,4,5-Tetrazines were condensed with isoxazolylcyclobutanones isoxazolylcyclobutanones in methanolic KOH to give conformationally restricted 6-isoxazol-5-yl-6,7-dihydro-5H-[ I,2]diazocin-4-ones 6-isoxazol-5-yl-6,7-dihydro-5H-[1,2]diazocin-4-ones <06JOC2480>. <06JOC2480>. HO2C.~Ar
~ N
NO2
"O")~''"
O
+ NH2XH ° +yy+ Ar / O O
Ar
° ° 18
17
16
~a), b)N-X'
20 61_95O/o
)
19
X = O, NH, NH, NPh NPh X=O,
N ' O /- ~ .r~~J~"~^ ' ' ~ Arii \)--N"X~ 21 48-90% 2148-90%
Reagents and conditions: a) piperidine (0.1 (0.1 equiv), EtOH, 60°C; 60 ~ b) H H20, 20, NaOH (4 equiv), reflux.
A four component one-pot procedure (4-MC) was developed for the synthesis of 3heteroarylpropionic acids acids 20 and 4-nitroisoxazolyl derivatives 21 from commercially available starting materials 16-19, 16-19, in high yields and without chromatographic purification <060L5157>. <06OL5 ! 57>. 5-Aminoisoxazoles 5-Aminoisoxazoles 22 have been synthesized by nucleophilic addition of lithiated alkyl nitriles to a-chloroximes ~-chloroximes <060L3679>. <06OL3679>. The cyclization of oxime dianions with diethyl oxalate afforded isoxazole-5-carboxylates 23 by acid-mediated dehydration of intermediate hydroxyisoxazolines <06S2515>. hydroxyisoxazolines
N"OH RlJ~'CI
R2~CN t-BuLi t-BuLi THF, THF, -78°C -78 ~
=.
1
wO . Iii ~ ")-NH NH22
R1\ .2 R R2 R 2234-91% 22 34-91%
R11 = Ar, c-C c-C6Hll, n-Pr, 3-thienyl, 3-thienyl, 2-pyridyl 2-pyridyl 6 H11 , n-Pr, Ph, Bn, i-Pr, i-Pr, cyclopropyl cyclopropyl R22 = H, Me, Ph,
. LN'OH I (CO2Et)2 "
Ar/~
i, ii
wO N--O
;. ~l-)- ~-~CcO2Et 02 Et Ar Ar"
2368-96% 23 68-96% i, BuLi, -78°C BuLi, THF, THF,-78 ~ - rt ii, TsOHHzO, TsOH-H20, toluene, toluene, reflux reflux
Functionalized isoxazoles were obtained in good yields from activated acetylenes and triphenylphosphine <06TL1627>. <06TLl627>. The use of alkyl 2-nitroethanoates in the presence of triphenylphosphine PPh PPh3/DDQ 3/DDQ offers a neutral and highly efficient method for the conversion of 2-hydroxyaryl 1,2-benzisoxazoles in excellent yields at room temperature aldoximes and ketoximes to 1,2-benzisoxazoles <06TL8247>. Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides uracyl-5-carbaldehyde oxides (and nitrones) derived from uracyl-5-carbaldehyde 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06Tl494>. 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde <06T 1494>.
291
Five-membered ring systems systems with 00 & N N atoms Five-membered
oo ,N-O .o :Jhl~ COPh A I OCOPh
oco .
PCOPh HN -=---./-
,/(J)7 24
b)
OMe ./[...~..# MeO
N 26
L
#)7
r
OMe
/
.
.
0
80%
80% + .(3-
25 25
OMe wO
..~ - ~ ~ /~ ~ I v OCOPh OCOPh =. A .~.[/ [~
/OCOPh PCOPh
-=---./-
a)= [MeO./L...~N# b)
N
)h #)7
90%
NY
N MeO~ "N"
27
Reagents and conditions: a) NH2OHHC1,Na2CO3,EtOH/H20, 20 ~ b) NaOC1,CH2CIz/H20,0-20 ~ l,3-DC of of carbohydrate dipolarophiles dipolarophiles with cerium(IV) cerium(lV) ammonium nitrate CAN(IV) in 1,3-DC corresponding acetone, acetophenone, or pinacolone as solvent yielded regioselectively the corresponding 3,5-disubstituted isoxazoles as stable pharmacophores pharmacophores for glycomimetic syntheses. For 3,5-disubstituted propynyl p-D-galactoside 28 gave derivatives 29 in satisfactory yields instance, peracetylated propyny113-D-galactoside <06SLl739>. Some derivatives provided inhibitory properties against galectins-l <06SL1739>. galectins-1 and -3 <06CC2379>. <06CC2379>.
AcO ...OAc O ACO~OAe
o
..-:;:; O~
AeO A cO~O~.~ OAe OAc 28 28
o O R"~
~
R~
AeO AcO/OAc ~ OOAe
l\-_'~-
0 (3"_N'\\-11 N:,,..__//O
<;>-
CAN(IV)-" AcO ~ ' ~ ' ~ O~ " ~ ' / CAN(IV) Aeo~O-----l.:::J '~R R OAe OAc MeCN, reflux MeCN, reflux 29 78-92% 2978-92% R= = Me, Me, Ph, Ph, CMe3 CMe3 R
A solid-phase synthesis of 3-substituted isoxazoles 31 in good yields and purities was situ generated nitrile oxides; achieved by 1,3-DC of polymer-supported vinyl selenide with in situ treatment of intermediate isoxazolines 30 with an excess of hydrogen peroxide resulted in the release of isoxazoles 31 while the use of MellNal MeI/NaI led to 3-substituted 5-iodoisoxazolines <06S2293>.
~se= :~:~:~t ~SQ-R T:';: ~Se
~Se
RCH=NOH O~N'~/ H202; NCS, NEt3 R THF,rt CHCI33,, rtrt CHCI 30 30 R R= = Ar, Ar, 2-furyl, 2-furyl,n-Pr, n-Pr, PhCH PhCH2CH2 2CH 2
O~N/~/ ++ Q-SeOOH ~SeOOH oF) R >'N/-- R 31 78-88% 3178-88% > > 95% 95% purity purity
A DFT-HSAB study provides a quantitative rationalization of regioselectivity in 1,3-DC of 4-substituted benzonitrile oxides towards methyl propiolate not amenable to FMO and electron-demand theory <06CEJ 1156>.
5.7.2 ISOXAZOLINES New applications of nitrile oxide 1,3-DC have been reported. Soluble, single-wall carbon nanotubes (SWNT) 32 functionalized with pentyl esters at the tips and pyridyl isoxazoline rings along the walls were prepared using pentyl ester-SWNT as dipolarophile. The complex
292
S. Cicchi, F.M. F.M Cordero, and D. Giomi
of SWNT 32 with a zinc porphyrin was studied and compared with the corresponding complex with pyridyl isoxazoline-functionalized [60]-fullerenes <06JA6626>.
I
a~)O~C',%__
1. NEt3 2. pentyl pentyl ester-SWNT ester-SWNT " 1,2-CI 1,2-CI2C6H CI" ~N 2 C6 H44 mw mw (150 (150 W, W, 45 45 min) min) OH
=
R R = n-pentyl n-pentyl
>,N..o
n
_
_
_ (/co2a
I~U 2L; . . . ~ ~ - . . . l ~ - . . . T ~ - ~ . . r ~ ~
C O2 R
RO2C R
,. O
2
~
~
32C
O
CO2R
2
R
25,27-Diallyloxycalix[4]arene 33 reacted with isophthaldinitrile oxide through a 1+1 double 1,3-DC to give the calix[4]arene 34 having an aryl-l,3-diisoxazoline cap on the lower rim. Under the same conditions, 5,17-diallylcalix[4]arene gave the corresponding 1+1 upper rim capped calix[4]arene <06TL8383>. Calix[4]arenes isoxazole and isoxazolines underwent molybdenum hexacarbonyl-mediated N-O bond cleavage in the presence of water to afford calix[4]arenes decorated respectively with a,p-unsaturated-p-amino o~,]3-unsaturated-~-amino ketones and p-hydroxy ]3-hydroxy ketones <06TL9077>.
+
C~~]NOH C & NOH ;I
+
A A (R=X) /
__ /
RO~R2 R O o ~ 5 R2 o 35 + +
+ _
ArC=N-O ArC-N+-O- """ ~
~I ~/./ "'~
~ 33 33
R11 R
"::
o
/~
(R=X)H20. H20 ' 25°C 25 ~
< Ark
pCO2x Ark
. .R1
,N,o/~,R1+ ',,R2
.N~{2
B B
.,R1 "N~o~,,R2 CO2H 39
xX = = ~-cyclodextrin ~-cyclodextrin substituted substituted at at aa C C66-position; -position; Ar Ar = = 4-t-BuC 4-t-BuC6H 6 H44
R1
O
CO2X
-C=N-O
1 1. NaOH 37 2. pill
Ar\ jCO2 H Ar\ (R (R = = H). H).. N~O~,,,,R1 THF THF ',,R 2 + 25°C 25 ~ 38
O,, /;
o/".-./
27% 27%
CI
36
O
NEt3 NEt3 ---MeOH MeOH NOH NOH reflux reflux 24h 24 h
4O R1 H Me Me H H
R2 H H H Me Me
38:39 (pathA) (pathB) B) (path A) (path 20: 20:11 1:10 110 >100: >100:11
1: 1" 20 <1:100 <1:100 1: 1 11
Polymeric isoxazolines were prepared by cycloaddition of of nitrile oxides to norbomadiene norbornadiene followed by ring-opening metathesis polymerization (ROMP) <06PLM3292; 06MM3147>. Isoxazolines 38 and 39 were obtained in different ratios by direct cycloaddition of 4-14-tbutylbenzonitrile oxide with acids 35 (R = H, path B) and by the intermediate formation of of cyclodextrin derivatives 36 and 37 followed by basic hydrolysis and acidification (path A). The reversed regioselectivity as well as an increased rate of of the cycloaddition step could be explained through the temporary association of the nitrile oxide with the cyclodextrin to give the inclusion complex 40 <06CEJ8571>.
293
Five-membered ring systems with 0 & & N atoms
3-Nitroisoxazolines N-alkoxy-3,3-dinitroisoxazolidines by thermally 3-Nitroisoxazolines were prepared from N-alkoxy-3,3-dinitroisoxazolidines induced ~-elimination. ]3-elimination. For example, isoxazolidines 42 synthesized by a three-component reaction of tetranitromethane with two equivalents of of alkenes 41, were converted into isoxazolines 43 by heating in boiling chlorobenzene <06S706>. O2 N C(NO2) = )l RRz2 + C(NO z)44 PE PE +
R1 R
rt 41 rt 41 PE =petroleum =petroleum ether
O2N
O" O RI-~ 42 R2 I NO2
PhCI reflux
R1
=
R2
Ph H P" BuO H -(CH2)5-(CHzk OAe H OAc
2 43
yield
71% 73%
74% 74% 72%
2-Isoxazolines 47 were prepared from O-propargylic hydroxylamines via tandem rearrangement-cyclisation reactions by heating in methanol. The proposed mechanism involves an initial 2,3-sigmatropic rearrangement to give the N-allenic hydroxylamine 44 followed by rearrangement to 45. Then, oxime 45 undergoes a 5-endo-trig 5-endo-trig cyclization to 3isoxazoline 46 which isomerizes to the more stable product 47 <06SL463>. HOMe R~I/ON HCIH2 K2CO3 H2N" O~1/ R2 MeOH reflux
R1
..'7/\ RN%~=~/1 W"R2HOMe MeOH HO
R1
H~N R1 OH 44
RN 1 -O~ R
R1N - O ~
H
45 R2
R2 46
_1
47 60-84%
R1 = 2-CIC6H4, 3-MeOC6H4, 4-CIC4H4, 3,5-(CF3)2C6H3, n-Pr, Et2NCH2, R2 = H; R1 = Ph, R2 = Me,/-Pr; R 1 = H, R2 = Ph, n-pentyl.
A detailed study of the role of the base in the formation of 2-isoxazolines by condensation of of primary nitro compounds with alkenes in the presence of of the tertiary diamine 1,4diazabicyclo[2.2.2]octane (DABCO) was published <06EJ04852; <06EJO4852; 06EJ03016>. 06EJO3016>. Isoxazolines N-oxides have been synthesized from primary aliphatic nitro compounds and I-halo-substituted siIyI alkenes by a two-step procedure consisting of 1,3-DC of a 1-halo-substituted silyl nitronate followed by halosilane haIosiiane elimination <06S2265>.
co .o
COzMe
III
Nu
(10 mol%)
o- O"'rOMe ,o..
I.el
l
N~)lR1
+ R R11 Nu/ R1 49 48 R11 = = n-C n-C5H11, = PPh PPh33 SH11 , Nu =
LiCI H20 40 ~
Ph
50
-Nu -Nu
Ph"
\ R1 51 68%
4-Isoxazolines were synthesized by a new regioselective and organocatalyzed nitrone 1,3DC with conjugated alkynoates in water. Both tertiary amines and phosphines catalysed the reaction which did not occur in absence of of the catalyst or in organic solvents. For example, C-phenyl N-benzyl nitrone reacted with alkynoate 48 in H H20/LiC1 of 10 20/LiCI in the presence of mol% ofPPh of PPha3 to give 4-isoxazoline 51 in 68% yield. In the proposed mechanism, the catalyst (PPh (PPh3) 3) adds to 48 to generate the zwitterionic allenoate 49 which is the reactive dipolarophile. Regioselective 1,3-DC of 49 with the nitrone affords the primary cycloadduct 50 which evolves to 51 by elimination ofa of a molecule of the catalyst <06CC2798>. New theoretical calculations of mechanisms of isoxazoline syntheses have been reported.
294 294
Cicchi, F.M. FM Cordero, and and D. D. Giomi Giomi S. CicchL
In particular, particular, the reactions of of electrophilically activated benzonitrile benzonitrile N-oxides with 3methylenephthalimidines with formation of of 2-isoxazolines and oximes and the cycloaddition between alkynyl metal(0) metal(O) Fischer carbenes and nitrones leading to 4-isoxazolines have been <061OC93 19; 06JOC6178>. 06JOC6178>. investigated by density functional theory methods <06JOC9319; Naturally aturally occurring occurring dimeric spiroisoxazolines (+)-aerothionin (52) and (+)-calafianin (53) have been synthesized in enantiopure form and their configuration unambiguously assigned <06TL727; 06OL927>. 060L927>. <06TL727;
0o
0
0o
N']~_N N={N~N N~ " ~ " ~ O H
H o"
~
H
"I
HO",
/'~NN~NA_N ~cd~'~2
(~N,7
H
Sr:::"" Sr Sr y 52 OMe 52 OMe OMe (+)-aerothionin (+)-aerothionin OMe /
5.7.3
Sr
/
!
o
H HC/ 0;:: " H
N~--N 0
r " (,
o o s3 53 o O (+)-calafianin (+)-calafianin
1
Br Sr
0O
ISOXAZOLIDINES ISOXAZOLIDINES
SOa
OH
MeO m....#"
::+
= N~NHHNI(NH =-NH 0 -'---NH 54 54 cylindrospermopsin cylindrospermopsin
-=:
0
: cY C C~ONHX ONHX
QH OH
H O ~ O H
MeO~ MeO~
I~ OH ~ 0 H ~~03 N H Meo~
IH
00
OH
HOV ....
0
A-J(N
-=:
7 ~
OH OH N ~ Ph 55 H gn Sn h 'e A A haouamine ,aouam ln HN-'' HN--'-.! pH .OH h C?HO H H~pO(OEt)2 i:PO(OEth
V-XiPh -
'/:f0 -
..0,... Bn Sn-N'
HO~
O
ib
('l \,,,. N---!, " ..)....CO H tlltl N -~ .. 'Phh N 2 "'" ....0 o " "~ N C0 22H H 00 H 57 HCI H 57 HCI OH H 56 ..' ", H .......56 O OH Hd ss H X (2S,4S)-pipecolic H OH HO 58 OH CI X= = (R)-PhMeCH (R)-PhMeCH (2S,4S)-pipecolic H~_ HCI ~oiH aCid HO = 0 ~ 0 fijOHH "'OH Ij f 7 _' -'::N 'OH HO H C0 2 Me HO N HO .N O N ' N:;::::.J -=: ~ 60 OH HO OH nv N
,N---X X
A
+
--(j{CO o
2
Me
HCI ....
N
59
(-1-1-homo,"""'Ii"e (-)-1-homoaustraline
61 61
59 (-)-7a-epi-cronatecine (-)-7a-epi-cronatecine
?J""I
62 OH OH OH 62
Isozazolidine rings ringsand and the the final final product productmoieties moietiesderiving derivingfrom fromthem themare are shadowed. shadowed. Isozazolidine
Isoxazolidines are valuable intermediates for the synthesis of natural products and other bioactive compounds. Recent literature shows more and more examples of the versatility and usefulness of this class of heterocycles. For example, isoxazolidine derivatives have been used as key intermediates in the synthesis of the natural alkaloids 54 and 55 <06T4549; 06OL2309>, the cyclic amino acids 56 and 57 <06E103235; <06EJO3235; 06TAI863>, 06TA1863>, the pyrrolidine 060L2309>, fucosidase inhibitor 58 <06EJ02384> <06EJO2384> the pyrrolizidine alkaloid analogues 59 and 60 <06JOC1614; 06CAR2005>, the hydroxyindolizidine 61 61 <06TA292> and the nucleoside <061OCI614; analogue 62 <06TL882 <06TL8821I>. >. ]]-amino alcohols which can be released Typically, isoxazolidines are employed as masked p-amino under mild reduction conditions, but other different transformations leading to a variety of useful functionalities are also available as shown by some of the following examples. The
295
Five-membered ring systems with 0 & & N atoms
conversion of of a vinyl group into a y-hydroxy-a-keto 7-hydroxy-o~-keto acid moiety was accomplished by 1,3-DC with N-tert-butyl N-tert-butyl C-ethoxycarbonyl nitrone and subsequent ring diastereoselective I,3-DC of some sialic acid opening under basic conditions. The process was applied to the synthesis of derivatives. For example, the 3-alkoxycarbonyl isoxazolidine 63 was converted into the L-Nacetylneuraminic acid (64) in 60% yield via C-3 deprotonation followed by N-O N-O cleavage and imine hydrolysis <06AGE7417>. <06AGE74 I7>. OH OH NHAc
Y=:C OH OH
OH OH
E
dioxane OH OH OH dioxane OH c
,N, t-BurN"" t-Bu 0
90% 91% ds
OH
: OH
O-N
OH 9H OH OH
[
/
NHAc NHAc ~ ~
/'..
__ ~
'("('(Ii OH
OH OH
N, B N.t_Bul t- u
l
~ ~
/'..
OH
- E
: OH
O-N
~
4J \ ~ ~t-Bu t-Bu J
L_
OH 9H O_H NHAc NHAc OH
]
,E E
E 2. H H20 20 60%
\ ~t-Bu t-Bu
63
____ l -~
r
1. NaOH NaOH FOH OH NHAc NHAc OH OH 1. ~] MeOH ~_ .-
NHAc NHAc
.-:E 30 C ~_ 11+ -
+
H~
'OH H "'OH HO _ ~ AcHN A c H N - - ~ ~ O0\ ~ c O 2 HH C0 2 HO '
,C02H
' ( " ( ' ( I ( CO2H OH OH OH 0 O
=
OH
64
= C0:2Et CO2Et E=
N-Unsubstituted isoxazolidines such as 65 undergo facile decarboxylative peptide (z-keto acids <06JAI452>. <06JA1452>. The use of water as solvent or cosolvent was couplings with a-keto particularly beneficial for the formation of of amides in high yields. The methyl a-keto o~-keto esters ]3-peptide chain obtained could be saponified to the corresponding o~-keto a-keto acids, and the B-peptide could then be extended by reaction with another isoxazolidine. O ./jj....
HN-O OMe HN-O + Bn~ J ~ / ~ ' O M e .~ t-BuOH/H 20 (0.5 CO2H ~CO2Me t-BuOH/H20 (0.5 M) M)
Bn~02Me 65
40 cC, ~ 1h
oO
Bn
0O
..OMe )lN~oMe N ~
H
O 0
93% 93%
I,2-Thiazetidine 1,2-Thiazetidine I,I,-dioxides 1,1,-dioxides (I)-sultams) ([3-sultams) 67 were directly synthesised from pentafluorophenyl (PFP) isoxazolidine-4-sulfonates isoxazolidine-4-sulfonates 66 under mild reducing conditions [MO(CO)6, N-O bond [Mo(CO)6, MeCN, H20, reflux]. The process is stereoselective and goes through N-O cleavage followed by intramolecular displacement of the PFP group by the amine <060L55 13>. <06OL5513>. O~/C)
R,~---N' 66 'Me
o0
o,co, o;i MeCN,H20 90~
OH
II=(OH R = = 2-naphthyl (58%), (58%), 4-MeOC 4-MeOC6H4 6H4 (53%), 0=8 I 4-ally10C6H4 4-allylOC6H4 (52%), (52%), 4-BrC6H4 4-BrC6H4 (50%), N 2-CIC 2-CIC6H4 (47%), Ph (37%), (37%), 4-CIC 4-CIC6H4 6H4 (37%), 6H4 (47%), Me' R 2-BrC 2-BrC6H4 (27%), c-C c-C3H 5 (27%), (27%), 3-BrC 3-BrC6H4 Me/ 67 67 R 6H4 (27%), 3 Hs 6H4 (26%)
of 5-Spirocyclopropane isoxazolidines are versatile intermediates for the synthesis of of heterocycles. Highly strained 3-spirocyclopropane B-Iactam ]3-1actam 71 (n == 2) different classes of was obtained by acid-catalyzed fragmentative rearrangement of bis-spirocyclopropane isoxazolidine 70 (n == 2) prepared by intramolecular cycloaddition of of 69 (n == 2). Under the 1) could not be isolated as it underwent ring same conditions, the lower homologue 71 (n == I) opening to give the I)-amino ~-amino acid 72 <06EJ05485>. <06EJO5485>.
s.S. Cicchi, F.M Cordero, Cicchi, F.M. Cordero, and D. Giomi
296
~ r~~J)"J ~ ~ O~ ~
)n a), b)
0 ()n ;:]
) ---~
b)=
O'N
68 68
69 69
n=1,2 n = 1, 2
n=1,2 n = 1, 2
M~ Mg
n
n=1
M MeN
H 70 70 n ==l 1 58% n = 2 58%
n
HOzC--h MeN~ MeN+J
-f
F3C~ F3C- '~0
H 71 71 n=2 n = 2 66%
0
H
71% 72 71 %
Reagents and 25 ~ DC, 3 h; MeNHOH.HCI, NEt3, NEt], 3 A MS; MS; c) TFA, MeCN, Reagents and conditions: conditions: a) a) pec, PCC, CH CH2C12, h; b) MeNHOH.HC1, TFA, MeCN, 2CI 2, 25 reflux, 15 reflux, 15 min. min.
Similarly, 3-spirocyclopropane monobactams 74 were prepared by a one-pot threecomponent cascade reaction of alkylhydroxylamine hydrochlorides, aldehydes and bicyclopropylidene. In particular, microwave heating of mixtures of of the three components in the presence of of sodium acetate in EtOH furnished the products 74 through nitrone formation, of isoxazolidine 73 <06EJO <06EJO1251>. 1251>. 4'1,3-DC and acid-catalyzed rearrangement of Chlorospiro[cyclopropane-l,5'-isoxazolidinesJ Chlorospiro[cyclopropane-l,5'-isoxazolidines] prepared by 1,3-DC of pyrroline N-oxides with 2-chloro-2-cyclopropylideneacetates underwent a cascade ring enlargement process in the presence of a base affording 5-oxo-indolizidinone derivatives <06JOC2417>.
NaOAc. EtOH, mw EtOH, mw 80-100 ~ 80-100°C
[R1_N~0 :
_
O~
•. ~--\ . Rf R RZ 73 74 49-78% 1 = Bn, Bn, PMB, PMB, PhzCH, Ph2CH, t-Bu, t-Bu, RZ2 = H; H; R11 = Bn, Bn, t-Bu, t-Bu, RZ2 = COzEt; CO2Et; R11 = PMB, PMB, RZ2 = COzMe CO2Me R1
+ R2CHO + ~
RIN'oH
RZ2 R
~/
Nitrone 1,3-DC reactions are still the most general approach to isoxazolidines. The stereocontrol is usually achieved by the use of chiral nitrones and/or dipolarophiles, but new interesting achievements on Lewis acid catalyzed cycloadditions are also frequently reported. Tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanatedionate) europium(III) [Eu(fod)JJ [Eu(fod)3] selectively activated the Z-isomer of C-alkoxycarbonyl nitrone 75 existing as an E,Z£,Zequilibrium mixture by forming the (Z)-75-Eu(fod)3 complex. (Z)-75-Eu(fod)3 reacted with electron-rich dipolarophiles such as vinyl ethers to give the trans-adducts trans-adducts with excellent diastereoselectivity <06T <06Tl2227>. 12227>. E E E--.~ + _ I~"E N N R"N'o R"N"o R/ '6R/ '6-
11+ (E)-75
r1+
(Z)-75
E= E = COzMe CO2Me R R == CHPhz CHPh2
OEt
.
~---'/OEt(20 equiv)= =.! (20 equiv)
R II O,-N/"'"'E N
+
}J,"E
+
R I O" N.~,E
y ) ~/ E EtO trans-76 EtO cis-76 cis-76 : 28 no additive, 36 h, 89% 72 :28 Eu(fod) (1 (1 equiv), equiv), 77 h, h, quant >98 : 2 Eu(fod)
CICH2CH2Cl CICHzCHzCI
OMe
u:lo 1+ \
R.. ~O~Eu(fod)3 R/N'O~--Eu(fodb (Z)-75-Eu(fodh (Z)-75-Eu(fod)3
Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a,~-unsaturated ~,~-unsaturated 2-acyl imidazoles. For example, C-phenyl N-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereoand enantioselectivity. Isoxazolidine 79 was then converted into W-hydroxy-~-amino ~'-hydroxy-~l-amino acid Pd(OH)z/C and cleavage of derivatives by hydrogenation of of the N-O bond in the presence of Pd(OH)2/C the 2-acyl imidazole with MeOTfin MeOTfin MeCN <060L3351>. <06OL3351>.
297
ring systems with 00 & & N atoms atoms Five-membered ring
N% N~
Ph
o~NMe o
N N
+
(77
Bn/
77
M
[~D"-
NMe 78 78(5 (5mol%) mol%)
~..~/~--\/'"
EtOAc, 4 A MS EtOAc,4AMS 0 ~ 17 h 0°C,17h 97%
Me Ph
N/
o
0
1...-:;
Ph",(~ I ~ \ ~)-Ph phlll Ph \--N-Ce-N-{ Pn' (OTf)4 Ph PI~ (OTf)4 Ph 78
O
Bn
79 13n >99% ds, 99% ee ee
The 1,3-DC of nitrone 80 with maleimide 81 is a new example of recognition-mediated 81e and reaction. The association between the urea moiety in 80 and the carboxylate ion in 81c 81d triggers a pseudointramolecular cycloaddition resulting in increased reaction rate and diastereoselectivity. A slower reaction with essentially no stereocontrol was observed using dipolarophiles lacking the carboxylate recognition site such as 81a and 81b. 8lb. The recognition 'off' in situ by the addition of base and acid, site on maleimide could be switched 'on' and 'off respectively <06CC3684>. Z
HN~O HN~O HN
O
~ Z~O
t-Bu t-Su
lO ~+
HN/ HN"
~ ~ I
/~O HN"kO
+ OyN'):::='-O do-acetone d6-acetone +
+ o~N'Ar O,__N~Ar
88 80 Ar 6 H4 Ar = = 4-t-SuC 4-t-BuC6H4
\d 81a-d 81a-
t-Su t-Bu
12.5 mM 12.5mM 10°C 10 ~ 36 h
b~ ~
Ar--N
+ + -_ + -_ + Z 3; d Z= = aa OMe; OMe; b b OH; OH; cO c O HNEt HNEt3; d0 O NSU4 NBu4
-3
t-Bu
HN
Z
° Iv-N~N o-
HN"
H
O
\-;,
O H O A
N
H 0 O 83a-d 83a-d H 0 82a-d H a and b: 40-41 40-41% conversion; 82/83 = ca. 1" 1 % ca. 1: c and d: 67-70% conversion; 82/83 = = ca. ca. 4: 4:11
3-0-Allyl carbohydrate nitrones prepared from aldehydes 84 with PhNHOH PhNHOH in aqueous 3-O-Allyl media in the presence of of the cationic surfactant cetyltrimethylammonium bromide (CTAB) underwent highly regio- and stereoselective intramolecular cycloaddition at room temperature. In all cases the exclusive formation of of a single isomer was observed. In particular, the more substituted prenyl derivatives gave pyran derivatives such as 87, whereas corresponding allyl and crotyl compounds afforded the bridged isoxazolidines 85 and 86 the corresponding containing an oxepane ring <06JOC345>. <06JOC345>. No reaction was observed in water without CTAB or under neat conditions, whereas in conventional organic solvents a mixture of of isomers was generally obtained. Ph
R RI1I I
Ph
H ,HH
i
0 '' ' " ~N" O -~ H 0/ H "'0
PhNHOH PhNHOH CTAS
H'"
~ 0 H
=
85 R R 11 = H H 85
"'O~
884% 4% 86 e 885% 5% 86 R R11 == M Me
?--N, H HO.,,,/
"H 2 0, rt
PhNHOH PhNHOH CTAS H20, rt
R2 = H
R 1 = R 2 = Me
87
R1
OHC_
O
O
78%
87 78%
B3LYP/6-31 G* study was performed performed on both thermal and BH3-catalyzed BH 3-catalyzed 1,3-DC of of A B3LYP/6-31G* nitrones >. nitrones with methacrolein methacrolein <06JOC9831 <06JOC983 I>. A A new stereodivergent stereodivergent synthesis of of optically optically pure 4-alkylisoxazolidin-4-ols 4-alkylisoxazolidin-4-ols starting starting from enantiopure 2-(alkyloxiran-2-yl)methanols 2-(alkyloxiran-2-yl)methanols has has been been reported. reported. In particular, particular, the (2R)-glycidyl enantiopure
298
S. Cicchi, F.M. F.M Cordero, and D. Giomi
tosylate and nosylate R-88 were respectively converted into the enantiomeric isoxazolidines S-91 and R-91. Treatment of of the tosyl derivative 88 (R=Ts) with PhthNOH caused the 5-91 of R-89 that cyclised to 5-90 S-90 upon selective opening of the epoxide ring with formation of addition of methanol and NEt3. On the contrary, the nosyl group in 88 (R=Ns) underwent direct displacement by PhthNOH with conservation of the oxirane ring, which was then NEt3 in MeOH opened with HCI. HC1. Eventually, chlorohydrin 5-92 S-92 gave R-90 by treatment with NEt3 <06TL7635>. HO¥-. OH R =Ns R =Ts ~ HO HO HC~N~O HC'~N~O O o ~ R=Ns R~O R=Ts ~ o H O OTs HOo.N~7~o/~ c) (N''o ~CI~ b) Cl d), e) 2 ~ " a) a) HO (N''o ~ ~ OT~b) o~~ oHO~N~ cr
HO¥-.
9
H 75% 750/o ~ 59 9O/o H Yo ' HCI O"/~Ar PhthN HCI Ar PhthN
°
R-91
R-90
8-92 S-92
1i:
590/0 59%.) RO R-88
C
9
~ 72% ./L----
Ar O Ar~O
PhthN PhthN
8-90 % S-90 41 41%
R-89
N H
HCI ~CI
8-91 S-91
Ar TsOH = Ar = = 2-Me02CC6H4; 2-MeO2CC6H4;TsOH = 4-MeC 4-MeC6H4SO3H; NsOH= = 3-0 3-O2NC6H4SO3H; PhthNH== phthalimide phthalimide 2NC6H4S0 3 H; PhthNH 6H4S0 3 H; NsOH Reagents and conditions: NEt}, 1,4-dioxane, 48 h; NEt}, 50°C, Reagents and conditions:a) a) PhthNOH, PhthNOH, NEt3, 1,4-dioxane,50°C, 50 ~ 48 h; b) b) MeOH, MeOH, NEt3, 50 ~ 2 h; h; c) c) HCl, HCI, h; d) NEt}, CH HCl, I1 h. h. H H20, 95 ~ 44 h; d) PhthNOH, PhthNOH, NEt3, CH2C12, 24 h; h; e) e) conc conc HC1, 20, 95°C, 2Ch, 24
New examples of of palladium-catalyzed cyclization of O-homoallylhydroxylamines to isoxazolidines have been reported <06TL927; 06SC1247>.
5.7.4 5 . 7 . 4 0OXAZOLES XAZOLES Several new methods for the synthesis of of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>.
°
O H2N \ Arl..~C I+ H2N Ar)lct \
1
O'•--NH
[
O}-NH \\
Ar11 Ar
~ PdCI2(PPh 3)2, CuI. N\\ + Ar2"J]"CI NEt NEt& THF, 0° 0~C Ar1 3 , THF,
O PdCI2(PPh3)2, Cul ~,~A
Ar2~CI
~
Ar1--Zo~""""Ar2r2
r
92
o
Ar2~"CI ArJlCI Pd(ll), Cu(l) Cu(I)" Pd(II),
Ok~_NH O}-NH Ar1 \ Arl
\
1
Ar2 Ar2]
~
°
~OJ
Ar11,, Ar Ar22 == Aryl, Aryl, Heteroaryl Heteroaryl49-75% 49-75% Ar Conceptually interesting is the synthesis of of the oxazole system 94 through a Beckmann rearrangement of a-formyl ~-formyl ketoxime dimethyl acetals 93 which demonstrated the possibility of a non-amino acid pathway in the biosynthesis of marine derived oxazoles <06CC 1742>. of <06CC1742>.
299
Five-membered Five-membered ring ring systems systems with with 0 & N N atoms atoms
HO.. HO'N
n-Bu n-Bu
Ni
nn-Bu~ - B u ~ n - B u n-Bu __ polyphosphoric acid .. po_,y_p_h_os_p_h_or_ic_a_c_id_ n-BuJo Beckmann n-Bu .. _~ Beckmann rearrangment rearrangment MeO OMe 97% 97%
.eo "
94 94
93 93
of 2,4,5-trisubstituted 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 A new approach to the synthesis of and 98, used 1-(methylthio)acetone l-(methylthio)acetone 95 with nitriles in the presence of of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy <06JOC3026>.
0]
o
= [ //s~ //s~~ S . v ~o S R-CNv ~ 95 95
RO O \ 1 ] ( Raney-Ni Raney-Ni. R1Jt:s
97p
96 96 OTf OTf
R-CN R-CN
97 / S
I~
Base Base
II
/sylo
'K
R
R
&)
alkyl, aryl R = alkyl, 70-90% 70-90%
NyO
The use of of Zn(OTf)2 with a Ru complex, TpRuPPh3(MeCN)2PF6, proved useful for the cyc1ization cyclization of propargyl alcohols 99 with amides. The reaction proceeded through the intermediate 100 which was also isolated from the reaction mixture when only the Zn catalyst was used. Upon heating with the mixture of the two catalysts, compound 100 was completely 1>. converted into the final oxazole 101 <06JOC495 <06JOC4951>.
OH OH
~
+
R1~+ R1 99
O
o .J~ Jl
RZ R2
Zn(OTf)2 Zn(OTf)z -{ mpauPPh3(MeCN)2PF6 TpRuPPh ~ ~ 3 (MeCN)zPF 6 R2 R11 R11 =aryl =aryl NH R R NH2z Toluene, Toluene, 100 100~C, C, 5h 5h • RZ~ 101 101 0 88-95% 88-95% RZ R2 =aryl, =aryl, alkyl alkyl 0
'" Zn(OTf)2"~ Zn(OTf)z"
/ Zn(OTf)z ~TpRu Zn(OTf)2 PPh3(MeCN)2PF6 TpRuPPh 3 (MeCN)zPF 6
/
\~t
R2(O)CHN~~0 1 RZ(O)CHN 100
--I zJ(JL +R2-~.O R1 R 0~ ~ R
+
1
101 101
Application of the Ritter reaction conditions on y-hydroxy-a,~-alkynoic 7-hydroxy-t~,[3-alkynoic esters, 102, 7-N-acylamino-~-keto ester 104 by reaction with produced ethyl 5-oxazoleacetates 103 or y-N-acylamino-~-keto aryl or alkyl nitriles respectively. The y-N-acylamino-~-keto 7-N-acylamino-13-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCb POCI3 <06TL4385>.
300
S. S. Cicchi, F.M F.M. Cordero, and D. D. Giomi Giomi
OEt OEt
oO
A'~O
0O
AIk-CN ,,. Ar~OEt A r ~ Alk-CN OEt H2SO 4 0 ~ C HN Alk AIk 55 78°/ H2 S04 ,' 0° C 104 HN - /0 104 [~ ( 55-78% oO
Ar~ ~ O
T~ lo2 OH OH 102
I
I
POCI 3/
A.... IH2SO4,0~C r~n ] 44_70%OEt
/DMF ,'~ DMF 70°C 70~ C
84-92% 84-92%
Ar~--~O NxO
"~103 Y = aryl, alkyl A new method for the solid phase synthesis of oxazole-containing peptides 105 was developed, based on cyclodehydration followed or preceded by oxidation in a biomimetic fashion. The oxazole nucleus was obtained starting from threonine or serine and the method <06OL2417>. is compatible with most protecting groups <060L2417>.
Ph Ph Ph~h \ H o O Dess-Martin ~ ess-Martm P D ' R R. N Periodinane R.'N R ~N.,v~o II ~~ Periodinane 'N
H
H
-...../'-.0..
•
:-
CH CH2Cl 2 hh" 2CI 22,, 2
oOHO/~ -
3, 12, DIEA \~H_..~O ~O ~~ PPh PPh3,12, ~o" H : N O O//~.,~
.
0O
R'~TN?O~
O~
HO~ R= Cbz, Cbz, Fmoc, Fmoc,AIIoc, AIIoc,H R=
Ph.. Ph,
0-\
"b-~
los
105
80-93% 80-93%
Comforth rearrangement of oxazole-4-carboxamides 106 efficiently A microwave assisted Cornforth afforded 5-aminooxazole-4-carboxylates 107. 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>.
-t
0 /o~ N R 2 NR2 N ~ Ph.-J(O
OEt
106
EtO7
E{tO r -0
_
mw
m
Ph
=~ (=-
o
w
R2 N
0~OEt
)-OEt
J~~ Ikl
-
===""
Ph
/
0
NR2
107 "107-
NR =primary alkyl amines NR2 primary and secondary alkyl 2= 19-99%
of novel pyrrole-oxazole analogues of of the insecticide Pirate TM ™ was A parallel synthesis of of acylaminoketones with POC13<06S POCh<06S 1975>. performed through the dehydration of of A multipurpose mesofluidic flow reactor was developed for the automated synthesis of of 4,5-disubstituted oxazoles. The process was based on the known reaction of of libraries of alkylisocyanoacetates and acylchlorides <06OL5231 >. <060L523 I>. of the oxazole nucleus, some examples Considering the reactivity and the transformations of of new reactivity were described as well as the application of of known reactions to the oxazole of nucleus. of oxazoles with various eerie ammonium nitrate (CAN) promoted oxidation of The ceric substitution patterns was investigated and yielded the corresponding imides 108 in good of functional groups and substituents on the oxazole moiety yields, tolerating a wide variety of <06OL5669>. <060L5669>.
301
Five-membered ring systems with 0 & & N atoms
_
oO 0O
2
N1
N N"- \ RR33
CAN
R1Jl.NAR3 H 108 108 H
9
rt
R11,, R R22,, R3 R3 = = Aryl, Aryl, Alkyl, Alkyl, Alkenyl Alkenyl R
O + + R2..J~OH
50-90% 50-90%
of the O-acy1 O-acyl carbonates 109 An N-heterocyclic carbene 110 catalyzed the rearrangement of into their corresponding corresponding C-acylated isomers 111, generating a C-C bond and a quaternary stereocenter with high efficiency <060L3785> <06OL3785> The same reaction can be performed enantioselectively using TADMAP TADMAP 112 <06JA925>. <06JA925>.
OR1
040
.o_ Oo
~N f hi. "N/
L CPh3 ;L~CPh3
t) IL;5 'OAc -~
,,0 109N~Ar THF, rt, 5min
N
l~'~'Ar 67-84%
TADMAP TADMAP
R1= Me, Bn, Ph R2 = Me, Bn, CHMe2, CH2CHMe2
112 112
2-Aryl-4-trifloyloxazoles 113 undergo rapid, microwave assisted coupling with a range of of aryl and heteroaryl boronic acids in good to excellent yields. The same procedure procedure is also effective using 4-aryl-2-chlorooxazoles and can be extended to the synthesis of of homo- and <060L2495>. Analogous results were obtained using heterodimeric 4,4'-linked dioxazoles <06OL2495>. oxazol-4-ylboronates with aryl and heteroaryl halides <06SL555>.
Arl___(O"~ Pd(0),Ar2B(OH)2 Arl---(O~i]. NI \OTf mw, dioxane -" Nf\Ar2 113 114 75-94% Ligand and base free conditions for the arylation of of azoles were developed, although with a modest yield especially for oxazole, affording 2-substituted oxazoles <06EJOC1379>. <06EJOC1379>. With the aim of of finding new antagonists for the type 5 metabotropic glutamate receptor (mGluR5) for use in the treatment of of drug abuse, two new 4-arylethynyl-2-methyloxazole derivatives 116 and 117 were synthesized starting from 2-methyloxazole-4-carboxaldehyde 115 <06S243>.
1) CBr4, CBr4, PPh3 PPh3 (86%) (86%) 1) 0 NaHMDS, MeLi, (P~2) \:~~ Me3SiC, ,~<~\:"T1 NaHMDS, MeLi, Me3SjCI~ ~
. N O N
~
115 H H 115
~
84%
lyyY I~J""r/'~~Y [I ..) ~
\ x -X ~
~
\'~. ~
"SiM e 3 SiMe3
.
-----{O~ N
~
'I
~
Y
~JYx f x? 116 Y=F 85% 116 Y =F X=CH X =CH 85% 117 =H X =N 52% 117 YY=HX=N52%
A review concerning the cross-coupling reactions of of azoles with two and more heteroatoms was published <06EJOC3283>. <06EJOC3283>. of oxazole containing natural compounds or their Several reports on the synthesis of analogues appeared in 2006. The synthesis oftelomestatin of telomestatin 118 was performed <060L4165> <06OL4165> as well as several analogues as 119 <06BMCL3891> and others <06Sl289; <06S1289; 06TL7897;
302
S. Cicchi, F.M. F.M Cordero, and D. Giomi
06JA13662> The synthesis of bengazole A 120, a marine bisoxazole natural products with antifungal properties was completed. This synthesis was the first to produce a single stereoisomer <06AG(E)6714>. A new synthesis of phorboxazole B was published <2006CEJ1185>. Towards the synthesis of diazonamide A a biomimetic approach to the <2006CEJI185>. indole bis-oxazole fragment by oxidation of a TyrVaITrpTrp TyrValTrpTrp tetrapeptide was reported <06CC2397>. The first total synthesis of of inthomycin B 121 was performed. The synthesis was based on the Stille coupling of a stannyl-diene with an oxazole vinyl iodide <06TL549>. Oxazoles substituted on C-2 with a carbonyl group and a long chain revealed interesting of fatty acid amide hydrolase (FAAH) enzymes <06JA14004>. inhibitors offatty <06JAI4004>.
~H°=\-
N~
~y~
~-~-{\-
°O
IN NNNt )~NH NNNt o/\ p o'"- \ HN OzN
N./.,,X....
N
N
0 Nt.,L.~
O~NH
N
~1212
0
I oK.-~
N
OH OH OH
bengazole A bengazoleA 120
N
!( '\
~
0
0
telomestatin telomestatin
O 0
~)
IK~
-
OH
0"~
119
inthomycin B
118
~
~
0
HO'" HO' ~ /
\
NH2 NH2
121 121
5.7.5
OXAZOLINES OXAZOLINES
New simple methodologies for the synthesis of variously substituted 2-oxazolines exploit aldehydes and amino alcohols as starting materials. For instance, the reaction of of aromatic or aliphatic aldehydes with amino alcohols in the presence of N-bromosuccinimide as oxidizing agent allowed the one-pot preparation of compounds 122 under mild reaction conditions and in high yields <06S2996>. Analogously, treatment of aromatic aldehydes and 2-aminoethanol with pyridinium hydrobromide perbromide (PHPB) in water led to 2-aryl-4,5dihydrooxazoles 123 <06SL <06SLl479>. 1479>. The copper(I)-catalyzed reaction of of aldehydes and methyl isocyanoacetate afforded ester derivatives 124 in almost quantitative yields and high <06TL864 I>. diastereoselectivity in favor of the trans trans diastereomer <06TL8641 >. 2 R33 R 1R R = Ar, pyridyl, R1, a) R.=Ar, pyridyl, R a) R1, stlryl, N ~ ,.O 0 stiryl, t-Bu, t-Bu, C 09H19 = - RCHO + 9 H 19 1 2 3 R1,, R R2,, R R3 == H, H, Me, Me, R [~" H2N Et, i-Pr, Ph, Bn R Et,/-Pr, 122 30-96% 12230-96% Me02C MeO2C
"H R•
,•
c)
RCHO + r~NC c) C02Me R R- = =Ar,/-Pr Ar, i-Pr
R3
b)
/~ 1\ -~ N.\.O NyO R = Ar "~ OH / RI= R2= R3= H Ar Ar
12358-95% 123 58-95% trans/cis ratio from 86:14 to >99:1 >99:1 N%,,O No/0 124 124 >99%
HR
h, then NBS, rt, 0.5 Reagents MS, CH Reagents and and conditions: conditions: a) 4A 4A MS, CH2CI2, 14 h, then NBS, 0.5 h; h; b) PHPB-H PHPB-H20, 10 mol% mol% i20, rt; c) 10 2Cl z, rt, 14 Pr2EtN, 55 mol% mol% CuCl, h. Pr2EtN, CuC1, 10 10 mol% mol% PPh PPh3, CH2C12, 40 ~ 2 h. 3, CH zCl 2, 40°C,
303
Five-membered ring systems with 0 & Five-membered & N atoms
~
=
1 N,~/O R Ar, CH NVO RI= CH3(CH2)n, 3 (CH 2 )n, PhCH2CH PhCH 2 CH 22 RI 11 2 H H, Me R2= R
o
1 ~• RR1002 R22 C02 R
a) a)
=
H2N
OH
n= a)
~ NyO
NyO
~OH ~ ~ n OH
n = 1-3
12564->99% 125 64->99%
126 52->99% 12652->99%
Reagents and Reagents and conditions: conditions: a) a) Zn4(OCOCF3)60 Zn4(OCOCF3)60(1.25 (1.25 mol%), mol%),toluene, toluene, reflux. reflux.
A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc Zn4(OCOCF3)60 as catalyst, essential for condensation and cyclodehydration cluster Z1l4(OCOCF3)60 of oxazolines 125 reactions. For example, the use of (S)-valinol allowed the easy synthesis of and 126 in satisfactory yields <06CC27 I I>. A one-pot direct preparation of <06CC2711>. of various 2substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent <06TL6497>. Bromoamidation of of cyclic olefins allowed the synthesis of of bicyclic oxazolines. For instance, treatment of of cyclohexene with N-bromoacetamide as the halogen source and BhEt20 and water, led to oxazolines different nitriles at 0 °C, ~ in the presence of of SnCl4 SnC14 or BF3Et20 trans-bromoamides 127. The scope of of the bromoamidation appears 128 through intermediate trans-bromoamides quite broad with regard to olefinic and nitrile components <06JA9644>.
o
3 CCI CCl3
H-O
irco -1 a:
a) r'J",Br
~NHCOR
=
t-Bu, Ph 127 75-77% R = t-Bu,
AU[P(C Au[P(C6F5)3]SbF 6 F5 h]SbF66
CCI ,CCl33
O~'NH (1-2 (I-2mol %) ,. O~N O/iroN ~>-R RR'~..~ 1. CICH W CICH2CH2CI' 0 °C ~ ri R/~ ~~ 2CH 2 CI, 0 ~ ~ H H H
OA NH
12892-93% 128 92-93%
129 129
R R = = H, c-C c-C6H11 n-C7H15, 130 74-98% 6 H11 'n-C 7 H15 13074-98% i-Pr, t-Bu, Bn . .
i-Pr,t-Bu,Bn
Reagents Reagents and and conditions: conditions: a) a) MeCONHBr, MeCONHBr,RCN RCN (15 (15 equiv), equiv), H H20 (1.2 equiv), equiv), BF BF3Et20 (0.4 equiv), equiv), CH CH2C12, 20 (1.2 3Et20 (0.4 2CIz, 0 NEt3 (2 equiv), DBU (0.2 equiv), DMF, reflux. ~DC; b) NEt3
Cyclization of of N-alkenylamides to 2-oxazolines was achieved in very mild conditions with tert-butyl hypoiodite <060L3335>. <06OL3335>. The 5-exo-dig 5-exo-dig gold(I)-catalyzed cyclization of propargylic trichloroacetimidates trichloroacetimidates 129 proceeded with remarkably efficiency under very mild conditions to give 4-methylene-4,5-dihydrooxazoles 130 in good yields. The mildness of of the protocol was clearly responsible for the lack of isomerization of of the final products to the <06OL3537>. corresponding, thermodynamically more stable, oxazoles <060L3537>.
O NsONHCO2 R2 __~ F3C ~ 7/ F3C' F3C..JJ......~.~R1 CaO .. F3C = -(~~~-NE" O~ CH2Cl2,rt N R1 "CO2R2 ~N'CO2R2 131
R1 _ Ph, O E t Et, t-Bu
R2 =
002R2 132
R1
J
R1 133 52-58%
CF CF3-Enones 3-Enones 131 showed different reactivity in amination reactions to nosyloxycarbamates. In particular, 4-oxazolines 133 were synthesized operating in the
304
S. Cicchi, F.M Cordero, CicchL F.M. Cordero, and D. Giomi
presence of CaO or Nail NaH as base probably through a domino sequence involving a fast rearrangement of of unstable trifluoroacetyl aziridines 132 <06JOC6295>. Tripodal oxazolines 136a,b were synthesized from protected (3-hydroxyphenyl)glycinol 134 and tricarboxylic acids 135a,b in a one-pot reaction. Deprotection followed by generation of of the corresponding phenoxide ions and subsequent treatment with 4bromomethylpyridine afforded preorganized C C33 symmetric pyridyl-oxazolines 137a,b in 62 trans-Pd(OTf)2(PEt3)2 in a 2:3 molar and 53% overall yields, respectively. Mixing 137b and trans-Pd(OTf)2(PEt3)2 ratio gave homochiral dimeric cage 138b with two well-defined internal binding sites for molecular recognition of of ammonium and enantiomeric a-chiral o~-chiral organoammonium ions <06CCI136>. Analogous tripodal oxazoline-based artificial receptors were synthesized and <06CC1136>. exploited for dopamine recognition in water <06JOC38> while related bis(oxazolinyl)phenols 139 were applied as fluorescence sensors towards primary amines of enantio-discriminating a-chiral ~-chiral amines <06T <06T11645>. 11645>. even capable of
R'O R'O
NH2 HO2C
R
CO2H
/x / _7 R'O.y~
a.
H§
/N..,
Oo~N
~~
~-~ ~ 2 0~.~
0,y
L c ) " ~ O
_~I N
R R b) ,,,-, ,,/I R'=TBS HO C R'=TBS
.N.~
d)
A L .R 0 ~ -'" ~.\ ~J ~ R ~~ O0 dO nv2,,., R == Me, Me Et Et \\ N~ R D-./~----~.----/ ~. ~ 2 R -?' ~ 134 135a,b ' O--~D & ~- - # s~ ), [ \~N 134 135a,b 0 "RR 136a,b 136a,b ~ t~1 64" N/"~0 RN~ Et3P~. P E3t 3 ~/"-O ~ 6+ ~ & N L..>~_~R ' ~ O Et 0 16+ 3 P. J:.'Et p--<:~ I \ N'R -?' ~ n~Pd-N~ /0-
OTBS OTBS
,-
°1""~cf 'Ll/
?--) ....
~O -
-
o~0v=\
,,-N
0
~ "NNN" ~
,
,--
N N
N ~N~e~Tl\\ o~"
~'--'~_~/I . ~z N\PEt_:~
JO.. ' f
~
r ~ "N ~ P|d 'Pd'=T' P.d ~ .____. o O U - 0 NN~--3'~ NEtP ~ "'NY \ ..... / I 3P ~ I/ Et ~ ~ I "::: ""'CO ~ Et P~Et N ~....O /; Et3P PEt3 _ ~ ~ 1~b
#~.//~ //
0O
)-0
/' N
o
v
. .R
o
~ 137a R = Me 62%
e) R R :)
b R = Et 53%
A (~N \"N R 0 Iz
R = Ph Me R=Ph,Me HO
0
O
H(Z)
~
139 Reagents and NEt 3, CH NEt3, DMAP, DMAP, CH NaOH, MeOH, MeOH, rt; d) Reagents and conditions: conditions: a) (COCI)l, (COC1)2,NEt3, CH2C12; MsCI,NEt3, CH2C12; aq. NaOH, d) 2CI 2; c) aq. 2CI 2; b) MsCl, NaH, DMF, Irans-Pd(OTf)z(PEt3)2 in Nail, DMF, 4-bromomethylpyridine, 4-bromomethylpyridine,CH CH2C12, rt; e) e) 137b 137b and and trans-Pd(OTf)2(PEt3)2 in 2:3 ratio, ratio, CH CH2C12, rt. 2Ch, rt; 2Clz, rt.
R1
140a ~2
W R1
9N
OH
140b ~2 R1
R\ 3/ R3 o-~,.o
_,,,,
o
141 "R3
305
Five-membered ring systems with 0 & & N atoms
Great attention is still devoted to the synthesis and applications of enantiopure oxazoline ligands and recent results related to the use of C C2-symmetric 2-symmetric bis-oxazoline ligands in asymmetric catalysis have been reviewed <06CRV3561>. <06CRV356l>. Concerning mono-oxazoline derivatives, two libraries of chiral N-heterocyclic carbene-oxazoline ligands 140a,b have been synthesized and their iridium(I) complexes successfully tested in the asymmetric hydrogenation of olefins <06CEJ4550>. A series of enantiopure thiophene mono-oxazoline N,O-ligands 141 with three sites of diversity were also prepared in two steps from the N,O-ligands corresponding thiophene carbonitriles and applied to the enantioselective phenyl transfer reaction of aldehydes <06TA2442>. A new family of optically active phosphine-oxazoline P,N-ligands 142 has been synthesized and evaluated in asymmetric allylic alkylation (AAA) reactions (ees up to 97%) <06TlI470>. <06Tl1470>. Different regioisomers of of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes <06JOC4609> and some aza-paracyclophaneI I> were prepared and tested in AAA reactions and allylation oxazoline N-oxides <06TL86 <06TL8611> of of aldehydes, respectively. Novel planar chiral PHOX ligands with a pentamethylferrocene backbone were synthesized and applied in Pd-catalyzed AAA reactions (ees up to 94%) <06JOC2486> while the use of P,N-ferrocenyl-oxazoline ligands with electron-rich or electron-deficient aryl groups on the P atom allowed high diastereoselectivity and excellent enantioselectivity (up to 98%) in Cu(I)-catalyzed asymmetric I,3-DC 1,3-DC ofazomethine of azomethine ylides to nitroalkenes <06AG(E)I979>. with <06AG(E)1979>. New chiral phosphine-oxazoline ligands 143 (SIPHOX) (SIPHOX)with a rigid and bulky spirobiindane scaffold were prepared in four steps in 40-64% overall yields: the corresponding iridium complexes catalyzed the hydrogenation of acyclic N-aryl ketimines (ees up to 97%) <06JAI2886>. <06JA12886>. Excellent results (ees up to 99%) in the iridium-catalyzed 2-aza-norbornane-phosphinehydrogenation of imines and olefins were also obtained with 2-aza-norbomane-phosphineoxazoline ligands <06CEJ2318>. <06CEJ23I8>. Potentially tridentate P,N,N-quinazoline-oxazolineP,N,N-quinazoline-oxazolinePd(0)-catalyzed AAA reactions containing ligands 144 have been synthesized and applied to Pd(O)-catalyzed <060L5l09>. <06OL5109>.
, "t-Bu ~~/N
t-Bu,,,
Ok~_
sO
0
N'~O Ar~"INo...~ ~~O
,,,Ar
145
The synthesis of different C C2-symmetric 2-symmetric bis-oxazoline ligands, such as 145, with an axialunfixed biaryl backbone has been reported as well as their diastereomeric equilibrium in solution and their application to Cu-catalyzed cyclopropanation of styrene with diazoacetate <06TA767>. A three-step procedure allowed the synthesis of C2-bis-oxazoline-amide ligands 146, tested in Pd-catalyzed AAA (ee's up to 98%) <06JOC6451>. <06JOC645 I>. Chiral C C2C12- and C 1symmetric bis-oxazolines with a cyclopentane backbone have been prepared and studied in transfer hydrogenation, cyclopropanation and Diels-Alder reactions <06TA620>. The synthesis of highly modular N,Y,Z,Y,N-pentadentate bis-oxazolines (Y =- N, 0, O, S; Z == N, NO, OH, OMe) such as 147 led to a variety of ligands in diastereo- and enantiomerically pure of helical metal complexes with predetermined chirality form exploited for the construction of <06T9973>. Single enantiomer, chiral donor-acceptor metal complexes were synthesized via the self-discriminating Zn(II)-compIexation Zn(II)-complexation of of a pseudoracemic mixture of donor/acceptorsubstituted bis-oxazoline derivatives <06OL2759>. <060L2759>. Chiral pyridyl-bis-oxazolines (Pybox)
306 306
CicchL F.M F.M. Cordero, Cordero, and and D. D. Giomi Giomi S.S. Cicchi,
were successfully successfully applied applied in in scandium(III)-catalyzed scandium(III)-catalyzed Sakurai Sakurai additions additions to to glyoxyamide glyoxyamide were <060L2071>, <06OL2071>, pyrrole pyrrole alkylations alkylations <060L2249> <06OL2249> and and cerium(IV)-catalyzed cerium(IV)-catalyzed nitrone nitrone cycloadditions of of a,~-unsaturated t~,13-unsaturated 2-acyl 2-acyl imidazoles imidazoles <060L335 <06OL3351>. Metal-complexes of of azaazaI>. Metal-complexes cycloadditions bis-oxazolines bis-oxazolines efficiently efficiently catalyzed catalyzed the the addition addition of of indoles indoles to to benzylidene benzylidene malonates malonates <06OL6099> and and to to nitroalkenes nitroalkenes <060L2115> <06OL2115> (up (up to to 98-99% 98-99% ee) ee) as as well well as as addition addition of of <060L6099> to nitroalkenes <06JA74 <06JA7418>. of pyridine N-oxide N-oxide aldehydes nitroalkanes to I 8>. Aldol reactions of were performed in in high high yields yields and and diastereoselectivity diastereoselectivity and and in in excellent excellent enantioselectivity enantioselectivity in in of chiral chiral copper(II)-bis(oxazoline) copper(II)-bis(oxazoline) complexes complexes <06CEJ3472>. <06CEJ3472>. the presence of A novel 1,1novel route to to cyclopropane cyclopropane derivatives derivatives has been described described from from 2-( 2-(1,1dimethylalkyl)dimethyloxazolines 148a 148a (R (R11== Me): conversion conversion into 1,3-diiodides 1,3-diiodides 149 149 via Pddimethylalkyl)dimethyloxazolines catalyzed catalyzed sequential sequential C-H C-H activation activation and and then radical cyclization led led to 2-(1alkylcyclopropyl)dimethyloxazolines 150 in satisfactory yields <060L5685>. <06OL5685>. The alkylcyclopropyl)dimethyloxazolines 2 1 4 8 b (R (R 2 = = Ph) were subjected to Pd-catalyzed alkylation of corresponding aryl derivatives 148b aryl C-H bonds with Sp3 sp 3 organotin reagents using benzoquinone as a crucial promoter to give aryl 151 <06JA78>. derivatives 151 1I
I---.~/~ I~
~
cat. Pd(OAc)z Pd(OAc)2 R R11 R R11 cat.
R1 R1 ~ _ N j ~ a) [ ~ ~ . ~ a) = R2X,~ 2 \/ R /' • R /' • R -O...j C6H 6, ~A EtOAc,~A = Ph Ph o C 0O - - . J EtOAc, 0 R22 = 6 H6, 150 81-91% 149 70-83% R11= Me Me Me, (CH (OH2) 151 62-88% 15081-91% 14970-83% 148a,b R11 = Me, 2 )nn 15162-88% 22=alkyl,CH2X,ester, OTBS, NPhth R R =alkyl, CH 2X, ester, OTBS, NPhth Reagents and and conditions: conditions:a) a) cat. cat. Pd(OAc)2, Pd(OAc)2,Me4Sn, Me4Sn,Cu(OAc)z, Cu(OAc)2,benzoquinone, benzoquinone,MeCN, MeCN,reflux. reflux. Reagents
, ~ =(PhC0 (PhCO2)2 IOAc 2 )z 2 ~ - ~ ~ R22 ~ / N~ R2 N,~ _ ~ 10Ac
Unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'dimethyl)oxazolinylpyridine 152 using LTMP versus LDA was observed providing 154, precursors of highly substituted nicotinic acid derivatives compounds 153 and 154, <060L6071>. Bicyclic 2-piperidinones 155 were obtained from 2-(butyn-4-yl)oxazolines <06OL6071>. through free-radical-mediated carbonylation and 6-endo cyclization of the resultant acyl <06JA77 12>. Sugar oxazolines were exploited in the radicals onto the oxazoline nitrogen <06JA7712>. of glycoproteins <06OL3081> synthesis of <060L3081> and glycosaminoglycans <06CEJ5962>.
y
Y
NY
w 1. LTMP, LTMP, w 1. LDA, LOA, N'"~ N R N~ B r r r r ' ) THF,-78~ THF,-78°C B r B r ~ o~ 2 Td HF' , -O. 7) 8 ~THF,-78°C B BE~ ~ B r ~ ij) ,O 0 • ~ 0 .,J,.\ -2. 2. Electrophile : -. I~I 2. Electrophile Electrophile ::-.. I Electrophile ::-.. [ R "N" N NH 4CI N 152 NH 4 CI N R" 3. NH4CI "N" 3. NH4CI 153 45-77% R == Cl, 154 51-89% 15345-77% CI, I, TMS, TMS, CO2Et, C02 Et, CH(OH)Ar, CH(OH)Ar, CH(NTs)Ar 15451-89%
O R R' ~J'~N~/ > V ~O 155 155
~~R
5.7.6 5.7.6 OXAZOLIDINES OXAZOLIDINES methods for the the synthesis of of the oxazolidine oxazolidine ring were were published published offering offering new Some new methods exploit the rich chemistry of of these these compounds. In aqueous media media tx-ketoamides a-ketoamides 156 156 ways to exploit with phenolic phenolic substituents substituents (Y == CN, CF3, CF 3, H) undergo undergo photocleavage photocleavage and release release of of the phenol with formation of of 5-methyleneoxazolidin-4-ones 158. The zwitterionic zwitterionic intermediate intermediate phenol eliminates eliminates the the phenolate phenolate leaving leaving group and the resultant iminium ion 157 157 undergoes undergoes cyclization cyclization <06JOC4206>. <06JOC4206>.
307 307
Five-membered ring systems with 00 & N N atoms Five-membered
oH'~ ..
,,
o
hydrogenhV I
R2~
trans'er 14 C4H40OH ,,+ N
R2I'~+ 1
-
.
O--~R2
OH
157 0
o
R1, R2 = alkyl
17-60%
of the oxazolidinone oxazolidinone 159 appeared appeared to be well established, established, the scale-up Although the synthesis of Although ofthe reproducible results. The synthesis was much more efficient using of the reaction gave poorly reproducible of activated charcoal <06S885>. <06S885>. diphosgene and a catalytic amount amount of diphosgene
Ph
OH
H ptfhh H2N~'p~ HzN
O o
CICO zCCI3 CICO2CCI 3 activated charcoal charcoal activated
oA
O/'~NH NH
P~'+-{
THF, overnight overnight THF,
Ph
159 Ph
25 g, 89% Another synthesis of ,3-oxazolidin-3-ones can be achieved using Au(I) to Another of 5-methylene-1 5-methylene-l,3-oxazolidin-3-ones catalyze the cyclization of of N-propargyl carbamates 160. The reaction proceeds proceeds under very <06SL2727>. mild conditions and was applied to a large number of of compounds <06SL2727>.
t-BuO.
Ri 3 ~ N. ~
-,~ 0 R2--,/~ RI
O R3N/JJ... O PPh3AuNTf2 \ / 65-99% 5 min-20,," h 5rnin-20
160
R2
R1, R2 = aryl, alkyl R3= H, Me
A previously described process - the synthesis of stannylated oxazolidines and their ring opening to afford N-(a-tributylstannylorgano)-(R)-phenylglycinol N-(tx-tributylstannylorgano)-(R)-phenylglycinol carbamates 161 - was completed by the transformation of these latter compounds into stannylated oxazolidinones 162. The ring closure of of compounds 161 can be achieved by treatment with two equivalents of of NaH Nail or by mesylation of the primary alcohol. The applicability of this process was demonstrated by the use of of the stannylated oxazolidinones as precursor of organolithium reagents <06S4151>. <06S4151 >.
O Bu3Sn,,~ " 1 N~ph
O:~OR1
R22Cuki RZzCuLi
o o., O.:::y-OR1 "~
I
o NaH Nail or or MsCI MsCl
• BU3Sn'y"'N~OH . u Sn. ~ _ .yI OH 161 161 RZ2 Ph Ph
9
O=< O
'I
W-" J
.u Sn z BU3Sn""'''. 162 R 162
Ph
Ph
0-90/o 50-93%
= Me, t-Bu t-Bu R11= Z R2 = alkyl alkyl R
The formation of 1,3-oxazolidin-2-ones by the reaction of phosgene or diphosgene with amino alcohols is a well established reaction, proceeding with retention of configuration of the stereocenters of the original amino alcohol. However exceptions were found with substrates containing the (2,3-anti)-3-amino-1 ( 2 , 3 - a n t i ) - 3 - a m i n o - l , ,2-diol 2 - d i o l moiety. As an example, the reaction of amino alcohol 163 with phosgene and diphosgene was described. The two reactions gave
308 308
S. Cicchi, Cicchi, F.M. F.M Cordero, Cordero, and andD. D. Giomi Giomi S.
different results results since since for for phosgene phosgene the the major major product product was was the the cis-oxazolidinone cis-oxazolidinone 164 164 while while different trans isomer isomer 165 165 <06T6392>. <06T6392>. with diphosgene diphosgene the the major major one one was was the the trans with oo Ph OH II )-{ CI/"-..CI
Ph~c,OHNEt3JLc.Ph,
-NH)
-
HO 163 163 HO
NEt3
° ~E~!1c'~~
HO
I N -V
O
76%
164101
O
NEt3
Ph I Ph
CI)lOCCI 3 OH OH
Ph~
Ph
_N)~__o~ Net~--~o occ,~ ~~"~1 -N>----<--OH }-OCCI occ, 3
o
o
HO\
/'~l
_
= ~ N~r],/o 45% 0 165 165
of selectivity can be obtained in the base catalysed epimerization of of 1,3A high degree of of the base and substituents a oxazolidin-2-ones 166 and 167. Through a proper choice of 99: 1 can be obtained for both the trans trans and cis cis isomers <06JOC5008>. <06JOC5008>. selectivity up to 99:1
-1 ,COzMe --~;-CO2Me - - ~ C O 2COzMe Me -1 )--{ R= Bn "
N O Bn-NyO Bn~ "~II 166
o O 166
R=Bn
R=H R =H LHMDS
)--{ N O -= wNyO LHMDS R" ",]]/ LHMDS II
- ~ t C O 2COzMe Me -1
LHMDS
oO
dr> dr > 99:1 99:1
';--{ HN ~O HNyO 167~]" 167 II 0O dr> dr > 99:1 99:1
Some reactions in which a preformed 1,3-oxazolidine ring is transformed into another oxazolidine derivative were described. A detailed study of the enantioselective reduction of N-tosyl-4-alkylidene-l,3-oxazolidin-2-ones under the catalysis of Rh salts and chiral ligands, was published <06T9237>.
(EtO)2P(S)a (EtO)zP(S)H AIBN AIBN
=
O J..--
S... ~OEt ~\OEt I'OEt
S~p/OEt
('11' 168 168
75% .J ~5~_) DPSO~ DPSO
1,3-Oxazolidin-2-ones were employed as nucleophiles in a new multicomponent reaction 1,3-0xazolidin-2-ones called UFU (Ullman-Finkelstein-Ullman). (Ullman-Finkelstein-Ullman). This This reaction allowed allowed the one-pot one-pot synthesis synthesis of of dissymmetrical dissymmetrical para-disubstituted para-disubstituted benzene scaffolds scaffolds from from I-bromo-4-iodobenzene 1-bromo-4-iodobenzene and and two nucleophiles <06TL4973>. The 1,3-oxazolidin-2-one 1,3-oxazolidin-2-one ring was used as as scaffold scaffold for for aa radical cyclization cyclization to obtain obtain compound compound 168, 168, in in aa synthetic synthetic process towards the synthesis synthesis of of substituted substituted quinuclidines quinuclidines <06JOC3656>.In aa similar similar way, the 1,3-oxazolidin-4-one 1,3-oxazolidin-4-one ring was used as as aa scaffold scaffold for for aa ring ring closing closing metathesis metathesis useful useful for for the the synthesis synthesis of of azepinones azepinones and and used azocinones azocinones <06TL3625>. <06TL3625>.
309
Five-membered ring systems with 0 & & N atoms
Several examples of the use of a,~-unsaturated o~,~-unsaturated imides of of chiral, or non chiral, 1,3oxazolidin-2-ones were published. These compounds were used in Michael additions <06JOC8572; 06TLl291> 06TL1291> and Diels-Alder reactions <060L539; <06OL539; 06Tl2398; 06T12398; 06T3095>. (NVinyl)-I,3-oxazolidin-2-ones Vinyl)-l,3-oxazolidin-2-ones were used as dipolarophiles in 1,3-DC reactions with nitrones <06SL3255>. A fluorinated a-bromo o~-bromo imide was used in a stereoselective Reformatsky-type reaction with imines <06CC3628>. Concerning natural and bioactive compounds, a short of cytoxazene 169 was reported <06T9349>. synthesis of
0 HN/L['-O
.
o
o
.....
o
o
~0..,]]/N___.~N~,,,IJ,,.N . ~ N--'~ H_.,~ N__,,,JJ,,..~ N-~OBn
~ cyt~
o
:
o
o
o
o
170
MeO
Three sets of oligomers containing the 4-carboxy-5-methyloxazolidin-2-one moiety, one example is compound 170, were synthesized with the aim of of verifying if these systems are [3-bend ribbon spiral <06JA241O>. <06JA2410>. able to give a ~-bend 5.7.7
OXADIAZOLES OXADIAZOLES
5-Alkyl- and 5-aryl-2-amino-I,3,4-oxadiazoles 5-aryl-2-amino-l,3,4-oxadiazoles were prepared by tosyl chloride/pyridinemediated cyc1ization cyclization of thiosemicarbazides in good yields (79-99%). Interestingly, thiosemicarbazides exhibited a higher rate of of cyc1ization cyclization than the corresponding semicarbazides. For example, 171 (X=S) was converted to oxadiazole 172 within 5 h <06JOC9548>. TsCI N-N O TsCl(1.2 (1.2equiv) equiv) N-N II \\ H..,n/H pyridine(2.1 (2.1equiv) equiv) Ph.v~o~,.,.N~Ph Ph~ . ~ N..N NvPh pyridine ... Ph ~O/'-.N./"-- Ph THF, H II THF,65-70 65-70°C ~ H X H X == 0: O: 23% 23%cony convafter after20 20 hh 172 X =S: X S 99% 99%cony convafter after55 hh 171 X 172
o O
O
[~~N
~2~N-JJ~ hI~
173 Me [4+2]
Me RE /
cycloaddition{ 0 ~ O ~ R N -,
~,
0-Cl2C6H4,180~ or TIPB, 230°C
"
Rz
61-94%
174 Me:: Me 174 E CO2Me COzMe
61-94%
= CH2OTBS,Ph,
Rz, R RE Me, Rz, E = H, Me, CHzOTBS, Ph, OBn, COzMe, CN
OBn, CO2Me, ON_N2 D. -N z
[3+2] [3+2]
t
cycloaddition| 0
~O
CoS:Ycloaddition
~ / ~ . +RN ?"'
'::+1
0 Rz -'N N. \ .,,,~,. ~~ [ -~N ,~....~,,. z N 'RE Me Me "]1 "RE Me --f ""RE COzMe CO2Me TIPB TIPB== 1,3,5-triisoproPylbenzene 1,3,5-triisopropylbenzene CO2Me
A systematic exploration of of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered
310 310
S. Cicchi, F.M. F.M Cordero, and D. Giorni Giomi
dipolarophile, dipolarophile, the 1,3,4-oxadiazole 1,3,4-oxadiazole C-2 and C-5 substituents, substituents, the tether lengths and sites, and bearing a tethered the central heterocycle were were examined. For instance, instance, derivatives 173, bearing indole as the dipolarophile trap of of the in situ different tethered situ generated carbonyl ylide and different dienophiles, dienophiles, were successfully successfully exploited leading in each case to a single diastereomer diastereomer of of the cycloadducts cycloadducts 174 <06JAl0589>. <06JA10589>. Treatment Treatment of of acylated adenosine-N-oxides adenosine-N-oxides with carboxylic carboxylic presence ofthiophenol of thiophenol produced produced 4-(5-substituted-I,2,4-oxadiazol-3-yl) 4-(5-substituted-l,2,4-oxadiazol-3-yl) acid anhydrides in the presence For example, 175 was converted to 176 by treatment with acetic nucleoside analogues. For anhydride followed by deprotection of of the amino group at C-5 with b I2 (0.5 mol equiv) in hot MeOH <060L4565>. MeOH <06OL4565>. /:N
Aco-- N. +"H2 AcO""
"OAc N ~ 175
~'~"O -
1. PhSH, (MeCO)20 2.1 2.12, 2, MeOH 3. NEt33,, CH CH2Cl 2 2CI 2
0
AcO
AcO'"
/r=N N ,~
"OAc NH2
N "O
176 98%
The rearrangement rearrangement mechanisms mechanisms of of 5-perfluoroalkyl-I,2,4-oxadiazoles 5-perfluoroalkyl-1,2,4-oxadiazoles such as the five-toring-rearrangements by hydrazinolysis six membered ring-rearrangements hydrazinolysis and the photoinduced photoinduced competitive competitive rearrangements have been investigated <06JOC8106; <06JOC8106; 06JOC2740>. 06JOC2740>.
5.7.8
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Five-membered ring systems with 0 & & N atoms
06EJ03016 06EJO3016 06EJ03235 06EJO3235 06EJO3283 06EJ03283
06EJO4852 06EJ04852 06EJ05485 06EJO5485 06JA78 06JA925 06JA1452 06JAI452 06JA2410 06JA6626 06JA7418 06JA7712
06JA9644 06JA9644 06JAI0589 06JA10589 06JAI2886 06JA12886 06JAI3662 06JA13662 06JAI4004 06JA 14004 06JOC38 06JOC345 06JOCI614 06JOC 1614 06JOC2417
06JOC2480 06JOC2480 06JOC2486 06JOC2486 06JOC2740 06JOC2740 06JOC3026 06JOC3026 06JOC322I 06JOC3221 06JOC3656 06JOC3656 06JOC4206 06JOC4206 06JOC4609 06JOC4951 06JOC5008 06JOC6178 06JOC6295 06JOC6451 06JOC8106 06JOC8572 06JOC9319 06JOC9548 06JOC9548 06JOC9831
06MM3147 06MM3147 060L539 06OL539 06OL927 060L927 060L2115 06OL2115 060L2249 06OL2249 06OL2309 060L2309 060L2417 06OL2417
311
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312 060L2495 06OL2495 060L2701 06OL2701 060L2759 06OL2759 060L3081 06OL3081 060L3335 06OL3335 06OL3351 060L3351 06OL3537 060L3537 06OL3679 060L3679 060L3785 06OL3785 06OL4165 060L4165 060L4565 06OL4565 060L5109 06OL5109 060L5157 06OL5157 060L5231 06OL5231 060L5513 06OL5513 060L5669 06OL5669 060L5685 06OL5685 06OL6071 060L6071 060L6099 06OL6099 06PLM3292 06S243 06S706 06S885 06S1021 06SI021 06S1289 06S1479 06S1975 06S1995 06S2265 06S2293 06S2515 06S2996 06S4151 06SCI247 06SC1247 06SL463 06SL555 06SL1739 06SLI739 06SL2727 06SL3255
06T611I 06T61 06Tl494 06T 1494 06T3095 06T4549 06T6392 06T9237 06T9349 06T9973
06T11470 06Tl1470 06TlI645 06T 11645
S. Cicchi, F.M. F.M Cordero, and D. Giomi
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Five-membered ring systems with 0 & & N atoms
06T12227 06Tl2227 06T12398 06Tl2398 06TA292 06TA620 06TA767 06TAI863 06TA1863 06TA2442 06TL549 06TL727 06TL927 06TLI291 06TL1291 06TLI627 06TL1627 06TL3625 06TL4385 06TL4698 06TL4957 06TL4973 06TL6497 06TL7043 06TL7635 06TL7897 06TL8247 06TL8383 06TL861 06TL8611I 06TL864I 06TL8641 06TL882I 06TL8821 06TL9077
313
Shiro, N. O. Tamura, N. Mita, Y. Imai, T. Nishimura, T. Kiyotani, M. Yamasaki, M. Shiro, Morita, I. Okamoto, T. Takeya, H. Ishibashi, M. Sakamoto, Tetrahedron 2006, 62, 12227. 12227. P.B. Wyatt, E.W.C. Cheng, R.T. R.T. Mandalia, M. Motevalli, B. Mothia, Y. Patanwadia, P.B. Tetrahedron 2006,62, 2006, 62, 12398. 12398. 2006,17, F. Pisaneschi, M. Piacenti, F.M. Cordero, A. Brandi, Tetrahedron: Asymmetry 2006, 17, 292. I. Atodiresei, I. Schiffers, Schiffers, C. Bolm, Tetrahedron: Asymmetry. 2006, 17, 620. W. Zhang, F. Xie, S. Matsuo, Y. Imahori, T. Kida, Kida, Y. Nakatsuji, I. Ikeda, Tetrahedron: Asymmetry. 2006, 17,767. 17, 767. L. Alvarez de Cienfuegos, N. Langlois, Tetrahedron: L./klvarez Tetrahedron." Asymmetry 2006, 17, 1863. 1863. Z. Chai, X.-Y. Liu, X.-Y. Wu, G. Zhao, Tetrahedron: Asymmetry. 2006, 17,2442. 17, 2442. M.R. Webb, C. Donald, RJ.K. R.J.K. Taylor, Tetrahedron Lett. 2006,47,549. 2006, 47, 549. T. Ogamino, R. Obata, S. Nishiyama, Tetrahedron Lett. 2006, 47, 727 KG. Dongol, B.Y. Tay, Tetrahedron Lett. 2006,47,927. 2006, 47, 927. S.J.K. Sauerland, E. Kiljunen, A.M.P. Koskinen, Tetrahedron Lett. 2006,47, 2006, 47, 1291. 1291. I. Yavari, L. Moradi, Tetrahedron Lett. 2006,47,1627. 2006, 47, 1627. A. Kamamura, K. Tanaka, T. Hayashi, Y. Ornata, Omata, Tetrahedron Lett. 2006,47,3625. 2006, 47, 3625. K.S. Rao, D.S. D.S. Reddy, M. Pal, K. Mukkanti, J. Iqbal, Tetrahedron Lett. 2006, 2006,47,4385. 47, 4385. R.T. McClain, S.E. N.B. Nolt, M.A. Smiley, S.L. S.L. Varga, R.T. S.E. Wolkenberg, C.W. Lindsley, Tetrahedron Lett. 2006, 62, 4698. 2006, 47, 4957. E. Rajanarendar, G. Mohan, P. Ramesh, D. Karunakar, Tetrahedron Lett. 2006,47,4957. 2006,47, P. Toto, lC. J.C. Gesquiere, N. Cousaert, B. Deprez, N. Willand, Tetrahedron Lett. 2006, 47, 4973. C.O. Kangani, D.E. D.E. Kelley, B.W. Day, Tetrahedron Lett. 2006,47,6497. 2006, 47, 6497. Singh, S. Batra, Tetrahedron Lett. 2006,47,7043. 2006, 47, 7043. V. Singh, B.P. Martin, M.E. 2006,47,7635. 9B.P. M.E. Cooper, D.K. D.K. Donald, S.D. S.D. Guile, Tetrahedron Lett. 2006, 47, 7635. S.K. Chattopadhyay, S. Biswas, Tetrahedron Lett. 2006,47,7897. 2006, 47, 7897. N. Iranpoor, H. Firouzabadi, N. Nowrouzi, Tetrahedron Lett. 2006,47,8247. 2006, 47, 8247. Y.-l Shiao, P.-C. W.-S. Chung, Y.-J. P.-C. Chiang, A. Senthilvelan, M.-T. Tsai, G.-H. Leeb, W.-S. Tetrahedron Lett. 2006, 2006,47,8383. 47, 8383. Q. Chai, C. Song, Z. Sun, Sun, Y. Ma, C. Ma, Y. Dai, M.B. Andrus, Tetrahedron Lett. 2006,47, 2006, 4 7, 8611. 861 I. D. Benito-Garagorri, Bocokic, K. Kirchner, Tetrahedron Lett. 2006,47,8641. Benito-Garagorri, V. Bocoki6, 2006, 47, 8641. J.K. Maity, M.G.B. Drew, B. Achari, S.B. S.B. Mandai, Mandal, Tetrahedron Lett. 2006, 47, B.G. Roy, lK. 2006,47, 8821. M.-T. Tsai, K.-C. Chang, W.-S. Chung, Tetrahedron Lett. 2006,47,9077. A. Senthilvelan, M.-T. 2006, 47, 9077.
314
Chapter Chapter 6.1
Six-membered ring systems: pyridine and benzo derivatives Heidi L. Fraser, Darrin W. Hopper, Kristina M. K. Kutterer, Aimee L. Crombie Chemical and Screening Sciences, River, NY, USA Sciences, Wyeth Wyeth Research, Pearl River, USA [email protected]. [email protected], [email protected], [email protected], [email protected], and [email protected]
6.1.1
INTRODUCTION
The presence of pyridines in an abundant number of natural products <06JAI1799; <06JAl1799; 06EJO4916; 060L2309; 06OL2309; 06TL3489> and pharmaceutically active 06JOC8384; 06TL6183; 06EJ04916; compounds <06JMC607; 06BMC4466; 06JMC971; 06JMC1939; 06JMC7278; 06JMC4698> continues to fuel the desire to develop new and improved methods for their synthesis as well as the synthesis of their benzo derivatives. Azacoumarins have been shown to be versatile biodynamic agents <06CUMC2795>. There have also been reviews on quinoline derivatives and their antibiotic properties in multidrug resistant Enterobacter Aerogenes isolates <06CDC843>. A number of important reviews highlighting the preparation of pyridines and their benzo derivatives have been published in 2006, including the synthesis of quinolines using the Skraup and Doebner-MiIIer Doebner-Miller methods <06CHC70l>. <06CHC701>. Fallahpour et al. discussed the utilization of oligopyridines as ligands in coordination chemistry <06COSI9>. <06COS 19>. The reaction of triallylboranes with pyridines and isoquinolines, as well as other heterocycles, was reviewed as a versatile approach to the construction of bicyclic and polycyclic nitrogen heterocycles <06PAC1357>. This chapter includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2006. It will cover selected advances in the field and will serve as an update to the review published last year in this volume.
6.1.2
PYRIDINES PYRIDINES
6.1.2.1 Preparation of Pyridines Cyclocondensations are one of the most widely used methods for preparing pyridines and dihydropyridines. The reaction is routinely employed in the synthesis of biologically important pyridines <06JMC607; 06TLI261; 06TL1261; 06T2799; 06JHCIOl; 06JHC101; 060L899; 06OL899; 06BMC4466; 06JMC3244; 06BMC5481; 06JMC3809; 06BMC8l76; 06BMC8176; 06JHC1169; 06JHCl169; 06SC97; 06SC1549; 06S1664> and those of interest in material sciences <06JOCI009; <06JOC1009; 06S1295; 06JOC4862; 06S2873; 06SCI72I; 06SC1721; 06TL837; 06JHCII77>. 06JHC1177>. In general, cyclocondensations are catalyzed by base, Bmnsted, Bronsted, and Lewis acids (e.g., Yb(OTf)3 <06TL1261>, A1C13 <06BMC8176>, and <06TLI261>, AlCh SC(OTf)3 <060L3473». Recently, efforts have been focused on employing multicomponent Sc(OTf)3 <06OL3473>). cyclocondensation reactions as one-pot procedures to conveniently synthesize diverse arrays
315
derivatives Six-membered ring systems: pyridine and benzo derivatives
of pyridine derivatives in an efficient, efficient, cost effective, and often times environmentally friendly manner <06JMC607; 06JHC985; 06JHC985; 060L899; 06OL899; 06S2873; 06S2873; 06SCl721; 06SC1721; 06TL837>. 06TL837>. For example, a one-step, three-component three-component cyclocondensation procedure for the synthesis synthesis of <060L899>. As shown below, pyridines and 1A-dihydropyridines 1,4-dihydropyridines has been described <06OL899>. structurally diverse aldehydes 1 combine with two equivalents of malononitrile 2 and various thiols 3 to form 2-amino-3,5-dicyano-6-sulfanylpyridines 2-amino-3,5-dicyano-6-sulfanylpyridines 4 and the corresponding 1,41,4dihydropyridines 5 in good yields. R'1 R1 R O
Base Base +
NC~/CN
+ R2SH EtOH EtOH reflux,2 reflux, 2 hh
R1~ H 1
~"
22 33 2 R', R1,RR 2 = Alk, AIk,Ar, Ar, or or HetAr HetAr
NC~CN N C~CN
NC.v~/CN ~ .~I
JlJl R
or
H N N N~ H2 2 / ~N H H
H2 N.- ~ N-/ ~ R2
55
4
=
2
~ R2
62-96% 62-96%
20-48%
The Hantzsch synthesis of pyridines is a cyclocondensation method of considerable importance. importance. This This route traditionally involves the condensation of four components, including two molecules of p-carbonyl [3-carbonyl compounds, compounds, an aldehyde, and ammonia to form 1,41,4dihydropyridines, which can be aromatized into into pyridines <06JOCl725; <06JOC1725; 06SC665; 06SC665; 06JC0829>. 06JCO829>. The reaction has conveniently been adapted to solid solid supported supported synthesis synthesis phase approach, <06SC665> and liquid-phase synthesis synthesis <06JC0829>. <06JCO829>. In a novel solution solution phase ionic liquid-phase liquid-phase bound the preparation of dihydropyridine 6 has been achieved by reacting ionic p-oxo ester 7 with dimedone 8 and aldehyde 9 in good yields and high purities. 13-oxo purities. Additional 1,4-dihydropyridine synthesis. synthesis. These These adaptations have been made to improve the Hantzsch 1A-dihydropyridine modified routes generally involve p-enaminones under involve the addition of enones enones with 13-enaminones conventional thermal conditions <06BMC4842; 06H2087; 06H2087; 06JHC1217> and microwave assisted conditions <06OBC3664; <060BC3664; 060BC3980>. 06OBC3980>.
~o
0Yl( o'~~o o 0
O• +
+
o
7 N<
.""
HO HO
+
+
oO
Ar 11 11
0 O
neat, ~C neat, 90 90·C 96% 96%
O o
MeOH, MeOH, reflux, reflux, 18 18 hh 80% 80% Ar = 3,4-(CH202)C6H 3
?
4
Ar/~H
8 11 equiv equiv NaOMe NaOMe
H
15equivNH,oAc. 1.5 equiv NH 0Ac
O
99
N...:
~O O
Ar 6
O
-""
o
1.1 equiv equiv DDQ DDQ 1.1
o
Ar 10 10
0
CH 2CI22 CH2CI
reflux, reflux, 22 hh 80% 80%
As improvements in Hantzsch 1A-dihydropyridine 1,4-dihydropyridine syntheses have occurred, attention has also been focused on advancing the aromatization processes used to produce pyridines from several oxidizing agents has been explored, including DDQ these precursors. The utility of several <06JFC865>, iodoxybenzoic acid (lEX) (IBX) <06S451>, sodium periodate catalyzed by Mn(III)salophen complex <06BMC2720> or polystyrene-bound Mn(III) porphyrin <06CJC1>, <06CJCI>, molecular oxygen catalyzed by N-hydroxyphthalimide and Cu(OAc)2 Cu(OAc)2 <06T2492>, and silica bis(trimethylsilyl)chromate <06SC77>. improvements in the gel-supported bis(trimethylsilyl)chromate Other improvements aromatization process have led to a rapid microwave-assisted reaction using commercially available manganese dioxide (in the absence absence of an inorganic support) support) <06S1283> and to a more environmentally friendly, yet effective oxidizing method utilizing methanesulfonic acid
316 316
H.L. Fraser, D. W. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
and sodium mtnte nitrite in the presence of wet Si02 SiO2 under heterogeneous and solvent free conditions <06JHCI99>. conditions <06JHC 199>. Several related polar cyclization processes have also been reported for the synthesis of pyridines <06T8398; <06T8398; 06BMC2837; 06JA4453; 06T6222; 06T6222; 06SLl437> 06SL1437> and pyridinones <06JOC1094; 06S2777; JHC1105; <06JOCI094; 06T3959; 06S2777; JHCII05; 06BMCL5668; 06JOC9895; 06JOC8146>. In some cases, the Vilsmeier reagent is used to effect the cyclization <06T8398; 06BMC2837>. As shown below, several chloronicotinaldehydes 12 are synthesized via the reaction of enamides 13 with the Vilsmeier reagent, generated by three different methods and at varying concentrations <06T8398>. <06T8398>. 2 R2
POCI 33 or 0°C-Ht~75°C R2nCHO or 0 ~ -~ rt ~ 75 ~ R2"~I//~i/CHO ,~ ~ ++ Triphosgene Triphosgene + + DMF DMF ------~. 1 "~ .--.: /.,L R N 0 or R1 N or 1 88-94% Diphosgene 88-94% R1" \ NN/ \CI CI R33 13 12
)
I
I "::
R
R 11 = H, Ph, or CO2Me R2 = H, Ph, or C0 2Me = H, H Alk, AIk, Ar, or C0 CO2Et R2 = 2Et = H or Bz R33 =
In addition to polar cyclization processes, pericyclic reactions are also used to produce pyridines and hydropyridines. Many of the most current strategies strategies employ [4+2] [4+2] cycloadditions to produce dihydropyridines, which can easily be converted to pyridines in a number of ways including oxidation or elimination processes. processes. The nitrogen of the pyridine ring can be incorporated either via the diene (e.g., 1- or 2-azadienes <06H975; 06JOC3494; 06T5454; 06T5454; 06JA1l799; 06JAl1799; 06H815; 06Tl095; 06T1095; 06SC1521; 06T7661; 06JOC8384>, oxazoles <06BMC2209>, 1,2,4-triazines 1,2,4-triazines <06TL869; 06T5736; 06TL7025>, or pyrazines 1». The utility of <06BMCL4537» <06BMCL4537>) or via the dienophile (activated imine or nitrile <06S255 <06S2551>). hetero-Diels-Alder approach to pyridines is demonstrated by its application in several this hetero-Diels~Alder syntheses of natural products as the key regioselective step <06H975; 06JA11799; 06JAl1799; 06SC1521; 06JOC8384; 06T5736>. 06T5736>. [4+2] cycloaddition reactions used for the synthesis of The scope and efficiency of [4+2] pyridines continue continue to improve. Recently, the collection of dienes participating in aza-Diels,3-butadienes, 3-azatrienes, and Alder reactions has expanded to include 3-phosphinyl-I-aza-l 3-phosphinyl-1-aza-1,3-butadienes, 1,3-bis(trimethylsiloxy)buta-l ,3-dienes (I ,3-bis silyl enol ethers), which form 1,3-bis(trimethylsiloxy)buta-l,3-dienes (1,3-bis phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06Tl095; <06T1095; 06T7661; 06T7661; 06S2551>. 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-l,3-butadiene 3-siloxy-l-aza-l,3-butadiene 15 synthesis (conveniently prepared from p-keto j3-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation irradiation to reduce reaction times and improve yields <06T5454>. 2.5 equiv equiv TBDMSOTf TBDMSOTf TBDMSOX TBDMSO~,,~ 0 x Me 2.5 / 2.6 equiv Et'Pr2N EtPr2N ~.
Me
"N
I OH 0H 16 16
CHzCl CH2CIz 2 ' h 0 0 0C ~ 5-18 , 5-18 h
." Me
)(X"::
. TBDMSO 2.0 eqUiv equiv DMAD DMAD TBDMS 2.0
.
N toluene ~ I W (180 OTBDMS laW (180 °C) ~ 2 2h h 15 OTBDMS !l 56%' 15 56%
Me" Me
CO Me CO2Me 2
.--.: "N N "CO2Me COzMe 14 14
Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing utilizing [4+2] [4+2] cycloadditions has been described <06JOC3494>. The process situ generation of l-aza-l ,3-butadiene from a palladium-catalyzed couplinginvolves the in situ 1-aza-1,3-butadiene isomerization reaction of aryl halides (e.g., 18) with propargyl N-tosylamines (e.g., 19). 19). The resulting butadiene then undergoes cycloadditions with N,S-ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17).
317
Six-membered ring ring systems: pyridine and benzo derivatives
CN CN
(Ph3P)2PdCI2 1. 2 mol% (Ph3P)2PdCl 2 mol% Cul Cui 11 mol%
CN CN
¢
Et3N, THF
[~
+ +
~ A NHTs
renux, 2. reflux, Et3N, T H F 524 .0 h
~Arr
Br
Br
18 18
Ar ==p-MeOPh p-MeOPh Ar
f)
2. 5.0equiv equiv /// ~ THF MeS/ \ NN/ THF MeS 20 I renux, 12 12 h h reflux, 20 IVle Me 64% 64%
19 19
] "~
AArr / N - ' ~ / ' ~ N Me 17
Another pericyclic transformation commonly used to synthesize pyridines is the cyclotrimerization reaction <06ASC2307>. Traditionally, this approach involves a transition metal-catalyzed [2+2+2] cycloaddition of diynes with nitriles. A variety of catalysts are 06CC1313>, ruthenium capable of effecting this transformation, including cobalt <06T968; 06CCI313>, <060L3565; 06JA4592>, rhodium <06£J03917; <06OL3565; <06EJO3917; 060L3489>, 06OL3489>, and nickel <06JOC5834> complexes and with the appropriate catalyst system (i.e., cationic rhodium(I)/modifiedEINAP BINAP complex), the aza-cyclotrimerization can be achieved chemo-, regio-, and enantioselectively <06EJO3917; <06£J03917; 060L3489>. 06OL3489>. Aza- [2+2+2] cycloadditions of diynes with nitriles can lead to a variety of fused pyridines, including those that are highly substituted and sterically hindered <06T968; 060L3565; 06OL3565; 06£J03917; 06EJO3917; 060L3489; 06OL3489; 06JOC5834>. Additionally, non-fused pyridines can be available via this route, as demonstrated by a solid-supported, cobalt-catalyzed cyclotrimerization shown below <06CC 1313>. Various alkynes 21 and nitriles 22 were combined with polymer <06CC1313>. bound propargylic alcohol 23 to rapidly construct libraries of diverse pyridines 25 in good yields and purities.
~
TrtO~ TrtO~
+
R1
"~N
'R2
23 23
CpCo(COh CpCo(CO)2 TMAO
a3 21
~TrtO~ ~"
toluene
N ~ , , % R2
80 ~ ·C, 48 48 hh 80
22
R1
=
1 R R21 = Alk AIk or or Ar Ar R R2 == H H or or Alk AIk R3 R3 = = Alk AIk or or Ar Ar
R2 Ra 25
..
--"
RI
24
1% TFA TFA 1% CH 2CI 2 CH2CI2 rt, l1hh rt,
R3
43-85% yield yield 43-85% >90% purity purity >90%
Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described <06JA4592>. This route is a two-step process that first converts readily available N-vinyl or N-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent rutheniumcatalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28).
~ O ...........
~ O
~
Ph'~J'N Ph N H H 26 26
:::""
1. 1.2 1.2 equiv equivTf20 1. Tf20 4.0 equiv 2-CI-pyr 2-Cl-pyr CH CH2Cl2 2CI 2
~~ ~
0---------1~
2. 2.7 2.7 equiv equiv TMSC=CCu TMSC-CCu Ph 2. THF, -78 ·C THF,-78 ~ 4--> 0 ·C ~ Ph 99% 99%
N :::"" 0
~
I
~
10 10 mol% mol% CpRu(PPh3)2Cl CpRu(PPh3)2CI A SPhos 10 mol% SPhos equiv NH4PF NH 4 PF6s 1 equiv N
~ 27 TMS
..
toluene, 105 ~·C ~" 70% 70%
~D O
PhU' Ph
28 28
318
D. W. W. Hopper, K.M.K. Kutterer, and and A.L. Crombie Crombie H.L. Fraser, D.
In addition to the examples above, several other interesting methods for synthesizing pyridines, hydropyridines, and pyridinones have recently been described. Routes involving pericyclic reactions as the key step include tandem [2+2] cycloadditions/electrocyclic ring openings <06JOC5328>, 1,3-dipolar cycloadditions <06T6398>, electrocyclic ring closures <06OL2611; 06BMC4341>, aza-Cope rearrangements <06S2085>, and aza-Wittig reactions <060L2611; <061OC6020; <06JOC6020; 06T4l28>. 06T4128>. Additionally, palladium-mediated Heck reactions <06TL3225; 06JOC8602>, electrophilic aromatic substitution reactions <06CC2586; 06BMC5765>, and 6-endo N-lithioketimine cyclizations <061OC8565> <06JOC8565> have been employed to produce pyridine 6-endo derivatives. 6.1.2.2 Reactions of Pyridines
Palladium reactions have continued to dominate the reactions of pyridines in the literature of 2006. Material scientists have utilized the palladium chemistry of pyridine to assemble 06JOC4155; 06S1141; 06Sl141; 06CC2071>. various core structures <06TL3471; 06CC4744; 061OC4155; Medicinal chemists have also utilized a large assortment of palladium chemistry in the construction of pyridine-containing targets. Many Sonogashira reactions have been performed on halopyridines <06BMCL4788; 06BMCL4792; 06EJM847; 06BMCL2270; 06JMC3581; 06S243; 061OC8673; While Suzuki reactions use both 06JOC8673; 06T2465>. pyridylboronic acids <06AG(I)1282; 06SL53> and halopyridines <061OC2000; <06JOC2000; 06T11734; 06Tl1734; 06S2855; 06BMCL4283; 06JMC7450; 06JMC221O; 06JMC2210; 06T6945>. Two different groups have examined Suzuki-Miyaura coupling reactions of amino-chloropyridines with various substitution patterns <06AG(I)3484; 060L1787>. 06OL1787>. Stille reactions employ both halo<06BMC6202; 06BMCL3150; 06BMCL3740; 06JHC 13 11; 06BMCL3209> and stannyl06JHC1311; <06OL2123; 06BMCL6832; 06BMCL3424; 06JMC2673> in cross-coupling pyridines <060L2123; reactions to obtain compounds of interest. Moreover, Heck reactions incorporate vinylpyridines as substrates <06BMCL3201> in addition to halopyridines <061OC6302; <06JOC6302; 06JOC2922; 06BMCL5378>. 06BMCL4048; 061OC2922; All of these palladium reactions may be used in concert to incorporate a large amount of <06BMCLl175; 06TL8917; 06BMCL1679; diversity into a heterocycle very efficiently <06BMCL1175; 06BMCL2000; 06E104257; 06EJO4257; 06JMC5324; 060L3549; 06OL3549; 06BMCL4567; 06BMCL3197; 06TL2337; 06T5862>. Scott and Maes separately utilized tandem palladium-catalyzed amination cyclization sequences to prepare imidazopyridiones and dipyridoimidazoles, respectively <06JOC260; 06SL2083>. Likewise, Cvetovich and Chung synthesized via palladium-catalyzed Heck-lactamization <06JOC8610; <06JOC861O; 06JOC8602>. naphthyridinone via Beebe et al. at. utilized a sequential van Leusen-Heck reaction to prepare a fused imidazopyridine <06TL3225>. The regioselectivity of of Suzuki cross-coupling reactions of 2,4-dibromopyridine 29 have been examined by Cid et et al. ai. <06Tl1063>. <06T11063>. They report two catalytic systems for the Suzuki coupling of 2,4-dibromopyridine 29 and arylboronic acids, which lead to a highly selective of 30 or 31. This illustrates that the C-Br bond at the 2-position method for the preparation of of the pyridine ring is more reactive toward palladium insertion than the C-Br bond at the 4position. The scheme below exemplifies how the alteration of of ligands, solvent, and additives can modify the major product of this reaction. Anhydrous conditions facilitate high selectivity for preparation of 4-bromo-2-arylpyridine 30. Conversely, for the preparation of presence of water is instrumental in the the symmetrical 2,4-diarylpyridine 31, the presence optimization of the reaction.
319 319
Six-membered ring systems: pyridine and benza benzo derivatives
Ph
Br Br
!
Cl· N
Ph
31
Pd2dba3, 2-BDBP 2-BDBP K P0 • K3PO 4 9 H20 3 4 1.5 H 2O PhB(OH)z PhB(OH)2 82%
Cl N
29
pd(PPh3)4, TiOH(aq) ' Pd(PPh 3)4, TIOH(aq), TH F, Pd2dba3/PCY3. ..THF, Pd2dba3/PCy 3, , K K3PO4/dioxane 3P04/dioxane Br PhB(OH)2 PhB(OH)z 43% 43%
Br Br
Cl N/.
Ph Ph
30
In addition to being substrates for palladium reactions, pyridines are also utilized as ligands for palladium <06HI233>. <06H1233>. Pleixats et al. exploited the complexation of pyridine to palladium to create a silica-bonded, reusable catalysts for Suzuki coupling reactions NHC-PdCl,-3-chloropyridine <06TL2399>. <06TL2399>. Organ and co-workers developed a series of NHC-PdC12-3-chloropyridine Pdo(NHC = = N-heterocyclic carbene) complexes that are easily reduced to a highly active Pd ~ NHC species, readily prepared in large scale and air stable <06CEJ4743>. <06CEJ4743>. Yu et al. developed two new types of unsymmetrical pyridyl-supported pyrazolyl-NHC ligands for the <06JOC5274>. The application of these ligands as assembly of transition metal catalysts <06JOC5274>. palladium complexes was explored; they exhibited good to excellent catalytic activity in the Suzuki-Miyaura reactions. Furthermore, palladium chemistry has also been used to form C-N and C-O bonds on pyridines. The latter has been utilized in the synthesis of oxygen substituted biologically <06EJM640; 06TL5333>. In the formation of C-N bonds this chemistry has active pyridines <06EJM640; also been used to prepare compounds of biological interest that contain amino-pyridine moieties <06BMCL3249; <06BMCL3249; 06JOC7322> 06JOC7322> in addition to amino-substituted terpyridines <06S2585; 06TL5079>, and pyridines that contain macrocycles <06TL2691>. Moreover, a palladium-catalyzed amidation reaction was used in the preparation a 2,3-fused pyridyl urea a potential drug target <06S27 <06S2716>. 16>. Yu and Che reported a catalytic amidation based on a <06JA9048>, illustrated in the cascade chelation-directed cyclopalladation approach <06JA9048>, preparation of amide 32 from 2-phenylpyridine 33 via the cyclic palladium intermediate 34.
~I: N/.
33 33
5 mol% Pd(OAc)z Pd(OAc)2 ,. K S 0 , H NCOCF K2S208, 3,, DCE 2 3 2 2 a H2NCOCF 80°C, 80 ~ 77 h, h, 92% 92%
I~ /.
N I Ac ~ AcO-Pd
_1 ___1__
v
2 2
I:
34 34
~ /
_J
0 =_ -I
~ /.
N
HN)lCF HN CF 3 3
I~ ~
32 32
Some amination reactions, while unsuccessful under palladium conditions, are <06BMCL5309; 06JMC3753; 06JMC3753; 06TL6011; accomplished via copper-catalyzed reaction <06BMCL5309; 06T4756; 06BMCL2689; 06BMCL2689; 06JMC3719; 06JMC3719; 06BMCL4400>. Yu and co-workers capitalized on the extensive literature of pyridyl as a directing group in C-H activation in a copper-catalyzed acetoxylation and halogenation of aryl C-H bonds to yield 35 and 36, respectively <06JA6790>. <06JA6790>. This new reaction can also be applied to cyanation to form 37, amination, esterification, and thioesterification of C-H bonds. Selected examples are shown in the scheme below. The broad scope of this reaction is postulated to be a result of the mechanism. The authors propose a single electron transfer to the pyridine, leading to a radical-cation intermediate. The radical-cation intermediate then reacts with available nucleophiles and facilitates formation of many possible products.
320
D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L. Fraser, D.W.
OAc
I":: /0
N
Br 1 1 equiv equivCU(OAC)2 Cu(OAc)2 Br2CHCHBr2 Br2CHCHBr2 65% 65%
36
33
HOAc-Ac20, 02 130 ~ 48 h, 37% 1 equivCu(OAc)2 C N [ / ~ l ~N ~CH3CN, TMSCN/
Fluorine containing pyridines are of interest in medicinal chemistry due to their unique <06JOC9420>. Two groups over the last year have attempted to improve electronic effects <06JOC9420>. both electrophilic and nucleophilic fluorination of pyridines. Hoyte et al. enhanced the nucleophilic fluorination of pyridines using microwave conditions <06BMCL3454>. Kinetic experiments showed an average relative rate ratio of 3: 3:1I for microwave versus conventional heating methods. Similarly, Sanford and co-workers describe the development of the first palladium-catalyzed C-H activation/C-F bond-forming reaction with electrophilic fluorine under oxidative conditions, utilizing microwave irradiation <06JA7134>. <06JA7134>. This has been illustrated with the ortho-fluorination ortho-fluorination of 2-phenylpyridine 38 generating difluoro 39 in good yield.
~
% N
F
I ":: ~
38
10 10 mol mol % % Pd(OAc)2 Pd(OAc)2 0.5 0.5 mL mL CH CH3CN in CF CF:~C6H5 3CN in 3CeH5 •= #W, 150 150 °C, ~ 1.5 1.5 hh IlW,
1\
[8] ~
F-N...r-N,,\ BF F BF4 4 2 ®"-.I® CI 69%
~
c:6 N
F
FF~ F
I ": ~
39
Additional publications from Sanford et al. describe the full exploration of palladiumcatalyzed chelate-directed chlorination, bromination, and iodination of arenes using Nhalosuccinimides as the terminal oxidant <06Tl1483>. Moreover, an electrophilic <06Tl1483>. fluorination of dihalopyridine-4-carboxaldehydes dihalopyridine-4-carboxaldehydes was reported by Shin et al. <06JFC755>. This was accomplished via transmetalation of the bromo derivative, followed by treatment with N-fluorobenzenesulfinimide N-fluorobenzenesulfinimide as the source of electrophilic fluorine. Several groups have studied the free radical chemistry of pyridines. Schiesser and coworkers used a free radical rearrangement of of 2-selenopyridines to prepare seleniumcontaining antioxidants <060BC466>. <06OBC466>. Additionally, Burgos and co-workers examined the radical cyclization and atom transfer reactions of pyridyl radicals in the preparation of annulated pyridines <06TL8343>. Pyridylmethyl radicals, prepared by direct selenation of 2methylpyridines, have also been shown to undergo 5-exo-trig 5-exo-trig and 6-exo-trig 6-exo-trig cyclization under standard free-radical conditions <06TL553>. Zard et al. presented a more unique free radical reaction of pyridines <06CC4422>. An unprecedented radical ring closure onto the pyridine nitrogen was observed when certain protecting groups were present in close proximity to the pyridine nucleus. This result was obtained upon changing the protecting group of the 2-aminopyridine 40 from acetyl to the more versatile t-butoxycarbonyl (Boc) group. Under otherwise identical conditions, alteration of the protecting group resulted in the formation of a different product. It was determined by X-ray and other spectroscopic means that the unexpected product 41, was formed from ring closure onto the pyridine nitrogen followed by electron transfer of the resulting radical to the peroxide generating a radical anion, quenching of the radical anion leads to a tetrahedral intermediate, which then collapses to give the observed pyridone 41.
321
Six-membered Six-membered ring systems: pyridine and benzo derivatives
~
C(S)OEt
~--{
Lauroyl peroxide, peroxide ~I s~ _Lauroyl ~I ":: DCE, reflux reflux A) f"\~ DCE, ~"A.) f"\~
Lauroyl peroxide peroxide oO • Lauroyl ":: DCE, reflux reflux ~ J N DCE, ~ •. 11 ~ "-R R = Boc; 55% CI N ~ R=Boc;55% CI I
o0
41 41
40 40
R = Ac; 50% R=Ac;50%
0
R R
CI CI
~ R I~
N 42 42
0
Sulfur containing pyridines have been shown to display interesting chemistry. Pyridine disu1fides disulfides have been used as a sulfenylating agent with a phosphine-promoted desulfurative allylic rearrangement to fuctionalize thiols <06OL3593>. <060L3593>. Tanaka and co-workers have reported an N-glycosylation, which uses a newly designed glycosyl donor bearing a pyridylmethyl group on the sulfur <06TL5147>. This moiety facilitates C-S bond cleavage via bidentate coordination of Sand S and N atoms to Lewis acid activators. N-2-Pyridylmethyl thioamides have been reported to participate in an iodine-mediated oxidative desulfurization <06OL5621>. cyclization, which is an efficient method for preparation of 2-azaindolizines <060L5621>. Pyridinedithioesters were used as a proficient heterodienophile when complexed with BF33 <06OL1033>. A hetero-Diels-Alder reaction using 3-pyridinedithioester 43 was used to <060Ll033>. generate a key intermediate 44 in the synthesis of racemic Aprikalim 45 as illustrated below.
s d's /-
N
43 43
I
s~s N
1. BF3
V
2· 2. ~ ' % ~
1..--:;
\
CH CH2CI2 2CI 2 35°C, 35 ~ 24 hh 91%
-
g N
1..--:;
3:1 3:1
:
S
44
e(9O"SS . ) ~
---
®
,":: /-
N
S
S
HN\ HN,
Aprikalim 45 Aprikalim
Due to their electron deficient character, pyridines are susceptible to nucleophilic attack. Rudler et al. has studied the reaction of pyridines with bis(trimethylsilyl)ketene acetals <06TL4553; 06TL4561>. In one instance, they examine the reaction of bis(trimethylsilyl)ketene acetals with 2-phenylpyridines activated with chromium tricarbonyl to give pyridine-substituted bicyclic -lactones. This reaction allows for the formation of up to five stereogenic centers in two-steps. A second report describes successive double nucleophilic additions of bis(trimethylsilyl)ketene acetals to pyridines. Modification of substituents on the ketene acetal and starting lactones makes it possible to drive the addition reactions either toward formation of tetrahydropyridines or the formation of highly substituted piperdines stereoselectively.
N
o
PMP N/,, ' 1. 1. LiHMDS, LiHMDS, THF THF
-78 ~ -5o::-5-'min ,. ~Ny),"'o' __-7.:....:8::-o--"COL' .-'m-",in-,-->
~J
....0 46 t-Bu t-Bu"O 46
2. CH 30COCI 2. CH3OCOCI 99%, dr = = 94/6
O
N
'
"
O~
"'"
;
OLi
.....
O.~ O2t-Bu
L
47 t-Bu/O
O~
48
Clayden and co-workers reported the dearomatiztion of an electron-deficient pyridine ring via intramolecular cyclization of an enolate shown in the scheme above <060L5325>. <06OL5325>. Generation of the amino acid derived enolate of 46, with simultaneous activation of the pyridine ring by N-acylation, leads to a stereoselective transition state 47. The authors postulate that the stereoselectivity arises from the manner in which the bulky PMP (p-
322
D.W. H.L. Fraser, D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
methoxy phenyl) group controls the approach of the enolate. This results in an enantiomerically enriched diazaspirocyclic amino acid derivative such as 48.
6.1.2.3 Pyridine N-Oxides and Pyridinium Salts Pyridinium salts continue to be targets of interests for several different applications. Bererine derivatives, which originated from Chinese herbal medicine, have been synthesized for examination of their antihyperglycemic activity <06BMCLl380>. <06BMCL1380>. These natural products <06BMCL1707>. are also of interest for their interactions with G-quadruples DNA structures <06BMCLl707>. The inhibitory activity of pyridinium salts towards acetylcholinesterase was also reported Kock reported the first total synthesis of viscosamine, a recently <06BMC472>. Moreover, K6ck natural product containing a pyridinium salt moiety <06S2580>. Material science 06EJO2727; applications of pyridinium salts include non-linear optics <06T7817; 06EJ02727; 06ACR3838> and chiral room-temperature ionic liquids <06JOC9857; 06JFC159; 06EJO3791>. Additionally, their unique physicochemical and photophysical properties 06EJ03791>. make pyridinium salts important compounds for electron transfer sensitizers <06JOC315>, photosensitizers <06JA751O>, <06JA7510>, and self-assembled films <06JA2142>. Over the past year, the dearomatization of pyridinium salts has been implemented in the synthesis of indoles <06AG(I)7803> and less obviously triazolyldienes <06JOC7805>. Typically, pyridinium salts are prepared through reaction of an intact pyridine with electrophiles. Marazano et al. used a three-component process as entry into 3-substituted pyridinium salts for the preparation of 49 as shown below <06TL5503>.
°
0,<
/O ) /
(
RR3
N'
RV'] LDA l_~RR22 20THF - 80%
R
X '-../0 vO
-0
\....d==!7R
LDA ;-0 THF 20 - 80%
51 51
2
52 ,52
50 50
~ R 2 R1 = H, Si(CH3)3 n-BuNH 2 = n-BuNH2 Q R2 CH3, n-Bu, H Hell MeS03H / 3SO3 R3 n-Bu, t-Bu HCI/MeSO3H MeOH, reflux reflux MeOH, n-Bu 49 X =-C(CH3)2-, -CH 260 -- 65% 65% 60
3-Substituted pyridinium salts of this nature were difficult to obtain by other methods. This sequence is initiated with condensation of the anions of imine 50 with malonaldehyde glulaconaldehyde monoacetals monoacelals 52. The monoacetal-aldehyde was monoacetals 51 to access glutaconaldehyde (n-BuNH,) to give 3-substituted pyridinium salts 49. When then reacted with primary amines (n-BuNH2) intermediate (R'=Si(CH 3») was used, substantially higher yields of intermediate the silylimino derivative (R~=Si(CH3)3) glutaconaldehydes were obtained. The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et et al. al. synthesized 1,2,3,7-tetrasubstituted 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts Et 3N, via via 1,3-dipolar 53 were reacted with alkenes or alkynes in the presence of Et3N, of the cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of KCNlMeOH afforded 1,2,3,7-tetrasubstituted 1,2,3,7-tetrasubstituted indolizines indoJizines 56 and 57 in good heterocycle with KCN/MeOH to excellent excellent yield. O..~O 0:(0
~
[~)
y
N
-..~/J
°O
e Q Br Br
53
R'CH=CHR22 R1CH=CHR Et3N Et3N,' TPCD" TPCD DMF, 90·C DMF, 96_99%90 ~
96-99%
~
O . ~
°
R1 ~ R2 54
O/'/'R
KCN/CH3OH O RR'1 KCN/CH 30H rt, ~"~ JJ.. ~ / rt, overnight overnight 50-90% _ 0 ~ -? ' ~ -=--50_90% O" -~R2 2 R = CH3, Ph ~ N R = CH3, Ph ~_./N.~b",.1 R R' = COCH , CN, COPh R12 = COCH3'3 CN, COPh ,i R2 == H, H, aryl, aryl, heteroaryl heteroaryl R
56 56
°
O \ ,..,//'~R
R
323
Six-membered ring systems: pyridine and benzo benzo derivatives ring systems:
53 53
--
R3 Et3N =90°C DMF, 90 ~ 97-99% 97-99%
R4
O ~
R3 ~ R4
55
O//'R
KCN/CH30 H O, rt, overnlght ~ ~ 62-75% .. O R = CH 3, Ph v "
R3 = COCH3' H R4 = COCH3
R3 4 R 57
d/''R
Similarly, Yli-Kauhaluoma and co-workers have studied the 1,3-dipolar cycloaddition of polymer-bound alkynes to azomethine imines, generated in situ from N-aminopyridine iodides, in the synthesis of pyrazolopyridines <06JCC344>. Dudley and co-workers have designed pyridinium triflate reagent 58 for the preparation of benzyl ethers <06JOC3923>. This reagent is easily prepared in two steps with good yield. Since it is also bench-stable and preactivated, the benzylation reaction occurs upon warming 58 in the presence of an alcohol with no need for acidic or basic promoters.
~ ClAN))
R--OH R-OBn R--OBn R-OH .,,,r KOH,BnOH BnOH,. r / -,]j MeOTf, MeOTf, PhMe PhMe ~ ~ ~ 1./ KOH, • ~ "'/, ~ o0 °C R = 1° 2°: = ~ tto ..1.~| R. --1-~ 18-e-6, o A )) y 18-c-6,PhMe PhMe BBnO/k~.N o rtrt "G:) ].1 _ ' 2~ ,,+ _ N -9101 BnO Yield> 80% HO ~ |eon reflux,95% reflux, 95% n 86-91% BnO" NN eOTt OOTf Yield>80% 86 10 I R R = 33°,~ aryl: II 58 Yield <~ 80%
I
I
=
A key reaction of pyridinium salts continues to be nucleophilic addition to form dihydropyridines or pyridinones. Specifically, the reaction of Grignard reagents with Nacylpyridinium salts has been used to generate pivotal pyridinone intermediates in the total al. <06OL2985> and (-)-FR901483 <06JOC9393>. Lavilla et at. synthesis of (-)-Barrenazines <060L2985> examined the addition of isocyanides to pyridinium salts 59 as an efficient entry into substituted nicotinonitrile derivatives 60 <060L5789>. <06OL5789>. The electron-withdrawing group helps to stabilize the nitrilium intermediate. The carboxamido group also undergoes dehydration in the generation of the observed product 60. HH2N(O)CD 2N(O)C~
I "'" N
R1CI
R1CI
H2N(O)C~
,.H2N(O)C;Q
e
I
G:)"",
Br (E) ~r~ Br R1
RR11==Bn, , Fmoe, Bn,C0 CO2CH Fmoc, Alloe AIIoc 2CH 33, =2,6-dimethylphenyl,I-Butyl, t-Butyl,Cyelohexyl Cyclohexyl RR22=2,6-dimethylphenyl,
59 59
CN
R2N=C NaOAc/MeOI--I NaOAcI MeOH'~ Yield Yield over over 22 sleps: steps: 60 60-- 71% 71%
N
~
O
R1~
NH R:~
60 60
Another classic reaction of pyridinium salts is reduction of the pyridine ring. Donohoe <06OBC1071>, and co-workers reported the partial reduction of N-alkylpyridinium salts <060BC1071>, which is accompanied by subsequent alkylation and hydrolysis to furnish a range of 2,3dihydropyrid-4-ones. This sequence has the potential to introduce a variety of functional groups at the C-2 position of 2,3-dihydropyrid-4-ones. Reduction of pyridinium ylides with sodium borohydride has also been reported in fair to good yields <06JHC709>. Both pyridinium salts and pyridine N-oxides are of increased interest as chiral catalysts in organic reactions. Connon and Yamada independently designed and examined pyridinium salts as chiral catalysts in the acylation of secondary alcohols <060BC2785; <06OBC2785; 06JOC6872>. These two catalysts can be used for kinetic resolution of various sec-alcohols sec-alcohols and dl-diols d/-diols in good to moderate enantiomeric excess. Pyridine N-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes <06JOC1458> and in the Strecker reaction <06T4071>. In the latter, latter. the chiral Noxides played a key role in the initial activation of the Si-C bond by coordinating an 0O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the
324
H.L. Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
authors. The preparation of these types of chiral N-oxide catalysts by oxidative dimerization has been examined by Denmark et at. al. and demonstrated in the synthesis of many chiral pyridine N-oxides <06TA687>. Alternatively, Sanfilippo and co-workers have examined the enzymatic kinetic resolution of pyridine N-oxides to produce several chiral N-oxides <06TA12>. <06TAI2>. Pro-chiral pyridine N-oxides have also been used as substrates in asymmetric processes. Jprgensen JCrgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine N-oxide carboxaldehydes 62 <06CEJ3472>. The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess.
R% ~
catalyst catalyst
~
Rll~/-
,.
~
R~®/-
X
0-
-0
< l,cu'lf~J_
, ~ O T M S CH2CI2,_40 ~ R-H ++ :>=\OTMS CH 2CI 2 , -40°C. O\ 0 H N N~/ 64 - 92% ~:: " / OMe "c~ ~ OMe ef) 0 (30 O 77 eo t-Bu / \ -t-Bu 77-- 99% 99% ee (90 OH OH 0O t-Be ZfO / ~OTf t-Bu TfO on 62 61 63 R = H, _6~3:...._.....I H, 6-Br, 6-Br, 6-Ph, 6-Ph, 5-Br, 5-Br, 5-Ph,-_ 5-Ph
r·
Pyridine N-oxides have been exploited in the reaction with silylaryl triflates 64 to prepare 3-(2-hydroxyphenyl)pyridines 65 regioselectively, as illustrated below <06JOC4689>. Treatment of the silylaryl triflate 64 with cesium fluoride generates the benzyne intermediate 66, which in turn tum undergoes 1,3-dipolar cycloaddition with the pyridine N-oxide 67 forming intermediate 68. Rearrangement of 68 to bicyclic 69 occurs rapidly; this intermediate is then deprotonated at the C-3 position to give the 3-phenyl regioisomer 65. Isomer 65 is observed when bicyclic 69 is substituted with electron-donating or electron-neutral group. The influence of electron-withdrawing groups on the pyridine ring (R = = CN) facilitates deprotonation at the C-2 carbon resulting in the 2-phenyl isomer 70. ~ g-ND-R67
CH 3CN
.
~ \"
"'N I[ .&~TMS)) \'l.& I~ 0
O --~ 66
us~-
II
.I
TfO.& TfO.,""-,,,,~* 64 ~
68
R R
~N
R=CN, EWG R = CN, EWG
N
Q-)J ~
/k~--N'\ x , / - ~ ~ I .L H R=CN;42%~~ @H _ /; ~ fast R 70 HO fast= ~ ~ .,' ~ ~---------~ H(3
R
R=CN;~
h
HO _~ 69 R - H, CH 3 52 - 80%
RHO
OD" II I
I'
N-
\\ \
65
Over the past year, two additional methods were reported to reduce pyridine N-oxides to the corresponding pyridines. Sandhu and co-workers have presented an efficient and general Cu(OTf) 2 <06SL39S>. <06SL395>. Zn(OTf)22 and Cu(OTf)2 method for the deoxygenation of N-oxides using Zn(OTf) Similarly, Fernandes et at. al. have developed a novel reduction method, with wide functional (PhSiH3) MoO2C12z to ) in the presence of a catalytic amount of MoOzCI group tolerance, using a silane (PhSiH 3 produce pyridines in excellent yield.
325
Six-membered ring ring systems: pyridine and benzo derivatives
6.1.3
QUINOLINES QUINOLINES
6.1.3.1 Preparation of Quinolines The development and use of environmentally friendly methods for the synthesis of quinolines and dihydroquinolines were represented in variety of publications in 2006. Many et ai. al. showed that silicaof the reports incorporated solvent free conditions. Perurnal Perumal et 2-amino-chaIcones 71 supported NaHSO NaHS044 as a heterogeneous catalyst for the cyclization of 2-amino-chalcones under solvent free microwave conditions results in a variety of 2,3-dihydroquinolin-4-ones 2,3-dihydroquinolin-4-ones 72 in high yields <06CJC1079>. et ai. al. also utilized a silica supported TaBrs TaBr5 catalyst to <06CJC1079>. Lier et cyclize 2-amino-chaIcones 2-amino-chalcones 71 forming a variety of of 2,3-dihydroquinolin-4-ones 2,3-dihydroquinolin-4-ones 72 under solvent free thermal conditions <06TL2725>. <06TL2725>. The use of of silica gel supported TaBrs TaBr5 under solvent free thermal conditions showed considerable improvement in yield for this cyclization compared to the reaction conducted in organic solvents. NaHS0 NaHSO4-SiO2 4-Si0 2 pW 2 min ';lW2min
NH20
I/~'~
'~A
r
R~" ~
71
._-.
° O
~ R)l~N~r ~
R R11 = H, 80 80-- 95% TaBr5-Si02 TaBr5-SiO2
1
1
R1
140 - 150°C, 150 ~ 3 - 5 min
r
72 72
"
=
R11 = H, 70 70-- 92% Br, 70 70--75% 75%
A
H H
Wang et et at. al. reported two different reaction conditions for a solvent free Friedlander Friedl~inder quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of B-diketoesters 13-diketoesters 74 using p-TsOH as the catalyst under microwave conditions to form substituted quinolines 75 <060BCI04>. BiCl3 as <06OBC104>. They also reported the same reaction using BiC13 the catalyst under thermal conditions <06LOC289>. Both sets of conditions afford high yields and simpler experimental procedures. R1
E,O C
o 2
73
+
R2"''~O 74
pW p-TsOH, ';lW 15 - 60 s
87-.%
ID
87 - 96%
R1
CO Et A
BiCI 3
74 - 178°C 74-178~ 2-5h 2- 5 h
N ..
R2
N2 = Me, Et, i-Pr
75
89 89-- 96%
In addition to their work with solvent free systems, Wang and co-workers reported a water mediated Friedl~inder Friedlander quinoline synthesis using hydrochloric acid and conventional heating to synthesize a variety of substituted quinolines in high yields <06TLl059>. <06TL 1059>. Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3phenylquinolin-2-(lH)-ones phenylquinolin-2-(1H)-ones under solvent free microwave conditions using an activated arylmalonate <06TL2395>. <06TL2395>. Reacting the desired substituted aniline with di-(2,4,6trichlorophenyl)-2-phenyl-malonate at 250°C 250 ~ with microwave irradiation for 15 min resulted They also in a variety of 4-hydroxy-3-phenylquinolin-2-(lH)-ones 4-hydroxy-3-phenylquinolin-2-(1H)-ones in good yields. demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors <06BMCL4620>. Friedlander quinoline <06BMCL4620>. Kumar et et al. al. have reported a variation of the Friedl~inder synthesis. They highlight the use of CeC1 C e C I 33e.7H,O 7 H 2 0 as a s a reusable catalyst in the reaction of 2-
326 326
HL Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L.
aminoarylketones 76 with ketones 77 in acetonitrile acetonitrile at room temperature to form a variety of aminoarylketones substituted substituted quinolines 78 <06TL8l3>. <06TL813>. R1
R1
R2
O+ 2
CeCI3.7H20 CH3CN, rt
65- 95%
R3
76
=
"
77
=
R11 = C C6H5 R 6 Hs 2 = CH R2 R R2= CH3, CO2CH3, CO2CH2CH3, 3 2CH 3. C0 2CH 2CH 3, COCH 3 3, C0 R3 , CH2CH3. CH 0CH CH NPht 3 = CH CH3, CH2CH3, CH2OCH2CH2NPht 3 2 2 2 R 3 R2 2 - R3 3 = COCH COCH2C(CH3)2CH2, (CH2)6, 2C(CH 3hCH 2, (CH 2)6, CH CH2CH(t-butyl CH2CH 2CH(t-butyl)) CH 2CH 2 2
78
=
co-workers developed a simple route for the synthesis synthesis of 3-aryl-I,2,3,43-aryl-l,2,3,4Xie and co-workers intramolecular reductive ring closure strategy tetrahydroquinolines 79 using a direct intramolecular tetrahydroquinolines <06TL7l91>. moderate; however, the <06TL7191>. The yields for the key reductive ring closure closure were moderate; simplicity simplicity of their route leads to an efficient synthesis synthesis of a variety of tetrahydroquinolines tetrahydroquinolines 79. 1 R1 O 1.ArCH2CN R1 R1 R 2~JJ 2 ~ H2 2,, Pd/C Pd/C R2 2 X ; x : J r Ar THF, H Na, C2H5OH R CH3OH Ar THF CH OH ,R 2. NaBH4 ,. R I ":: . 3 R3 ..--:; NO~N 7 74 % • R R3" ~ " "NO2 R3~~'k" NoC2N 7-74% 4 R4 R4 R
Ar
79
synthesis of 4-amino-substituted 4-amino-substituted quinolines quinolines 80 or 4-quinolones 4-quinolones A novel reaction for the synthesis 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted o-oxazoline-substituted anilines 84 and 85 in the presence presence of of a catalytic amount amount of p-toluenesulfonic p-toluenesulfonic acid (p(p-TSA) anilines TSA) in dry n-butanol n-butanol led to 80 and 81, respectively <06T9365>. <06T9365>. To the authors' authors' surprise, surprise, the reaction of acetophenones acetophenones 82 lead to a different outcome than that of of the cyclic or acyclic containing more than one carbons carbons a. ~ to the ketone. ketones 83 containing
R10 i ' ~ R2 +
+ R
82
R5 NH2 N.~.R NH N~R66 10 mol% mol% p-TSA ~ / ~ '2O I / ~) n-butanol. n-butan~ reflux ~ R4 24hreflux ":: ° 24 h R ~,. I
~ ~ ..--:;
R~... R6 NH 2 N . I ~
O ph..~ R7
~/j.~o,) +
83 83
84 84
85
0
R 5 R6
HN/V~
•
N
R4
10 p-TSA 10 mol% mol% p-TSA n-butanol. reflux 24 h =,,
n-butanol, reflux24h 88%
88%
R2
/.
75 7 5 -- 89%
80 80
ro
R77 .R
N
Ph
(I ":: / ~ [ ..--:;
R3
O oII
81 HH 81
Ph
The use of cerium(IV) cerium(IV) ammonium ammonium nitrate (CAN) as a catalyst catalyst for an aza-Diels-Alder aza-Diels-Alder publications. In one report Perumal reaction was reported in two different publications. Perumal and co-workers co-workers react a variety of anilines 86 and aldehydes 87 with enamine 88 in the presence of 5 mol% CAN CAN to form a series of tetrahydroquinolines tetrahydroquinolines 89. The reactions reactions were performed at room temperature with very short reaction times and in good yields. In addition, temperature addition, the resulting tetrahydroquinolines could be oxidized tetrahydroquinolines oxidized to the corresponding corresponding substituted substituted quinolines quinolines using 2.5 CAN in high yields <06TL3589>. <06TL3589>. eq of CAN
327
Six-membered Six-membered ring systems: pyridine and benzo derivatives
H
H2N
-O--
R1 +
86
R2 "~1_ + O 87
O L~ 88
5 mol% CAN 5mol%CAN HzO H20 or aq CH CH3CN 3CN
=
rt 82-- 86% 86% 82
. ~ ~ ,.
R2
R1 ~ 0
=
R1~ = H, CI; RZ2 = H, Me, Me, OMe OMe
89
Yu and co-workers also used CAN to catalyze an aza-Diels-Alder reaction <06TL3545>. Aryl imines were reacted with N-vinylpyrrolidin-2-one or N-methyl-N-vinyl-acetamide in the presence of 10 mol% CAN resulting in the desired 2,4-cis-tetrahydroquinolines 2,4-cis-tetrahydroquinolines in good yields. An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme ~,~below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a,~ unsaturated esters 92, resulting in the formation of the desired dihydroquinolines dihydroquinolines 90. | 0
~
Q. /./
NHMs+
91 91
H () kOH ~ ~N%/S 20-30mo1% 20-30mol% - - - - - - - -..... 1 5 mol% mol% Pd(OAc}z Pd(OAc)2 12 mol% mol% PPh PPh3, equiv/-Pr2NEt 12 i-PrzNEt 3 , 5 equiv t-BuOH (0.1 (0.1 M), M), 50°C 50 ~ t-BuOH
~No/S
I
HM
AcO~R 92
98-- 99% 98
cxY 0
R1 R1
[
/./
N t
Ms
90 90 R11 = COzEt, CO2Et, COzt-Bu, CO2t-Bu, CN CN R
A novel metal free approach for the synthesis of substituted quinolines 93 was reported HCl in DMSO using a HCI(cat)-DMSO system <06JOC800>. <06JOC800>. A catalytic amount of HC1 activates aldehydes 94, which react with benzylideneanilines 95 to form substituted quinolines 93.
+ 94
0
R11 = (CH (CH2)5CH3, (CH2)2Ph, z)sCH 3 , (CHz}ZPh, N 5 mol% mol% HCI HCI N ~ CH2Ph CH 2 Ph N _D_M_s_o_,_a_ir____:CO"~ R2 DMSO, air _-- ~ ~ ~---R RZ2 = H, H, 4-BrPh, 4-BrPh, 4-0CH 4-OCH3Ph, Z 3Ph, L R 3 /./ /./ R 3 1 4-CO H, furan, Ph; 55 82% R I ~ 4-CO2H, furan, Ph" 95 55 - 82% R z 95 R33= = H, H, 4-BrPh, 4-BrPh, 4-0CH 4-OCH3Ph, 93 3 Ph, 4-CO 4-CO2H, 2-OCH33,, Ph Ph zH, 2-0CH
"'01;
RZ
\\
3 R R3
In a similar one-pot synthesis of substituted quinolines, Wang et aZ. al. used molecular iodine (l (1 mol%) to catalyze the reaction between enolizable aldehydes and imines in refluxing benzene. The advantage of this method is that it is metal free, takes place with short reaction times, and produces good yields <06TL3l27>. <06TL3127>. Metal-catalyzed methods for the synthesis of quinolines continue to be of interest. In an alternate new strategy, SnCl SnC122 was used to mediate tandem reactions for the synthesis of highly functionalized quinolines 96, derived from Baylis-Hillman adducts <06T8740>. The reduction of the nitro group of 97 initiates a highly regioselective intramolecular cyclization involving the amino and carbonyl group, which is introduced through a SN2 SN2 substitution reaction as shown in the scheme below.
328
HL Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L.
S'.R 2
-I-
1. DABCO rt, 15 min (80 - 86%) CH2CI 2 2. AcCI, pyr, CH 2CI 2 (78-- 84%) 2-3 h (78
O
)ro .; ": OAc OAc
R' R
---------
Ii
~
O R2
R2
O O R3~f/[j.,, R4
O
R R3 3 ~ / 'U [ J ' R R44 DABCO OA CO
R c06 "0" R;2 R~..~.. /J,.....R )..; ": R
I
68 - 85%
N02
~
N0
2
97
SnCI2, 150_- 86% 2 , MeOH !50 SnCI / reflux 2
V
°
R "~/ R O R\'4" ~ "JJ" 3 R>.; ~'" ~"l / ~ " R % .~ . . ~ NN / / ' - R R44 96
R1 = H, 5-CI, 3,4-0CH 3,4-OCH20 R 20 2 CO Me, CN R2=CO2Me'CN R 2 R33== Me, Ph, OEt 4 = Ph, OEt R4 1
11
=
I ":
NiBr,(dppe) was used to catalyze the In another metal-catalyzed quinoline synthesis, NiBr2(dppe) reaction of 2-iodoanilines with aroylalkynes in acetonitrile at 80°C 80 ~ <06JOC7079>. The resulting 2,4-disubstituted quinolines were synthesized in good yields and this method was reported to tolerate a broad range of functional groups. Konakahara and co-workers reported the first direct synthesis of a quinoline skeleton 99 via homodimerization of ethynylanilines 98 in the presence of InBr33 in refluxing methanol <06JOC3653>. R1
1
~
InBr 3, MeOH, MeOH reflux, 24 h InBr3' ' .. 56 - 89% R1 R11 = H, Me, F, CN, N0 NO22 R2 R22= H, Me
R R2" ~ 98
~NH 2
=
R2
99
6.1.3.2 Reactions of of Quinolines
A novel approach for the direct conversion of quinoline N-oxides to 2-aminoquinolines <06OL1929>. was developed using an isocyanate intermediate <060Ll929>. This regioselective conversion was achieved by treating a primary amide 100 with oxalyl chloride and reacting the resulting isocyanates with quinoline N-oxides 101 to give the desired 2-amidoquinolines 102 in good yield.
R1 [].\~°o
R1\~NH2 NH2 1
V
100
1.2.oxa,y, oh.or,de CH2Cl2
1. oxalyl chloride
R2 R11 = = H, R2 2= = 3-CN, 91% 11 2 = 6-C0 6-CO2Et, R = H, R2 2Et, 82%
CH 2CI 2
= ~ |
~R2
102
=
=
3,, R2 2 = H, 81% R11 = 3-CF 3 4-OMe, R2 2 = H, 79% R11 = 4-0Me,
=
=
101
The synthesis of N-heterocyclic isothiocyanates has been a difficult challenge due to their propensity to oligomerize by autocatalysis. In an attempt to alleviate this issue, silver thiocyanate was used in a novel synthesis of 4-quinolyl isothiocyantes <06TL2161>. Reaction of 4-chloroquinoline with silver thiocyanate in refluxing anhydrous toluene for 12 h results in the desired product in quantitative yields and excellent purity. The asymmetric hydrogenation of quinoline continues to be of interest. Li et al. reported the asymmetric hydrogenation of a variety of 2-substituted-quinolines 2-substituted-quinolines to the corresponding tetrahydroquinolines using an Ir-catalyst with a BINOL-derived diphosphonite ligand
329 329
pyridine and benzo derivatives derivatives Six-membered ring systems: pyridine
of this catalytic system gave gave enantiomeric enantiomeric excesses excesses ranging ranging from 73<06CC2159>. The The use of <06CC2159>. 96% of >96% >96% in most most cases. In another another report report involving involving an asymmetric 96% with conversions conversions of of 2-substituted-quinolines, 2-substituted-quinolines, a [{IrC19cod)}2]/(S)-segphos [{ IrCl9cod) }yes )-segphos catalyst was was used used to hydrogenation of hydrogenation good enantiomeric enantiomeric excesses excesses <06AG(I)2260>. <06AG(I)2260>. In this reaction, reaction, which provides provides a new new achieve good of heteroaromatic heteroaromatic systems, the quinoline quinoline was was first activated activated approach for the hydrogenation hydrogenation of approach chloroformates forming the N-acylpyridinium salt. Using a metal free BrCnsted Brpnsted Acid with chloroformates et al. reported a new organocatalytic reduction of of transfer hydrogenation hydrogenation Rueping Rueping et catalyzed transfer quinolines <06S1071> <06S1071> and its application in the synthesis of of alkaloids <06AG(I)3683>. <06AG(I)3683>. 2quinolines reduced in the presence presence of of Hantzsch Hantzsch dihydropyridine 104 and Substituted quinolines quinolines 103 are reduced Substituted 105 in benzene benzene at 60 60°C tetrahydroquinolines 106 in good to high catalyst 10S ~ to give the desired tetrahydroquinolines yields and high enantiomeric excess.
E t O2C 2 C ~X C OX 2 E02 t Et Et0
! I
~
N
en! ~
N"-:
103 103
rn
H 1~4
~ ; R= =2-naphthyl, 2-naphthyl, 93% yield, yield, >99% >99% ee 104 Ar l -----'-'''--'-A-r-----· 3-bromophenyl, 92% = ~~,A 3-bromophenyl, 92% yield, yield, 98% 98% ee R N R 1,1'-biphenyi-4-yl, 1,1'-biphenyl-4-yl, 91% yield, yield, >99% >99% ee R H 2-furyl, 93% yield, yield, 91 91% H 2-furyl, % ee O...OO O'R 106 n-pentyl, yield,90% ee n-pentyl, 88% yield,90% o'P~oH 0' 'OH
9-phenanthryl Ar = = 9-phenanthryl
105
Arr
pyrano[3,2-c]quinolin-2,5(6H)-dione 107 was reported through the A one-pot synthesis of pyrano[3,2-c]quinolin-2,5(6H)-dione 4-hydroxyquinolin-2(lH)-ones condensation reaction of chlorocarbonyl ketenes 108 with 4-hydroxyquinolin-2(1H)-ones 109. This simple procedure was shown to be a convenient synthesis of pharmacologically active compounds in high yields <06S435>.
~. UN~O c5+ OH
109
R R
O
j CI...~C O 108
anhyd CHCI CHCI33 anhyd 20 20-- 30 30 min, min, rt
~0'1° ~ 0 Oph
)KPh R" \O OH
R= = Et; Et; 90% 90% R Me; Me; 85% 85% Ph; 92% 92%
Ph;
R,N
0
OH 107 107
Kappe and co-workers developed two general microwave methods for the synthesis of symmetrical (hetero)-biaryls 110 from 4-chloroquinolin-2(lH)-one 4-chloroquinolin-2(1H)-one 111 <06JOCI707>. <06JOC1707>. The two methods include either a Pd(O)Pd(0)- or Ni(O)-mediated Ni(0)-mediated homocoupling, as exemplified below.
Method 11 Method PdCl2(dppf),[B(pin)12, [B(pin)]2 KOH, KOH, BuCI BuCl PdCI2(dppf), I1W, I~W, 130 130 - 145 145 cC, ~ 35 35 'min min 68-91% 68 - 91 % •.
CI
Cl
W
R 4 y-R
R3
~
~
I
N
R2
R1
111 111
O , ~ ,,
R~ N
R 2 ~ ~
R4 , ~~3
~"
,/-
0
Method 22 Method NiCI NiCI22,, PPh PPh33,, Zn, Zn, DMF DMF pW, 205 205oc, 25min I1W, cC, 25 min 41 -- 98% 98% 41
R3.-11- ~ /J R'
2 R2
U-~N-R1 N'R 1
=
Ph=
110 Me, 110 0O R1l=Me,Ph
R22,, RR33,, RR44 = H, H, OMe OMe R
330
6.1.4
H.L. Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
ISOQUINOLINES ISOQUINOLINES
6.1.4.1 Preparation of Isoquinolines Pictet-Spengler reaction continues to be a popular area of research for the synthesis of The Pictet-Spengler (x-amino acids like L-DOPA can be reacted isoquinolines. In one report it was shown that a-amino <06SL 1903>. with benzaldehyde to form the corresponding isoquinoline in quantitative yield <06SLl903>. This Pictet-Spengler Pictet-Spengler reaction was conducted under very mild conditions, allowing the reaction to take place in the presence of unstable functional groups. In another version of the Pictet-Spengler Pictet-Spengler reaction, AuCl/AgOTf AuC13/AgOTf was used to catalyze the cyclization of imines 112 to of tetrahydroisoquinolines 113 in good yields <06JOC2521>. a variety oftetrahydroisoquinolines
MeO....~ 1___..~..... A) )A) 11 mol% mol%AuCI AuCl3, 2 mol% mol%AgOTf, AgOTf, MeO...~l __..T/....~ A R= = C0 CO2Et, 81% M eO M eAo w R 3, 2 2 Et, 81% II I I 9 -----------N N~ P-N0 ~ II I p_NO2C6H4,78 % 2 C6 H4 ,78% MeO~ [~N 1 equiv equivAcCI, equiv 2,6-lutidine, 2,6-1utidine, MeO M e O ~ - . ~ N ~ A c 'Ac p-MeOC p-MeOC6H4, MeO AcCI, 1 equiv 6 H4 , 82% 112 CH 3CN, rt, 113 Ph,73% 112 R IR CH3CN, rt, 12 12 h 113 R R Ph, 73%
I,?
I,?
r
Chen et et al. reported a more environmentally friendly version of the Pictet-Spengler Pictet-Spengler <06H1651>. In this report, a series of 2-phenylsulfonyl-l,2,3,4reaction <06HI65l>. tetrahydroisoquinoline- 1-carboxylic acid ethyl ester derivatives 114 were synthesized in good tetrahydroisoquinoline-l-carboxylic yields through the cyclization of N-phenylsulfonyl-~-phenethylamines N-phenylsulfonyl-13-phenethylamines 115 with a-acyl o~-acyl bis(trifluoroacetate) (PIFA) in ionic liquid ([bmin]PF ). sulfide 116 using phenyliodine(III) bis(trifluoroacetate) ([bmin]PF6). 6 The use of the ionic liquid allows for a simple purification and [bmin]PF66can conveniently be recycled.
R1 PhO2S CO2Et R
NH+ L-..S I
R
115
PIFA, [bmin]PF6 R1 50 ~ 1 h R2 J. A 3 ~ ~ N [bmin]PF6 = @ ~ R PF61N Q-,~N~n-Bu
R1, R2, R3 = H, 88%
R1, R2 = H, R 3 = OMe, 78% R 1= H, R2, R 3 = OMe, 85% "SO2Ph R 1, R2 = H, R 3 = Ci, 75% CO2E t
114
116
Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 <06S2934>. Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4disubstituted isoquinolines 117.
R2 R l ~ O M eBr v 118
R2 Et20,n-BuLi~0 = R IO ~M"Lie ~ 119
R2 R3CN'360_~
R ~ N 117
R3
Kobayashi and co-workers have also reported an alternate synthesis of of 1,4-disubstituted isoquinolines and a new synthesis of of 1,3,4-dihydroisoquinoline derivatives <06BCJl126; <06BCJ 1126; 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1-amino-4-substituted l-amino-4-substituted isoquinolines 121 in moderate yields.
331 331
Six-membered ring systems: systems: pyridine pyridine and and benzo benzo derivatives derivatives Six-membered
Ph
2
R Li 122 122 or or R2Li LiNR32 LiNR32 124 124
R~oMe OMe
R
P
I
~
~CN ">" "CN
R'[~.]/N
Ph R R11 == H, OMe R R22 == Ph, s-Bu, N(R3)2 N(R3l2 R R33 == i-Pr, Et
-78°C -78 ~ to rt 41 -- 76% 76% 41
123
121 R2
of 125 with phenyl Additionally, Kobayashi and co-workers demonstrated the reaction of electrophiles results in 1,3,4-trisubstituted 1,3,4-trisubstituted lithium, followed by treatment with different electrophiles <06BCJ1126>. dihydroisoquinolines 126, as shown below <06BCJ dihydroisoquinolines 1126>.
~ ~CN
Ar R1 Ar
PhLi, -78°C °C 1. PhLi,-78 ~ to 0 ~ R1X 2. RlX
125 125
R1
c¢
R11 = =H, 69% Me, 59% Bn, 62% Bn,62%
126 126 Ph
Bravo et et al. synthesized a series of 1-alkyll-alkyl- and 1-aryl-3-aminoisoquinolines l-aryl-3-aminoisoquinolines 127 <06JHC235>. <06JHC235>. Treatment of 2-acylphenyl-acetonitriles 128 with amines 129 and a catalytic I-alkyl or 1-aryl-3l-aryl-3amount of trifluoroacetic acid results in the formation of 1-alkyl aminoisoquinolines 127 in a single reaction step and in good yields. aminoisoquinolines
ce; [~C
°CN
I~
O
N
+
R2NH2 R2NH2 129
H •-" EtOH, EtOH,!l A
1
R R'
128
NHR2 R I = E t , R 2=Me,92% R 1 = Et, R2 = Ph, 86% R 1 = Ph, R2 = Ph, 76%
H|®
127
R -I
4-hydroxy-l-oxo-l,2-dihydroisoquinoline-3An improved method for the synthesis of 4-hydroxy-l-oxo-l,2-dihydroisoquinoline-3carboxylic acid derivatives 130 was presented <06S1971>. This improved three-step method efficiently converts phthalic anhydride 131 to the desired dihydroisoquinolines 130 in high yields over three steps with only one purification. R1NHCH2COR2 oO ~:1. ~~~~~H2COR2
~°° I
~
131 O
O. /
• I
R1 R1 = Me Me, t-Bu R22 = = OMe, OEt, OEt, NHEt, NEt2 N(Me)Ph, NEt2
O~e,
NaOR1
c¢0/ '0::::
~
° °
~0R2R2
°R
OH
O
64-- 83% 83% 64 130 O
In a facile and rapid stereoselective, three-component, one-pot reaction, a series of cisisoquinolonic acids 132 were synthesized using silica supported sulfuric acid to catalyze the reaction between homophthalic anhydride 133 with different aldehydes 134 and amines 135. This three-component cyclocondensation offers a variety of advantages including high yields, easy experimental work-up, and the use an inexpensive, non-toxic, readily available, and recyclable catalyst <06JHCI87>. <06JHC 187>.
~o ~O O
O
133 133
O
2 CH0134 R2CHO 134 R
R 1 NH 2 135
Si0 SiO2H2SO4 2·H2S04 CH CH3CN, 3CN, rtrt 81 - 90% 90% 81
O ,.
N "R1 ~
H
2
HO2C
132
4-CIC6H4, 4-MeC6H4, 4-MeC6H4, PhCH PhCH2, R11 = Ph, 4-CIC6H4, 2, PhCH PhCH2CH 2CH 22,, benzimidazole R22 = Ph, Ph, 4-CIC 4-CIC6H4, 4-NO2C6H4, 6H4, 4-N0 2C6H4, H , H 4-BrC 3-CIC BrC6H4 4-BrC6H4, 3-CIC6H 4, 2-BrC6H4 6 4 6 4, 2-
332
D. W. Hopper, K.M.K. Kutterer, and A.L. AL Crombie H.L. Fraser, D.W.
Chang et al. and Yamamoto et et al. reported two notable intramolecular hydroaminations of alkynes to form tetrahydroquinolines. Chang and co-workers were able to synthesize a tetrahydroisoquinoline system using a catalytic one-pot procedure in good yield <06JA12366>. In an enantioselective approach, Yamamoto et et al. have developed a <06JAI2366>. palladium-catalytic intramolecular asymmetric hydroamination of alkynes using a chiral catalyst derived from Pd,(dba)3.CHCI3 Pd2(dba)3eCHC13 and (R,R)-renorphos to form tetrahydroisoquinolines in high yield and good enantiomeric excess <06JOC4270>. Isoquinolines 6.1.4.2 Reactions of Isoquinolines
C-1 position of 3,4The asymmetric addition of different types of nucleophiles at the C-I dihydroisoquinolines were highlighted in a number of publications. Schreiber et et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP <060LI 43>. The resulting I-substituted <06OL143>. 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases.
Meo:ca~:MeI
mol% CuBr, CuBr, 5 mol% 5.5 mol% QUINAP, M 5"5m~ 1 equiv Et Et3N, CH2CI 3 N, CH 2CI 22,,
OMe
MeO~~~"~ [
MeO .eO
'
~
B@r~
/O~
137 137
Br
~
Br
-55°C -55 ~ 71 % yield 71 - 91 91% 94-99%ee 94 - 99% ee
H + R R~1 -~ + 136 136
OMe e
A
e O ~
~
N~
MeOnr "~ MeO MeO * N
I
138
[[
R1 = Ph, Si(Me)3, OEt, CH2OMe
Br
R11 R
Two recent publications highlight the first catalytic allylation of cyclic imines. In a formal total synthesis of (-)-Emetine, Itoh et al. describe a catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline 3,4-dihydro-6,7-dimethoxyisoquinoline using CuCI, CuC1, (R)-tol-BINAP (10 mol%) and TBAT (10 mol%) as the catalyst to achieve moderate to high yields in moderate enantiomeric excess <060LI295>. <06OL1295>. Chong et et al. detailed a general asymmetric methodology for the synthesis of I-substituted tetrahydroquinolines 139 via 1-substituted via an enantioselective allylation of 3,4dihydroquinolines 140 with the allylboronate 141. High yield and high ee were achieved using this method and its utility was highlighted by its application to the synthesis of various known alkaloids (crispine A, coniine.HCI, coniineeHC1, ent-corynantheidol) ent-corynantheidol) <06JA9646>. <06JA9646>.
x;o
1
R
R2
R1
141 141 9 ~ N -,-------,-----. R 11,, R R 22 = = H, H, 92%, 92%, 95% ee R2 ~ N R R 11, R R 22 = = H, 78%, 78%, 98% ee ee R R 140 = OCH OCH20, 86%, 95% ee 139 139 140 R11, R22 = 2 0, 86%, 2 R 1, R 2 = CI, 88%, ee R1, =CI, 88%, 95% ee
1'-'::
H
/0
R11 = H, H, R22 = N0 NO2, 90%, 99% ee ee 2 , 90%,
~-
~ v
3,5-(CF3)2-C6H3
--.r=
0, O;B~ O,B O
141 141
3,5-(CF 3 )rC6 H3 -3,5_(CF3)2_C6H3
A Pd(II)-catalyzed asymmetric addition of malonates to dihydroisoquinolines was also reported <06JA1401O>. <06JA14010>. This method provides highly optically active C-l-substituted C-l-substituted tetrahydroisoquinolines in good yields. An efficient asymmetric hydrocyanation of 6,7tetrahydroisoquinolines dimethoxy-3,4-dihydroisoquinoline to yield 1-cyano-l,2,3,4-tetrahydroisoquinoline dimethoxy-3,4-dihydroisoquinoline I-cyano-I ,2,3,4-tetrahydroisoquinoline was also described <06SLI595>. <06SL1595>. This asymmetric Strecker reaction, which utilizes Jacobsen's thiourea-containing catalyst, resulted in high yield and high enantiomeric excess of tetrahydroisoquinolines. In another report, the enantioselective addition of vinylzinc reagents
333
pyridine and benzo derivatives derivatives Six-membered ring systems: pyridine
3,4-dihydroisoquinoline N-oxides were shown to produce produce the desired 1-substituted I-substituted 1,2,3,41,2,3,4to 3,4-dihydroisoquinoline tetrahydroisoquinolines in good good yields and high enantiomeric enantiomeric excess. However, However, to achieve tetrahydroisoquinolines equivalents of of chiral ligand must be used enantiomeric excesses, excesses, 1.2 equivalents these high enantiomeric <060L3979>. <06OL3979>. hydrogenation of of isoquinolines isoquinolines that were first activated with An asymmetric hydrogenation chloroformates was reported by Zhou and co-workers using an [{IrC19cod)}2]/(S)-segphos [( IrCl9cod) l,]/(S)-segphos chloroformates 1,2-dihydroisoquinolines with good enantiomeric excesses catalyst to synthesize 1,2-dihydroisoquinolines <06AG(I)2260>. In another asymmetric hydrogenation, 1-substituted-3,4-dihydroI-substituted-3,4-dihydro<06AG(I)2260>. isoquinolines were reduced using a water soluble ruthenium(II)complex catalyst in water isoquinolines with sodium formate as the hydrogen source. This environmentally friendly method resulted of the desired tetrahydroquinolines in high yields and high enantiomeric excess of <06CC1766>. <06CC 1766>. et al. at. developed a mild and efficient efficient one-pot protocol for the synthesis of of Kundu et dihydroindazoloisoquinolines 142 via via an unprecedented SnC12-mediated SnCI,-mediated intramolecular intramolecular dihydroindazoloisoquinolines <060LlS2S>. As illustrated below, the cyclization substrates 143 <06OL1525>. cyclization of nitro-aryl substrates via the hydroxylamines 144 and leads to the formation of dihydrooccurs via indazoloisoquinolines 142 in high yield and purity. indazoloisoquinolines
R 1 0 ~
1. SnCI SnCi2.H20,PhSH 1. 2 'H 20,PhSH,' TEA, CH 3CN, rt, 15 min • - ~ N ON0 22 R R11,, R R22 = CH CH3, _CH2 2-~ 3, -CH 3 = H, H, CH3, CH3, OCH OCH33 R3 R3"~ 4 R44 = H, H, CI, el, OCH OCH33 R
=
143 R
~R 10
m
Rlo R20
/NH
/
~_
R3"~ 4 144 R
2. T s c I R 2 0 ~
N
2. TsCI, rt 15 15 min m[n rt
88 - 91 % 88-91 0/o
_
R3/----~R4
142
A one-pot procedure was developed by Bai and co-workers for the ring enlargement of (Xc~chloromethyl N-containing heterocycles <06JHC321>. Chloromethyl tetrahydroisoquinoline 145 was treated with alkylbromides and potassium carbonate in refluxing acetonitrile resulting in good yields of desired 2,3-dihydro-IH-benzo[d]azepine-5-carboxylate 2,3-dihydro-lH-benzo[d]azepine-5-carboxylate 146. The proposed transformation involves the formation of aziridinium salts 147 followed by bond breaking between the nitrogen and the tertiary carbon atom.
E t O ~
EtO H3002C
RBr, K2CO3'refluxCH3CN~ E t O ~ l l I *~ CI
145 6.1.5
Allyl, 85%
EtO H30020 147
= EtO'~~/N
~R
H3CO2C
146
PIPERIDINES PIPERIDINES
There have not been any comprehensive reviews related to piperidines published in the past year. A review on sulfur-nitrogen containing compounds such as sulfinimines (N(Nsulfinyl imines) and N-sulfonyloxaziridines includes the use of N-sulfinyl imines in the synthesis of di-, trio, tri-, and tetra-substituted 4-piperidones <06JOC8993>. Another account describes chiral cyclic imide-based synthetic methodologies for the asymmetric synthesis of naturally occurring or pharmaceutically interesting hydroxylated heterocyclic derivatives including (S)-6-alkyl-S-hydroxy-2-piperidinones (S)-6-alkyl-5-hydroxy-2-piperidinones and 2-alkyl-3-piperidinols <06SLlI33>. <06SL1133>.
334
H.L. Fraser, Fraser, D.W. D. W. Hopper, K.M.K. K.M.K. Kutterer, and A.L. Crombie H.L.
Preparation of Piperidines Piperidines 6.1.5.1 Preparation The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinylcontaining a,~-unsaturated cz,13-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs' 2'd 2 n~ generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures <06EJOl166>. <06EJO 1166>.
~
1\ I1 77mo, ~ ' ~ z 2.5-5 2 5-5 mol% mol%G2, G2, F - ~ mol% G2 G2, F n R-N R-N N-R N-R toluene, 100 100 'C, ~ toluene, toluene, .{ ~ toluene, o .= z Ph Ph. ~ O 30-60 min I RR2 1 30-60 min N Bn'N Bn..N R R11 100 100 'C, ~ 44 h" h 0 N R R1 "=Ru'CI ~=Ru 'CI 74% 99% N 80% 99% B 1 R . j 74% 99% R1 0 / RI"N~ 80%- 99% 13n CY3P R1 O / ~CI R11 = n CY3P CI "~ o R = H or or F O 148 11= F~ R Boc or Ts, 149 ~ CHzOC(O)C(F)CH 148 R = 2,4,6-triMePh F R = Boc or Ts, 149 CH2OC(O)C(F)CH2 R =2,4,6-triMePh z Z = OMe or substitutedbenzylamine R2 = R OMe or substituted benzylamine
Y
"
F"-.A
Vu
Two RCM reactions were employed in a new and efficient route to a key chiral )-catharanthine intermediate, isoquinuclidine isoquinuclidine 150, in the synthesis of alkaloid (+ (+)-catharanthine <06AG(I)5334>. <06AG(I)5334>. The first RCM makes use of chiral enone lSI, 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system.
oO
cO
~ [ ~nO
0O
- Jl-7
10mol%G2, 01[ ~ CHzCl CH2CI2, reflux, z, reflu/ ~/~ N........~ \....-N~ 18h II ~ 87% 87% O 151 151
°
I -----= •"
0
\....-N
o ;N .N~ MeO2 " MeOzC
II
° O
~O 0
152 152
I
MeO2C\ 4 Meozc~ N
10 mol% rnol~ G2, G2 CHzCl CH2CIz2,, reflux: reflux. 20h 20h 84%, >99% >99% ee ee 84%,
/ /'I~ J ~ O
0
O~.../~ °0 150
150
153
Additional RCM reactions have been reported for the synthesis of piperidines and related lactams. Pearson et al. have reported the use of RCM as the key step in the generation of the trans-3,4 iminosugars <06BMCL3262>. A RCM reaction piperidine ring in a synthesis of trans-3,4 has also been employed in the generation of fused bicyclic derivates from the octahydroquinolizine octahydroquinolizine chemical class of compounds <06JMC7278>. <06JMC7278>. Grubbs' first generation PhCH=RuCliPcY3)2) was used in the preparation of a lactam structural Ru catalyst (G1, PhCH=RuC12(Pcy3)2) analogue of the polyketide passifloricin lactone <06T4086>. Niida et al. reported the generation of diastereomeric lactams utilizing mild RCM reactions at room temperature <06JOC4ll8; <06JOC4118; 060L613>. 06OL613>. In the synthesis of cyclic ~-amino 13-amino esters 154 and 155, via RCM, Grubbs' second-generation catalyst was superior, leading to lower reaction temperature and <06JOC3317>. higher yields compared to those achieved with the first generation catalyst <06JOC33 17>.
~ / 5 mol% or G2,G1 HN~ orG2,. H ~ CH2Cl2,221~ CHzClz, h0 '-/ ~ G1 ( G1 (rt) (rt) = 79% CO2Me G2 (rt) (rt) = 85% COzMe G2
--l ./"-
= =
j)J(0 N H 154
OMe
~ 55 mol% G1 mol% G1 orG2 or G2,
B~ ~ BoeN
~ ~
CO M
CO2Me z e
QJO
CH2Cl2,4h OMe CHzCl N, OMe z: 4 h'" G1 (reflux) (reflux) = 45% 45% Boe Boc 155 155 G1 (rt) = = 92% G2 (rt)
Another form of olefin metathesis widely used for piperidine formation is ring-rearrangement metathesis (RRM), as shown below. The versatility of this reaction can be seen in its ability
335
Six-membered ring ring systems: pyridine and benzo derivatives
to produce piperidines from different sized cyclo-ene rings tings (e.g. cyclopentene 156 and cyclooctadiene 157). The RRM reaction proceeds in high conversion and with good diastereomeric ratios <06AG(I) 1302>.
p
r---=-:---.
Cl,, /PCy3
0
0
OO=
O [5
ethylene, ethylene,rtrt
I d.L d.r. =5:1-::::? 5:1J 89%, 89%,
0--
156
"" ....~ / /
c,.",,,us_
~
mol%B, B, MeOzG" MeO2R ;= 55 mol%
MeO2C~ MeOzC\ / TsN TsN
o ~
Cl.. IH2Mes
c,' U%h
CY3P B
ethylene,~A N~ ethylene, =• TsN Ts /; 0 o o, 95%, d.r. = = 14:1, 14:1, d.L trans/cis tron"o;,
~
157 157
A new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction <06JOC3656>. This reaction proceeds with complete regioselectivity to create the 6-exo-trig 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers.
(EtO)2P(S)H,AIBN, AIBN, O (EtOhP(S)H, ~\ oOX~ / . ~ ' N cyclohexane, 80 ~ " _/~"N~\P(S)(OEt)2 cyciohexane, 80 °C ~t:-J~"P(S)(OEt)z }-~ F\ 75% ~ O~ '-OOPS 75%diphenylsilane O ODPS OPS DPS== ten-butyl tert-butyl diphenylsilaneuxw~.~~/*~ODPS OOPS
r-Y
158
159
Other radical cyclization approaches to the synthesis of piperidines include a CANmediated stereoselective cyclization of epoxypropyl cinnamyl amines <06TL705> and a cyclization of (-trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality <06JOC8481>. The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acidcatalyzed) and a closely related Prins cyclization (B, BrCnsted Bronsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 <06JOC2460; 060BC51>. 06OBC51>. Of note, in the formation of di-substituted derivatives, R' = Hand =H and R' R2= = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R' = = t-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. Th Ts
Th Ts
Th Ts
OH OH
OH RZ OH 161 161 -- ttrans rans
A. -27 h [~ 1 [a A. MeAICl MeAICIz2,, CHCI CHCI3, 61 ~ 16 16-27 h 3 , 61°C, R",~Ny 64-84%,upt02:98cis:trans. R\, N R"'QN RI"~IN ~ O~ RB. 1B"64HCI ,CHzCl ci-Rs:tranSCH2Ci up to 2:98~ 2,-78 16 h " R 1 0 -, , ""'''" ' l l R2 b~._Rl'~/ g HCI, 2=84%, z, -78°C, 16 h RZ2 73-- 94%, 94%,up up to to >98:2 >98:2cis:trans cis:trans .... RZ2 I R 73 Q " " C RZ ""CR 1
[
o
RZ
= H; H; RZ = H, H, CH CH33,, -(CHzln-(CH2)n- [n=2,3.4] [n=2,3,4] R1 = 1 R = R1= CH CH33,, Bn, Bn, i-Pr; i-Pr; RRZ2 == HH
I1~,.,~ [z .R 160 cis 160 - CIS
Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(tBu),(o-biphenyl)]CI) (Au [P(tBu)2(o-biphenyl)] C1) as the catalyst
336
H.L. Fraser, D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L
[Li(THF)n][Yb[(R )<06AG(I)1747> and the other makes use of an ytterbium ate complex [Li(THF)J[Yb[(R)C,oH N,(C ,H,,)],] <06JOC25 14>, generating spiro-piperidines in high yield. C20H,2N2(C,2H22)] 2] <06JOC2514>, both I2 I The utility of a new lanthanide catalyst 162 for hydroamination and hydrosilylation is highlighted below<06CC874>. Application of this new lanthanide catalyst resulted in excellent yields of piperidines such as 163 and 164 with reduced reaction times. H
V-N~ 2.2 mol% mol% 162 162,, ~
f\NH NH22
Ph ~Ph
>(}-
60 ~ 22 h 60°C,22h quantitative quantitative yield yield mol% 162 2 mol% ~ 100°C,4 100 4 hh
163 163
Ph Ph ,TMS TMS Ph,~h "/P_-N \ /N(SiHMe2)2 F::-N, /N(SiHMe2h ~ La..... 'pN/La ~'N(SiHMe2)2 P:"'N/ N(SIHMe2)2 Ph ~h Ph' TMS i~h TMS 162 162
<
164 164
cr
Ph 2 mol% 162 = / ' ~ k /Ph / Ph Ph 2mol%o 162. PhSiH PhSiH3, rt, 44hh \ / 3 , rt, yield for 2 steps steps '--NN, 99% yield SiH2Ph SiH 2Ph
Cr '\
Chang et et al. reported a mild tandem intramolecular intramolecular hydroamination of yne amines to form an endo-adduct endo-adduct intermediate, which reacts with electron-deficient electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>.
\ 0 ~ +
+ H N-R H2N_ R 2
-
r
D
1
2 mol% tool% Pd(TFAh, Pd(TFA)2, [ | H - WR N'R "",.-~ 2 4 mol% ® \ _ ~r-I~ mol% Xantph0s, Xantphos ,.~ 2N 10 mol% mol% PhC0 PhCO2HRH2N -=~ 2H RH PhMe dL PhMe," 110°C 110 ~ 5-48 5-48 hh L 166 166 pi PdLnJ 165 n 165
R= = Ph, Ph, 80% 80% R R= % = 3-pyridyl, 3-pyridyl, 41 41% R= = Sn, Bn, 68% R= = phenethyl, phenethyl 72% 72% R
Hydroamination of olefins under most catalytic conditions proceed with Markovnikov addition of the N-H bond across the olefin. Shown below is a rhodium-catalyzed intramolecular, anti-Markovnikov, hydroamination developed for the synthesis of 3arylpiperidines 167 <06JA6042>. Further evaluation of this reaction as a synthesis of multisubstituted piperidines revealed that substrates with substituents ao~ or 7y to the amino group did not produce the expected piperidine, however, substrates with a substituent 13 p to the amino group produce piperidines in high yield.
II
Ar
13
,NHMe ~NHMe y7
ao~
5 mol% mol% [Rh(COD)(DPPB)]BF [Rh(COD)(DPPB)]BF4, 4,
THF, 80°C, 80 ~ 24 hh THF, 71 -- 83% 83% 71
/--k (k ~N ~ Ar/ Ar 167
>=N-
Ar = = Ph, Ph, 4-0MePh, 4-OMePh, Ar 3,4-0MePh, 3,4-OMePh, 4-FPh, 4-FPh, 3,4-FPh 3,4-FPh
An interesting example of a gold-catalyzed cycloisomerization of p-aminoallene 13-aminoallene 168 to tetrahydropyridine 169 is depicted below <060L4485>. <06OL4485>. Patil et al. report a similar goldcatalized hydroamination of allenes to produce 2-vinyl piperidine 170 in good yield <06TL4749>.
337 337
systems: pyridine pyridine and benzo derivatives Six-membered ring systems:
,0 5moo,oAuc b 5 mol% AuCl,
5 mol%pyrid,ne pyridine, n" nBu "::: 5mo, 9 CH 2CI 2, rt, 6 d HN CH2CI2, HN..v.J 76% 76%
n
H2 N H2N
169 t69
168 168
~
5mo,AUC THF 24
5 mol% AuCl" ( l C5 H11 THF, rt, 24 h ~,,~ NHCbz 5Hll 80% " N C5 H11 80% Cbz C5H Cbz 170 170
(PdCl/PPh)) reactions for the Palladium-catalyzed (PdC12(PPh3) 2) decarboxylative carbonylation reactions formation of lactams are known known to proceed proceed under under carbon carbon monoxide at a pressure of of 60 procedure utilizing a different different Pd catalyst, atmospheres. The scheme below highlights a new procedure where the formation of of lactams 171 from oxazolidinones oxazolidinones 172 takes place at atmospheric pressure <06S227>. <06S227>. pressure
1: \\
_.O~:~O 0'-,;:::::-0
R R
/ NTs 172 172
RT~":::
55 mol% RsN ~ 2 (dba)3 mol% pd Pd2 (dbah 10 mol% Ph3P Ph 3P 9T --'-'---'-'-'-'--'...:..-'--'-"'----CO (1 atm), atm), benzene, benzene, 60 ~ 44 hh O 171 60°C, 0 171
R = i-Pr, i-Pr, 74% 74% R= R ==Ph, 77% R= = Bn, Bn, 75% 75% R R = CH2OTBDMS, CH 20TBDMS, 71% 71 % R=
A report on a regiospecific 6-exo radical cyclization for the generation of lactams 173 highlights a remarkable halogen-substitution halogen-substitution effect on the direct reactions of unsaturated N-H amides on vinylic halogen substituents <06OL2647>. <060L2647>.
oo
X~NH2 NH2
X
OY~~XX I
Pb (OAC)4 / 12, CH2CI2, (OAc)4 /12, CH2Cl2, rt h, 70hv, 4 h, 70 - 89% X = CI, CI, Br, I
O
-~
U
173
The following two schemes exemplify the synthesis of piperidines via 1,4-addition IA-addition of coupling/double Michael addition, amines. In the first scheme below, a one-pot Stille coupling/double starting from readily available vinyl stannanes, is used to generate piperidinones piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted.
II
BU3Sn~R3 0.5 Bu3Sn 0.5 mol% mol% [allylPdCllz, [allylPdCl]2
0
TH~ ./~
R1
HO
./y"£
R1
R2-NH2' NaBH R2-NH2,THF NaBH44,, i-PrOH i-PrOH• ~ N , R 2 1 mol% 60°C, 0, rt, 1 d = ~N'R2 mol% PPh PPh33 60 ~ 2 h -" ~N'R2 R2 H H20, rt, 2 R1~COCI THF, 52 R3 R3 R1~ ' ~ / c O c l THF,60°C, 60 ~ 3 h 52-- 70% 70% 3 174 R~ 175 2 3 NHPhth, CH(NHTFA)C0 1 R 1 = Me, Me, Ph Ph R2== CH CH2CO2t-Bu, CH2Ph, CH2CH=CH2 CH(NHTFA)CO2t-Bu 2CH=CH 2 R3 = NHPhth, 2t-Bu 2C0 2t-Bu, CH 2Ph, CH
An interesting synthesis of enantiopure cis-decahydroquinolines, cis-decahydroquinolines, which involves enol ether hydrolysis, double bond isomerization, and intramolecular lA-addition 1,4-addition of an amino group across a cyclohexenone has been reported <06T9166>. The process is stereoselective, with the exclusive formation of both cis-isomers 176 (43% over 3 steps) and 177 (17% over 3 steps) of the decahydroquinoline ring. H H .,,OH ~ . ),.,, \OO H H 2N HCI .,DH D ;:t).,\OH 2N HCl. 176 ''OH I~ ~ I [ ., 70 176 O 70 °~C, 3.5' h O . ~ N H . ",, , . oO" 00 H N '"" "ION 'I v.. . / %"'I , [Bn2N [ H H I IJn2N I 2
~ D)
H ~
177 '''OH .,,,
Other routes to piperidines involving lA-addition 1,4-addition reactions include the incorporation of a Michael addition reaction as the piperidine ring formation step in the total synthesis of Histrionicotoxin <06JAI2656> <06JA12656> and the use of an intramolecular lA-addition, 1,4-addition, 6-endo-dig ring
338
H.L. Fraser, W. Hopper, Fraser, D. D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie Crombie
closure of a nonattenuated amine into a pendant ynone in excellent yields, as demonstrated in the synthesis of enaminones <06JA8702>. Bargiggia and Murray reported a novel double (,| diester to afford predominantly the cis 1,4-addition of hydroxylamine to a bis (,®-unsaturated <06TL3191 >. isomer of a N-hydroxypiperidine <06TL3 191>. Another route to the formation of piperidine heterocycles is cyclization via reductive amination utilizing various hydride sources. The scheme below depicts a bis reductive amination, using sodium triacetoxyborohydride as the hydride source, to generate exo-178 and endo-179 azabicyclo[3.2.I]octane azabicyclo[3.2.1 ]octane amino acids in moderate yields <06JOC8467>. t"~ k ROC~ RO2~'\_I..L... 2
R= = Me; Me; (±)-(1S*,5S*,6S*)-exo-178; (+)-(1S*,5S*,6S*)-exo-178; 61% 61% R .~ MeOCHN'-~[_~...\ R = = (-)-8-Phenylmenthyl; (-)-8-Phenylmenthyl; •= MeOCHN OHc\,D"'CHO 178 NH (-)-(1S, 5S,6S)-exo-178; OHC'"'~/'"CHO p-methoxybenzylamine, p-methoxybenzylamine, 178 "NH(-)-(1S' 5S,6S)-exo-178;57% 57% AcOH (cat.)d:t .CliO NaBH(OAc)3, AcOH CHO NaBH(OAch, NHCOMe R R= Me; (±)-(1R*,5R*,6S*)-endo-179; (+)-(1R*,5R*,6S*)-endo-179;53% 53% c,~ R D CICH2CH2CI, ClCH2CH2CI' 25°C 25 ~ (cat.),/[-- NHCOMe = Me; CO 2R = (-)-8-Phenylmenthyl; (-)-8-Phenylmenthyl; ~''''V2r~ 2 •= ~ / ~ _ ~ C O C02R R= '" NHCOMe (-)-(1R, OHC"" NHCOMe HN 179 (-)-(1R, 5R,6S)-endo-179; 5R,6S)-endo-179;58% 58% OHC NHCOMe RO2C R0 2C .~NHCOMe
1'\.,
HN
179
Gheorghe et af. al. make use of sodium cyanoborohydride as a hydride source in the synthesis of 5-arylpiperidines <060Ll653>. <06OL1653>. Kellehar and Kelly report the formation of a spiro TM-Iactam rM-lactam using sodium borohydride in the key reductive amination step <06TL3005>. A number of reports have been published this year that describe the use of hydrogenation over various catalysts as a process to generate the source of hydride ion in reductive amination. Palladium catalysts used in these types of synthesis of various piperidines include PdlC Pd/C <06SL487; 06H2129>, Pd/CaCO J3 <060Ll569>, <06OL1569>, and Pd(OH), Pd(OH)2 <06T9942>. Reductive amination can also be performed via hydrogenation in the absence of catalyst, as reported by Calderon Calder6n et af. al. <06JOC6258>. <06JOC6258>. Finally, a one-pot hydroformylation reductive amination (HRh(CO)(PPh3)3) and XANTPHOS sequence was reported using a rhodium catalyst (HRh(CO)(PPh,)3) XANTPHOS under microwave irradiation conditions to form cyclic enamides in good yields <060L3725>. <06OL3725>. Nucleophilic displacement of leaving groups, such as mesylates, tosylates, triflates, or halogens, as well as nucleophilic ring opening of epoxides, cyclic sulfates, cyclic hemiacetals, or lactones is still a common route to piperidine cores. Nucleophilic displacement of of mesylates, tosylates, or triflates have been used to generate diverse piperidine containing cores such as imidazolo[1,2-a]-L-arabino-piperidinoses imidazolo[I,2-a]-L-arabino-piperidinoses <06EJO610>, <06EJ06IO>, trans-4-hydroxypipecolic acids <06EJO3235>, <06EJ03235>, (S)-3-hydroxypiperidin-2-one <06T7459>, <06T7459>, trans-4-hydroxypipecolic 2,3-disubstituted 2,3-disubstituted piperidines <06OL4051>, <060L405 I>, 2,3,4,5-substituted 2,3,4,5-substituted piperidines <06JMC2989>, <06JMC2989>, a bicyclic diamine <06TL2581>, <06TL2581>, iminosugars <06S2242>, <06S2242>, bicyclic iminosugars <06S827>, and a 2'-deoxy-2'-N,4'-C-ethylene-bridged nucleoside <06JA15173>, <06JAI5173>, generally in excellent yields. An interesting variation on nucleophilic nucleophilic displacement of of halogens halogens includes includes the use of of Nsulfinylamide 180 to generate optically pure pure 2-(1-hydroxybenzyl)piperidine 2-(l-hydroxybenzyl)piperidine 181 <06S687>. <06S687>. ~
...-:;:.
TolOS
Q;O' 9)) [ J
F
1. LDAo,THF, TolOS\ 711 0IOS CI TolOS 1. LDA, THF, ",' _78°C. ~H - ~ 2. -78°C rt ...-:;:. 2.-78 ~ to rt, ' hh OTIFI~ I[ ~. LTo,OS OTIPS _J TolOS TolOS TolOS OTIPS ~ oN" S,Tol CI\ '3 ~ ~: 180 66%
9, I
OTI~§
I'
0
~
I'
...-:;:.'
--- -
2 steps
Ph
:;0' ~ 0
OH 181
339
Six-membered ring systems: pyridine and benzo derivatives
of the nucleophilic displacement displacement of of halogens in a An effort to improve the efficiency of of primary amines with alkyl dihalides dihalides for the synthesis synthesis of of Ncyclocondensation reaction of of microwave irradiation (80-100 (SO-100 W, 120 120°C, phenylpiperidine through the use of ~ 20 min, 96% <06JOC135>. yield) was reported this year <06JOC135>. Stereocontrolled nucleophilic nucleophilic opening opening at the C 1-position I-position of of epoxides epoxides to furnish Stereocontrolled TMSOTf or substituted piperidine 182 was accomplished through the use of Lewis acids TMSOTf SC(OTf)33 <06CC2156>. Sc(OTf) H
°
O ,Ph TTS-NQ s-NJ~ Ph TMSOTf, DCM, rt, 2 d, 98% or =• 1182 82 LV Sc(OTfh, DCM, rt, 3 d, 92% " TTs/ s / N ''-./~ - - . / ~ fZ-&" Sc(OTf)3, Phhd ~OH P H N
_
D-manno and L-gluco L-giuco iminosugars 183 and 184, The synthesis of enantiomerically pure D-manno respectively, was achieved via reduction of an isoxazoline to an amine, which subsequently of the cyclic sulfate moiety <06JOC894>. <06JOCS94>. acts as a nucleophile in a spontaneous opening of O-N .-O" N
°~ 9O ' ~
.,'
I
9
O ~•. . O .2. .~~ ~ O B IIn o:::::~-O O
1. Hz, H2, Pd/C, Na Na2CO3, HO%/'-~P'~OB n ZC0 3, MeOH, rt, HO~oBn I I 5 •9 5 h, h, 77% 77% 183 HO~NH H20, H H2SO4, 40 ~ HO ~'''-/NHJ" 183 OBn 2. HzO, ZS04 , dioxane, 40°C, 36 h, 93%
HO"'rl"""OBn HO"'r"~ ....~OBn
HO4k..../NH HO~NH
184 184
The scheme below depicts a reduction of an azide on a sugar moiety followed by nucleophilic ring opening of the sugar to obtain either an aza-sugar piperidine 185 <06TA2006> or an aza-sugar lactam 186 <06HCA635>. H N3 HO~tJ O ~ , BnO'" BnO'"
*
X;X°
1. TFA, H20, H~h H".~N3 O XHJ H H 1. TFA, HzO, ~ N3 1 N 1. H2 (1 (1 bar) bar), EtOzC EtO2C~,...-N...,~O 2. H H2, PtO2, H 40 ~PtO' NH"1 EtO2C',~O.,,~. O ,z 10% Pd/CaCO3, 40°C 2h -~HO [~1/ N ' 2 EtOzC 10% Pd/CaC0 3, / [ H'"\ f EtOH 4 h 9 , ,.-.,'~ " H'" "'OBn ""O ' 25'bar, , h. HO'" Nu " "J"J",.-..-. u~n 20bar, ~, rt, 12 12hh .,L....I " ~-~.. 2 EtOH.4 N-~ 12h 3 HO" "OH '.", 2 ," Nz, 12 h 60----1-.~ 3.,H Hz 2, Pd/C Pd/C, HO'"""J-'"OH --" --' ', :BnO OBn 0 OBn OBn 65% / 5 bar, OH 65 Yo bar, rt, 24 h 80% 185 186
°",
: °
° °
Other examples of nucleophilic ring opening of a sugar to generate an aza-sugar piperidine include the synthesis of l-deoxy-homonojirimycin 1-deoxy-homonojirimycin analogues <060BC3675> <06OBC3675> and 1-deoxynojirimycin <06S 1035>. Likewise, Kikuchi et ai. al. report the nucleophilic opening of a cyclic hemiacetal to generate a 2,3-substituted piperidine <06JMC469S>. <06JMC4698>. Amide bond formation as a route to piperidine lactams continues to be widely employed. Formation of the amide bond can be effected through the use of coupling reagents such as dicyclohexylcarbodiimide/4-pyrrolidinopyridine dicyclohexylcarbodiimide/4-pyrrolidinopyridine <06TL53l7>, <06TL5317>, N-hydroxysuccinimide/EDCI <06T10S15>, <06T10815>, or by direct cyclization of an amine on a methyl or ethyl ester <06T4011; 06CC674; 06TL2257; 06TLS667; 1722; 06TS73l; 06TL8667; 06BMCL417; 06T4907; 06AG(I) 06AG(I)1722; 06T8731; 06BMC2620>. Bicyclic lactam 187 was generated via a Staudinger reaction to reduce the azide, followed by thermal cyclization of the amine on the ester <06SL271>. EtO2C,,,~ .,,~OTBS
1. PH PH3P, H20, 1A-dioxane, 1,4-dioxane, reflux, 40 h • 3P, HzO, 2. xylene, reflux, 6 h, h, 95%
N~"'~h
°tz
} HN
Ph
187 OTBS
340
H.L. Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
Intermolecular or intramolecular cyclizations via alkylation of an enolate with a large variety of electrophiles continues to have widespread usage. One form of these cyclizations involves displacement of a halogen or mesylate. Pu and Ma have reported the use of alkylative cyclization involving displacement of an iodide under mild conditions to generate a bicyclic enone in excellent yield <06JOC6562>. Kropf et al. report an intramolecular cyclization involving alkylation of an enolate, an (-/('-unsubstituted cyclohexanone, and a ]nonane ring systems in good yields tethered 4-alkyl electrophile to form bicyclo[3.3.l bicyclo[3.3.1]nonane <06JOC2046>. Double intermolecular alkylation with a dibromide on methyl cyanoacetate or a bis-mesylate on indene was used to generate the piperidine core of (,(-cyclic-®(,(-cyclic-| aminohydroxamic acids <06BMCL2699> or spiropiperidine fused indenes <06JMC4801>, respectively. Other electrophiles used in intramolecular cyclizations with enolates include esters and alkenes. Esters were utilized in the generation of 5,6-dihydro-4-hydroxy-2pyridones <06H555> and ®-keto lactams via Dieckmann condensation <06JOC4969>. | Hanessian et al. report anion cyclization onto a terminal alkene and the formation of a chain extended piperidine through concomitant trapping with allylbromide <06JMC4544>. Intramolecular Mannich reactions have been used in the synthesis of piperidines. An intramolecular Mannich-type reaction was used as the key step in a highly diastereoselective and concise preparation of novel trifluoro-substituted analogues of di- and trisubstituted piperidine alkaloids <06EJ03421>. <06EJO3421>. In the scheme below, an intramolecular Mannich reaction is shown as the key step in the asymmetric synthesis of the 2,3,6-trisubstituted Nuphar piperidine core 188 of the antitumor N u p h a r alkaloids <06JOC4222>.
NJbenzene, TsOH.H20, 60~ 6 /
NO~ ~~
~° °
~
~
ij
TsOH'HzO,
benzene, 60 "C, 6
76%
h
0 188
76%
The application of [4+2] cycloaddition reactions for the synthesis of piperidines has received a considerable amount of attention this year. Palacios et al. have reported the hetero-Diels-Alder reaction of 3-azatrienes with enamine pyrrolidinecyclohexanone affording hexahydroisoquinolines in 42% yield <06T7661>. Denmark and Montgomery reported the first [4+2] cycloaddition of an N-vinyl nitrone with a tethered dienophile I 1>. providing a somewhat unstable tetrahydropyridine N-oxide in 86% yield <06JOC62 <06JOC6211>. Another interesting route to a tetrahydropyridine core enlisted an inverse electron demand Diels-Alder reaction of an electron-deficient N-sulfonyl-1-azabutadiene N-sulfonyl-I-azabutadiene with an electron-rich Diels-Alder dienophile <06JA11799>. <06JAI1799>. Diels-Alder reactions using imines as azadienes have been reported. Alves A number of aza Diels-Alder et et al. reacted 3-(3-(tert-butyl-dimethylsilyloxy)buta-l,3-dienyl)oxazolidin-2-one 3-(3-(tert-butyl-dimethylsilyloxy)buta-l,3-dienyl)oxazolidin-2-one with 2Hazirines at room temperature for 4-5 days with no catalyst to obtain cycloadducts in moderate to good yield <06T3095>. Venkatraman et al. reported the hetero Diels-Alder reaction of a chiral imine with cyclopentadiene, using catalytic BF3,O(C2Hs) BF3o()(C,Hs),'2, generating an azabicyclo[2.2.l]heptene azabicyclo[2.2.1 ]heptene derivative <06BMCLl628>. <06BMCL1628>. A [4+2] cycloaddition was used in the Yb(OTf)33 catalysed reaction of an imine with Danishefsky's synthesis of piperidones via a Yb(OTf) diene <06BMC5955>. Boglio et al. reported an improved catalyst, a weaker POM-Yb Lewis acid (TBAsH,[(I-YbP,W1706I)) (TBAsH2[(,-YbP2W1706,]) <06AG(I)3324>. An aza Diels-Alder Diels-Alder reaction of optically active sulfinimines with the Rawal diene and catalyzed by TMSOTf TMSOTf is reported to lead to enantiomerically enriched dihydropyridones with enantiomeric excesses up to 90% <06TAI420>. <06TA1420>. Dandapani et al. reported a scandium triflate-catalyzed [4+2] aza-annulation
341
Six-membered ring systems: pyridine and benzo derivatives derivatives
in the synthesis of pipeco1ates pipecolates <06JOC8934>. <06JOC8934>. Takasu et et al. studied the synthesis of substituted piperidin-4-ones piperidin-4-ones 189 via via an imino Diels-Alder reaction catalyzed by triflic imide. They then expanded this reaction to a one-pot multicomponent reaction of 2-siloxy-1,32-siloxy-l,3<06T11900>. situ generated aldimines as depicted below <06Tl1900>. butadiene 190 with in situ TBSO~ R2_NH2 TBSO~ 2 -NH 2 R 190| 190
~
Ph Ph
0 Rl-ffO RL3'
TBSO~/~-I~'R1 R11 = Ph, Ph, R R 22 = = Ph, Ph, 78%, 78%, trans-cis (80:20) (80:20) 2 mol% Tf2NH, -" ~ ' R11 = = Bn, Bn, R R2 = = Ph, Ph, 74%, 74%, trans-cis trans-cis (80:20) (80:20) R MS 4A, CH2CI2, 9 ~ N. 1 2 0~ 4h 18 = R2 Bn, R R2 = = tPr, iPr, 16% R1 = Bn, Ph
Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality <060L5369>, <06OL5369>, thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot.
°
~l O II EtO-P.. EtO-P"-.. EtO/ \
Eta'
l
..~N 2
n-BuLi, THF ,. n-BuLi
~RZj
R1--CN ·78 -78 OCto'", ~ to rt, 55 h' h R 1 '( R;-CN R -CHO R2--CHO
192
3 AR
R3 .~ MeO2C MeOzC NC = 32 .98% - 98% • R1 32
Z R:
R~33 i-Pr, 2-furan R 2 ~R R11 = Ph, i-Pr, Z NC '" NC R R2 = = aromatic,
R'~O I
H 191
heteroaromatic, and a,~
heteroaromatic, and (z,~-
unsaturated unsaturatedaldehydes H, Ph, Ph, p-chlorophenyl p-chlorophenyl R33 = H,
=
Raja and Perumal reported the synthesis of novel noveI2,6-diaryl-3-(arylthio)piperidin-4-ones 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and Further elaboration of this four methylamine or ammonium acetate <06CPB795>. component reaction to a novel five component tandem Mannich-enamine-substitution Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below When this five-component tandem reaction involves para-substituted <06T4892>. para-substituted benzaldehydes, the cis cis (193) and trans trans (194) diastereomers of thiazones are obtained. Alternatively, artha-substituted ortho-substituted benzaldehydes form only the trans trans (194) diastereomer along with an air-oxidized product 195. O O oO o O O 0 Jl HN ~o~S~ ~O"J~Sv~ EtOH, rt, 5-7 d EtOH, rt, 5-7 d • s 2 NH40Ac ~S NH4OAc 42--74% 74% 42 ": 2 Ar-CHO Ar--CHO Ar,,,'~',,,ASr A r ~ ~I ~NN ~ iAr r Ar Ar"" N ""Ar Ar,,,.~~~N~2r p-CI-Ph, P-CH3-Ph, p-CH3-Ph, p-F-Ph, 0oAr = Ph, p-CI-Ph, H H H CI-Ph, CI-Ph, o-CH o-CH3-Ph, o-OCH3-Ph 3-Ph, O-OCH3-Ph 195 193 194
°
°
ex'1
HN~
Ar",·lN~Ar
HN~
ix
Another frequently used method for preparing piperidines is via reduction of the corresponding pyridine. These reductions can be accomplished through catalytic hydrogenation with platinium(IV) oxide <06JMC4116; <06JMC4116; 06BMCL395; 06BC248; 06TL1729>. 06TLl729>. Chong et al. reported the use of rhodium on alumina to generate enantiomerically pure cis-2,6-piperidinedicarboxylic cis-2,6-piperidinedicarboxylic acid from the corresponding 2,6pyridinedicarboxylic acid <06JMC2055>. Ohigashi reported an improved reduction of 3cyanopyridine to its tetrahydropyridine derivative utilizing a NaBH4-ethanol NaBH.-ethanol reduction system <06OPRD 159>. <060PRDl59>.
342
D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L. Fraser, D.W.
The conversion of pyridines to their tetrahydropyridine or pyridinone derivatives is frequently accomplished via a pyridinium salt intermediate. Bennasar et et al. reported the use of a Grignard reaction to generate a pyridinium salt, followed by reduction with NaBH 44 producing a substituted tetrahydropyridine in excellent yield <06JOC1746>. The Grignard reaction of a 4-methoxypyridinium salt, followed by acidic hydrolysis of the intermediate methyl enol ethers, to generate pyridinone derivatives has been reported in three separate instances <060L2985; <06OL2985; 060BC1071; 06OBC 1071; 06AG(I)932>. Br~ickow and Wanner reported the conversion of 4-substituted pyridines to their Brackow corresponding 4,4-disubstituted piperidines by trapping 4-substituted N-silylpyridinium ions et al. with dialkylmagnesium reagents, followed by NaCNBH 33 reduction <06T2395>. Xu et reported a regio- and diastereoselective double dinucleophilic addition of bis(OTMS) ketene acetals to pyridine to generate lactones <06TL4541; 06TL4553>. The remaining section highlights various other methods of generating piperidine cores. via an The scheme below depicts a simple route to piperidines heterocycles, such as 196, via intramolecular Homer-Emmons Horner-Emmons cyclization of phosphonate 197 <06JAI2743>. <06JA12743>. 0
0
0
(EtO)2P
~ N"'x'--~ 197
H ph/
Ph
Ph ~Ph
MeONa, MeONa,MeOH MeOH rt, rt, 16 16 hh 61% 61%
O~JPh Ph
196 196
Thompson et al. reported the use of a [3+2] cycloaddition reaction on an N-alkyl pyridine <06BMCL811>. A salt to generate an azabicyclic core with varied substitution on the bridge <06BMCL81l>. remarkable four-step, one-pot reaction, starting from azide building block 198 and utilizing a Homer-Wadsworth-Emmons [3+2]-1,3-dipolar Horner-Wadsworth-Emmons [3+2]-l,3-dipolar cycloaddition cascade to generate the pivotal piperidine core 199 in an expeditious stereoselective synthesis of (-)-Cassine (-)-Cassine 200, is shown in the scheme below <060BC524>. <06OBC524>.
O CO o
~ n
o
P
0ii
~OEt 6~?Et
O'1 n =n7 0 A c OE( 0':::"~A/N3 O~ 1~~~98 a3 -
198
I
W
1. CH CH3CN, DIPEA, 1. 0 3 CN, DIPEA, rt, 3 d .,~, N rt, •_-- , , ~ ~ . N.0 2. Rh Rh2(OAc)4, rt, 2. 2 (OAc)4, rt, 12 h, 74% 12 h, 74%
(nO) H (L'~O-~ H 0
OAC
~
OH
~ ___
-
0 O
199n=7 199n = 7
200n=9 200n = 9
An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 06JA15114>. <06T5338; 06JAI5114>.
N3-~(
O O--TES ,
Et Et3P, Phil 3P, PhH rt, rt, 66hh 75% 75%
..
HO
==
~E S TES
o-~~~ TES 202
TES
0 201
Reggelin et et at. al. reported the application of methylated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines 203 for the synthesis of highly substituted aza(poly)cyclic ring systems 204 under complete stereocontrol <06JA4023; 06S2224>.
343
Six-membered ring systems: pyridine and benzo derivatives derivatives
1. n-BuLi, -78°C n-BuLi,-78 ~ 2. CITi(Oi-Prb, CITi(O/-Pr)3,-78 ~ to to 00 °C ~ 2. -78°C ,. 3. 205, 205, toluene, • toluene, 0 °C ~ H N~OTBS N .,,,,r,,,,"~OTBS O:::( .NPhth 205 O~NPhth
~0 rll~ _
H OH
H OH ~
y
_
S
/"--..
hydrazine
~ to to ~rt N~hthth-78 -78°C
1a
203
OH~fl,.~
sla" H 204
transformation of A novel route to 3,4-disubstituted 3,4-disubstituted piperidines piperidines 206 via ring transformation of 2(haloalkyl)azetidines 207 is shown below. During these reactions, bicyclic azetidinium (haloalkyl)azetidines intermediates are formed and then ring opened intermediates opened by a variety of nucleophiles nucleophiles generating stereospecific substituted substituted piperidines piperidines in excellent excellent yields <060LlI05>. <06OL1105>.
R20~,~
Br
2
-°L8-1
CH3CN, A, 3h. R2R'aLt"' e",eN, ", 3" .lR '
1
2oT'R' 207 R
L
-
Gil I 1 R
J
..R2-O
206
Other routes to piperidines, Other piperidines, lactams, and piperidine piperidine diones include the conjugate addition of piperidine aminal of 1,2-ethanedithiol 1,2-ethanedithiol onto a 1,5-amino-ynal, 1,5-amino-ynal, followed by cyclization to a piperidine N-substituted ~-enamino <06JOC27l5>. <06JOC2715>. Calvet-Vitale Calvet-Vitale et al. reported the formation of of new N-substituted 13-enamino ester piperidines tetrasubstituted double bond piperidines featuring an exocyclic tetrasubstituted bond through the <06JOC2071>. A biomimetic biomimetic intramolecular cyclization intramolecular cyclization of of linear amino-~-keto-esters amino-13-keto-esters <06JOC2071>. approach to the pentacyclic substructures of of indole alkaloids perophoramidine perophoramidine and approach pentacyclic substructures via intramolecular intramolecular cyclopropanation communesin proceeds via communesin has been reported. This approach proceeds cyclopropanation followed by nucleophilic nucleophilic ring opening of of the resulting activated cyclopropane cyclopropane ring, with an in situ generated aniline, to form both the tetrahydropyridine tetrahydropyridine and lactam rings of pentacyclic situ of the pentacyclic substructure substructure <060L2187>. <06OL2187>. Amat and co-workers co-workers reported the cyclocondensation cyclocondensation of of (R)phenylglycinol methyl4-formylhexanoate phenylglycinol with racemic methyl 4-formylhexanoate stereoselectively affording a bicyclic cis-lactam <06TA1581>. Chen et al. reported a [3+3] annulation cis-lactam derivative in good yield <06TA1581>. annulation of of a-sulfonyl ~-sulfonyl acetamide with a,p-unsaturated a,13-unsaturated esters in the synthesis of of bicyclic glutarimides <060L3033>. et al. made use of <06OL3033>. Lastly, Ge et of a condensation condensation of of a protected protected amino acid with bromoacrylamide piperidine dione intermediate intermediate <06EJ041 06>. bromoacrylamide to generate a piperidine <06EJO4106>.
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06BCJ 1126 06BCll126 06BMC472
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344 06BMC2209 06BMC2209 06BMC2620 06BMC2720 06BMC2720
06BMC2837 06BMC2837 06BMC434I 06BMC4341 06BMC4466 06BMC4466 06BMC4842 06BMC4842 06BMC548I 06BMC5481 06BMC5765 06BMC5765
06BMC5955 06BMC5955 06BMC6202 06BMC6202 06BMC6832 06BMC6832
06BMC8176 06BMC8176 06BMCL395 06BMCL395
06BMCL417 06BMCL811
06BMCL 1175 06BMCLI175
06BMCLI380 06BMCL1380 06BMCL1628 06BMCLI628
06BMCL1679 06BMCLI679
06BMCLI707 06BMCL 1707 06BMCL2000
06BMCL2270
06BMCL2689 06BMCL2689
06BMCL2699 06BMCL2699
06BMCL3150
06BMCL3197 06BMCL3197
H.L. Fraser, D.W. Crombie D. W. Hopper, K.M.K. Kutterer, and A.L. Crornbie
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Six-membered ring ring systems: systems: pyridine pyridine and and benzo benzo derivatives derivatives Six-membered
06BMCL3201 06BMCL3201 06BMCL3209 06BMCL3209 06BMCL3262 06BMCL3262 06BMCL3424 06BMCL3424
06BMCL3454 06BMCL3454 06BMCL3740 06BMCL3740
06BMCL4026 06BMCL4026
06BMCL4048 06BMCL4048
06BMCL4283 06BMCL4283 06BMCL4400 06BMCL4400 06BMCL4537 06BMCL4537 06BMCL4567 06BMCL4567
06BMCL4620 06BMCL4620
06BMCL4788 06BMCL4788 06BMCL4792 06BMCL5309 06BMCL5378 06BMCL5378 06BMCL5668 06CC674 06CC874 06CC1313 06CC 1313 06CCI766 06CC1766 06CC2071 06CC2156 06CC2l59 06CC2159 06CC2586 06CC2586 06CC4422 06CC4422 06CC4744 06CC4744 06CDC843 06CDC843 06CEJ3472 06CEJ3472 06CEJ4743 06CEJ4743
345 345
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346 06CHC701 06CICI 06CJC1 06CICI079 06CJC 1079 06COSI9 06COS 19 06CPB795 06CUMC2795 06EJM640 06EIM640 06EIM847 06EJM847
06EJO610 06E10610 06E101166 06EJO 1166
06E102727 06EJO2727 06EI03235 06EJO3235 06EJO3421 06EI03421 06EI03791 06EJO3791 06EI03917 06EJO3917 06EI04106 06EJO4106 06E104257 06EJO4257 06E104916 06EJO4916 06H555 06H815 06H975 06H 1233 06H1233 06H1651 06H2087 06H2129 06HCA635 06JA2142 061A2142 061A4023 06JA4023 061A4453 06JA4453 061A4592 06JA4592 06JA6042 061A6042 06JA6790 061A6790 061A7134 06JA7134 061A7510 06JA7510 06JA8134 061A8134 061A8702 06JA8702 061A9048 06JA9048 061A9646 06JA9646 061AI1799 06JA11799
06JA 12366 061A12366 061A12656 06JA12656 06JA12743 061A12743 061A14010 06JA 14010 061AI5114 06JA15114 061A15173 06JA15173 061CC344 06JCC344 061CC829 06JCC829 061FC159 06JFC 159 061FC755 06JFC755
D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie H.L. Fraser, D.W.
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Six-rnernbered systerns: pyridine pyridine and benzo derivatives Six-membered ring systems:
06JFC865 06JHC 101 101 06JHC187
06JHC 199 06JHC199 06JHC235 06JHC321 06JHC709 06JHC709 06JHC781 06JHC985 06JHC1105 06JHC 1105 06JHC 1169 06JHC1169 06JHC 1177 06JHCl177 06JHC 1217 06JHC1217 06JHC1311 06JHC 1311 06JMC607 06JMC607
06JMC971
06JMC1939 06JMC1939
06JMC2055 06JMC2055 06JMC2210 06JMC2673 06JMC2673 06JMC2989 06JMC2989 06JMC3244 06JMC3244 06JMC3581
06JMC3719 06JMC3719
06JMC3753 06JMC3753
06JMC3809 06JMC3809 06JMC4116 06JMC4116
06JMC4544 06JMC4544 06JMC4698 06JMC4698 06JMC4801 06JMC5324 06JMC5324
06JMC7278 06JMC7278
347
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Bertrand Le Bourdonnec, Bourdonnec, Mathieu Michaut, Hai-Fen Ye, Thomas M. Graczyk, Serge AJ.G. Belanger, Torsten Herbertz, Glenn P. A. Yap, Robert. N. DeHaven, and Roland E. Dolle J. Med. Chern. Chem. 2006,49, 2006, 49, 7278.
348 06JMC7450
06JOC135 06JOC260 06JOC315 06JOC800 06JOC894 06JOCI009 06JOC 1009 06JOCI094 06JOC 1094 06JOCI458 06JOC1458 06JOCI707 06JOC1707 06JOCI725 06JOC 1725 06JOC1746 06JOC 1746 06JOC2000 06JOC2046 06JOC2071
06JOC2460
H.L. Fraser, D.W. D. W. Hopper, K.M.K. Kutterer, and A.L. Crornbie H.L. Fraser, Crombie
M.V. Patel, T. Kolasa, K. Mortell, M.A. Matulenko, A.A. Hakeem, U. J.J. Rohde, S.L. Nelson, M.D. Cowart, M. Nakane, L.N. Miller, M.E. Uchic, M.A. Terranova, O.F. EI-Kouhen, E1-Kouhen, D.L. Donnelly-Roberts, M.T. Namovic, P.R. Hollingsworth, R. Chang, B.R. Martino, J.M. Wetter, K.e. K.C. Marsh, R. Martin, J.F. Darbyshire, G. Gintant, G.e. G.C. Hsieh, R.B. Moreland, J.P. Sullivan, J.D. Brioni, A.O. A.a. Stewart, J. Med. Chern. 2006,49,7450. Chem. 2006, 49, 7450. Y. Ju, R.S. Varma, J. Org. Org. Chern. Chem. 2006, 71, 135. K.TJ. K.T.J. Loones, B.U.W. Maes, C. Meyers, J. Deruytter, J. Org. Org. Chern. Chem. 2006, 71,260. D. Zhang, EJ. 71,315. E.J. Dufek, E.L. Clennan, J. Org. Org. Chern. Chem. 2006, 71, 315. S.-y. Tanaka, M. Yasuda, A. Baba, Baba,J J. Org. Org. Chern. Chem. 2006, 71,800. 894. E. Gallienne, T. Gefflaut, Geffiaut, J. Bolte, M. Lemaire, 1. J. Org. Org. Chern. Chem. 2006, 71, 71,894. I. Eryazici, e.N. C.N. Moorefield, S. Durmus, G.R. Newkome, J. Org. Org. Chern. Chem. 2006, 71, 1009. L. Zhao, F. Liang, X. Bi, S. Sun, Q. Liu, J. Org. Org. Chern. Chem. 2006, 71, 1094. L. Pignataro, M. Benaglia, R. Annunziata, M. Cinquini, F. Cozzi, J. Org. Org. Chern. Chem. 2006, 71, 1458. J. Hashim, T.N. Glasnov, J.M. Kremsner, e.O. C.O. Kappe,J Kappe, J. Org. Org. Chern. Chem. 2006, 71, 1707. S.J. Chang, SJ. S.J. Wittenberger, J. Org. Org. Chern. Chem. 2006, 71, W. Li, G.S. Wayne, J.E. Lallaman, SJ. 1725. M.L. Bennasar, T. Roca, F. Ferrando, J. Org. Org. Chern. Chem. 2006, 71, 1746. 71,2000. F. Hoffmann-Emery, H. Hilpert, M. Scalone, P. Waldmeier, J. Org. Org. Chern. Chem. 2006, 71, 2000. 71,2046. J.E. Kropf, I.C. Meigh, M.W.P. Bebbington, S.M. Weinreb, J. Org. Org. Chern. Chem. 2006, 71, 2046. M.-C. Fargeau-Bellassoued, G. Lhommet, J. Org. S. Calvet-Vitale, C. Vanucci-Bacque, M.-e. Chern. Chem. 2006, 71, 2071. J.T. Williams, P.S. Bahia, B.M. Kariuki, N. Spencer, D. Philp, J.S. Snaith, J. Org. Org. Chern. Chem. 2006,71,2460. 2006, 71, 2460.
06JOC2514 06JOC252I 06JOC2521 06JOC2715 06JOC2922 06JOC 3317 06JOC3317 06JOC3494 06JOC3653 06JOC3656 06JOC3923 06JOC4118 06JOC4155 06JOC4222 06JOC4270
06JOC4689 06JOC4862 06JOC4969 06JOC5274 06JOC5328 06JOC5834 06JOC6020 06JOC62 II 06JOC6211 06JOC6258 06JOC6302 06JOC6562 06JOC6872 06JOC7079 06JOC7322 06JOC7805 06JOC8146 06JOC8384 06JOC8467 06JOC848I 06JOC8481 06JOC8565
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Six-membered ring systems: pyridine and benzo derivatives
06JOC8602 06JOC861O 06JOC8610 06JOC8673 06JOC8934 06JOC8934 06JOC8993 06JOC9393 06JOC9420 06JOC9420 06JOC9857 06JOC9857 06JOC9895 06JOC9895 06LOC289 06OBC51 060BC51 060BC104 06OBC 104 060BC466 06OBC466 06OBC524 060BC524 06OBC2785 060BC2785 060BC3664 06OBC3664 060BC3675 06OBC3675
06OBC3980 060BC3980 060BC1071 06OBC1071 06OL143 0601143 060L613 06OL613 060L899 06OL899 06011033 06OL1033 06OL 1105 06011105 06OL1295 060L1295 06011525 06OL1525 06OL1569 06011569 06011653 06OL 1653 06OL1787 06011787 06011929 06OL1929 060L2123 06OL2123 060L2187 06OL2187 060L2309 06OL2309 060L2611 06OL2611 06OL2647 060L2647 06OL2985 060L2985 06OL3033 060L3033 060L3473 06OL3473 06OL3489 06013489 060L3549 06OL3549 060L3565 06OL3565 06OL3593 06013593 06OL3725 06013725 06013979 06OL3979 06OL4051 060L4051 06OL4485 060L4485 06OL5325 060L5325 060L5325 06OL5325 06OL5369 060L5369
06OL5789 060L5789
349
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350 060PRDI59 06OPRD159 06PAC1357 06PACI357 06S227 06S243 06S435 06S45 06S451I 06S687 06S827 06S1035 06SI035 06S1141 06Sl141 06S1283 06S1295 06S1664 06S1971 06S2085 06S2224 06S2242 06S2551 06S255I 06S2580 06S2585 06S2777 06S2855 06S2873 06S2934 06SC77 06SC97 06SC665 06SCI521 06SC 1521 06SCI549 06SC1549 06SClni 06SC1721 06SL53 06SL271 06SL395 06SL487 06SL547 06SL1071 06SLI071 06SLlI33 06SL1133 06SLl437 06SL1437 06SLl595 06SL1595 06SLl903 06SL 1903 06SL2083 06SL2716 06T968 06T1095 06T2395 06T2465 06T2492 06T2799 06T3095 06T3959 06T4011 06T4071 06T4086 06T4128 06T4756
H.L. Fraser, D.W. H.L. D. W. Hopper, K.M.K. Kutterer, and A.L. Crombie
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Six-membered ring systems: pyridine and benzo derivatives
06T4892 06T4892 06T4907 06T5338 06T5454 06T5454 06T5736 06T5736 06T5862 06T6222 06T6222 06T6398 06T6945 06T7266 06T7266 06T7459 06T7661 06T7817 06T7817 06T8398 06T8731 06T8740 06T9166 06T9166 06T9365 06T9650 06T9942 06T9942 06T10815 06TlI063 06T11063 06Tl1483 06T11483 06Tl1734 06T 11734
06T 11900 06Tl1900 06TA12 06TA687 06TAI420 06TA1420 06TAI581 06TA1581 06TA2006 06TL553 06TL705 06TL813 06TL837 06TL869 06TLI059 06TL1059 06TL1261 06TL 1261 06TL1729 06TL 1729 06TL2161 06TL2257 06TL2337 06TL2395 06TL2399 06TL2581 06TL258I 06TL269I 06TL2691 06TL2725 06TL3005 06TL3127 06TL3191 06TL3225 06TL347I 06TL3471 06TL3489
351
V.P.A. Raja, S. Perumal, Tetrahedron 2006, 62, 4892. A.S. Paraskar, A. Sudalai, Tetrahedron 2006, 62, 4907. S. Nguyen, l. J. Xu, CJ. C.J. Forsyth, Tetrahedron 2006, 62, 5338. M.D. Fletcher, T.E. Hurst, TJ. T.J. Miles, CJ. C.J. Moody, Tetrahedron 2006, 62, 5454. T.M. Lipinska, Tetrahedron 2006, 62, 5736. T. Cailly, F. Fabis, S. Rault, Tetrahedron 2006, 62, 5862. M.G. Ferlin, V.B. Di Marco, A. Dean, Tetrahedron 2006, 62, 6222. A. Hamid, H. aulyadi, Oulyadi, A. Daiech, Tetrahedron 2006, 62, 6398. W.T. McElroy, P. DeShong, Tetrahedron 2006, 62, 6945. Z.M. Zhao, P.S. Mariano, Tetrahedron 2006, 62, 7266. c.-G. Y.-P. Ruan, P.-Q. Huang, Tetrahedron 2006, 62, 7459. C.-G. Feng, lJ. Chen, Chert, l.-L. J.-L. Ye, Y.-P. Ruan, X. Zheng, P.-Q. F. Palacios, E. Herran, C. Alonso, G. Rubiales, Tetrahedron 2006, 62, 7661. F. lara, Jara, M. Dominguez, Dominguez, M.C. Rezende, Tetrahedron 2006, 62, 7817. B. Gangadasu, Gangadasu, P. Narender, S.B. S.B. Kumar, M. Ravinder, B.A. Rao, C. Ramesh, B.C. Raju, VJ. V.J. Rao, Tetrahedron 2006, 62, 8398. V. Singh, G.P. Yadav, P.R. P.R. Maulik, S. Batra, Tetrahedron 2006, 62, 8731. S. Madapa, V. Singh, S. Batra, Batra, Tetrahedron 2006, 62, 8740. M. Mena, N. Valls, Vails, M. Borregan, J. Bonjoch, Tetrahedron 2006, 62, 9166. F.-T. Luo, V.K. Ravi, C. Xue, Tetrahedron 2006, 62, 9365. A.C. Fernandes, Fernandes, C.C. C.C. Romao, Tetrahedron 2006, 62, 9650. S.R.V. Kandula, P. Kumar, Tetrahedron 2006, 62, 9942. A.-L. Johnson, J. Bergman, Tetrahedron 2006, 62,10815. 62, 10815. C. Sicre, J.L. Alonso-Gomez, M.M. Cid, Cid, Tetrahedron 2006, 62, 11063. D. Kalyani, A.R. Dick, W.Q. Anani, M.S. Sanford, Tetrahedron 2006, 62, 11483. A.S. Voisin, A. Bouillon, 1. I. Berenguer, l-C. J.-C. Lancelot, A. Lesnard, S. Rault, Tetrahedron 2006,62, 2006, 62, 11734. K. Takasu, N. Shindoh, H. Tokuyama, M. Ihara, Tetrahedron 2006, 62, 11900. C. Sanfilippo, N. D'Antona, G. Nicolosi, Tetrahedron Asymmetry 2006, 17, 12. S.E. Denmark, F. Yu, Tetrahedron Asymmetry 2006,17,687. 2006, 17, 687. R. Kawecki, Tetrahedron Asymmetry 2006, 17, 1420. O. Lozano, N. Llor, R. Griera, E. Molins, J. Bosch, M. Amat, C. Escolano, A. Gomez-Esque, a. Tetrahedron Asymmetry Asymmetry 2006,17, 2006, 17, 1581. G. Le Bouc, C. Thomassigny, C. Greek, Asymmetry 2006,17,2006. Greck, Tetrahedron Asymmetry 2006, 17, 2006. J. Ward, V. Caprio, Tetrahedron Lett. 2006,47,553. 2006, 47, 553. V. Nair, K. Mohanan, TD. T.D. Suja, E. Suresh, Tetrahedron Lett. 2006,47,705. 2006, 47, 705. D.S. Bose, R.K. Kumar, Tetrahedron Lett. 2006,47,813. 2006, 47, 813. 2006,47,837. A. Kumar, S. Koul, T.K. Razdan, K.K. Kapoor, Tetrahedron Lett. 2006, 47, 837. a.N. D.N. Kozhevnikov, V.N. Kozhevnikov, Kozhevnikov, A.M. Prokborov, Prokhorov, M.M. Ustinova, V.L. Rusinov, O.N. Chupakhin, Chupakhin, G.G. Aleksandrov, Aleksandrov, B. Koenig, Tetrahedron Lett. 2006,47,869. 2006, 47, 869. G.-W. Wang, c.-S. 2006,47,1059. C.-S. Jia, Jia, Y.-W. Dong, Tetrahedron Lett. 2006, 47, 1059. N. Sakai, D. Aoki, T. Hamajima, T. Konakahara, Tetrahedron Lett. 2006,47,1261. 2006, 47, 1261. O. Dirat, A. Clipson, J.M. Elliott, S. Garrett, A. Brian Jones, M. Reader, D. Shaw, a. Tetrahedron Lett. 2006, 2006,47,1729. 47, 1729. B. Zhong, R.S. R.S. AI-Away, AI-Away, C.Shih, J.H. Grimes Jr., M. Vieth, C. Hamdouchi, Hamdouchi, Tetrahedron Lett. 2006,47,2161. 2006, 47, 2161. A. Mitchinson, W.P. Blackaby, S. Bourrain, R.W. Carling, R.T. Lewis, Tetrahedron Lett. 2006,47,2257. 2006, 47, 2257. V. Mamane, Y. Fort, Tetrahedron Lett. 2006,47,2337. 2006, 47, 2337. A. Rivkin, B. Adams, Tetrahedron Lett. 2006,47,2395. 2006, 47, 2395. M. Trilla, R. Pleixats, M.W.C. M.W.C. Man, C. Bied, IJ.E. J.J.E. Moreau, Tetrahedron Lett. 2006,47,2399. 2006, 47, 2399. EJ. Corey, Tetrahedron Lett. 2006,47,2581. F.H.V. Chau, E.J. 2006, 47, 2581. A.D. Averin, a.A. Beletskaya, O.A. Ulanovskaya, Ulanovskaya, A.A. Borisenko, Borisenko, M.V. Serebryakova, Serebryakova, I.P. Beletskaya, Tetrahedron Lett. 2006, 47, 2691. N. Ahmed, J.E. van Lier, Tetrahedron Lett. 2006,47,2725. 2006, 47, 2725. F. Kelleher, S. Kelly, Tetrahedron Lett. 2006,47,3005. 2006, 47, 3005. 2006, 47, 3127. X.-F. Lin, S.-L. Cui, Y.-G. Wang, Tetrahedron Lett. 2006,47,3127. 2006, 47, 3191. F.C. Bargiggia, W.V. Murray, Tetrahedron Lett. 2006,47,3191. 2006,47,3225. X. Beebe, V. Gracias, S.W. Djuric, Tetrahedron Lett. 2006, 47, 3225. P. Gavina, S. Tatay, Tetrahedron Lett. 2006,47,3471. 2006, 47, 3471. Y. Yoshimura, J. Inoue, Inoue, N. Yamazaki, Yamazaki, S. Aoyagi, Aoyagi, C. Kibayashi, Kibayashi, Tetrahedron Lett. 2006,47,3489. 2006, 47, 3489.
352 06TL3545 06TL3589 06TL4365 06TL4541 06TL4553 06TL4749 06TL5079 06TL5147 06TL5317 06TL5333 06TL5503 06TL6011 06TL6183 06TL7025 06TL7191 06TL8343 06TL8667 06TL8917
H.L. Fraser, D. D.W. K.M.K. Kutterer, and A.L. Crombie Crombie HL W. Hopper, K.M.K.
B. B. Han, Han, X.-D. X.-D. Jia, Jia, Z.-L. Z.-L. Jin, Jin, Y.-L. Y.-L. Zhou, L. L. Yang, Yang, Z.-L. Liu, Liu, W. W. Yu, Yu, Tetrahedron Tetrahedron Lett. 2006, 2006, 47, 3545. 47,3545. B. B. Savitha, Savitha, P.T. P.T. Perumal, Perumal, Tetrahedron Tetrahedron Lett. 2006,47,3589. 2006, 47, 3589. T. T. Nemoto, Nemoto, T. T. fukuda, fukuda, Y. Y. Hamada, Tetrahedron Lett. 2006,47,4365. 2006, 47, 4365. Y. Y. Xu, Xu, H. H. Rud1er, Rudler, B. B. Denise, A. A. Parlier, P. P. Chaquin, P. P. Herson, Tetrahedron Tetrahedron Lett. 2006,47, 2006, 47, 4541. Y. Y. Xu, E. E. Aldeco-Perez, H. Rudler, A. Parlier, C. Alvarez, Tetrahedron Lett. 2006,47,4553. 2006, 47, 4553. N.T. N.T. Pati!, Patil, L.M. Lutete, N. Nishina, Y. Y. Yamamoto, Tetrahedron Lett. 2006,47,4749. 2006, 47, 4749. K. Araki, Tetrahedron Lett. 2006,47,5079. 2006, 47, 5079. J.-D. Cheon, T. Mutai, K. K. K. Mitsudo, W. W. Matsuda, S. S. Miyahara, H. Tanaka, Tetrahedron Lett. 2006,47,5147. 2006, 47, 5147. J.M. Andres, R. R. Pedrosa, A. Perez-Encabo, Tetrahedron Lett. 2006,47,5317. 2006, 47, 5317. P.S. Humphries, S. Bailey, Q.Q.T. Do, J.H. Kellum, GA G.A. McClellan, D.M. D.M. Wilhite, Tetrahedron Lett. 2006, 47, 5333. M.D. M.D. Sanchez-Salvatori, A. A. Lopez-Giral, K. K. Ben Abdejelil, C. Marazano, Tetrahedron Lett. 2006, 47, 5503. 2006,47, V.S.C. Yeh, P.E. P.E. Wiedeman, Tetrahedron Lett. 2006,47,6011. 2006, 47, 6011. S. S. Hosokawa, S. S. Kuroda, K.1mamura, K. Imamura, K. K. Tatsuta, Tetrahedron Lett. 2006,47,6183. 2006, 47, 6183. D.N. D.N. Kozhevnikov, a.v. O.V. Shabunina, D.S. D.S. Kopchuk, P.A. P.A. Slepukhin, V.N. Kozhevnikov, Tetrahedron Lett. 2006,47,7025. 2006, 47, 7025. 2006, 47, 7191. W.Chen, B. Liu, C. Yang, Y. Xie, Tetrahedron Lett. 2006,47,7191. A. Sanchez, A. Nunez, C. Burgos, J. Alvarez-Builla, Tetrahedron Lett. 2006,47, 2006, 47, 8343. Y.D.V.K. 2006, 47, 8667. K. Jayakanthan, Tetrahedron Lett. 2006,47,8667. Y.D.V. M.-Y. Jang, S. De Jonghe, L.-J. L.-J. Gao, P. Herdewijn, Tetrahedron Lett. 2006,47,8917. 2006, 47, 8917.
353
Chapter 6.2 (2005) (2005)
Six-membered ring systems: systems" diazines and benzo derivatives (2005) Michael P. Groziak California State University East Bay, Bay, Hayward, CA, USA USA [email protected] michael.groziak @csueastbay.edu
6.2.1 INTRODUCTION INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, cinnoline, phthalazine, quinazoline, phenazine once again played a central role in phthalazine, quinazoline, quinoxaline, quinoxaline, and phenazine many investigations. investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, computational, spectroscopic, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. whenever
6.2.2 REVIEWS R E V I E W S AND AND GENERAL G E N E R A L STUDIES STUDIES 6.2.2
One review covered the functionalizations functionalizations and synthetic applications of pyridazin-3(2H)pyrimido[4,5-c]pyridazine-5,7(6H,8H)ones <05JHC353>, <05JHC353>, while another on the reactions of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones with nitrogen nucleophiles nucleophiles highlighted their ability to undergo nucleophilic nucleophilic <05JHC375>. The synthesis and heterocyclizations heterocyclizations of 3-alkynylsubstitution of hydrogen <05JHC375>. 4,5-c ]pyridazine-5,7 (6H,8H)-diones and their lumazine analogs was 6,8-dimethylpyrimido[ 6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones compounds containing containing functionalized compounds reviewed <05JHC413>, <05JHC413>, as was the synthesis of functionalized pyridazine rings <05JHC361>. <05JHC361>. In the medicinal arena, pyrazolo[4,3-e]l,2,4-triazolo[1,5-c]pyrazolo[4,3-e]l,2,4-triazolo[I,5-c]pyrimidines as A 33 adenosine receptors ligands were covered in a review <05MIl319>, <05MI1319>, as were biologically active pyridazinoquinoxalines pyridazinoquinoxalines <05JHC387>. <05JHC387>. Finally, the history of the discovery of the diarylpyrimidine anti-HIV drug Rilpivirine {R278474, {R278474, 4-[[4-[[4-[(1£)-24-[[4-[[4-[(1E)-2cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile} } was covered <05JMCI90l>. <05JMC1901>. Homoheteraryl coupling mediated by Pd(OAc), Pd(OAc) 2 was used to form the aryl-aryl bonds in new diazines <05JHCI423>. <05JHC1423>. The pyrazine alkaloids botryllazine A and B from Botryllus compounds (la-c) (la-e) were prepared by a regioselective metalation/crossleachi and related compounds metalationlcrosscoupling approach starting from chloropyrazine chloropyrazine <05JOC2616>. <05JOC2616>. The pyridine ring of the
354
M.P. M.P. Groziak
pyridin-2-yldiazines 2-4 was used as an artha-directing ortho-directing group for metalation <05T9637>. The regioselectivity observed was similar to that found for 'H 2H incorporation (percentages ~ shown next to ring positions) after generating the anions with 3-4 eq. LTMP in THF at -78 T for 15 min. The 35Cl 35C1 NQR and IH 'H NMR relaxation times in a 1:2 hydrogen-bonded (chloranilic acid)-(l,3-diazine) acid)-(1,3-diazine) complex 5 were measured, giving an indication of partial Htransfer to the diazines <05BCJl241>. <05BCJ1241>. Aryl substituted diazines 6 and 7 were obtained by Bu3Sn-substituted Stille cross-coupling of Bu 3Sn-substituted precursors, themselves prepared via nucleophilic Bu3SnLi <05T2897>. The metalationffunctionalization substitution of halodiazines with Bu3SnLi metalation/functionalization of 2bromopyrazine, 2,4-dibromopyrimidine, and 3-bromo-6-phenylpyridazine was reported, together with an improved preparation of these halodiazine starting materials <05JHC509>. The ring metalation of cinnoline, quinazoline, and quinazolinone sulfoxides was found to be effective, but curiously that of a quinoxaline sulfoxide was not <05T8924>. 21%
b, RI=H, R2 = 4"HOC6H4CO; c, R1 = 4-HOCsH4CO, R2=H
HO
14
19%
N 81%
N
16%
100%
2
N
11 o
3
o
4
OH
Cl
N
(N)~ N ,
o
o-.,,,.
CI
5
N "
~~~/)
l
~N
N
N
66
"
~-..J v
7
~...J v
DERIVATIVES 6.2.3 PYRIDAZINES PYRIDAZINES AND AND BENZO BENZO DERIVATIVES
X-ray crystallography continued to expand our knowledge of the solid state structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethylpyridazines. The crystal structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethyl7,7a-dihydro-6aH-cyclopropa[d][1,2,3]triazolo[4,3-b]pyridazine <05AX(E)o2142>, 7,7a-dihydro-6aH-cYclopropa[d] [1,2,3]triazolo[4,3-b]pyridazine <05AX(E)02 I42>, 3,6-bis(4-methoxybenzyloxy)pyridazine <05AX(E)02486>, <05AX(E)o2486>, and ethyl 3-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-I ,6-dihydro-I-pyridazineacetate fluoromethyl)phenyl]- 1,6-dihydro1-pyridazineacetate <05AX(E)0 <05AX(E)o 1561> 1561> were determined. N I2 and Ag N I2 metallacycles with a para-cyclophane In the organometallics field, neutral Cu Cu4NI2 Ag4N~2 4 4 framework were prepared by treating Cu(I) and AgO) Ag(I) pyrazolates with pyridazine, and three of these were solved crystallographically <05CCI619>. <05CC1619>. Finally, [pyridazin-3(2H)-one-6-yl]ferrocenes 8 were prepared and characterized by a wide variety of methods, including IR, 1D and 2D NMR, and X-ray <05JOM802>. Q =-(CH2)n-, (E)-CH=CH-,
(N) 8
355
Six-membered ring ring systems: diazines and benzo derivatives (2005) (2005)
6.2.3.1 Syntheses
Condensation approaches to the synthesis of pyridazines were once again popular. A microwave-assisted cyclocondensation reaction involving -diketones and hydrazine in the presence of DDQ produced 3,4,6-trisubstituted pyridazines <05SL2743>. New tricyclic pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones were prepared from 2,3-dihydropyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones thiopyrano[2,3-b]pyridin-4(4H)-ones via condensation with glyoxylic acid followed by thiopyrano[2,3-b]pyridin-4(4H)-ones <05AP126>. hydrazines. Their binding affinity at the benzodiazepine receptor was studied <05API26>. Hydrazonoyl halides were used to access many heterocycles, including pyrazolo[3,4-d]pyridazines <05JHC527, 05SC249>, pyrrolo[l,2-b]pyridazines pyrrolo[1,2-b]pyridazines were among the many heterocycles accessed using -(cyanomethyl)benzylidene-malononitrile as a starting material <05SC2251>, and methyl 3,3,3-trifluoropyruvate was used in a two-step synthesis of 4trifluoromethyl-(2H)-pyridazin-3-ones <05SLl907>. <05SL1907>. Pyridazino[3,4-a]carbazoles Pyridazino[3,4-a]carbazoles 9 were trifluoromethyl-(2H)-pyridazin-3-ones obtained by the reaction of substituted 2-benzylidene-I,2,3,4-tetrahydrocarbazol-I-ones 2-benzylidene-l,2,3,4-tetrahydrocarbazol-l-ones and thiocarbohydrazide or thiosemicarbazide <05CCC223>.
N H
(H2NNH)2C=S KOH, KOH, EtOH EtOH-
0 o
9 N'N~
pyridazino[4,5-b]A new tetraazaheterocyclic system was accessed when substituted pyridazino[4,5-b][l,8]naphthyridin-6(7H)-ones [1,8]naphthyridin-6(7H)-ones like 10 were prepared from 1,8-naphthyridine-3-carboxylates <05H(65)329>. A regioselective synthesis of pyridazines 11 was developed from the cycloaddition of phosphorylated I,2-diaza-1 ,3-butadienes with olefins. Cycloadduct 1,2-diaza-l,3-butadienes formation occurs via an endo transition state with styrene, cyclopentadiene, and dihydrofuran, but via an exo one with norbornadiene <05EJOI142>. <05EJO1142>. The regioselective cycloaddition of tetrazines and alkynylboronic esters gave highly substituted pyridazine boronic esters 12 <05AG(I)3889>. Pyridazine derivatives 13a-c 13a-e were formed via Diels-Alder reaction of di(benzoyl)acetylene and 1,1 ,2,2-tetra(cyano)ethylene <05CJC57>, and 1,1,2,2-tetra(cyano)ethylene pyridazino[4',3'A,5]thieno[3,2-d]-1,2,3-triazines were prepared along a heterocyclization pyridazino[4',3':4,5]thieno[3,2-d]-l,2,3-triazines route <05PS591>.
Ph Ph
Ph Ph
c~ NC~"': "': C02 Et ..-:
..-:
EtO
R1
R1
~
NH
1..-:..-: N
N
N
..-: N
Me
10 10
Br Br
4
C
CO2Et / ~+N'~N ~
NC:CcX",: NH
Br Br - - EtO
N~ N~/---~.N
EtO
N
O 0
R1 " N
B(OR)2 R1 12
Me O=PPh2
PhOC PhOC
CO2Et = ~N'N . ~ ""0 _ "2 O=lSPh2 11
~ == +
COPh N=N N=N COPh ~- A Ar---~\ + r y /)-AAr r Ar-C=N-N=C-Ar PhMe PhMe Ar-C=N-N=C-Ar H H A PhOC COPh COPh PhOC H H '" 13a-c, R = Me, OMe, CI
Some unusual pyridazine syntheses were reported. A dye-sensitized photooxygenation reaction of ribofuranosyl furans gave a new entry to pyridazine C-nucleosides 14
356
M.P. Groziak M.P. Groziak
<05JOC6503>, and new pyridazino-psoralens 15 were prepared via a furan ring expansion NH,NH 22 reaction <05T4805>. The reaction of 3-acetylcoumarins with alloxan followed by NH2NH easily produced 3-(2-oxo2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c ]pyridazine-5,7-diones 3-(2-oxo-2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c]pyridazine-5,7-diones <05JHC1223>. <05JHC1223>. Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenylphosphonium salts <05HAC56>. Me Me 1.102
R
O R(f
~
O
";OR Me
ii
2. Et2S
N
-9 RO
3. NH2NH2~
RO"
;OR Me
CO2Me
14 CO2Me N.~N
?N
A
0
C02Me
~ o0 / ~ h-
If \
o
+
~
o
o0 / / h-
_
If \
CN Ph3p ~ [~CN
o
N'N N-N--~ 0 H H 16
I
~
CN CN
If \
o
+ +
N. N-r 0 N'N
e)=! / ~ J 17(39%) 17 (39%)
16
15
M Me
N..., I N.'NN~--~-.O.~',.Me 0 Me 18a, X X == NH NH (13%) (13%) 18a, b, X=O X = O (19%) (19%) b,
6.2.3.2 Reactions
Removal of the MOM group from 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones 19 with HCI HC1 gave, with certain alkynyl substituents, 5-(2-chloroalkenyl)pyridazin-3(2H)-ones like 20a-d <05T4785>. 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione was transformed into thieno[2,3-c]pyridazines and pyrimido[4',5':4,5]thieno[2,3-c]pyridazines pyrimido[4',5':4,5]thieno[2,3-c]pyridazines <05PS413>. thieno[2,3-c]pyridazines Alkyl/aryl pyridinazinyl ethers were prepared from the corresponding halopyridazinones <05JHC639>.
O o
O
M~
.c, N
= Ph
R
H~~ N ~
c, 91
N~R Ph Ph
20a, R = H, 20a, b, b, R R =CH = CH2OH, 2 0H, c, R R == CH(OH)Me, CH(OH)Me, c, d, d, R R == CH CH2CI 2CI
19
6.2.3.3 Applications Applications
Pyridazines continued to playa play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-
Six-membered Six-membered ring systems: diazines and benzo derivatives (2005)
357 3S7
pyridazin-3-one and related compounds were prepared as aldose reductase inhibitors . Pyrazolo[l',S':1,6]pyrimido[4,S-d]pyridazin-4(3H)-ones <05JMC6326>. Pyrazolo[l',5': 1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones were examined as PDEs5 inhibitors , <05BMCL2381>, pyrazolo[3,4-c]pyridazines as cyclin-dependent kinase (CDK2) inhibitors , <05JMC6843>, pyrazolo[3,4-d]pyridazines as antibacterials and <05EJM401>, and polyfunctionally substituted pyridazines and their fused antifungals , <05HEC89> and certain pyrrolopyridazine cycloadducts <05H(65)1871> were all derivatives prepared as antimicrobials. Some pyridazines were developed as inhibitors of p38 MAP kinase , <05BMCL2409>, others as acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors , <05JHC395>, and still others as GABA-a GABA-t~ receptor ligands . 05JMC7089>. Finally, certain 3(2H)pyridazinones were prepared as fungicides and herbicides . <05JHC427>.
6.2.4 PYRIMIDINES DERIVATIVES PYRIMIDINES AND AND BENZO BENZO DERIVATIVES
We have learned more about the physicochemical properties of pyrimidines through some IS substituted pyrimidines detailed investigations. For example, the electronic structures of 15 like 21a-d were studied by computational methods , <05EJO522>, and mono- and multinuclear Mn(H), Mn(II), Co(lI), Co(II), and Cu(H) Cu(II) complexes of bisazo-dianils containing a pyrimidine moiety were synthesized and examined by a variety of spectroscopic methods (IR, electronic <05JCC683>. The intramolecular stacked conformation of pyrazolo[3,4-d]absorption, ESR) . pyrimidines tethered by a trimethylene linker was documented in solution by 'H NMR and in the solid state by X-ray , <05JMS179>, and complexes between the tautomers of the RNA pyrimidine bases and L-leucine were characterized by ab initio computational methods <05TC31>. Tautomerism in N-methyl regioisomers of uracil, S-fluorouracil, 5-fluorouracil, and thymine . <05TC201>. 4,S,6,7-Tetrahydro-2-methyl-2,4-diphenyl4,5,6,7-Tetrahydro-2-methyl-2,4-diphenylwas also examined this way . 4,7a,12b-triazadibenzo[e,g]azulene-1,3,8-triones 4,7a,12b-triazadibenzo[e,g]azulene-l,3,8-triones 22 were prepared as members of a Aspergillus alkaloids pyrimidine-annulated pyrrolobenzodiazepine ring system related to Aspergillus <05EJO1781>, and their prototropic tautomerism was studied by 'H NMR . <05H(65)625>. , The 4,9-methanoundecafulvene-related [S-( 4,9-methanocycloundeca-2',4',6',8',1 O'-pentaenyl[5-(4,9-methanocycloundeca-2',4',6',8',10'-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones] 23 were prepared, and their physical properties were idene)pyrimidine-2,4,6(l,3,5H)-triones] examined by UV-Vis, cyclic voltammetry, and NMR. The rotational barrier about the 12.55 kcalomol-', <05T7384>. In a kcalomor', by a VT-NMR study . exocyclic C=C was determined to be 12.SS 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H),3,SH)similar fashion, a set of S-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1 triones 24 was prepared by reaction of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid followed by chloranil-mediated oxidation, and these too were extensively characterized by NMR, UV-Vis, cyclic voltammetry, MO computations, and X-ray crystallography <05T8616>. . R R33
R4~R2
N.. N
NyN
R11 R 21a, 21a, R R11 == H, H, C=CH, C-CH, NH NH2, NMe2; 2, NMe2; b, R2 =H, Me, 2= Me, CI, CI, OH, OMe, OMe, NMe2; NMe2; c, r R33 == H, H, C",CH, C-CH, Me, Me, iPr; iPr; OMe d, R44 = H, Me, CI, OMe
O
c(-p
O~-Phh OMe~~ph'O Me
Ph 0
22 22
358
M.P. Groziak M.P. Groziak
ct:r I
-....o:
~
....-::
O
00
N
o0
R R
0,H 0
H
O~r/)=00 + +
ct:::r<; "'::
Ac~O, 120 ~ lh O O
I
-....0:
~....-::
o0
0
,~,
NR R N
R
23
O
N, R
+
'~--' ~-~' ' ~ "'~~
,
+) ~ ~
H
N
,~-~
)=0 -- [ :,
N N,
-~ ~ )=0o -oo
ctJ{0 ,H
H
N
>
-)=0 /
N /)--N, , O 0 R
R R
N
- ' )=0 )~=O N, R
24a, X = O 0
b, X= X = NMe NMe b,
There was again a large number of X-ray crystallographic determinations of pyrimidine1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one (25) <05AX(E)0594>, <05AX(E)o594>, 2,3based structures. 1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline <05AX(E)02746>, bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline <05AX(E)o2746>, 2,4,6-tris(pyrimidin-2-yl2,4,6-tris(pyrimidin-2-ylsulfanyl)-l,3,5-triazine <05AX(E)o1133>, 4-(2-naphthyl)pyrimidine <05AX(E)02256>, <05AX(E)o2256>, and sulfanyl)I,3,5-triazine <05AX(E)0 II33>, 4-(2-naphthyl)pyrimidine 2-chloro-4-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine 1821> were among the 2-chloro-4-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine <05AX(E)0 <05AX(E)o1821> simpler ones. Others were 3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno[3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one [3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one <05AX(E)02663>, <05AX(E)o2663>, 10"-(4-chlorobenzylidene)10"-(4-chlorobenzylidene)5"-(4-chlorophenyl)-4'-(2,4-dichlorophenyl)5 "-( 4-c hl orophe n y 1)-4'-(2,4-di c hl orophe n y 1)- 1I'-methyl-2,3,2",3",7",8",9", '-meth y 1-2,3,2 ",3 ",7 ", 8 ",9", 10"-octahydro10"-oc tah y dro- IH, 1H, 5"H,6"Hindole-3-spiro-2'-pyrrolidine-3'-spiro-2"-cyclohepteno[ ,2-a ]pyrimi5"H, 6"H-indole3- spiro- 2'-pyrrolidine- 3'- spiro- 2"-cyclohepteno [ 1,2-d]thiazolo[3 1,2-d] thiazolo [3,2-a] pyrimidine-2,3"-dione <05AX(E)0 1411>, 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]<05AX(E)ol411>, 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]pyrimidin-4(3H)-one <05AX(E)02649>, pyrimidin-4(3H)-one <05AX(E)o2649>, and 10"-(4-methoxybenzylidene)-5",4'-bis(410"-(4-methoxybenzylidene)-5",4'-bis(4methoxyphenyl)-1l'-methyl-2,3,2",3",7",8",9",l '-methyl-2,3,2",3",7",8",9", 1O"-octahydromethoxyphenyl)0"-octahydro- IH,5"H 1H,5"H and 6"H-indole-3-spiro6"H-indole-3-spiro2'-pyrrolidine-3'-spiro-2"-cyclohepteno[ 2'-pyrrolidine- 3'- spiro- 2"-cyclohepteno [ 1,2-d]thiazolo[3,2-a]pyrimidine-2,3"-dione 1,2-d] thiazolo [3,2- a] pyrimidine- 2,3"- dione <05AX(E)02086>. ,2,3]triazolo[5', 1':6,1]<05AX(E)o2086>. Still others were 3-methyl-6,8-di(2-pyridyl)-[1 3-methyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',l':6,1]I,3,4,4a,5,6,7,8a-octahydro- 2Hpyrido[2,3-d]pyrimidine <05ARK71 >, 4-(o-methoxypheny1)pyrido[2,3-d]pyrimidine 4-(o-methoxyphenyl)- 1,3,4,4a,5,6,7,8a-octahydro-2Hpyrano[2,3-d]pyrimidine-2-thione 1228>, 4-(E)2-[3-(3- [(E)- 2-(4-cyanopheny1)pyrano[2,3-d]pyrimidine-2-thione <05AX(E)0 <05AX(E)o1228>, 4-(E)-2-[3-(3-[(E)-2-(4-cyanophenyl)I-diazenyl]hexahydro-l-pyrimidinylmethyl)hexahydro-I-pyrimidinyl]-I-diazenylbenzonitrile 1-diazenyl]hexahydro- 1-pyrimidinylmethyl)hexahydro- 1-pyrimidinyl]- 1-diazenylbenzonitrile <05MI297>, ,3,7-triphenyl-2,3,5,6,7,7a-hexahydro-lH-pyrrolo<05MI297>, 4,7-bis(4-methoxyphenyl)-1 4,7-bis(4-methoxyphenyl)- 1,3,7-triphenyl-2,3,5,6,7,7a-hexahydro1H-pyrrolo[2,3-d]pyrimidine-2,5,6-trione [2,3-d]pyrimidine-2,5,6-trione (26) <05AX(E)0635>, <05AX(E)o635>, and the related 4-p-tolylI,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one (27) <05AX(E)0 I049>. 1,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one <05AX(E)o 1049>.
/~_N
.X-'-N--
N\ ~ " ' S ~ " 25 25
O
'S"
~176
O~O ?" OMe Ph, I
iX
N
~:::o-..
INN MeO/tt-..~ ph~ N-..~Nph MeO ~ Ph" I( 'Ph
o0
26
~
Oy~ O.~N HN
HNo~ o
:::0-..
Me
Me
I
27
27
,5-a]pyrimidine-3In addition to these, 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile <05AX(E)02506>, <05AX(E)o2506>, 7"-benzyl-9"-benzylidene-4'-[4-(dimethylamino)phenyl]-1 7"-benzyl-9"-benzylidene-4'-[4-(dimethylamino)phenyl]-l'-'methyl-5"-phenyl-2",3",6",7",8",9"-hexahydro-lH-indole-3(2H)-spiro-2'-pyrrolidine-3'-spiromethyl- 5 "-phen yl- 2 ",3 ",6", 7", 8 ",9"-he xah y dro- 1H- indo 1e- 3 (2H)- spiro- 2 '-p yrroli dine- 3 '- spiro2"-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2"-dione I830>, ethyl 3-cyano-72"-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2"-dione <05AX(E)0 <05AX(E)o1830>, methylpyrazolo[I,5-a]pyrimidine-6-carboxylate methylpyrazolo[ 1,5-a]pyrimidine-6-carboxylate <05AX(E)01459>, <05AX(E)o 1459>, methyl 2-[2-(5,7,2,4-triazolo[ 11,5-a]pyrimidin-2-ylsulfanylmethyl)phenyl]-3-methoxyacrylate ,5-a]pyrimidin-2-ylsulfanylmethyI)pheny1]-3-methoxyacrylate dimethy1-1 dimethyl- 1,2,4-triazolo[ 3-[(3-{ (E)-2-[4-(methoxycarbonyl)phenyl]-I<05AX(E)01992>, <05AX(E)o1992>, and methyl 4-«E)-2-{ 4-((E)-2-{3-[(3-{(E)-2-[4-(methoxycarbonyl)phenyl]-l-
359
Six-membered ring ring systems: systems: diazines diazines and benzo derivatives derivatives (2005) (2005)
diazenyl }-5,5-dimethylhexahydro-I-pyrimidinyl)methyl]-5,5-dimethylhexahydro-I-py}-5,5-dimethylhexahydro- 1-pyrimidinyl)methyl]-5,5-dimethylhexahydro- 1-pyrimidinyl }-l-diazenyl)benzoate }-1-diazenyl)benzoate <05MI307> were also analyzed by X-ray crystallography. The isostructural compounds 5-methyl-2-(4-methylphenyl)- (28), 2-(4-chlorophenyl)-5methyl-, and 2-(4-bromophenyl)-5-methyl-7,S-dihydro-6H2-(4-bromophenyl)-5-methyl-7,8-dihydro-6H- cyclopenta[g]pyrazolo[1,5-a]pyrimidines displayed chains linked by a single CH...1t(arene) CHooo~(arene) H bond, but the 5-methyl-2-ptolyl- derivative was found linked by a single CH"'NH CHoo~ bond into chains, which themselves were linked into sheets by a 1t-1t ~-~ stacking interaction <05AX(C)o452>. 7-Hydroxy-3methoxy-4-methyl-5,6,7,S-tetrahydropyrido[1,2-c]pyrimidin-l(9H)-one 29 was shown to methoxy-4-methyl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidin-l(9H)-one have a planar pyrimidine ring involved in three CH...1t CHo~ interactions interactions <05AX(C)o15S>. <05AX(C)o158>. 5-(4Methoxybenzoyl)-4-(4-methoxyphenyl)-I-( 1-(4-methoxyphenyl)-ethylideneamino) Methoxybenzoyl)-4-(4-methoxyphenyl)1-(1-(4-methoxyphenyl)-ethylideneamino) <05AX(E)o622> and 5-(4-methoxybenzoyl)-1-(4-methoxybenzylideneamino)-4-(45-(4-methoxybenzoyl)- 1-(4-methoxybenzylideneamino)-4-(4methoxyphenyl)- <05AX(E)o637> pyrimidin-2(1H)-one (30a and b, respectively) were each solved crystallographically. OMe OMe
o Me
- .;: N,,,: Me --Q-(X . _ ~ . ~~
Me
-~
'
t5N"Me ~ ~ W~N //
}--N
it{
HO HO~ •• ~
MeO MeO
Me
28 28
0 o
OMe }-OMe
-~_ -N
~--~_OM e
~---{N-~~OMe
29 29
OR~ R
'No
R=H H 30a, R = Me; b, R
In the organometallic field, a complicated nonanuclear Ni(II) complex containing the 7,S7,8dihydro-l,2,4-triazolo[4,3-a]pyrimidin-7-one anion 31 as a ligand was characterized by Xdihydro-1,2,4-triazolo[4,3-a]pyrimidin-7-one ray <05EJI2779>, <05EJl2779>, as were bis(pyrimidine-2-thiolato)bis(triphenylphosphine)ruthenium(II) bis(pyrimidine-2-thiolato)bis(tripheny1phosphine)ruthenium(II) 32 cis, cis, trans:N, N; P,P; S,S-[bis(triphenylphosphine)] [bis(pyrimidine-2<05AX(E)m714>, trans:N,N;P,P;S,S-[bis(triphenylphosphine)][bis(pyrimidine-2<05JCC429>, and catena-poly[[[(acetonitrilethiolato)]ruthenium(II) catena-poly[[[(acetonitrile- N)silver(I)]- 2N1:N 11 tetrafluoroborate] 165S>. In bis(pyrimidin-2-ylsulfanyl)methanebis(pyrimidin-2-ylsulfanyl)methane-2NI:N1] tetrafluoroborate] 33 <05AX(E)m <05AX(E)m1658>. the biological-medicinal field, pyrimidines solved crystallographically included 3-bromo-1(2-deoxy- -D-erythro-pentofuranosyl)-lH-pyrazolo[3,4-d]pyrimidine-4,6-diamine -D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 34, a DNA stabilizing nucleoside <05AX(C)o67>, the herbicide isopropyl 2-(5,7-dimethyl-l,2,4duplex stabilizing isopropyI2-(5,7-dimethyl-l,2,4triazolo[ 1,5-a ]pyrimidin-2-yloxy)benzoate <05AX(E)o2079>, and 2-methyl-7-oxo-5,6,7,Striazolo[1,5-a]pyrimidin-2-yloxy)benzoate 2-methyl-7-oxo-5,6,7,8tetrahydropyrimido-[4,5-d]pyrimidin-3-ium chloride 35, from the thermal decomposition of the HCI HC1 salt of nimustine {1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3{ 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3nitrosourea, 36}, an antitumor DNA cross-linker for treating malignant glioma <05AX(E)o544>.
_ 0"-%./N"',/~N,
O~yN'N ~N-.5
31 31
Ph3P\/PPh3 3 P\!Ph 3 Ph
N:) AI
S~'-" Ru····'''''8 .........S 8 - Ru
N~CN 32
N
C
y
/ON
-
(8 8
N",+ Ag
t
CH 3CN
33 33
nBF nBF44-
n
360
M.P. Groziak
Br\
Cl CI
'NH2 I
"---( N:)-; Me_--~N.__y .k /;) ~ Me-{ H, + NH2
a-- -N-~- NH2
Me...~N I.~ N...~---.0 H
0 H 34
CII- N C
35 35
)
0
< ,9 < N-N N-N'
HN-{ H'N-fk00
36, 36, nimustine nimustine
6.2.4.1 6.2.4.1 Syntheses
Cyclization routes to pyrimidines continued to be a rather popular approach for preparing H-I ,2,3-triazolo[4,5-d]pyrimidin-7-ones like 37 were prethese heterocycles. 3,6-Dihydro-7 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones pared via cyclization of guanidine intermediates <05CLl022>, <05CL1022>, and 3-substituted 4-oxo3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic 3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid esters were prepared along a heterocyclization route <05PS95>. A new route to pyrido[4,3-d]pyrimidines like 39 relied upon an intramolecular cyclization of 4-amino-5-(tert-butyliminomethyl)-2(methylthio)-6-(phenylethynyl)pyrimidine 38 <05CHE268>, <05CHE268>, and a regioselective, radical cyclization-based synthesis of pyrimidine-annulated spiro-heterocyclic compounds was photo-induced oxidative cyclization reaction, areno[b]reported <05SCI96l>. <05SC1961>. Using a photo-induced perchIorates and tetrafluoroborates 41 were pyrimido[5,4-e ]pyran-2,4(1 ,3H)-dionylium perchlorates pyrimido[5,4-e]pyran-2,4(1,3H)-dionylium prepared from alkylidenated barbituric acids 40, and were characterized by NMR, UV-Vis, 19>. and X-ray <05T49 <05T4919>. o
"i"NN~~N/~j Ph
H2:~N
N PI~
>-=N MeS
37
NHEt
0 Me'N ~ ~ "
r."
<~)
_
CHCl3
38
AC20 ,II O "J 60%HCLO4 M e . N ~ . 9 I'~, hv,
-
r .
HBF O 42% ----4, ,', or____L._ O"~N "O ,, aerootc,r.t. Me 40 "-- I
~j
H2N
Ag.o
N
,
Me
F--N~ Ph
~-=N MeS 39 r."
"O" Y
I'~,
,',
, 41 ~'-~.-'~ |!
CIO 4(BF4)
2-Amino-5-methyl-7 H-I ,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones in a sequence beginning 2-Amino-5-methyl-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones <05JHCl105>. A with the condensation of 2-bromo-5-amino-I,3,4-thiadiazole 2-bromo-5-amino-l,3,4-thiadiazole and diketene <05JHC1105>. three-component condensation route to 5-aryl-5,8-dihydroazolo[ I ,5-a]pyrimidine-75-aryl-5,8-dihydroazolo[1,5-a]pyrimidine-7carboxylic acids was developed, and the solvent effect on regioisomer production was studied <05S2597>. A condensation approach to pyrrolylthieno[2,3-d]pyrimidines and thieno[2,3-d][4,5-d]dipyrimidines was described <05PS633>, as was the preparation of pyrimidines by condensation of N-substituted lactams and Viehe's salt (dichloromethylenedimethylammonium chloride) <05TLlI77>. <05TL1177>. Carbonylative alkynylation followed by cyclocondensation constituted a new four-component pyrimidine synthesis of 42 (variolin B) and 43 (variolin D), tricyclics related to the meridianins 44 <05AG(I)695l>, <05AG(I)6951>, and condensation of
diazines and benzo derivatives (2005) Six-membered ring ring systems: diazines
361
6-[(dimethylamino)methylene]aminouracil 6-[(dimethylamino)methylene]aminouracil with aryl isocyanates and isothiocyanates gave Me,NH from the initial adduct <05TL1433>. The pyrimido[4,5-d]pyrimidines upon loss of Me2NH diketo 2-(2-oxocyclohexylcarbonyl)benzoic acid ester was condensed with NH2NH NH,NH,2 to give <05PS 163>. an indazole, which was subsequently transformed into a fused pyrimidine <05PSI63>. H2N"
N OH
.CO2Me
H2N" N N/~
~
N
~
?=N
R 4 R4
H2N H 2N
42, variolin variolin B 42,
variolin D 43, variolin
meridianins 44, meridianins R R1-R H/OH/Br 1-R 44 = H/OH/Br
The use of microwave acceleration in pyrimidine syntheses continued to grow. For example, a microwave assisted synthesis of pyrimidines from ketones and formamide in the presence of HMDS was reported <05TL7889>, as was one which generated pyrazolo[l,5-a]pyrazolo[1,5-a]pyrimidines from enaminones and 5-amino-1H-pyrazoles 5-amino-lH-pyrazoles <05JHC925>. A microwavet~,~-unsaturated esters generated carbocyclic assisted Michael addition of pyrimidines to a,~-unsaturated nucleoside analogs <05S419>, and a microwave-assisted one-pot synthesis of 2-amino-6,7disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one from 2,6-diaminopyrimidin-4-one, aldehydes, and acyclic 1,3-dicarbonyl compounds was found to proceed in very good yields in the absence of a catalyst <05ARK76>. Microwaves accelerated the synthesis of imidazo- and pyrimidopyrido[4',3':4,5]thieno[2,3-d]pyrimidines from a thienopyridinecarboxylate and pyridothienopyrimidine <05ZN(B)221>, and an improvement in the microwave-assisted synthesis of 1,2,4-triazolo[4,5-a]pyrimidin-5-ones 1,2,4-triazolo[4,5-a]pyrimidin-5-ones was noted when a paste-like medium was employed <05S2833>. The use of microwave acceleration in combination with solid-phase approaches was used as well. Tetrahydropyrimidinones were obtained via microwave assisted, solid-phase intramolecular cyclization <05TL5747>, and a microwave-assisted solid support synthesis of dihydropyrido[2,3-d]pyrimidines was also described <05TL1345>. Resin-bound amidines were condensed with -dicarbonyl <05JCO517>. compounds to give 2-alkyl/aryl-pyrimidines and related 3H-pyrimidin-4-ones <05JC0517>. Solid-phase approaches to pyrimidines were used both to generate libraries of compounds and simply for convenience. A combinatorial library of 3,5,6-trisubstituted pyrrolo[3,2-d]pyrimidines (9-deazapurines) was generated by a solid-phase synthetic approach <05JC0977>, <05JCO977>, and the solid phase preparation of pyrido[2,3-d]pyrimidin-7-ones was described <05TL8749>. Solid-phase approaches to trisubstituted IH-pyrido[2,3-d]pyrimidin1H-pyrido[2,3-d]pyrimidin<05JCO589>, 4-ones <05JCO96>, <05JC096>, 3-substituted pyrrolo[3,2-d]pyrimidine-6-carboxylates <05JC0589>, and 3H-imidazo[1 ,2-a ]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[ I ,2-a]pyrimidin-23H-imidazo[1,2-a]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidin-2ones, and 3,4,6,7,8,9-hexahydro-1H-pyrimido[ 1,2-a][ 1,3]diazepin-2-ones were developed 3,4,6,7,8,9-hexahydro-lH-pyrimido[1,2-a][1,3]diazepin-2-ones <05TL5289>. A solid-phase synthesis of N-(pyrimidin-2-yl)amino acid amides relied upon <05ARK172>, and a traceless nucleophilic aromatic substitution using 2-fluoropyrimidine <05ARKl72>, solid-phase sulfone linker approach was used to prepare 3,4-dihydropyrimidin-2-ones <05JC0721>. <05JCO721>. Solid-phase approaches were not solely used to generate libraries, however. A pyrazolo[1,5-a]pyrimidines were prepared via large number of 7-trifluoromethyl-substituted pyrazolo[I,5-a]pyrimidines parallel solution-phase synthesis <05JC0236>. <05JCO236>.
362
M.P. Groziak M.P. Groziak
Efficiency in pyrimidine synthesis was sometimes achieved by the use of metal-catalyzed reactions. 4-Substituted and bicyclic pyrimidines were prepared via a Pd-catalyzed reaction of -Me and -methylene ketones with formamide. Among the products obtained, S,65,6dihydrobenzo[h]quinazoline and 4-naphth-2-ylpyrimidine were characterized by X-ray dihydrobenzo[h]quinazoline methods . <05H(65)2593>. 6-[(Phosphonomethoxy)alkynyl- and alkyl]pyrimidines 45 and 46 Pd-C/CuUPPh 3-catalyzed were prepared via Sonogashira coupling , <05CCC247>, and the Pd-C/CuI/PPh3-catalyzed Sonogashira coupling of 3-iodopyrazolo[I,S-a]pyrimidines 3-iodopyrazolo[1,5-a]pyrimidines with propargylic and homopropargylic reagents followed by catalytic hydrogenation gave -functionalized 3-(3I,S-a ]pyrimidines . OH (NH2)
OH (NH2)
3..
N,~N~ H2N
-q 45
n = 1,2
H2N 46 . ~ O v
POaH2
OvPO3H 2
Often, simply conducting several steps in a one-pot fashion or using more than two components in a reaction was found to generate pyrimidines efficiently. A one-pot preparation of pyrimidines relied on the condensation of a,~-unsaturated ~,~-unsaturated imines and amidines or guanidines , <05TL1663>, and another of 2-arylimidazo[I,2-a]pyrimidines 2-arylimidazo[1,2-a]pyrimidines from ketones, [hydroxy(tosyloxy)iodo]benzene, and 2-aminopyrimidine was found to be accelerated by the use of an ionic liquid as solvent . <05SC1741>. A one-pot synthesis of substituted 1,2,3,4-tetrahydropyrimidines 1,2,3,4-tetrahydropyrimidines from N,S-acetals, formaldehyde, and diamines was <05JHC975>, as was a one-pot, three-component, KF/alumina-catalyzed synthesis reported , of pyrido[2,3-djpyrimidines 1921>. A one-step synthesis of 2-amino-7-chlorothiazolopyrido[2,3-d]pyrimidines . 2-amino-7-chlorothiazolo[S,4-djpyrimidines [5,4-d]pyrimidines 48 from 4,6-dichloro-S-aminopyrimidine 4,6-dichloro-5-aminopyrimidine (47) gave a ready entry to 2,7diaminothiazolo[S,4-djpyrimidines 49 , and -dicarbonyl compounds were diaminothiazolo[5,4-d]pyrimidines <05JOC10194>, found to add regioselectively to 2-ethoxymethyleneaminonitriles 2-ethoxymethyleneaminonitfiles in a one-pot, [S+l]-annula[5+ 1]-annulation synthesis of quinazolines and fused pyrimidines . A one-pot synthesis of 3,4dihydropyrimidin-2-(lH)-ones dihydropyfimidin-2-(1H)-ones developed using Bi(lI!) Bi(III) nitrate as catalyst represents an improvement over the classical Biginelli reaction conditions . <05ARK74>. A three-component, base-mediated reaction of 2-alkyl-4,S-dichloropyridazin-3(2H)-ones 2-alkyl-4,5-dichloropyridazin-3(2H)-ones 50 with p-cyanophenol and 2-mercaptopyrimidine (51) gave 2,4,S-trisubstituted-pyridazin-3(2H)-ones 2,4,5-tfisubstituted-pyfidazin-3(2H)-ones like 52a-d, together with S-cyano-S-(pyrimidin-2-yl)-2,7-dialkyl-SH-dipyridazino[ 4,S-b:4,S-e]5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyfidazino[4,5-b:4,5-e]4H-thiopyran-I,6-diones 4H-thiopyran-l,6-diones . <05T5389>. Finally, tri- and tetrasubstituted pyrimidines like 53 were prepared by a four-component coupling reaction involving a silane, two aryl nitriles, nitfiles, and an acetal . <05OL4705>. CI
CI
N~NH2 II
/.
"N
47 47
CI CI
base
\ N//~ S 48
NHR2
H+ or base MW, 150 ~
S 49
363
Six-membered ring systems: systems: diazines diazines and and benzo benzo derivatives derivatives (2005) Six-membered
CI
OH
C C ' ~ Nl .n N O N,N
°
¢
+ +
+
R so 50
SH
Yy
N~N
base
V
CH 3CN CH3CN
° N'~
O
I
51 Sl
CN CN
52a, 52a, X X= =CI, CI, Y Y= =SAr; SAr; b, b, X X= =SAr, SAr, Y Y= =OAr; OAr; rc, XX ==OAr, OAr, Y Y= =SAr; SAr; d, d, X X= =YY ==SAr SAr
base= Xx ~ Nn .N
+ L~ N + N
R
R)C~' I 1 OR4
R1CH2SiMe33 ++ BuLi SuLi R1CH2SiMe
R2CN R2CN
R h RI'"
R3CN R3CN
R2
NH 2
~2
I
1l
N
.
(R 4O)4C (R40)4C
R3
RI~N
R2
N
53 R3
thieno[2,3-e] [1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones The preparation of 2-substituted thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones isomerization of the corresponding [4,3-c] isomers was reported <05H(65)2683>, and was by isomerization pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, pyrido[3",2":4',5']thieno[3',2':4,5]pyrimidopyrido[3",2":4',5']thieno[3',2':4,5]pyrimidothat of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, [1,6-a]benzimidazoles, polyheterocyc1es <05JHC1069>. 2,32,3[1,6-a]benzimidazoles, and related fused polyheterocycles 54a-c were generated by a sterically stericaUy induced Dihydroimidazo[I,2-a]pyrimidin-5(lH)-ones 54a-e Dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones 1,2-a]pyrimidin- 5(3H)-ones multihetero-retro-ene fragmentation of the 8-alkoxyimidazo[ multihetero-retro-ene 8-alkoxyimidazo[1,2-a]pyrimidin-5(3H)-ones 55a-c initially formed by reacting 2-alkoxyiminoimidazolidines 2-alkoxyiminoimidazolidines and acetylenedicarboxylates 55a-e acetylenedicarboxylates <05T5303>. <05T5303>. 3-Formyl- and 3-cyano coumarin N-functionalized amidines amidines were used as starting materials for the preparation of[1 of [1]benzopyrano[4,3-bj-[4,3-d]pyrimidin-5-ones ]benzopyrano[4,3-b]- and and-[4,3-d]pyrimidin-5-ones <05T4957>, and 6-hydroxy-4H-4-oxo[lj-benzopyran-3-carboxaldehyde like 56 <05T4957>, 6-hydroxy-4H-4-oxo[1]-benzopyran-3-carboxaldehyde was shown to be a versatile starting starting material for the preparation of pyrimidines like 58a,b when condensed with barbituric or thiobarbituric acid (57a or 57b, respectively) <05HAC20>. H H N [~NN~=N'OCH2R' R2 =~ N NCO2R3 /~~-R .- 3 O H
C>=N
R2 or or
~NN~~_R2OCH2R,
N~R2
°O
O
54a-c, 54a-r R R1 1 = = H; R22 = = Me, Me, Ph, Ph, C0 CO2R 2R
55a, R 1 =
o CH3CO2- NH4+
N ~N
H;
r R 1 = H, R2 = Me
o R1
R 2 =
b, R1 = Ph, R2 = H;
PhMe, A PhMe,L'.
N
O
=- R1
0~~
56
o
o )NH
O~N~X o x H H
57a,b, X = = O,S O,S 57a,b,
o
o
° ° [ I x ° ° NAX H
H O W X " , , : NH [
~
H
58a,b, X =a,s = O,S 58a,b,
A tandem aza-Wittiglheterocumulene-mediated aza-Wittig/heterocumulene-mediated annulation route was developed for the ,2,4-triazolo[11,5-a]pyrimidin,5-ajpyrimidinefficient production of 6,7,8,9-tetrahydro-benzothieno[2,3-d]-1 6,7,8,9-tetrahydro-benzothieno[2,3-d]- 1,2,4-triazolo[ 10(3H)-ones <05S160l>, <05S1601>, and an amine amine oxide rearrangement was key to the regioselective IO(3H)-ones preparation of pyrrolo[2,3-d]pyrimidines <05S1164>. <05S1164>. Hexahydro-2-phenacylideneHexahydro-2-phenacylidenepyrimidines gave -lactam fused fused 8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[l,2-ajpy8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[1,2-a]pyrimidine-6-ones when treated with (COC!), (COC1)2 in the presence of NaH Nail <05IJH87>, <05IJH87>, and methyl
364
Groziak M.P. Groziak
N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates underwent base-catalyzed ring closure and rearrangement to 6-substituted 4-methylamino-5-nitrosopyrimidines 4-methylamino-5-nitrosopyrimidines or 9<05TL1841>. Pyrrolo[2,3-djpyrimidine-2,4-diones Pyrrolo[2,3-d]pyrimidine-2,4-diones were prepared from methylpurin-8-ones <05TLl84l>. N-(5-vinyluracil-6-yl)sulfilimines by sunlight-mediated photolysis <05TL555l>, <05TL5551>, and thieno[2,3-d]pyrimidine-6-carboxaldehydes were prepared for the first time by oxidation of thieno[2,3-djpyrimidine-6-carboxaldehydes thieno[2,3-d]pyrimidin-6-ylmethanols with 112 <05CHE800>. thieno[2,3-djpyrimidin-6-ylmethanols <05CHE800>. 2 A general approach to 1,6-dihydro-7H-pyrazolo[4,3-djpyrimidin-7-ones 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-ones from 4-amino-l4-amino-1<05JHC751>, a reaction of alkyl-3-propylpyrazole-5-carboxamides was developed <05JHC75l>, carbodiimides and secondary amines or alcohols was found to give 5-dialkylamino or 5H-l ,2,3-triazolo[4,5-djpyrimidin-7-ones <05S2544>, the new ring systems alkoxy 77H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones ,2-a]pyrimidinone, and indeno[ 1,2-e]indeno[ 1,2-djpyrimidinone, 1,2-e]pyrrolo[ 11,2-a]pyrimidinone, 1,2-d]pyrimidinone, indeno[ indeno[1,2-e]pyrrolo[ indeno[1,2-e]pyrimido[1,2-a]isoindole pyrimido[1,2-a]isoindole were accessed via ring expansion of azetidinone and ring closure of <05ARK416>, and substituted pyrazolo[4,3-djpyrimidin-7pyrazolo[4,3-d]pyrimidin-7amino esters and 1,3-diamines <05ARK416>, <05JHC1085>. Enaminones ones were prepared from pyrazole-5-carboxylic acid precursors <05JHC1085>. were used to access pyrazolo[I,5-a]pyrimidines pyrazolo[1,5-a]pyrimidines <05JHC307>, <05JHC307>, sulfone-containing sulfone-containing ,5-a]pyrimidines were obtained <05JHC609>, and tetrahydropyrazolo[ pyrazolo [11,5-a]pyrimidines <05 JHC609>, 2(1H)quinazolinones and cyclopenta[dj-2(lH)pyrimidinones cyclopenta[d]-2(1H)pyrimidinones were prepared from 2(lH)quinazolinones alkoxyvinyl trifluoromethyl ketones <05SC3055>. <05SC3055>. Triazolino[4,3-a]pyrimidines Triazolino[4,3-a]pyrimidines were among <05PS149>, and new the various heterocycles prepared using hydrazonoyl halides <05PSI49>, naphtho[2,1-b]furo[3,2-djpyrimidines naphtho[2,1-b]furo[3,2-d]pyrimidines were prepared and examined for biological activity <05IJH 189>. <05IJHI89>. As for biologically-related pyrimidines, a chemoenzymatic asymmetric total synthesis of the polycyclic pyrazolo[3,4-djpyrimidine pyrazolo[3,4-d]pyrimidine analogs S9 59 of a phosphodiesterase phosphodiesterase (PDE) inhibitor was reported <05JOC2824>, <05JOC2824>, and the conversion of 2-amino-4,6-dichloro-52-amino-4,6-dichloro-5pyrimidinecarboxaldehyde pyrimidinecarboxaldehyde to methyl 2-amino-4-(methoxy)thieno[2,3-djpyrimidine-62-amino-4-(methoxy)thieno[2,3-d]pyrimidine-6carboxylate for obtaining antifolates was optimized <05JHC1305>. <05JHC1305>. Heptadienes containing containing building blocks for carbocyclic pyrimidine nucleic acid bases were prepared as building oligonucleotide <05SC1003>, l',3'-anhydro- -D-psicooligonucleotide analog synthesis <05SC 1003>, pyrimidine-based pyrimidine-based 1',3'-anhydroand -sorbo-furanosyl nucleosides nucleosides were obtained from 02,3'-anhydroO2,3'-anhydro- -D-fructofuranosyl<05SLl683>, and the total synthesis of of N-malayamycin A and related pyrimidine uracil <05SL1683>, 60a-c achieved <05JOC672l>.The preparation of 1,3nucleosides nucleosides 60a-c was <05JOC6721 >.The preparation dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium dimethylcyclohepta[4,5]pyrrolo[2,3-djpyrimidine-2,4( 1,3H)-dionylium ions like 62, models <05JOC9780>. The dionylium ion 62 can be reduced NAD+/NADH, were reported <05JOC9780>. reduced with for NADTNADH, NaBH 44 to give an NADH-like H- delivery agent (61) effective at reducing ketones to r2 ~ alcohols. o
Ph'N'~ ;
:
H2N"~NH I-I- O Bn
59 59 (and (and enantiomer) enantiomer)
/"~~
R~ ~...O/~ ;OH O R22 == Me; 60a, RR11 == OOMe, Me, R b, R1 R1 = = F, F, RR2 == H; H; b, rC, R 11 ==OMe, R22 == H
O
365
Six-membered ring systems: diazines and benzo derivatives (2005)
Ph Ph
H HH H
oO I I )l
Ph Ph
Me, N N.A ~ A .1(1 Me N M e / 1,Me N
o~ ~ I _ \ Me Me'
'00
61 61
/
R11"p4''R R R22
to
,
Me "Me
~
OH
R1'''k" R2 Ph . MeikI ~
Ph ~
Me
N
Y 0 O/
NaBH4
M~
'(3
62
O'
"Me
6.2.4.2 Reactions reactivity of Cyclization reactions of pyrimidines were studied, for instance, the reactIvIty tetrahydropyrido[ 4,3-b ]pyrimidines with DMAD leading to dihydropyrimidinylethylamines tetrahydropyrido[4,3-b]pyrimidines <05TL1975> and pyrimido[4,5-d]pyrimidines obtained efficiently by hetero Diels-Alder <05TLl975> cycloaddition of methyl 6-methyl-4-phenyl-2-thioxo-1 ,2,3,4-tetrahydropyrimidine-56-methyl-4-phenyl-2-thioxo-l,2,3,4-tetrahydropyrimidine-5carboxylate (64), a Biginelli compound, with N-arylidine-N'-methylformamidines to form 63 and N-arylidine guanidines to form 65. The mechanism of this cycloaddition was probed using semiempirical MO methods <05T4237>. Acetylenic pyrimidines underwent microwave-assisted intramolecular hetero-Diels Alder reactions to form fused bicyclic pyridines <05TL3423>.
HN~-N/EAr S~N.H PhH S~N.-'Ph Ir'Ar S.~NH p hH H . H r ' ' ~ ' '~CO2Me .,Me"N~/'N HN'~~CO2Me H2N ni,i~r./-.~r~A ,. rl,,l~l//....h ~ u ~ ,~CO2Me , Me"l I Me'll Ar Me..N,,,~ N
Me
63
HNyN
64
65
NH2 Nucleophilic addition/substitution addition/substitution reactions of pyrimidines were investigated as well. The selectivity of nucleophilic substitution in 2,4-disulfanyl-substituted 2,4-disulfanyl-substituted thieno[2,3-d]pyrimidin-6thieno[2,3-d]pyrimidin-6carboxylic acids was studied <05JHC84l>, <05JHC841>, as was the SN(ANRORC) S,(ANRORC) reactivity of substituted 5-ethoxycarbonylpyrimidines <05JHC557>. Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with nucleophiles by SNAr S,Ar and Suzuki and Stille cross-couplings was achieved <05TL585l>. <05TL5851>. The regioselectivity of conjugate additions to 3-(pyridin-3-yl or pyrimidin-2-yl)-propenoates and their N-oxides (66) to give 67a,b was studied by a <05EJO3297>, and 4-azido-2combination of theoretical and experimental methods <05EJ03297>, pyrimidinone nucleosides 68 were shown to react with nucleophiles at the modified base's C2 report. position, giving tetrazole nucleosides 69 <05JOCI96l>, <05JOC 1961>, contrary to a previous report.
CO2Et (O,),,,N,~ ~L~J 66 66
CO2Et PESH ? ; ' ~ N R2 NaOet~ (O EtOH ~L,,~IJ 67a, 67a, R R 11 = = H, H, R R 22 = = SPr SPr b, R 11 = SPr, SPr, R22 = H
N--N Jl ,, /~N'~:
N.. .N~N N N" "NI
x'~-~a )-NH NuH NuH
-=
~ (
Nu Nu N~O N%
AcO ACO~
AcO AcO" 68
AcO" Aco"
69 69
366
M.P. Groziak M.P. Groziak
Rearrangements of pyrimidine compounds were also reported. 9H-Cycloalka[I,2-e]9H-Cycloalka[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones were found to undergo intramolecular rearrangement in oxazolo[3,2-a]pyrimidin-7- and -5-ones (70 and 71, refluxing xylene to give cycloalkyl-fused oxazolo[3,2-a]pyrimidin-7respectively) <05T4453>. A regioselective thio-Claisen rearrangement starting from 5-prop<05T10774>, and 2-ynyl/enyl-sulfanyl pyrimidinones generated thienopyrimidinones 72a,b <05Tl0774>, O
Q o
RCH2__~Oi ~
:2 "~RCH,-{_\ 0 RCH,-{_<:Q
C02 Et
+ [~n/CO2Et .~ RCH2 NH2 n = 1,0
~
R2
)n
70
N
iv} n
r~
NJ.--W~~ ~S'Y"'JN" R N N 1.-. R11 R1 pTsCI, Et3N, ~ ~-.....~. NII . , ~ '0 N ~ anhyd. CH2CI2 " ~ "O 73a,b, R R = = H, H, Me Me SR 73a,b, r.t. SR33 72a-b, R3 3 = CH CH2C=CH, CH2CH=CH 2 2C",CH, CH 2CH=CH 2
d
N"J~'N .,Jl Me2N
O 0 n ++ RCH2__~oSL~, ~ N 71 71
N "::
l'
an acid-catalyzed O-N-type Smiles rearrangement reaction was noted in 2-pyrimidinyloxy-N<05SL1239>. Ru(II) complexes arylbenzylamines, giving the corresponding phenols <05SLl239>. containing hemilabile 2-(pyridin-2-ylmethylthio)pyrimidine ligands 73a,b were shown to interconvert between N,S- and N-coordinated species <05EJI2423>. In the first example of catalytic C-C coupling involving activation of a C-F bond in the presence of a C-CI C-C1 one, 5-chloro-2,4,6-trifluoropyrimidine (74) reacted with arylboronic acids in the presence of a Ni(II) catalyst to generate 5-chloro-2-fluoro-4,6-diarylpyrimidines 75 <050M4057>. <05OM4057>. A theoretical and experimental investigation of the structure and reactivity of 4-(4-chlorophenyl)pyrimidinium ylides was undertaken <05ARK7>, and the structure, stability, and reactivity of 4-methyl- and 4-(halophenyl)pyrimidinium (4halobenzoyl)methylides (76a-d and 76e-h, respectively) were examined by theoretical and experimental methods <05HCA2747>. The Biginelli 3,4-dihydropyrimidin-2(1H)-one 77 was converted in two steps to a variety of multifunctionalized pyrimidines with general structure 78 <05JOCI957>. <05JOC1957>. In a more biological light, N,N'-bis(3-aminopropyl)-2,7-diamino1,S-naphthyridine 1,8-naphthyridine was found to stabilize a single pyrimidine bulge in dsDNA <05BMC4507>. Finally, separate enantioselective microbial reductions of 6-oxo-S-[4-[4-(26-oxo-8-[4-[4-(2pyrimidinyl)-1-piperazinyl]butyl]-S-azaspiro[4.5]decane-7,9-dione pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 79 generating either of the 2° 2 ~ alcohol epimers (80a,b) was reported <05TA277S>. <05TA2778>.
F N F F. N 10% 10%
F
1'+ II
~'t~
"~CCI V I
F
Ph3P-Ni-PPh3 Ph3P-~i-PPh3
N'~N F
~R
itr
.~
F~ F
F CI 74
THF, THF,CS Cs2CO 3 2C03 PPh 3, PhS(OH)2 PPh3'PhB(OH)2
N Ph
d I"::
N
X Ph
CI 75
NVN
0
~
76a-d, R R = = Me, Me, X = F, CI, CI, Sr, Br, I 76a-d, X= e-h, e-h, R R == 4-CIC 4-CIC6H4, = F, F, CI, CI, Sr, Br, II 6 H4 , X =
367
Six-membered ring ring systems: diazines and benzo derivatives (2005) Six-membered
Ph
Ph
HN.fi...~/CO2Me 2. I.[0] Null,base ,.
0"~ N M%e77H
N~CO2M
~:RIHi ~:R ~N 0 R [H] 0
e
,'~N)3 {-PBr -PF6Nu"~"N %Me78
O
0 ° ° 79, 6-keto Buspirone
°
HO 80a,b
79, 6-keto Buspirone
R =4-(pyrimidin-2-yl)piperazin-1-yi 4-(pyrimidin-2-yl)piperazin-l-yl
R
6.2.4.3 Applications
Some interesting non-medical applications were found for pyrimidines. The combination of Pd(OAc), Pd(OAc) 2 and 2-aminopyrimidine-4,6-diol 81 was discovered to form a stable, efficient catalytic system for the Suzuki-Miyaura cross coupling of arylboronic acids and aryl halides <05SLl897>, <05SL1897>, and it rendered the Sonogashira cross-coupling of aryl halides with terminal alkynes efficient and copper-free <05EJ04256>. <05EJO4256>. New rhodium 1,3-dialkyl-3,4,5,6tetrahydro-2-pyrimidinylidene complexes 82 prepared as aromatic aldehyde arylation catalysts were characterized by multinuclear NMR <05JOM5849>. Supramolecular systems were constructed from complexes of 2,6-disubstituted 1-oxa-4-thia-3,5-diazine l-oxa-4-thia-3,5-diazine 4,4-dioxides with symmetric triazines <05RJ0289>. <05RJO289>. 6-Substituted 2,4-bis(acrylamido)pyrimidines 83 were used as the key pieces in the construction of optically responsive imide receptors 4-amino-l-methyl-5-nitroso-6-oxo-l ,6-dihydropyrimidin-2-yl)-N'<05JOC2729>, and N-( N-(4-amino-l-methyl-5-nitroso-6-oxo-l,6-dihydropyrimidin-2-yl)-N'[bis(2-aminoethyl)]ethylenediamine [bis(2-aminoethyl)]ethylenediamine 84 was synthesized and characterized by multinuclear NMR methods. It's use as an ion receptor was investigated by assessing it's ability to adsorb Zn(H) Zn(II) and Cd(H) Cd(II) out of aqueous solution when anchored to activated carbon <05EJI3093>. 1-dimensional coordination polymers [M(N0 [M(NO3)2(pyrimidine)(H:O)2]= = Mn, Co, ),(pyrimidine)(H,O),]= (M = A set of I-dimensional 3 Ni, or Zn) like 85 was prepared and their phase purity was determined <05EJIl572>. <05EJI1572>. The pressure-sensitive magnetism of guest-tunable weak ferromagnets of the type [Fe{N(CN),},(pyrimidine)](guest) [Fe{N(CN)2}2(pyrimidine)](guest) (guest = - EtOH or pyrimidine) was studied <05CL974>. Metal complexes with the new ditopic ligand 4-[6-(2-pyridyl)-2-pyridyl]-6-(2pyridyl)pyrimidine 86 were shown to self-assemble into 2x2 grid complexes which had - ions. These complexes were characterized by X-ray <05EJI894>. encapsulated NO 3J
RI~~/I
(Br)
+
R2~
HO cat. /~--N~__NH2 ~N
HO
,R R' k//~N ~ N ~ /
81
k~N _
cat. Pd(OAc)2
~'k~---f/ - -
o
n2
N- - /
'R' R'
82
CsCO 3, CH3CN
Me'N@N'O HN'~N | I~NH2 ~I 84
N03- PH 2 ~ \:2+ 2[=\, /~ ~ \.-" N N N-Mn N--Mn 2+-N -N x /.NN U '==J /~/ \ \ 'L3 H20 -OaN H -03N 20
85
[~
~ ~=N Y--N ,---4 f/ ~,k~-/x--~N ~-'~1_.#'
/ o
83 o
,..~ N.-~ N//L..N.~./ ~, '," 7 r H ! H O%/N...~.O
~ ~t--%./N.Bn
86
I
N(CH2CH2NH2)2
As for nucleic acid applications, the syntheses and fluorescent properties of the DNA nucleobase replacements like the 1,2,3-triazolo[4,5-d]pyrimidine 2'-deoxyribofuranosides 87
368
M.P. Groziak M.P.
were reported . <05HCA751>. A 4-(2'-pyridyl)-pyrimidinone deoxyriboside was prepared and was shown to form a self-pair in the presence of Ni(II), stabilizing dsDNA as in 88 . <05CC1342>. Chiral 2-(aminoalkoxy)-substituted 4-(2-thienyl)pyrimidines and 4,6-bis(2thienyl)pyrimidines were prepared as dsDNA intercalators. Their binding constants showed up to a 2.4: 2.4:11 discrimination of the (S)-enantiomers over the (R)-counterparts <05BMCL2720>. Finally, DNA-intercalating annelated pyrrolo-pyrimidines were prepared . from substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles . <05BMC1545>.
oO
g::.."',.Ni2.~
H~~~'N ~.. JL~ HN
N
~N.
:Ni:+
H:~ HO-
87 87
.~J: I
l:Xo0
"~,v
~II
OH OH
0
88 88
oNVV
I
. gN"N .-..
~I[
oNVV
1- and 2-Alkyl-4-aminopyrazolo[3,4-d]pyrimidines were developed as adenosine deaminase inhibitors , I ,S-c]pyrimidin<05JMC5162>, 2-(2-furanyl)-7-phenyl[ 1,2,4]triazolo[ 1,5-c]pyrimidin, antagonists , 05BMCL3675>, 2 pyrazolo[ 4,3-e] 1,2,4-triazolo[ 1,S-c]pyrimidines were prepared as human A 33 adenosine pyrazolo[4,3-e]l,2,4-triazolo[1,5-c]pyrimidines <05JMC152>, 5-phenyl-7-(5-deoxy- -Dand 4-substituted S-phenyl-7-(S-deoxyreceptor antagonists , ribofuranosyl)pyrrolo[2,3-d]pyrimidines (diaryltubercidins) , <05JMC7808>, 6,7-disubstituted ribofuranosyl)pyrrolo[2,3-d]pyrimidines 4-aminopyrido[2,3-d]pyrimidines , <05BMCL2803>, and S-(3-bromophenyl)-7-(6-morpholin5-(3-bromophenyl)-7-(6-morpholin4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine <05BMC3705> were prepared as inhibitors of adenosine kinase. Pyrimidine-based compounds compounds continue to be of interest as antimalarial agents. Among the <05BMC4645> ones synthesized for this bioactivity were 2,4,6-trisubstituted pyrimidines and 4-pyrido-6-aryl-2-substituted aminopyrimidines . <05BMC6226>. Libraries of 2,4,6trisubstituted pyrimidines were prepared and screened for antimalarial activity 05BMCL3130> and also for topoisomerase II activity , <05BMCL47>, while other libraries of 6-aryl-2-substituted pyrimidin-4-ylphenols <05BMCL4923> and trisubstituted pyrimidines <05BMCL5218> were prepared and screened for antimalarial and 5-Substituted pyrimidine nucleosides were examined as antiantitubercular activities. S-Substituted mycobacterial agents , 05BMC6663>, spiro-pyrazolo-3,3'-thiopyrano[2,3-b]spiro-pyrazolo-3,3'-thiopyrano[2,3-b]pyridines were prepared as antifungal and antibacterial agents , <05JHC221>, a set of pyrimidine-based antifungal agents was synthesized , <05AAC2226>, and some unusual [1,2,4]triazolo[I,S-a]pyrimidine-based [1,2,4]triazolo[1,5-a]pyrimidine-based triorganotin(IV) complexes 89 were prepared and characterized by IR and Mossbauer spectroscopy and quantum chemical calculations . <05JOM4773>. These had good antifungal and antibiofilm activities. Bu I/
Bu \
-O-Sn-O~O-Sn-o -- O- S n - ~ , - - O . \ / , ~ ~O--Sn-~--O
I' Bu Bu
1 ~I
HN
1\
Bu N Bu Bu 'N N-.'l' 89
'II
N- and O-Substituted terpenyl pyrimidines <05EJM552> as well as dihydropyrido[2,3-d]pyrimidines <05BMC6678> were prepared as antileishmanial agents. S-Alkynyl5-Alkynyl- and 6<05BMC1239>, alkyl-furo[2,3-d]pyrimidine acyclic nucleosides , acyclic furo- and
369
Six-membered ring ring systems: diazines diazines and benzo derivatives (2005)
pyrrolo[2,3-d]pyrimidine nucleosides <05JMC4690>, and bicyclic furano pyrimidine nucleosides were synthesized as antiviral agents <05AAC1081>. Other bioactivities sought were pyrimidine-5-carboxamides as tyrosine kinase inhibiting anti-allergic agents <05BMC4936>, <05BMC4936>, mono, bi and tricyclic pyrimidines as analgesics and anti-inflammatory agents <05BMC6l58>, <05BMC6158>, and 2,4,6-trisubstituted pyrimidines as pregnancy interceptive agents <05BMC1893>. Substituted pyrimidines containing a thiazolidinedione moiety were investigated as hypoglycemic and hypolipidemic agents <05EJM862>. Pyrimidine heterocycles were examined as receptor site agonists or antagonists. Among 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl these were 2-phenylpyrazolo[ 1,5-a jpyrimidin-3-yl acetamides for the benzodiazepine receptor <05BMC4821>, <05BMC4821>, 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-diones for the a,-adrenoceptor oq-adrenoceptor <05JMC2420>, bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7thiazolino[3,2-c]pyrimidine-5,7diones, prepared by treating 2-methyloxazolines or -thiazolines with chlorocarbonyl or-thiazolines isocyanate, for the hGnRH receptor <05BMCLl407>, <05BMCL1407>, piperidinyl- and 1,2,3,65-HT,a receptor <05BMCL2990>, and tetrahydropyridinyl-pyrimidines selective for the 5-HT,u substituted 3H-pyrimidin-4-ones for the calcium receptor <05BMCL2537>. Pyrimidines were also prepared as enzyme inhibitors. Many of these were kinase inhibitors, including 2anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones pyrido[l1',2': ',2': 1,5]anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones <05BMCLl931> <05BMCL 1931> and pyrido[ pyrazolo[3,4-d]pyrimidines <05BMCL3778> <05BMCL3778> as kinase inhibitors, 4-aminofuro[2,3-d]pyrimidines as tyrosine kinase inhibitors <05BMCL2203>, <05BMCL2203>, pyrazolo[ pyrazolo[1,5-a]pyrimidines 1,5-a jpyrimidines as inhibitors of human cyclin-dependent kinase 2 (CDK2) <05BMCL863>, pyrido[2,3-d]pyrimidin-7-ones as inhibitors of cyclin-dependent kinase 4 (CDK4) <05JMC2371>, and substituted aminobenzimidazole pyrimidines as inhibitors of cyclin-dependent kinase <05BMCLl973>. {4-[2-(3-chlorophenylamino)pyrimidin-4-ylj<05BMCL1973>. A short synthesis of 33-{4-[2-(3-chlorophenylamino)pyrimidin-4-yl]pyridin-2-ylamino}propanol, pyridin-2-ylamino }propanol, a protein kinase C inhibitor, relied on the Negishi crosscoupling reaction of a pyridine zincate and 2,4-dichloropyrimidine (90) to generate the key intermediate 91 <05JOC52l5>. <05JOC5215>.
N;:>-znl +N~CI J-N Znl
F F
+ N
CI
CI
90 90
N~
Pd[PPh3]4, N Pd[PPh 3]4, THF, reflux, reflux 4 h F F ' 90%
,,,
91
N
Cl
CI
2-Amino-3-nitropyrazolo[l,5-ajpyrimidines 2-Amino-3-nitropyrazolo[1,5-a]pyrimidines were prepared as inhibitors of coxsackievirus B33 replication <05BMCL37>, fused pyrimidines as PDE 77 inhibitors <05BMCLl829>, <05BMCL1829>, and pyrimidinetriones as inhibitors of MMPs <05BMCLl807>. <05BMCL1807>. Methylated 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one nucleoside analogs 92 incorporated into triplex-forming oligonucleotides were shown to selectively bind CG inversions <05CC2555>, and pyrimidine-linked biphenyl anionic RSV fusion inhibitors were found to be less active than <05BMCL427>. their corresponding triazine-linked counterparts <05BMCL427>. R
eo/~--"H
H
370
M.P. Groziak M.P.
anticancer field, 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones In the anticancer <05BMCL4731> and 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones 6-[I-(2,6-difluorophenyl)ethyl]pyrimidinones <05JMC6776> <05JMC6776> were <05BMCL4731> prepared as cytotoxic/antitumor agents, pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides prepared <05BMCLl591> and thieno[2,3-d]pyrimidin-4(1H)-ones thieno[2,3-d]pyrimidin-4(lH)-ones <05BMCL3763> <05BMCL3763> were prepared prepared as <05BMCL1591> tumor cell antiproliferative agents, and 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines <05BMC5475>, trimethylene-bridged 2,4-diaminopyrrolo[2,3-d]pyrimidines <05JHC1127>, <05JHCI127>, 2,4-diamino-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidines <05JHC589>, and pyrrolo[2,3-d]pyrimidines <05JMC7215> were prepared as dihydrofolate reductase (DHFR) inhibitors. 5-Substituted furo[2,3-d]pyrimidines and 6-substituted pyrrolo[2,3-d]pyrimidines <05JMC5329>, 2-amino-4-oxo-5-arylthio-substituted pyrrolo[2,3-d]pyrimidines <05BMCL2225>, and 2-amino-4-oxo-5-substituted benzylthiopyrrolo[2,3-d]pyrimidines <05JHC165> ofthymidylate <05JHC 165> were all synthesized as antifolate inhibitors of thymidylate synthase.
6.2.5 PYRAZINES PYRAZINES AND AND BENZO BENZO DERIVATIVES DERIVATIVES 6.2.5
Our understanding of the physicochemical properties of pyrazines has deepened. The internal rotation and IR spectrum of 2,5-pyrazinedicarboxamide were studied by quantum chemical calculations <05TC73>, and ab initio MO calculations at the MP2/6-31++G(**) MP2/6-31++G(**) level were used to explain the electronic and vibrational properties of complexes of pyrazine and HX linear acids <05JMS2822>. MM and MO calculations were used to investigate the conformational and electronic properties of odor-active pyrazines <05JMS 169>, and NMR, pyrido[1,2-a]pyrazinium IR, X-ray, and DFT methods were used to examine the structures of pyrido[ 1,2-a]pyrazinium bromide <05JMS7>. The amino-imino tautomerism in 2,3-disubstituted pyrazines in both solution and the solid state was investigated by NMR and X-ray methods <05JMS67>. Metal complexes containing a pyrazinecarboxamide ligand were investigated by a variety of spectroscopies <05JCC1241>. Pyrazine-based heterocycles examined by X-ray crystallography included 5, 1O-dihydroxy-5H, lOH-diimidazo[1,2-a: 5,10-dihydroxy-5H, 10H-diimidazo[ 1,2-a: I',2'-d]pyrazine l',2'-d]pyrazine 93 <05AX(C)o361> <05AX(C)o361 > and 7-ethyl-2methy1-4-phenylhexahydropyrazino[ I ,2-a]pyrazin-3-one <05TL51>. Those within an methyl-4-phenylhexahydropyrazino[1,2-a]pyrazin-3-one Ca(II) complex with pyrazine-2,3-dicarboxylate ligands organometallic complex included a Ca(H) <05JCC891>, a Ag(I) complex containing the trans-2-(2-phenylethenyl)pyrazine trans-2-(2-phenylethenyl)pyrazine ligand catena-bis( -pyrazine-2,3-dicarboxylato-N, 0, 0 )zinc(II) <05JCC931 >, <05JMS37>, O,O)zinc(II) <05JCC931>, diaqua(pyrazine-2,3-dicarboxylato-N, 0:0',0 ')calcium(II) <05JCC963>, and 0:0', O')calcium(II) Ni(II) complexes containing pyrazine-2-carboxylate ligands <05JCCI429>. <05JCC1429>. In addition, X-ray crystallography was used to examine the one-dimensional coordination polymer 94 of Cu(II) with 2-pyrazinecarboxylate <05AX(E)m499>, osmium clusters like 95 containing 2,3-bis(2pyridyl)pyrazine as a chelating ligand <05JOM622>, and pyrazine-bridged benzyl dicobaloximes 96a,b, which were also characterized by cyclic voitammetry voltammetry <05JOM3746>.
371
Six-membered ring ring systems: diazines and benzo derivatives (2005)
CH2Ar OH .... O ~
a '1'\;
~ , N
I/OH2 ---N
9
OH
-
"=N
N-Cu
Z r-j OC -;.
93 _
94
b
_ n
N
R
N
./
~ .'" OC-Os-OS(CO)4 OC-Os--Os(CO)4.../
O/No
o ~ 11[,.
N~ c
O--~- HO
~1 k~ ~-/; (~'\;
OH ,,~-...N .--'~'~.~N <~N~.~.. NI~
~N R
OH .... O
R~_~ I ~ ~ / R
~l~ c~ ~
OC "~/s Os
95 (CO)4 (CO)4
R
NI /
O--
~N I
,-,
n
- HO
CH2Ar
96a,b, R = Me, Ph
6.2.5.1 Syntheses
A modified Ugi four-component condensation route was used to prepare substituted 4<05JCO806>. Microwaveoxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxamides <05JCOS06>. 2(1H)-pyrazinones via "click assisted reactions enhanced the synthesis of substituted 2(lH)-pyrazinones chemistry" <05JC0490>, <05JCO490>, and 6,S-diarylimidazo[1,2-a]pyrazines 6,8-diarylimidazo[1,2-a]pyrazines were prepared from 1-(2aryl-2-oxoethyl)-2-aryloylimidazoles using NH4OAc/AcOH NH40Ac/AcOH under microwave conditions <05JHC3l9>. <05JHC319>. A regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines 98 from 2,3-dichloropyrido[2,3-b]pyrazine (97) was reported <05JOC2878>, and a solid-phase synthesis of substituted 2(lH)-pyrazinones 2(1H)-pyrazinones was developed <05JOC2S7S>, for future generation of libraries of these heterocycles <05JC090>. <05JCO90>. Furoxano[3,4-b]pyrazines were prepared by treating 2-alkoxy-3,5-dinitro-6-chloropyrazines with NaN 3J <05JHC691>. Polyfunctional tetrahydropyrido[3,4-b]pyrazines like 99 were prepared in a CsFsN and diamines <05JOCnOS>, <05JOC7208>, while the sequential reaction of one-pot reaction using CsFsN CsFsN CsFsN with sodium phenylsulfinate and a diamine generated polyfunctional tetrahydropyrido[2,3-b]pyrazines like 100 <05JOC9377>. O Me'Nl
r(YNyCI
t.AA N N CI
A
F N.Me FnN'Me
97 97
'-R
MeO MeO"
NN 99 99
N)
NEt2 NEt2 100
Pyrazino[1,2-a]indoles 101 and 102 were prepared by intramolecular cyclization of 2acyl-l-propargylindoles and NH J3 <05JOC40SS>. <05JOC4088>. Pyrrolo[1,2-a]pyrazin-l-ones 103 were obtained from 2-acylpyrroles <05T1077>. Pyrazines doubly activated with MeO,CCI MeO2CC1 in the presence of bis(TMS)ketene acetals generated polycyclic -lactone products <05TL3449>. SeO 2 to give 2,5-dimethylpyrazine-3,6-dicarboxaldehyde, Tetramethylpyrazine reacted with SeO, which in turn reacted with (iPr),NH (iPr)2NH to give 2,5-dimethyl-3,6-bis[(2,6-diisopropylphenyl<05ZN(B)22>. imino)methyl]pyrazine, a chelating ligand for transition metal complexes <05ZN(B)22>_
372
M.P. Groziak M.P. Groziak
Finally, trialkyl-substituted pyrazines 104 were prepared in a regiocontrolled manner from <05OL5529>. nitroketones by reaction with -amino ketones .
~R
~ N N : :,. . I
V--NI\'o
~R'
Q-rO H
f--./
N
"R 'R
/"
Pd(OAc): Pd(OAc)2 NaOAc NaOAc BU4NCI .u4.c,
DMSO DMSO
R1 ~-./N" R /
0 +
R
102
NO2
R2" '-0
\
"----iCHR' CHR'
CH2R'
101
~
H
103
R3 octylviologen I-
Na2S406 K2003
-~
R)[N R 1
R22
r
3
N N
104
6.2.5.2 Reactions Palladium-catalyzed reactions on pyrazines were the subject of quite a few investigations. 3,S-Dichloropyrazinones 3,5-Dichloropyrazinones 105 were shown to undergo regioselective Suzuki and Heck reactions to give 3-substituted 3-substituted products, while the less reactive S-position 5-position could be corresponding S-bromo 5-bromo or -iodo derivatives functionalized only after transhalogenation to the corresponding . <05T3953>. The Suzuki, Sonogashira, Heck, and Buchwald-Hartwig reactions were explored using 7-bromo-2,3-diphenylpyrido[2,3-bJpyrazine 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine as the key starting material . <05S1345>. bi-2(lH)-pyrazinones were obtained by homocoupling homocoupling in a Functionalized, symmetric bi-2(1H)-pyrazinones Suzuki-type reaction involving an in situ generated boronic acid , <05SL777>, while highly substituted bipyrazines like 107 were obtained by a Suzuki cross-coupling approach from 2amino-5-bromopyridazine (106) . <05JOC388>. The Pd-catalyzed heteroannulation amino-S-bromopyridazine heteroannulation of N-(3chloropyrazin-2-yl)methanesulfonamide with alkynes was used to prepare 6,7-disubstituted5H-pyrrolo[2,3-b]pyrazines <05TL 1845>. SH-pyrrolo[2,3-b Jpyrazines . OMe (HO)2B - - ~ B ( O H ) 2
Bn (Ph) (Ph) ~n
N
OMe _N
I
R
N
0
c,1NXc, CI
N
1115 105
Cl
;
N ~
106
Br Pd[PPh3]4, Na2C03 THF, reflux, 24 h 56%
MeO 107
Olefinic pyrazines like 108 were shown to react with C C6H TfOH to give oH66 in the superacid UOH anti-Markovnikov addition products like 109 . <05OL2505>. The orientation observed is presumed to be due to the multiply charged heterocycle adjacent to the olefin. Pyrazine 0oquinodimethanes underwent Diels-Alder condensation with meso-tetraarylporphyrins meso-tetraarylporphyrins to give new 1t-extended n-extended porphyrins . <05TL2189>. A one-pot formation of polycyclic - and lactones like 111 was developed using the reaction of pyridine and pyrazine (110) with bis(trimethylsilyl)ketene acetals. Many of them were characterized by X-ray . <05EJO3724>.
373
diazines and benzo derivatives (2005) Six-membered ring systems: diazines
~N~
N
CF3SO3H= ~ N ~ P h
N
C6H6, 80 ~
N
96%
108
l)
MeO2C Me N L...Me 1" Me2C=C(OSiMe3),. 2 ~ " ~ O
~ iN~ 2. CICO2Me 110
109
"N/-O MeO2C 111
6.2.5.3 Applications Applications 6.2.5.3 The non-medicinal applications reported for pyrazine-based compounds were extremely diverse. By studying substituent effects, the rate-determining step for chemiluminescence in 6-arylimidazo[I,2-a]pyrazin-3(7H)-ones was indicated to be a single electron transfer from 6-arylimidazo[1,2-a]pyrazin-3(7H)-ones 0z2 <05TL7701>. Reaction of the diamide ligands N,N'-bis(2the anion to triplet O pyridylmethyl)pyrazine-2,5-dicarboxamide and N,N'-bis[2-(2-pyridyl)ethyl]pyrazine-2,5dicarboxamide 112 with Cu(BF4)2o4H20 Cu(BF4)204HP gave dinuclear Cu(II) complexes which were <05EJII530>. The Cu(II) Cu(H) complex [Cu characterized by EPR <05EJI1530>. characterized [Cu2(pyrazine-2,5z(pyrazine-2,5dicarboxylato)(l,1O-phenanthroline)4](N0 3) z~o lOHP 113 was examined by X-ray dicarboxylato)(1,10-phenanthroline)4](NO3)2 crystallography, and the magnetic exchange through the pyrazine bridge was studied <05EJI2586>. The colorimetric sensor properties of solvatochromic substituted 2UVNis and SM1phenylimidazo[I,2-a]pyrazin-3(7H)-ones phenylimidazo[1,2-a]pyrazin-3(7H)-ones 114a-e ll4a-e were examined by UV/Vis COSMO computations <05T10073>. <05Tl0073>. Pyrazine itself was found to bind to the cavities formed Mn(H), Fe(II), Fe(H), Ni(II), and Cu(H) in Mn(II), Cu(II) complexes bridged with squarate molecules, forming a supramolecular network. The X-ray crystal structure of a similar Zn(H) Zn(II) complex was determined <05BCJ445>. Two axially chiral quinazoline-equipped phosphinamine ligands, 115a and 2-(2-pyrazinyl)quinazolinap 115b, 2-(2-pyridyl)quinazolinap l15a l15b, were prepared, resolved, and their diastereomeric palladacycles were examined crystallographically ll6a-f were also prepared. A total of 27 volatile <05T9808>. Other related quinazolines like 116a-f pyrazines such as 117-120 were isolated and characterized from the myxobacterium Chondromyces Chondromyces crocatus crocatus and marine bacteria <05EJ04141>. <05EJO4141>.
~
\ ,,--" N
Me-N:'N~O
N n= 1 or2
N
[": .&
112
O N(~
R
R == NMe2' NMe2, 114a-e, R
OMe,H, H, CI, CI, CN CN OMe,
X y ~
~
NyC ] N /ON
I"
PPh 2
115a, 115a,XX==CH; CH;
b,X=N
N~. R NyR
y
[
~
~
~
"
N /ON PPh PPh22
116a-f, 116a-f, R R= = Ph, Ph, Me, Me, Pri Bu!, But, H, H, Bn Bn Pri,
>-{}-\ 117 117
MeO MeO
MeO
\
R-~ 119 119
(i~ 118 118
N N
Me Me
MeiNXSMe Me N SMe 120
374 374
M.P. Groziak Groziak M.P.
In medicinal medicinal applications, applications, [1,2,4jtriazolo[1,5-a]pyrazines [1,2,4]triazolo[1,5-a]pyrazines have have been been examined examined as as In adenosine receptor antagonists <05H(65)2321, 05BMCL4809>, pyrazolo[4,3-ejadenosine A A2,~ receptor antagonists <05H(65)2321, 05BMCL4809>, pyrazolo[4,3-e]2U pyrrolo[I,2-ajpyrazines pyrrolo[1,2-a]pyrazines were were prepared prepared from from l-phenyl-5-(pyrrol-1-yl)-lH-pyrazole-31-phenyl-5-(pyrrol-l-yl)-lH-pyrazole-3carboxylic acid acid azide azide as as antibacterials antibacterials and and antifungals antifungals <05M217>, <05M217>, and and pyrazinones pyrazinones were were carboxylic examined as as inhibitors inhibitors of of the the TFNIIa TF/VIIa complex complex <05BMCL3006> <05BMCL3006> and and as as non-nucleoside non-nucleoside examined reverse transcriptase inhibitors (NNRTIs) (NNRTIs) <05JMC191O>. <05JMC1910>. New thrombin inhibitors were built around around aa pyrazinone core <05EJM782>, pyrazinone monoamides were prepared as as ascaspase-3 ,2,4jtriazolo[4,3-a jpyrazines as ascaspase-3 inhibitors <05BMCLlI73>, <05BMCL1173>, and and 5,6-dihydro[1 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazines as dipeptidyl peptidase IV (DPP-IV) (DPP-IV) inhibitors <05JMCI41>. <05JMC141>. A QSAR study study on 1,2,3,41,2,3,4dipeptidyl tetrahydropyrrolo[ I ,2-a jpyrazine-4-spiro-3'-pyrrolidine-1 ,2',3,5'-tetrone as tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-l,2',3,5'-tetrone as aldose aldose reductase <05BMC1445>, the synthesis <05JMC1886> <05JMC1886> and SAR SAR inhibitors was conducted <05BMC1445>, <05JMC4892> <05JMC4892> of pyrazine-pyridine biheteroaryls as vascular endothelial growth factor (VEGF) receptor-2 inhibitors were reported, and the effect of L-pyrazinylalanine as a <05JMC4025>. Finally, the phenylalanine replacement in a somatostatin was explored <05JMC4025>. <05AAC804> and resistance <05AAC444, <05AAC444, 05AAC221O> 05AAC2210> of Mycobacterium Mycobacterium susceptibility <05AAC804> tuberculosis to pyrazinamide was further investigated. tuberculosis
6.2.6 REFERENCES REFERENCES 05AAC444 05AAC444 05AAC804
05AAC1081 05AACI081 05AAC2210 05AAC2210 05AAC2226 05AG(I)3889 05AG(I)6951 05AG(I)6951 05AP126
05ARK7 05ARK71 05ARK74 05ARK76 05ARK172 05ARKI72 05ARK416 05AX(C)o67 05AX(C)067 05AX(C)o158 05AX(C)0158 05AX(C)036I 05AX(C)o361 05AX(C)0452 05AX(C)o452
05AX(E)m499 05AX(E)m714
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05BMCLll73
05BMCL1407 05BMCLl407 05BMCL1591 05BMCLl591 05BMCL1807 05BMCLl807
05BMCL1829 05BMCLl829 05BMCL1881 05BMCLl881 05BMCL1931I 05BMCLl93 05BMCL1973 05BMCLl973
05BMCL2203 05BMCL2203 05BMCL2225 05BMCL2225 05BMCL2381 05BMCL238I 05BMCL2409
05BMCL2537 05BMCL2537 05BMCL2720 05BMCL2720 05BMCL2803 05BMCL2803
05BMCL2990 05BMCL2990 05BMCL3006 05BMCL3006
05BMCL3130 05BMCL3130
M.P. Groziak Groziak M.P.
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378 05H(65)2321 05H(65)2321 05H(65)2593 05H(65)2683 05HAC20 05HAC56 05HCA751 05 HCA2747 05HCA2747 05HEC89 05IJH87 05IJH189 05JCC429 05JCC683 05JCC891 05JCC931 05JCC963 05JCC1241 05JCC 1241 05JCC1429
05JCO90 05JC090 05JC096 05JCO96 05JCO236 05JC0236 05JCO490 05JC0490 05JC0517 05JCO517 05JCO589 05JC0589 05JC0721 05JCO721 05JCO806 05JC0806
05JCO977 05JC0977 05JHC165 05JHC221 05JHC307 05JHC319 05JHC353 05JHC361 05JHC375 05JHC387 05JHC395 05JHC413 05JHC427 05JHC509 05JHC527 05JHC557 05JHC589 05JHC609 05JHC639 05JHC691 05JHC751 05JHC841 05JHC925 05JHC975 05JHC1069 05JHCI069 05JHC1085 05JHCI085
M.P. Groziak
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Six-rnernbered Six-membered ring systerns: systems: diazines and benzo derivatives (2005)
05JHCII05 05JHC 1105 05JHCl127 05JHCl223 05JHC1223 05JHCl305 05JHC1305 05JHC1423 05JHC1423 05JMC141 05JMCl41
05JMC152 05JMCl52 05JMCl886 05JMC1886
05JMCl901 05JMC 1901
05JMCl910 05JMC1910
05JMC2371 05JMC2420 05JMC2420 05JMC4025 05JMC4690 05JMC4690 05JMC4892 05JMC4892
05JMC5162 05JMC5162
05JMC5329 05JMC5329 05JMC6004 05JMC6004 05JMC6326 05JMC6326
05JMC6776 05JMC6776 05JMC6843 05JMC6843
05JMC7012 05JMC7012
05JMC7089 05JMC7089
05JMC7215 05JMC7215 05JMC7808 05JMC7808 05JMS7 05JMS37
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380 05JMS67 05JMS169 05JMS 169 05JMS179 05JMS2822 05JOC388 05JOC1957 05JOC1961 05JOC 1961 05JOC2616 05JOC2729 05JOC2824 05JOC2878 05JOC4088 05JOC5215 05JOC6503 05JOC6721 05JOC6721 05JOC7208 05JOC9377 05JOC9780 05JOC10194 05JOM622 05JOM802 05JOM3746 05JOM4773 05JOM5849 05M217 05MI297 05MI307 05MI1319 050L2505 05OL2505 050L4705 05OL4705 050L5529 05OL5529 050M4057 05OM4057 05PS95
05PS 149 05PS149 05PS163 05PS339 05PS413 05PS591 05PS633 05RJ0289 05RJO289 05S 131 05S131 05S419 05S1083 05S1164 05S 1164
M.P. Groziak
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Six-membered ring systems: diazines and benzo derivatives (2005)
05S1345 05S1601 05S2544 05S2597 05S2833 05SC249 05SCI003 05SC 1003 05SC1741 05SC1921 05SCI921
05SC1961 05SCI961 05SC225I 05SC2251 05SC3055 05SL777 05SLl239 05SL1239 05SL1683 05SLl683 05SLl897 05SL 1897 05SL1907 05SL I907 05SL2743 05TI077 05T1077 05T2897 05T3953 05T4237 05T4453 05T4785 05T4805 05T4919 05T4957 05T5303 05T5389 05T7384 05T8616 05T8924 05T9637 05T9808 05T 10073 05TI0073 05TI0774 05T10774 05TA2778 05TA2778 05TC31 05TC73 05TC201 05TL51
05TL 1177 05TLlI77 05TLl345 05TL 1345 05TLl433 05TL1433 05TL1663 05TLl663 05TL 1841 05TLl841 05TLl845 05TL 1845
381
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382 05TL1975 05TL2l89 05TL2189 05TL3423 05TL3449 05TL5289 05TL5551 05TL555I 05TL5747 05TL5851 05TL7701 05TL7889 05TL8749 05ZN(B)22 05ZN(B)221
M.P. Groziak
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383
Chapter 6.2 (2006) (2006)
Six-membered Six-membered ring systems: systems- diazines and benzo derivatives (2006)
Keith Mills Ware, Ware, Hertfordshire UK [email protected] [email protected]
6.2.1
INTRODUCTION INTRODUCTION
The chemistry of diazines remains an area of of intense interest, both academic and industrial, with applications in many areas, from biomedical to materials science and electronics. They are versatile, having very varied reactivity, giving many opportunities for manipulation of substituents. Nucleophilic substitutions, electrophilic substitution in oxy and amino derivatives, organometallic and transition metal-catalysed coupling reactions are all subjects of substantial research effort. There are obvious similarities in reactivity of the three diazine systems but also many interesting and practically important, often subtle, differences. All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often "one pot", ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction.
The main emphasis of this review will be on the synthetic and reactivity aspects of the three diazine systems and their benzo-derivatives, although some other interesting and significant applications will also be covered. Generally one or two representative examples of reactions or syntheses will be given and it is understood that further examples will usually be found in the original paper. However, this is flexible and generic reactions or products may be shown if this is considered more appropriate.
6.2.2
GENERAL STUDIES STUDIES GENERAL
The Negishi coupling reactions of a number of of amino-chlorodiazines have been reported. The aminopyrazine 1 was used as the substrate for optimisation but examples involving the other diazines were also given. Dialkylzincs and alkylzinc halides reacted successfully and a particularly useful in situ formation of of primary alkylzinc halides by exchange of an alkyl halide with diethylzinc could be carried out. Fortuitously, this alkylzinc exchange was catalysed by the nickel catalyst used for the following coupling <06TL341>.
384
K. Mills K.
R R= = Pr, Pr, 92%; 92%;cyciopentyl, cyclopentyl,46%; 46%;PhCH PhCH2CH2*, 42%; 2CH 2*, 42%; PhCH PhCH2*, 50% 2*, 50%
RZnX, Ni,CI2.(dppp? R
similar similar couplings couplingswith with (e.g.): (e.g.):
N
n
NH [~..r/NH2 I"~N 2 CI'~"N CI
(* (* prepared preparedin situ from from RBr RBr++ Et2Zn) Et2Zn)
NH2
Br~ "~N
Me"Y"~ N
H2NIN/---j
N-:.N
H2N1 NT/L"..Cl
A study of the a-arylation of diazine mono N-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme I). 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very <06AG(I)77811>. >. substantial improvement in yield <06AG(I)778
N N ~ ~
(:J N+ N+ [
Pd(OAcb Pd(OAc)2,t-BU3P.HBF4 t-Bu3P.HBF4
(:l N1 N
.
K K2CO3'di~176 ZC0 3, dioxane, 110°C
~N~+~A 1
ArX
Arr
N
N N ~ /~A
(:l
Hz, Pd or HCO zNH 4, Pd H2'Pd~ •
N
Arr
[
06-
06-
75% yield yield 75%
86% 86% yield yield
Ar = 4-tolyl 4-tolyl for for optimisation optimisation studies studies Ar similarly: similarly:
N
6-
68% yield 68% yield
e
N
6-
~N
N
I)
)l.NN~ .J+ Ar Ar
N+ [
[
06-
06-
r
73% yield yield
6-
r
6-
standard standard conditions, conditions, 17% 17% yield
with 10 10 mol% moi% CuCN, CuCN, 61% yield
Scheme 1I Scheme A metal-iodine exchange has been carried out on all three diazine systems under very mild conditions using lithium tri-n-butyl magnesate, although only one substrate from each system conditions 3-iodo-6-phenylpyridazine, 4-iodo-2-methylthiopyrimidine 4-iodo-2-methylthiopyrimidine and 2-iodopyrazine. 2-iodopyrazine. was used: 3-iodo-6-phenylpyridazine, The pyridazine example was most problematic, problematic, possibly due to solubility problems. benzophenone and diphenyl disulfide were used as the electrophiles electrophiles <06SL <06SLl586>. Aldehydes, benzophenone 1586>.
1,nBu3M0.iTHF
N
~ 1O~
! 2) PhSSPh,-10 ~ to r.t.
N N
SPh
86% yield
similarly similarly
MeS
[~.1.... SPh SPh
85% 85% yield yield
Ph~J'L'N'N 62% yield 62%
385
Six-membered ring systems: diazines and benzo derivatives (2006)
The copper-catalysed N-arylation of diazinones diazinones by aryl halides, but mainly using 2-fluoro-4iodoaniline, was described as part of a paper devoted primarily to pyridones. Pyrazin-2-one, iodoaniline, pyrimidin-4-one and pyridazin-3-one all reacted successfully but pyrimidin-2-one failed to give any product <06TL7677>. N
NH2
[ NN.~.
[~ ~ + (1+ N O N H
0
¢r' ~ F
1//
Cui, Cul, 8-hydroxyquinoline, 8-hydroxyquinoline, K ZC0 3, DMSO, K2003, DMSO,130 130 ~
°9
II
H
43% yield
(1 N O ~
N
~ ~
similarly similarly prepared prepared
0
N:\ O llN 0 t ,~,r
Ar
28% 28%
M MeN e . N ~n
F F
~'N
NH NH2z
0 O
t
Ar ,Ar
6.2.3
59%
PYRIDAZINES DERIVATIVES PYRIDAZINES AND AND BENZO BENZO DERIVATIVES
The relatively rare discovery of a new pyridazine natural product product-- azamerone 2 - has been reported <060L2471>. <06OL2471 >.
oO
O
N
CI
CL,CX CI ~
t
2
2 H
OH
azamerone azamerone
6.2.3.1 Synthesis
A number of pyridazines have been prepared by standard condensations of enediones with hydrazine but a general synthesis of the intermediate intermediate enediones is notable. This involved iodine-copper exchange of an iodoenone 3, followed by reaction of the resulting cuprate with chlorides. However, only a few of these enediones were actually converted into acid chlorides. pyridazines <060Ll941>. <06OL 1941 >. o
0 o
,Jl
A,
I) NpthylzCuLi, Npthyl~CuLi, THF THE 1)
~
-100~ . ~ "~"RR -100°C. = Ph Ph Ph II 2) 2) (J-( ~/~... Ph 3 O0 COCI COCI 3
I
OR
R
0
Et
R
N~H~.H~O,EtOH
reflux
?' 0
R= = pentyl, pentyl,78% 78%yield yield R
I
N
Ph -96% yield 96% yield
similarly similarly prepared prepared
NN
~ I
[
. Me3S1 Me3Si
t
/- N
?' S -
The one-pot synthesis of the dibromopyridazinone 4 has been optimised up to a 22 kg scale in a process research project. One key feature was the use of hydrobromic acid, rather than
386 386
K. Mills Mills K.
hydrochloric hydrochloric acid, acid, for for the the diazotisation diazotisation step step to to avoid avoid partial partial halide halide exchange exchange in in the the final final condensation <06TL8733>. <06TL8733>. condensation Br Br
F F~L..
Br Br
HO~O HO O
-
F NaNO2,HBr;SnCl2 F . ~
Br Br
_______
NH2
Br O Br~o "~~
l-w~yyF %N.N F
NHNH
~ FF
44
82% 82% yield yield
Useful vanatlOns variations on another standard synthesis of pyridiazines by Inverse-ElectronDemand Diels-Alder reactions included the regioselective reactions of 1,2,4,5-tetrazine sulfoxides with enols, enamines and alkynes (Scheme 2). These suIfoxides sulfoxides have greater reactivity than the previously used sulfides but, more importantly, showed a reversed (complementary) regioselectivity. The reactions of the sulfoxide 5 appeared to be totally regioselective apart from one case (with 2,3-dihydrofuran). The Cbz amine 6 also reacted with <06JOC 185>. high regioselectivity in most cases but there were several exceptions <06JOCI85>.
N-N
,,
0
Ph Ph CH 2CI 22,, 25°C, --~( CH2CI 25 ~ 11 hh OTMS
=<
fSMe
-==
or
"
Ph dioxane, dioxane, 100°C, 100 ~ 11 hh Ph
90%yieid 90% yield
5
Ph
Ph
o0
M~N~eN NHCbZ NHCbz
CH2CI ~ 6 h= M Me.s 25°C, CH 2CI 2, 2, 25 e,S II II
o0
6
n Me
NHCbz ~Et /X OEt
IIII
O o 83% yield yieid
/x.. N-. N "S,, 0
WNyNHCbZ N'N~-'h/
0H2012, 25°C, 25 ~ 2 h Me'S)lN-;.N Me.s~.N;N CH2CI2,
II II
Me
Me
NHC z . --< ~NHCbZ ~TMS OTMS Me. S Me'S)lNJ
Ph ~SMe
94% 94% yield yield
I, N W
58% yield yieid 58%
+ +
Me)CXNHCbZ M e / ~ N ~ N NHCbz I, N 7% yield Me,S Me. S W
" 0o II
The use of of an alkynylboronate 77 as the dienophile dienophile allowed allowed the synthesis synthesis of of pyridazin-4pyridazin-4The ones ones <06OBC4278>. <060BC4278>.
I-# U B"
T7 IIII
4+
R R R ==H, Bu, Bu, Ph, Ph, TMS TMS
RnCi oo
c,
O.. O O'B/
N" ~ N
xylene xylene
I~.~N CI
reflux " reflux
O"B"O
R N~~NCI CI
H202, Na2CO3
630 yield, R = H 86% yield, R = TMS
"
RN~.NCI I I CI CI HHW
N
73-85% yield yield 73-85%
387
Six-membered ring systems: diazines and benzo derivatives (2006)
In a study of of the use of microwave irradiation for the preparation of of pyridazines by the cycloaddition of of alkynes to 3,6-bis-(2-pyridyl)-1,2,4,5-tetrazine 3,6-bis-(2-pyridyl)-l,2,4,5-tetrazine 8, it was found incidentally that acetone reacted, via its enol, with this tetrazine, also giving a pyridazine. Aldehydes reacted similarly but with variable yields and other ketones gave mixtures of of products derived from both possible enols. In the one example (acetone) where it was tried, conventional heating gave an only marginally lower yield than microwave heating <06JOC4903> (The room temperature, base-catalysed, addition of of aldehydes to tetrazines has previously been reported but this may be mechanistically different <79JOC629». <79JOC629>). 2-py 2-py N.fl'~ N~NN
2-py 2-py N . ~ . . Me Me
Me2CO
Nl N
NyN II
ac, 30 min; min; 75% yield yield
MW, 150 ~
I
ac, 30 min; min; 69% yield yield
Conventional Conventional heating, heating, 150 ~
II
.&
2-py 2-py
2-py 2-py
8
Conversion of of other heterocyclic systems into pyridazines has also been used, for example the reaction of of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation <06T9718> and the more unusual utilisation of of a 1,2,4-triazole 1,2,4-triazole 10 as the source of of the N-N unit <06T8966>. In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates <06S2885>.
" C)): '
o
.
NzH4 H-.. NHz zO
0
99
CXX [
CI
Li Li
.A .!A ry x"OH ~ t/ j : OH
98% yield 98% yield
Br Br Br2 Brz
R A A r ~ Nr, n Nx~,R
I
~N
2) triazole 2) triazole
COZMe CO2Me
,N tN.~~ I W N;N
88% 88% yield yield
R R 1) 1) R R _~
o;r ~
.
CAN,MeOH CAN, MeOH
~ , _ _ _ ~ N,N N"N H H
Ar
O A~CI O~
CONHNHZ
[
N/~'" N N I \;:::N ~N
NaOH NaOH
N+
Arn [ ,N
R
W
W'7
~....~N/ l:::N
11 11
10
NTol NTol
NHTol
R2
LiHMDS THF THF LiHMDS,
+
Me~ 12
NTol
RnNHTOI ~ I ~ N . N NHT~
[
D,
O
R1
-78 -78 ac ~ to to rtrt
R1
I
W
N
I
Me
R1 = Me, Me, RZ2 = H; H; 93% 93% yield yield R1
In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of of the isoxazole of the intermediate
388
K. Mills
14 gave the required pyridazine amino alcohol. The sequence is interesting, despite the low yield, which was due in part to instability of the bicyclic intermediate 14 <06TL2257>.
N-N OH
N2H4.H20
"
NH22 NH
eN
o,N K,,o.N 14 14
k~o.N 13
Ph+"N
H2, Pd 2,Pd Ar H ~ HO HO~Ar '" [ -N N' 9% yield (2 9% yield (2 steps) steps)
C r AAr r
[
o
N
[
",N
Ar Ar
H
A cyclocondensation involving the carbonyl of a benzoquinone was used for the synthesis of a cinnoline 15 of interest as a potential anti-fungal agent <06BMCL <06BMCLl850>. 1850>.
O
CN
°O
Me1):°CI
I I
Me
CI
EtOH, NH 40H, rt
°
°O
CI CI
EtO Me«1 N2H4 .H20, EtOH I I CO Me • Me 2 reflux
31% yield O 31 % yield
C0 CO2Me 2Me
H O W ' " NH
CN CN
Me
~ 15
2
I N~ N
Me Me
46% 46% yield yield
Improved conditions for the cyclisation of 2-alkynyl diazonium salts to cinnolines, using aqueous sodium chloride, have been described <060PPI476> <06OPPI476>
6.2.3.2 Reactions
of halo-pyridazines has been published A review of the palladium-catalysed reactions of <06SL3185>. <06SL3185>. The regioselective O-sulfonylation of 4-bromopyridazine-3,6-dione 16, using a hindered sulfonyl chloride, allowed efficient sequential boronic acid couplings. 2,4,6-Triisopropylbenzenesulfonyl chloride was the only sulfonyl chloride to give essentially complete regioselectivity, whereas the corresponding 4-phenyl pyridazinedione gave a highly selective reaction even with tosyl chloride. <06TL6125>.
Lo Br
ON ~ . N H O O~N'~H H
Br Br ,. ArS02CI, py. ~OO ArSO2CI,py ArSO20~ N ~ . NH
ArS020~N'~H
16 16
ArS02 = ArSO2 = 2,4,6-triisopropylbenzene 2,4,6-triisopropylbenzene sulfonyl sulfonyl
Ar
AF
SuzukiArSO20/q~" ~ N" O NH
90% 90% yield, yield, >95% >95% regioseiectivity regioselectivity
At'
U
A paper concerned with the synthesis of of pyridazino[3,4-b]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with <06T121 >. reductive dehalogenation, and usefully summarised previous work <06Tl21>.
389
Six-membered ring systems: diazines and benzo derivatives (2006)
Cl
Cl
N~O
N2H4 H2NH
Me
17
Lo CuSO4 ~N~~N.
Cl O
0
LW~-Me Me
Me
""'~"~ NH2 O
O/~N~~ o N"
via Suzuki Suzuki
79
Me POCI3
CI
I
O2N/)"~'N" N'Me
O2N
also prepared prepared 4-Br also 3-NO2 compounds 3-N0 2 compounds
Me
18
IVle
The divergence of oxidative addition and nucleophilic substitution was shown by the reaction of the dichloropyridazinone 19 with phenoxide, which displaced the 6-chlorine, vs. a Suzuki coupling, which showed selectivity for the C-3 halide <060BC4278>. <06OBC4278>.
oo
o o CI
Rn I I N PhO")4" W N "N PhO CH CH2Ph 2 Ph
PhONa, THF
...- - - -
o o
R nCI PhB(OHh, Pd
RnPh
N CI"&'NW"N CI CH CH2Ph 2 Ph
CI Cl
I [
•
19
=
70% yield, R = Bu
19
I [
N,N CH2Ph CH 2Ph
62% yield, R R = Bu Bu 62% yield,
The microwave-assisted dipolar cycloaddition of pyridazinyl quaternary salts such as 20 was shown to be substantially better than the reaction using conventional heating. Novel regioselective reactions using monosubstituted dipolarophiles were also included <06SL804>. :co, ==
, CO2Me "
e C0 2Me
Me02C
Et Et3N, Phil 3 N, PhH
MeO2C
==
30% yield
I
~ 20 I'CO2Me
58% yield yield
C0 2Me
Et3N, PhH Phil Et3N,
MW, 5min MW,5min (previous thermal thermal conditions)
N
CO2Me MeO2C
CO2Me
59%yield 30% yield
BENZO DERIVATIVES DERIVATIVES 6.2.4 PYRIMIDINES PYRIMIDINES AND AND BENZO
A useful discussion of the metallation of of pyrimidines is to be found in a more general <06EJ01593>. review on metallation <06EJO 1593>. A full issue of Chemical Reviews was concerned with DNA damage and repair, parts of which may be of of interest relating to pyrimidine reactivity
390
K. Mills K.
<06CRV213>. Biginelli compounds were included in an account of heterocyclic glycolconjugates <06ACR45 I>. Other reviews cover the chemistry of quinazoline alkaloids <06ACR451>. <06T9787> and pyrimidine chemistry in crop protection <06H561> <06H561 > 6.2.4.1 Synthesis
The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas.
EtO2C~ R
R
R'CHO R'CHO +
NH2
+
O
Biginelli Biginelli reaction reaction
!
EtO2C.....~ NH
H2N''~--'O
H
New variations in conditions include the use of of antimony trichloride as a catalyst for the of monastrol analogues, with modifications in the aryl ring and replacement of thio synthesis of by oxo <06BOCI73>. <06BOC173>. The use of ionic liquids <06SCI503> <06SC1503> and microwave enhancement <06BMCL4893> have also been reported. Nanosynthesis (single bead reaction) has been carried out <06AG(I)3102> and highly enantioselective reactions have been achieved using the catalyst 21 <06JACSI4802>. <06JACS 14802>. 5-Nitro-dihydropyrimidines such as 22 have been prepared using a-nitroacetophenone in place of the usual keto ester and shown to have potential as anti<06BMCL 1418>. arrythmic agents <06BMCLl418>.
=
Z
OH
Et0 EtO2C 2C
I~"
Qp,~..O
NH
I A S monastrol Me..~N/~-~. Me N S monastrol
~'~O' v
OH
O2N
Ph
g
H
Ph"~N"~O
[
IR R
21
H
22
A surprisingly infrequent use of of Biginelli compounds to make aromatic pyrimidines has also eerie ammonium nitrate gave pyrimidinones 23 or been reported. Dehydrogenation with ceric pyrimidinediones 24, depending on conditions <06T9726>.
EtO2C~ .
Ph NH
o-- -..Zo H 24 24
CAN, AcOH AcOH CAN, a = 80 80 ~ C
61% 61% yield yield
Ph EtO2Cv.J... NH H
CAN, aq.Me2CO CAN, aq.Me2CO -5 -5 ~ ac ~_
Ph EtO2C...~N
83% yield yield 83%
H
23 23
of the Biginelli Biginelli reaction has been developed A general method for the guanidine analogue of using the two reagents which overcome some of of the limitations limitations of of the the direct direct reagents 25 and 26, which
391
Six-membered ring systems." systems: diazines and benzo derivatives (2006)
guanidine condensation. The choice between the two reagents depended on the acid-stability of of the substrate <06JOC7706>.
RCHO RCHO
i
/CO2Et C02Et
Me Me-~O0
R R R'
R'
- -..
~ NH 2 HN"~NH2 HN
R
EtO C Et02C 0" N
N Jl..NJlI"L" R' R'
"
Me Me
I z
Me"~ N//[" NH2
strong acid for for 25 25 or or strong acid BOC20; NH3; Boc20; NH3; TFA TFA for 26
I
H H O R
Me'N"~N'Me
!
HN'~NH2
LN'J 2s
or
or
HN..~NH2
~ N "N
26 HN'~NH2
A number of of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-l-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of of an a-chlorobenzyl isocyanate with N-substituted aminocrotonates <06SL375>.
ArCHO ArCHO
EtO2CNH2 Et° 2CNH 2 H H2SO 4 cat., cat., 150°C 150 ~ 2S04
=• ArCH(NHC0 ArCH(NHCO2Et)2 2 Eth
EtO2C~.~ NCO NCO
PCI 3
Ar---~ Ar--< CI CI
Me NHR CH2CI2, reflux
Ar EtO2C..~[-..NH Me/J~...N...~__..O ~,
=
Ar Ar = Ph, Ph, 68% 68% yield yield
27
Ar == Ph, Ph, RR == Me, Me, 64% 64% yield yield Ar Ar Ar = Ph, Ph, RR = 4-CIC 4-CIC6H 63% yield yield sH44,, 63%
=
=
Another multicomponent synthesis giving N-3-substituted compounds 28 consisted of the of metallated phosphonoacetates, in one pot, with a nitrile then an sequential reaction of aldehyde and finally an isocyanate. This was an extensive study of the scope and limitations of of the different substituents on all the components. The most important feature was that, for good yields, the isocyanate should bear an electron-withdrawing group - tosyl was the most successful. However, an exchange reaction could be carried out by reaction of of the tosyl products with aryl isocyanates under microwave irradiation, giving the N-3-aryl derivatives 29 <06CEJ7178>.
392
K. K. Mills
P(O)(OEt)2
R1-j
a3
1) BuLi 2) R2CN
Rt ~
R4
3) R3CHO R3CHO 3)
4 NCO 4) R R4NCO 4) All reactions between -78 and rt
=
alkyl, aryl, aryl, C0 CO2Et, P(O)(OEt)2 R 11 = H, alkyl, 2 Et, P(O)(OEth R22 = S-alkyl, S-alkyl, aryl aryl R R3 = (alkyl), (alkyl), aryl aryl R3
=
R44 = Ts, Ts, RCO, RCO, (Ar) (Ar) R 28
~ A 4 = Ts) rNCO, MW R~J
R3
R3 R4
R~N-Ar
vial NH R2.V'~N.-~O
29 H
The dihydropyrimidinethione 30 has been obtained by microwave-induced rearrangement of a dihydrothiazine, using silicon carbide as a passive heating element <06JOC465 <06JOC46511>. >. Ph EtO2C-.~S MeIN/~..NH H
oC MW, SiC, toluene, 220°C MW, SiC, toluene, 2 2 0
.
Ph EtO2C-.~NH MeIN.~__.. S H
30
68% yield
There has been significant emphasis on the use of pyrimidine thio ethers for further selective functionalisation by nucleophilic displacements of either the alkylthio or alkylsulfone and general syntheses of pyrimidines often include methylthio as one of the representative substituents. The reaction of enolisable ketones with nitriles under the influence of triflic anhydride is a useful general method for the synthesis of2,4-"symmetrically" of 2,4-"symmetrically" substituted pyrimidines. l-tetralone with aryl cyanides or methyl thiocyanate, followed by aromatisation Reaction of 1-tetralone with DDQ gave good yields of benzoquinazolines. The further transformation of the methylthio product 31, via oxidation and selective sequential nucleophilic substitution of of the resulting sulfones, illustrates the utility of this substituent. 2-Tetralone reacted similarly but substantial amounts ofby-products of by-products were formed <06T2799>.
393
Six-membered ring systems: diazines and benzo derivatives (2006)
O
°
oJ
Tf20, MeSCN MeSCN TfzO, CH2CI2, rt
~NySM' __D_DO_.... N~
lJYN
SMe
DDQ
SMe
IN~ SMe QNySM'
lJyN
31 31
70% yield
SMe
93% yield 93% yield
1 mCPBA
'-'::
QNyOM' N ~ ~1,~ N~OMe
lJyN
NaOMe, NaOMe,MeOH, MeOH, ref!. refl.
NH3, rt
85%
74%
NH NH2z
~ ~
N~r.,.SO2Me N~(sOzMe
: :,.-. I /- N
yield SOzMe SO2Me 85% yield
The same general method has been applied using N-benzylpiperidone 32 as the ketonic component (note the cleavage of of the benzyl group) <06TL5463>.
°O
6
NN,
TfzO, RCN
TfN~r 9~ ~ N
R R = Me, Me, Tol, MeS (45-65% (45-65% yield) yield) R Tal, MeS
/
CH2Ph CHzPh 32
R
The use of alkyl esters in place of of ketones resulted in the formation of of alkoxypyrimidines 33 which could be converted in high yields, via selective sequential nucleophilic substitutions, into amino dialkoxy and trialkoxy pyrimidines 34 <06EJ03332>. <06EJO3332>. SMe
RCHzCOzEt RCH2CO2Et +
-I-
MeSCN
R ~ R~N
Tf20
I,,
/[~I N~/L,x. ~
EtOANASMe EtO SMe
33
= alkyl, alkyl, Ph (not H) R=
42-71% yield
Nu
33 steps steps
R R~N EtOANANU' EtO Nu'
34 e.g. Nu = = NH z2,, OMe; OMe; Nu' Nu'==OMe
The condensation of anilides or enamides with nitriles was developed as a general method for the synthesis of pyrimidines or quinazolines such as 35 and 36 <06JACS14254>. <06JACS 14254>.
394
K. Mills
MeO.
Meoo
I
C7 Q
+
TfzO Tf20
+ NHCOPh NHCOPh CN CN
h-
similarly similarly
o
.~_
-78 ~ to 45 ~ -78°C to 45°C
-~NHCOPh ~.~
°
Cy
II NJ-. C1 CI
:
(-~
MeOsCN
N//L..Ph 90% yield 35
R
O~N/_~
NHCOPh
Ph 36
A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of of a group of of closely related pyrimidinones such as 37, by condensation condensation of of a number of of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine: 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06TlI714>. <06T 11714>.
Me Me Me
CN ~ ' ~ add addKOt-Bu "XCO,EI Ar~CO2Et
6
~ -t-
KOt-~u r
_
~
py PY
N
1
[ ~ ~ a Add MeNCSthen thenMel Mel Add MeNCS
I
ID
J
NH NH
GazEt CO2Et
I""
N~_.) N h-
Reaction Reactioncarried carriedout out on on 77 mol mol scale scale
N.Me .Me
N
N//["-SMe N~SMe 37 37
51% yield 51%yield
Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of of amidines with the cyclopropane ester 38 <06EJOC2753>. <06EJOC2753>.
CI 38
+
R /J/~.
CO2Me HN
NH2
R ==aryl, aryl,MeS MeS R
.
Et rt 3N, dioxane, Et3N' di~ rt~
N~..R nfNyR ~
~NH ,,~, NH
39
39
aO
43-83%yield yield 43-83%
PhSO2~ Phsaz~
- - _ .p 175 175 °G ~
D;
A N.~ RR 2 / ~ I Y ~NH
hSO PhSa z
NH
aO
39-84% yield 39-84% yield
of a pyrimidine 40 by reaction of of an amidine with an isoxazole is an The synthesis of of interconversion of of heterocycles <06TL3209>. In another heterocycle interesting example of interconversion, the reaction of ,2,4-oxadiazole with hexafluoropentane of 3-amino-5-phenyl-1 3-amino-5-phenyl-l,2,4-oxadiazole hexafluoropentane dione gave a mixture of the hydroxaminopyrimidine 41 and aminopyrimidine N-oxide 42. This was in contrast to previous work where pentanedione pentanedione gave a high yield of of only the corresponding corresponding amino N-oxide. The mechanism of of the reaction was discussed, based on the <06TI158>. isolated by-products <06T1158>.
395
Six-membered ring systems: diazines and benzo derivatives (2006)
Me Me N,' N Ph
HN~NH2HCI
q0
K2C0 3 , MeCN
;,N
O 0
31% yield yield 31%
1:
O 0
N ~ Ph Ny-Ph
I "
/ON
~"~ N Me 40 Me
1: CF3
CF3
F3CA.)lCF 3
Ph--
O
N,' N Ph
=
[L~ N Me Me
NH2 N-{
Me Me
Ph Ph
F F3C 3C
HC10 HCIO4, MeCN 4 , MeCN
~)( N
NHOH NHOH
F3C
41 41 39% 39% yield yield
~j( N+ [ 0O-
NH NH22
21% yield yield 42 21%
substituents have been prepared by reaction of Pyrimidin-2-ones 43 with fluorinated substituents imines with fluorinated nitriles, nitriles, followed by cyc1isation metallated imines cyclisation with triphosgene <06Tl444>. <06T1444>.
Me RI
.
R Rff / ~ NH2
LDA, RtCN
N2
t
RI
R1
O ~
N "t-:JR2
Rf ~ RI
a 1lmainly aryl, Ra22 alkyl alkyl or aryi R mainly aryl, or aryl or R1 ,R 2 =(CH 2 b or = (CH2)3
.~.
=
O R2 43 70-94% yield
R Rff = CF CF2Ph or C 07F15 2 Ph or 7 F 15
N
R2 69-87% 69-87% yield yield
A straightforward preparation of pyrimidinones and pyrimidinethiones 45 involved reaction of isocyanates or isothiocyanates with the readily available starting starting material 44, which had same authors. authors. A particularly interesting interesting application was the previously been described by the same use of sugar isothiocyanates to give nucleosides. nucleosides. Nucleophilic displacements of the sulfur groups in the products were also reported <06EJ0634>. <06EJO634>.
SMe SMe
MeS~NH MeSt:;"
/J<'N AN
SMe RNCX, Et3N.~
X NMe2 NMe2
IR
44 44
45
lNAS ~N"~S
R R == alkyl, alkyl, aryl, aryl, sugar sugar
I~N/~. N
O = S, O o=s,O
Nu
BzO\ BZ0'l
" .~
Q
I
including e.g. e.g. " ~ O including OBz OBz OBz 1
r
The nickel-catalysed co-trimerisation of acetylenes with isocyanates gave good yields of uracils 46, depending on the isocyanate substituents, pyridones being unwanted by-products
396
K. Mills
in some cases. Trimethylsilyl and tri-n-butyltin were favoured as the acetylene substituent, the latter being carried through to an in situ situ Stille coupling <06T7552>.
O Me m+ TMS TMS Ni cat.= T M S . . ~ N . R Me
==
Similar reaction reaction with with Similar
+
RNCO RNCO
Me"~ N ' ~ O
a
Yields up to 83%
Me Me
~ ==
SnBu3 SnBu3
followed followed by by in situ Stille Stille coupling coupling (75% (75% overall, overall, R R = Et) Et)
46
An efficient preparation of 5-cyanouracils started from N-ethoxycarbonylcyanoacetamide N-ethoxycarbonykyanoacetamide 47, the carbonyl of the urethane finally being incorporated into the uracil ring <06BMC3399>.
oO
oO
N CJ NC~-~NH NH
t., ~ N..~O N~O
oO (EtOhCH, t (EtO)3CH, MeCN MeCN RNH2 RNH2 N NC~C 3N Et Et3NII • I JJ...NHCO2Et NHC02Et NC~NHC02Et RHN NC NHCO2Et RHN
Y
47
R R generally>70% generally >70% yields yields overall overall
Uracil 5-carboxylates 48 were prepared by reaction of of aminomethylene malonates with (lh chlorosulfonyl isocyanate. The reaction was greatly accelerated by microwave irradiation (lh vs. 2-3 d in refluxing toluene), although the microwave yields were somewhat lower than those from the thermal reactions. The chlorosulfonyl group was lost during work-up and chromatography. The method was compatible with sugar residues <06TL 1989>.
EtO2C~CO2Et NHR
O EtO2C~ ..~ ~ NH
CISO2NCO = MW, MW, benzene benzene 1 h or or toluene reflux toluene reflux 2-3 dd
R R = Ph, Ph, yield yield 60% 60% (thermal), (thermal), 44% 44% (MW) (MW)
OAc ~ O
IR 48 48
R= R=
ACO~O\ AcO
'1.-
~ " ~ O A c '~ ~~ OAc
yield yield 70% 70% (thermal) (thermal) 58% (MW) 58% (MW)
An improved synthesis of 11C-2 IIC_2 thymine 49, for use in PET scans, was made possible by an IIC-phosgene, previously reported <02NMB345> by the same efficient and rapid synthesis of llC-phosgene, authors. II11C C is a particularly interesting challenge due to its very short half life (20 minutes) and the whole sequence and purification from the end of of the bombardment took 16 minutes. The scale was necessarily small (0.2 mg) <06TL5321>.
397
Six-membered ring systems." systems: diazines and benzo derivatives (2006)
0 O
Et0 Me EtO2C~/Me 2C
H2NHN~]Me H2N~Me
3 steps steps 3
yI
CHO CHO
HN, COR
14N2++ HH2 14N2 2
.
18 18 MeV MeVproton protonbeam beam= 11CH 11CH44 10 10 min min
O 0
KOt-Bu, KOt-Bu,DME DME,.
O~C'N H H
11COCI 11COCI2 2
//
= 11CCi4 _11CC1 4
Me HN~Me I
11'
49 49
16 min min 16
A number of new conditions and catalysts have been used for the synthesis of quinazolinones 50 from anthranilic acids, amines and ortho esters, including bismuth trifluoroacetate with an ionic liquid <06TL356l>, <06TL3561>, lanthanum nitrate or tosic acid under solvent-free conditions at room temperature <06TL4381> <06TL4381 > and Nafion-H <06SL2507>. O
[~
CO2H
R1NH2,R2C(OR3)3 r ~ ~ ~ " - NR1 50
NH2
=
~[...~.~N/..~R2
Quinazolines 51 have been prepared by the condensation of N-aryl carbamates with hexamine, followed by aromatisation of the dihydro intermediate. A variety of mono- and dimeta-substituted starting materials giving 7-substituted substituted anilides were used, meta-substituted quinazolines <06Tl235 I>. Benzoquinazolines were also prepared similarly from <06T12351>. naphthylamine carbamates <06OL255>. <060L255>.
Me~.~ MeY')
~NHC02Et NHCO2Et
hexamine,TF~ TFA hexamine,
Me~~
reflux reflux
I
C02Et
K3Fe(CN)6,KOH M M ee aN V:"N 51 ~I J 51 =~ ~ ' ~ NN/-~ 49% 49% yield yield
The convenient synthesis of dichloroquinazolines 52 from anthranilonitriles by reaction with diphosgene was also applied to fusion of pyrimidine rings onto other heterocyclic aminonitriles <06SL65>. CI
[~
CN
CI3COCOCI
NH2
MeCN, MeCN,130°C 130~
~N//j~
52 CI
86% 86%yield yield CI CI
N
Bn
,.CN
CI3COCOCI,.
NH2
MeCN, MeCN100°C 100 ~ '
, N ~ ~N/_.j..N N~N :~JLNAcl N
Br~ B~
Cl
51%yield 51% yield
Yields for Yields for 6-substituted 6-substitutedcompounds compoundsrange range from 41 % (CF from41% (CF3) to 80% 80%(Me) (Me) 3 ) to
398
K. Mills
of 2-isothiocyanato benzonitrile benzonitrile with aryl acetonitrile anions was used to prepare prepare The reaction of quinazoline thione derivatives 53 <06S3067>. NC I Ar ~CN ]~CN
ArCH2CN,Nail
~NCS NCS
NH~N~.S53 H
Quinazoline diones 54 were also available from 2-bromobenzoates via via a palladiumpaUadiumofureas<060L5089>. catalysed N-arylation of ureas<06OL5089>. O o
Cl..~CO2Me v
NHBu
"Br
Pd2(dba)3, 3 Pd 2(dbah, Xantphos, Xantphos, Cs2CO CS2CO~
+H2N ' ~ O
100°C dioxan, 100 ~
CI'(J(W CI
I
:::....
BU
N NI "Bu 54 54 N~O
H 85% yield
Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of of success, for a better anti-malarial activity/ toxicity balance <06BMCLl854>. A number of <06BMCL1854>. of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55 <06TLl777>. <06TL 1777>.
N
H
0 febrifugine
ocP ::/'[
'\:
~
N H H
lN N ~ SMe
55
55
R~n-/"~/cO2H [~_..1... NH2 reflux reflux 24h
O
AcOH
~~:b:~ lJlN~-\ --R
H H - R rutaecarpine (R (R =H) =H) 85% 85% yield yield rutaecarpine
Malayamycin A has been synthesised by a lengthy route, starting with the reaction of a protected ribonolactone with a lithiated pyrimidine <06T5201>. A much shorter synthesis of the fused quinazoline asperlicin D involved direct cyclisation of a diamide <06TL693>.
399
Six-membered ring systems: systems." diazines and benzo derivatives (2006)
OMe OMe
~
+
~..~
+
Li'C
oO )l
NH H H~N~NH
H2 N
N
I..) ~N//L..oM e N~OMe
0 o
MeO~O, ~~N>=o
22 22 steps steps
lO+-0-NH maiayamycin malayamycinAA
H H OH OH
n
H
33 steps steps O
~ ~ N O H NH2
MgCl2,DMF
0:;[ ~
MgCI 2 , DMF - - - - + - . ""
O ~CO2Me
130~
N~N N
NH
o : ~e 35% yield 35% Id
0_
[D
O
asperlicin 0D asperlicin
H
N H H
The synthesis of both enantiomers of vasicinone has been carried out using almost entirely polymer-supported reagents. The route was based on functionalisation of of deoxyvasicinone by a highly selective bromination then via via enantioselective reduction of the derived ketone <06SL2609>.
~'PPh2
oO
e¢n ~N/~ N
~
oO [ ~ N N / ~N
e¢~
NMe3+Br3,,
98%yield 98% yield
99% yield 99%yield
Br Br
I 33 steps steps 1
o¢~ O
~ / ~
similarly10S-vasicinone 10S-vasicinone similarly
OH OH
10R-vasicinone 10R-vasicinone
O
NaBH NaBH4, TMSC, 4 , TMSCI
o¢J:{ ~
Polymer-supported Polymer-supported chiral chiralligand ligand
~
O
87% yield 0 87%yield
Me2N.
f~N.2
NH2 HN'~ NH2.HCl K2003
o
BnHN
x
79% 79%yield yield
N
NH2 NH2
.-.....
H2N variolin B2 variolin B2
,,
~,
-~__e ~
H2N
\ 56
NH2
400 400
Mills K. Mills
Some analogues of of the marine alkaloid variolin B2 were prepared prepared as potential potential cytotoxic Some interesting as its synthesis synthesis included included the simultaneous simultaneous compound 56 is particularly interesting agents. The compound of two pyrimidine rings <06JMC1217>.<06JMCI217>.formation of 6.2.4.2 Reactions Reactions 6.2.4.2
Two examples of of pyrimidines 57, 58 were included in a study of of direct magnesiation of of of these metallated selectively at C-4 using "inverse addition" i.e. substrate heterocycles. Both of <06AG(I)2958>. added to the metallating agent <06AG(I)2958>.
Br Br,,,,~ N LIN ) 57 57
N
-fA-
F MgOI.LiCl /Br~"J'~ N
I
MgCI.LiCI
I
MgCI.LiCI
BrlC N
/
12
-55°C to -40 ~ °C -55 ~ to-40 (inverse addition) addition) (inverse
B r-~~ N Br'C N
I)
I)
MgCI.LiCI
similarly similarly
//L.,"
IN~CICI
eN
58 58
=
67% 67% yield yield
N
N
MgCI.LiCI ~/~
IN~CICI
eN
4-C 6H4 CHO 4-C6H4CHO
Ar OH Ar OH ~~N//L,, N 68% yield
Cl 6S%y~ld N
CI
Conditions for the magnesium-iodine exchange in 5-(4-iodophenyl)pyrimidine with isopropylmagnesium chloride have been optimised. It was found that addition of of bis-[2-(N,Ndimethylamino)ethyl] ether greatly inhibited the major side reaction, addition to the <060L314l>. Selective halogen exchange at C-5 of pyrimidine ring <06OL3141>. of 5,6-dibromo-2,45,6-dibromo-2,4dimethoxypyrimidine 59 was carried out using isopropylmagnesium chloride. The second bromine also exchanged, but much more slowly, allowing a clean "one pot" sequential replacement of both <060L3737>. <06OL3737>.
OMe OMe Br0N Br..v~ N~ Br Br
)L..NOMe ~ OMe
e
R'COCl i-PrMgCI, /-PrMgCl,rt; rt; RCHO RCHOthen then i-PrMgCI; i-PrMgCl; R'COCI "one "one pot pot conversion" conversion"
s9
O...~- N/-A"-OMe ~~~
69% yield yield 69%
Nucleophilic substitution of leaving groups is probably the most important area in pyrimidine reactivity and, in particular, the differential reactivity of C-2 and C-4 is the most investigated topic. The displacement of 2- and 4-sulfide and sulfone groups is referred to in the synthesis section. The selective hydrolysis of 4-amino-2-chloropyrimidines under acidic conditions has been studied in great detail by a process research group <060PRD92 <06OPRD921I>. >. The selective displacement of the 4-chlorine in 2,4-dichloro compounds can be capricious but a much better result was obtained starting with 4-chloro-2-methylthiopyrimidine 60. A displacement of chlorine was followed by oxidation of the methylthio to sulfone and displacement of sulfone <06BMCL5633>
401
Six-membered ring systems." systems: diazines and benzo derivatives (2006)
Me
Me
CI
HN
=
SMe
A. Ph
[]/J.\N./\SMe 88% yield
60
HN.-']'-.ph
5-azabenzimidazole K K2CO3 ZC0 3
N x',,
= 76% yield
A number of palladium-catalysed reactions of the triflate 61 have been reported but the nucleophilic displacement with primary aliphatic amines was, surprisingly, surprisingly, very slow in irradiation the reactions were very rapid refluxing THF (24-92h). However, under microwave irradiation and gave high yields, although even with microwaves, secondary amines and anilines failed to react <06TL4437>.
Me
Me
O
OTf
5-12 min
O
NHR
61
reactions of 6-aryl-2,4A useful investigation has been published on the comparison of the reactions dichloropyrimidines towards nucleophilic nucleophilic substitution substitution with amines vs. palladium-catalysed selectivity (ca. 4:1) amination. In many cases, the nucleophilic reactions showed moderate selectivity while the corresponding palladium reactions were highly selective (often 98-99%) for C-4, although this was quite ligand-sensitive, ligand-sensitive, with dppb being the ligand of choice <0601395>. <06OL395>. Another study showed modest selectivity for C-4 in 2,4-dichloropyrimidine 62 using tbutylamine, while the Sonogashira reaction showed high selectivity <06OL269>. <060L269>. TMS
CI CI
A "N
I N~CI
Sonogashira
.
,,q
NHt-Bu
I N~CI CI
t-BuNH z
I N~CI N//L'-.CI
CN
CN reflux reflux
62 62
yield 87% yield
yield 65% yield
CI CI +
I N~NHt-BU NHt-Bu
CN
26% yield
Another example with the same substrate substrate was a highly C-4-selective Negishi coupling (ArZnCI/ Pd) <06T2380>. (ArZnC1/Pd) CI CI
I
NHBoc
d.
62
n-BuLi, n-BuLi, ZnCl ZnCI2z
~_
I
(:1 ]~N/~C1
ArZnCI ArZnCI
N
CI
Pd cat
=
g
NHBoc
~N~/~ NHB~
75% yield
"N C15% yield
I .)
N~CI
402
Mills K. Mills
of the regioselectivity of of Suzuki couplings on 2,4-dihalo2,4-dihalo- and 2,4,5A detailed study of trihalopyrimidines and some related substrates under microwave conditions has been reported <06TL44 I5>. In another paper, Sonogashira reactions on the 5-bromo-4-chloropyrimidines <06TL4415>. 63 were, surprisingly, found to be selective for the chlorine, although for the corresponding 5(I>CI) returned <06TL3923>. Another investigation in iodo compounds normal selectivity (I>C1) this area showed that the Suzuki coupling of 5-bromo-2-chloro-4-piperidinylpyrimidine was <06SL861>. selective for the C-5 bromine <06SL861 >. R
Br~.!~Ii m
CI Sonogashira
Br~J~ N
Me-~m~
~e-~-mAx 63
X = NH2 or MeS
There is always interest in the photochemistry of the pyrimidine nucleic acid bases and related simple pyrimidinones, due to its importance in genetic mutation. In addition to damaging DNA, photo-induced reactions may also repair the damage, as in the reduction, by FADH, of the thymine glycol 64 back to thymine <06JACS 10934>. Another report related to repair of of DNA involved a model study, by means of the linked dimer 65, of the involvement of tryptophan in the electron-transfer leading to reversion of thymine oxetane adducts <060BC29 I>. <06OBC291 >. O
oo
~e
:t.. A
OH
o
FADH FADH hv
oOANAoH N OH
O
II
DNA
P"
HN
--
64
O I
Hm
DNA
6 5 L 65
Me02C
RN~ Other model studies related to DNA photo damage include the photocyclisation of 5 and 6benzyluracils 66, 67 <060L681> <06OL681> and the related cyclisation of 5-phenylthio uridine, incorporated into a dinucleotide 68 <060L2527>. <06OL2527>. o
o
o
o hv
or
;j
N 66
o
o
H 67
~h
O
H
403
Six-membered ring systems: diazines and benzo derivatives (2006)
oO H N~SPh I J ~ SPh
HN,.J O.J-
O hv hv
HN-~.
S\
N
68
POH O, 0,
~
O\
0
HO O-dGuanosine O-dGuanosine
HO O-dGuanosine
A computational study was concerned with the effect of solvation on the radical ion involved in CDP photolyase enzyme-catalysed reversion of thymine and uracil cyclobutane dimers stimulated by visible light <06T6490>. Photo-induced conversions are also important synthetically. The photocycloaddition of 5substituted uracils 69 with ethylene has been used for the synthesis of 2aminocyclobutanecarboxylic acids. The addition reaction worked well with carbon and fluorine substituents and also with a Cbz-protected amino. However, uracils with other 5nitrogen substituents (NH N0 2) failed, only starting material being recovered. (NH2, 2, NHBn and NO2) The sequence also worked for the 6-isomers but somewhat less consistently <06SL <06SLl394>. 1394>.
O R.~N
H 2C=CH 2 H2C-CH2
H
LN"~O H 69
hv = aq. Me2CO Me2CO aq,
oO I(
d'" R
i__~.,,,1~.NH NH 0,5M 0.5M NaOH NaOH
I I ""N~O N'~O rt" Lt. H Yield R Yield 85% Me 85% Ph 36% Ph 36% 80% F 80% NHCbz NHCbz 81% 81% C0 80% CO2H 80% 2H
[~,Rco2H
~
NaN0 NaNO2, HCI 2, HCI
"NH /.~ O NH2
[
R R
~'CO2H [(C0 2H "NH "NH22
R Yield(2 steps) R Yield(2 steps) Me Me 65% Ph 30% Ph F 74%% F 74%% NHCbz NHCbz 36% C0 N.R. CO22 H N.R. (The CbzNH CbzNH comound comound (The also gave gave 31% 31% amine) amine) also
of 6-chlorouracil occurred on attempted displacement of the An unusual C-5-alkylation of chlorine by the aminoindane 70. The reacting species was thought to be the stabilised <06JOC7053>. carbonium ion 71, generated by loss of the amino group <06JOC7053>.
o
~
CI
NH
N'~O H
Me2N
Me2N
Me2N~ +
+
~ 70 70
NH22 NH
oMso Et3N,
Me2N?y0 1\
~
I
Et3 N, DMSO
• 130 DC, 130 °C-140 ~ ~ 4h 4h
CI
+ Me2N+~1 Oe2N
NH
via via
I
N~O
N H H
75% yield 75% yield
~
[
71 71
404
K. Mills
Surprisingly mild conditions, using a multi-component reaction with aldehyde, amine and isocyanide, were sufficient for replacement of oxygen by amine at C-2 or C-4 of of pyrimidinones. The reaction was thought to proceed via O-alkylation followed by a Smiles <060L40l9>. A more rearrangement 72. The method also works with 2-ones and 2-thiols <06OL4019>. regular direct replacement of of oxygen by amines in uracil and other pyrimidinones used BOP 73 as the activating agent <060L2425>. <06OL2425>.
Et CY\ ./J" O
O 2NH , EtCHO CyNC, CyNC, R R2NH2, 2 EtCHO
Me
H
R1
MeOH, MeOH, 60°C 60~
.
Me
CY..N Et..~
R2 N N
R1
via.
89% 89% yield yield R11 == Ph; Ph; R R22 == 4-CI 4-CI benzyl benzyl R
72
O o
O NH
RNH2
RNH 2
BOP, BOP,DBU DBU im
O11 ~
NHR2
cC
NH similarlywith ~~Nl J~JH
;:2
2
similarly with
"~ N
lN~O N1 O R e.g RI=Bn, R2=n-Bu
N
1
e.g.9 R1=Bn, R2=n-Bu
Br~ Br N
t.,N N~O
NH CI
~N' N',
/0 P'/O Me 2NbP ((Me2N)3 + +
_
PF 6
O
H H
73% yield yield 73%
[r?JI\ ~N PF6
73 73 BOP BOP
An efficient method has been developed for the conversion of pyrimidine-2-thiol into the sulfonyl chloride 75, which was reacted in situ situ with amines. A modified method gave the rather more stable (and storable) sulfonyl fluoride 74 <06JOCI081>. <06JOC 1081 >.
I~N//J"'SO2F NaOCI' I ~ N / / JKHF2 "'"
eN
NASH 74
NaOCI, HCI
[(lso,cl ]
SH NaOCI' I ~ N ~/ -HCI ~ - =2 5 [ -25°C
SO2Cl
RNH22
_RN_H_.... Cls02NHR
= I~N/~...SO2NHR
75
The use of more polar solvents (acetonitrile, DMF) improved the N:O ratio Mitsunobu alkylation of 3-benzoyl thymine with cyclopentanol <06SL324>. N N selectivity in the alkylation of of 2-pyrimidinones has been investigated and the rationalised on the HSAB principle <06T6848>. 2-Phenylthioethyl has been used as a protecting group for N-3 of thymidine manipulation of the sugar. It was removed via oxidation to the sulfone <06SL845>.
in the vs. 0O-
results during
The reaction of N-methyl nitropyrimidinone 76 with aminocrotonates has been used for the synthesis of of 4-aminonicotinates. The only example using a dialkylamino crotonate gave a similar yield, but the equivalent reactions using aminoenones and 4-substituted aminocrotonates gave only very modest yields <06SLl437>. <06SL 1437>.
405
Six-membered ring systems." systems: diazines and benzo derivatives (2006)
O O2N~N I,Me
EtO2C~ +
Me
NHR ~ ~ . /CO2Et
MeOH MeOH
NHR
R R
Yield Yield 88% 88% Ph 48% Ph 48% CH2CH2OH 80% 80% CHzCHzOH
Pr Pr
-"
reflux reflux
76
(10 other otherexamples) examples) (10
6.2.4.3 Applications
The 5-anthranylpyrimidinone 77 was designed to be a selective sensor for fluoride ion <06JOC2143>
O 0 O
N
I NANAW II II n-Bu N.]~N,n-Bu H H
H H
H H
77
Amino pyrimidine-terminated oligothiophenes such as 78 were components of donor-acceptor photovoltaic devices <06T2050>. /--k 1 \ 0O
oO
NH2 .s.
H2N .s.
NH2 78
Some peptide sensors were based on binding to the zinc chelate of of ligands such as 79, with specific quenching of of the fluorescence of nearby tryptophan residues in the peptide <06Tl2l91>. <06T12191>.
HO2C\
R
HO2CvNvCO2H
N
R N
:....~.v H
N H
N
O
79
N,N H O
N,NHBoc H
of the interaction of 6-pyridinium substituted uracil mesomeric betaines 80 with A study of <060BC3056>. nucleic acid has been reported <06OBC3056>.
406
K. Mills K.
O
_
R2N
O
80
2-Amino 4,6-dihydroxypyrimidine is a useful ligand for copper-catalysed arylations of other heterocyclic NH <06JOC8324>.
6.2.5
PYRAZINES AND BENZO DERIVATIVES
A review discussed the use of 3,5-dichloropyrazin-2-one as a versatile scaffold for synthesis <06S2799>. A feature article was concerned with the synthesis of dragmacidins <06CC3769>. 6.2.5.1 Synthesis
A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione <06JOC5897>. In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The N-methyl was lost and N-N bond <06SL2403>. direct aromatisation occurred, presumably, due to cleavage of the N-N R11 R R2020" N* N R202C'N~N~ 81 81
Me Me
= R 4- ~NH2
benzoquinone benzoquinone dihydropyrazine dihydropyrazine or Pd-C Pd-C mixture =
N R
N
Me
R1 = CO2Me, CONMe2, P(O)(OEt)2etc NHMe ~CO2Me R1 R2020..N.N~NACO2Me Me Me
NaOEt
NaOEt .. THF, THF, reflux reflux
Me2NOC N N ~ ~ Me Me I N N" "00 H yield 44% yield
Me 2 Noc
11
82
82
of The thermal rearrangement of 1,2-dialkynylimidazoles gave intermediate cyclopentapyrazine carbenes 83, which then trapped the solvent (benzene) to give a phenylsubstituted products products 84 <06TL353>.
407
Six-membered ring systems: diazines and benzo derivatives (2006)
Ph R2 !/!
,.
R2
R2 80-100 ~
N
38-88% yields
R1
84
83
R1
benzene-l,2-diamines in Quinoxalines 85 have been prepared by the reaction of diols with benzene-1,2-diamines the presence of a ruthenium catalyst <06TL5633>. Iodobenzene diacetate has been suggested as a less toxic alternative to lead tetraacetate for the oxidative cyclisation of iminooximes to quinoxaline N-oxides 86 <06TL4969>. HO QNH
~ "~
R
HOXR' HO
Z
Ru Nu cat., cat., KOH KOH
NH z "NH2
R
N
R' R'
~
II
II +
QNXPh N N
85 85
0-
OH
~
X
O ~ N I
Ph Ph
Phl(OAc}z CHzCl z, rt CH2Cl2, rt
Ph 86 QIN i ~ N/O Ph N
containing the core system of dragmacidin has been A route to an intermediate 87 contammg described, which involved the three-point fusion of an indole onto the seven-membered ring <060L4775>. <06OL4775>.
OTIPS&NTS N I ~
Q
I "
~
I
N/O
OMe--
0 O
~
OTIPS&NTS
Q/ f~ -
BnO
N
"
I/O
I
I~
NOMe
--
~
N
Ac
87
6.2.5.2 Reactions Reactions 6.2.5.2
The reaction of of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06Tl2084>. <06T12084>.
408
K. K. Mills Mills
OTMS
CO2MeR
OTMS
N
(j N
RJ-~OTMS R~OTMS •"
MeO2CCI
CO2MeR
N
~ ~ O N i CO2Me
N
similarly [ ~
/'~O O N i CO2Me
88
An interesting iridium-catalysed 5-CH boronation of 2,3-dimethylpyrazine was reported incidentally in a paper mainly devoted to the reaction of pyridines. The product 89 was used in a Suzuki coupling <06AG(I)489>. Selective mono coupling of 2,6-dichloropyrazine with boronic acids, followed by amine displacement of of the second chlorine has been used to prepare potential anti-cancer compounds <06JMC407>. A full paper has been published on the chelation-driven selective Suzuki coupling of the pyridinium ylides 90 <06TL6457>.
(:c
:c
N N~ Me Me BB2Pin 2,[lr(cod)(OMe)b [Ir(cod)(OMe)]2(2.5 (2.5mol%) mol%) N~ Me Me 2pin 2' ~ L (5(5 mol%), mol%),hexane, hexane,ft,rt, 16 16~h ~~O ~...~ L N Me Me Me N ~O'6 NN Me
i
N
t-Bu
fJ-Pd
Br
Pd
89 89
t-Bu
~Bu
s
~Bu
.
d
N
[
'"
~ S
Me
NrMe " ~
N Me Me
N
34%yield
34% yield
L=h M ~r~J L-
I
-N N Br
Suzuki
Suzuki
N
Br
I
-N N Ar
N
Br
90
An abnormal (fe/e) (tele) substitution of chlorine in both 2,3- and 2,6-dichloropyrazines 91, 92 ipso-substitution occurred on reaction with dithiane anion, while morpholine gave the normal ipso-substitution <06TL31>. Another paper described the highly selective ipso monosubstitution of of the 2,3dichloro compound by enolates in toluene <06T9919>.
N Cl (N~C ' 91
~ ~SLi -78°C -78~
morpholine 1morpholine IN,,: CI
N ~S
N~C' 73%yield
N
S~S~
N
]'1 similarly CI C,.~ N/~.~C.N~CI
similarly
92 92
= ~i": 69%yield
69% yield
409
diazines and benzo derivatives (2006) Six-membered ring systems." systems: diazines derivatives (2006)
6.2.5.3 Applications and 6.2.5.3 Applications and structural structural studies studies
Quinoxaline bis-N-oxides have been investigated as potential anti-cancer agents 93 <06BMC69 I7> and anti-trypanosoma1agents <06BMC6917> anti-trypanosomal agents 94 <06BMC5503>. In the latter case, a vanadyl complex was prepared in order to increase bioavailability.
o o- N4"NH
oN.;..CN
,.,.,
o;q
I
0-
93
2
94
Several papers were concerned with the synthesis of and mechanism of of luminescence of Cypridina Cypridina luciferin and its analogues <06T6272; 06TL753; 06TL6057>. The binding of of the diuretic amiloride 95 to DNA has been studied <06CCI185>. <06CC1185>. The chiral camphor-derived pyrazine ligand 96 showed monomeric coordination to Cu and Zn, in contrast to the bidentate polymeric behaviour of of related earlier compounds <06ARK218>.
NH2 HN'~NH 96 96
amiloride95
amiloride 95
H
There has been continued interest in the potential of pyrazines for use in materials science and electronics. Studies of of the solid state behaviour have been carried out on pyrazine perchlorate and tetrafluoroborate <06JACSI5775> <06JACS15775> and of of alkyl-substituted pyrazine bis-Nof oxide-TCNE complexes <06TL4569>. The crystallisation and self-assembly of derivatives of hexaazatriphenylene (hat) 97, were also of interest, such as the copper complex 98 <06JACSI5799> <06JACS15799> and tri-benzo compound 99 <06JACS13042>. Fluorescent hexakis (biphenyl) derivatives have been investigated as "light-harvesting" systems <06JOC5752>.
CN N
NC.N. .
N ~N
! j
97
hexaazatriphenylene(hat)
hexaazatriphenyiene (hat)
NC~N
N
~--"N N~CN CN
CN
2Cu.__N ,' '~" IIOet
Cu',eto EtO. >N.
/4-. .N,,
NC"'~N" "~/ "N' L2Cu ' , ~. 1. N ~ c N 98
OEt
410
K. Mills
N;7 R o
Jl O H~ ~ \:N~
N[~~NII N
N
~
N~
"n-octyl n-octyl
R
99 99
The quinoxaline 100, with self-contained donor-acceptor donor-acceptor properties, has potential in optoelectronic <06JACS 10992>. Electroactive dendrimeric bis-quaternary bis-quaternary salts have been <06JACS10992>. prepared by direct quaternisation of pyrazine using dendrimeric benzyl bromides <06TL4711 >. <06TL47 11>. R I
¢X ~
N
l N" /-
N N
Q
R
R= C6H4R'or NMeAr 100
6.2.6 6.2.6
REFERENCES R EFERENCES
06ACR451 06ACR45I 06AG(I)489 06AG(I)2958 06AG(I)3 I02 06AG(I)3102
06AG(I)7781 06AG(I)778I 06ARK218 06BMC3399 06BMC5503
06BMC6917
06BMCL1418 06BMCLI418 06BMCLI850 06BMCL1850 06BMCLI854 06BMCL1854 06BMCL4893 06BMCL5633
06BaCI73 06BOC 173 06CCI185 06CC 1185
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Six-rnernbered Six-membered ring systerns: systems: diazines and benzo derivatives (2006)
06CC3769 06CEJ7178 06CEJ7I78 06CRV213 06EJ0634 06EJO634 06EJO1593 06EJ0I593 06EJ02753 06EJO2753 06EJ03332 06EJO3332 06H561 06JAI0934 06JA 10934 06JA10992 06JAI0992 06JA13042 06JAI4254 06JA14254 06JAI4802 06JA14802 06JA15775 06JA15799 06JAI5799 06JMC407
06JMC 1217 06JMCI217 79JOC629 06JOCI85 06JOC 185 06JOC 1080 06JOCI080 06JOC2143 06JOC465I 06JOC4651 06JOC4903 06JOC5752 06JOC5897 06JOC7053 06JOC7706 06JOC8324 02NMB345
06OBC291 060BC29I 060BC3056 06OBC3056 060BC4278 06OBC4278 060L255 06OL255 06OL269 060L269 0601395 06OL395 060L68I 06OL681 060Ll941 060 L 1941 060L2425 06OL2425 06OL2471 060L247I 060L2527 06OL2527 06OL3141 060L3141 06OL3737 06013737 060L4019 06OL4019 060L4775 06OL4775 060L5089 06OL5089 06OPPI476 060PPI476 06OPRD921 060PRD92I
411
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412 412 06S2799 06S2885 06S3067 06S3835 06SCI503 06SC 1503 06SL65 06SL324 06SL375 06SL804 06SL845 06SL861 06SLI394 06SL1394 06SL1437 06SLI437 06SL1586 06SLI586 06SL2403 06SL2507 06SL2609 06SL3185 06TI21 06T121 158 06TI 06T1158 06T 1444 06TI444 06T2050 06T2380 06T2799 06T5201 06T6272 06T6490 06T6848 06T7552 06T8966 06T97 I8 06T9718 06T9726 06T9787 06T9919 06T99 I9 06TII714 06T11714
06T12084 06TI2084 06TI2191 06T12191 06T12351 06TI2351 06TL31
06TL341 06TL34I 06TL353 06TL693 06TL753 06TL1777 06TLI777 06TLI989 06TL 1989 06TL2257 06TL3209
K. Mills
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Six-membered ring systems: systems." diazines and benzo derivatives (2006)
06TL3561 06TL356I 06TL3923 06TL4381 06TL438I
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414
Chapter 6.3 6.3 Chapter
Triazines, tetrazines and fused ring polyaza systems G6mez de la Oliva Pilar Goya and Cristina Gomez /nstituto fa Cierva, Instituto de Quimica Medica M#dica (CS/C), (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail: [email protected]
6.3.1
TRIAZINES
1,2,3-Triazines 6.3.1.1 1,2,3-Triazines Computational studies of hydrogen bonding complexes between 1,2,3-triazine 1,2,3-triazine and water have been carried out <06JST83; 06MI401; 06MI209>. A theoretical study of 1,2,3-triazine 1,2,3-triazine in water has been reported <06JST87>. Ternary complexes of europium(III) ions and triazine have been prepared. A complex containing 5,6-diphenyl-(2-pyridyl)-1,2,3-triazine 5,6-diphenyl-(2-pyridyl)-l,2,3-triazine produced efficient electroluminiscence <06MI489>. l-(alkylamino)pyrazolones 1 allowed the preparation of monocyclic 1,2,3Oxidation of 1-(alkylamino)pyrazolones triazin-4(3H)-ones 2, which are a new class of ofheterocycles heterocycles <06EJO3021>. <06EJ03021>.
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The reaction of of 1,2,3-triazolium-l-aminides 1,2,3-triazolium-l-aminides 3 with propiolate esters led to fluorescent 2,5-dihydro-l,2,3-triazine derivatives 4 in one pot, involving a Huisgen cycloaddition 2,5-dihydro-l,2,3-triazine of rearrangements <06JOC5679; 06TL 06TLl721>. followed by a sequence of 1721>. These reactions can be carried out in acetone, in water, or under solvent-free conditions.
415 415
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4
X
6.3.1.2 1,2,4-Triazines A convenient way to modity calix[4]arenes, calix[4]arenes, based on the direct C-C coupling reactions of of 1,2,4-triazines has been reported <06JOC8272>. <06JOC8272>. A theoretical study their phenol moiety with 1,2,4-triazines of the tautomerism of of 6-substituted 6-substituted 1,2,4-triazin-3-thion-5-one 1,2,4-triazin-3-thion-5-one has been carried out of <06JSTl23>. A new complex derived from 5-methoxy-5,6-diphenyl-4,5-dihydro-2H<06JST123>. 5-methoxy-5,6-diphenyl-4,5-dihydro-2H[1,2,4]triazine-3-thione [1,2,4]triazine-3-thione (LH (LHzOCH3) zOCH3) with methylmercury chloride was synthesized and LPtCIz and [L characterized <06POL <06POLl464>. 1464>. Complexes of of the types LPtCI2 [L2Pt]X-2 zPt]X-2 (L=substituted 3(pyridin-2-yl)-1 ,2,4-triazine) were synthesized and characterized for the first time by X ray (pyridin-2-yl)-1,2,4-triazine) crystallography <06IC7l82>. <06IC7182>. A one-pot procedure for preparing 3-pyridyl-5-substituted 1,2,4-triazines 7 from (Xo~hydroxyketones 5 and 2-pyridyl amidrazone 6 has been described <06TL3865>.
-~.
O
+ H2N~ OH H2N'N
5
PY
MnO2,A 60-70% 60-70%
6
R ' ~ N'''~NPY N 7
Substituted 1,2,4-triazines were conveniently prepared in one pot by the condensation of amides and 1,2-diketones followed by cydization cyclization with hydrazine hydrate <06MI67>. A new class of cyclic dipeptidyl ureas, namely 3-hydroxy-6-oxo[1,2,4]triazin-l-ylalaninamides 12, have been synthesized using the Ugi reaction. This reaction involved an (Xaketo-acid acid 8, an isocyanide 9 and semicarbazones 10 to give the Ugi adducts 11, wich were then stirred with sodium ethoxide <06JOC4578>. 0
Ugi o MeoH Ar.,~O + R3NC + HN"J'L'NH2 N R2 reaction
Ugi HNJlNH z reaction .. ArXO + 3 R NC + I Z MeOH NyR HO 0 99 HO" 8"O "~ 3days 3 days R1 8 R1 46-73% 46-73%
10 10
Ar O ArX
NH2 o.2 OY\N_NH~=O
NHz }=O N-NH o O...~~ RZ
°0
~ R R11 HN.R3 HN'R3 11 11
EtONa ~"'EtONa etOH .. EtOH 12hh 12 53-84% 53-84%
Ar. :.N OH ArxNyOH O
I'~ "
N2 N,N Z I '1 O...~.~ *R oy R1 ~ R1 o
HN.R3 HN'R3 12 12
Several 3-mercapto-l,2,4-trizines 3-mercapto-l,2,4-trizines have been synthesized through the condensation of thiosemicarbazide with diketones under microwave irradiation in a solventless system <06PS87>. The synthesis and cydocondensation cyclocondensation reactions of 3-substituted-5-(2aminobenzyl)-lH-[l,2,4]triazin-6-ones aminobenzyl)- 1H-[ 1,2,4]triazin-6-ones have been reported <06JHC6l3>. <06JHC613>.
416
P. P. Goya Goya and C. C.G. G. de fa la Oliva
The reactivity and use of l,2,4-triazine 1,2,4-triazine 4-oxide have been described <060M2972>. <06OM2972>. Thus, readily available (3-pyridyl)-1,2,4-triazine (3-pyridyl)-l,2,4-triazine 4-oxides 13 were used to prepare 2,2'bipyridines 15. The reaction course involves a nucleophilic substitution of hydrogen and an aza Diels-Alder (DA) reaction <06TL869>. Ar"r(N,
Ar-..../Nz+.~.x
~+l N Py Py
H H
~
oO -
Ar~ Au"~
Null •~-- u....kL.Ar""/N" 2,5-norbornadiene 2,5-norbornadiene~
NuH
RCOCI RCOCI 28-56% 28-56%
N
N
Py
82-90% 82-90%
•
N Nu
)l,A Py N Py 15 15
14
13
The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to 3-aryl-l,2,4-triazin-5(4H)triazinones was employed in the reaction of C-nucleophiles with 3-aryl-l,2,4-triazin-5(4H)ones 16 and N-protected amino acids 17, to form l-acyl-6-Nu-3-aryl-l,6-dihydro-l,2,41-acyl-6-Nu-3-aryl-l,6-dihydro-l,2,4triazin-5(4/-/)-ones 18 in high diastereomeric excess <06TL7485>. triazin-5(4H)-ones
. N
+ O
16
N.R2 R1 17
NuH •
~
14-18% 14-18%
Nu
H o@N'R2 R1 18
Chiral 4-(l-arylpropyl)amino-3-mercapto-6-methyl-4H-l ,2,4-triazin-5-ones were 4-( 1-arylpropyl)amino- 3-merc apto- 6- methyl-4H- 1,2,4-triazin-5-ones synthesized easily through enantioselective diethylzinc addition to the exocyclic C=N double bond of of 4-arylidenamino-3-mercapto-6-methyl-4H-l 4-arylidenamino-3-mercapto-6-methyl-4H- 1,2,4-triazin-5-ones ,2,4-triazin-5-ones <06TA2617>. <06TA26l7>. The pyrolysis in the gas phase of of 4-benzylidenamino- and 6-styryl-l,2,4-triazine-3,5(2H, 6-styryl-l,2,4-triazine-3,5(2H, ,2,4-triazin-5(4H)-ones has been studied 4H)-diones and 6-styryl-2,3-dihydro-3-thioxo-l 6-styryl-2,3-dihydro-3-thioxo-l,2,4-triazin-5(4H)-ones <06T1182; 06T6214>. <06Tl182;06T62l4>. The DA reaction of of 5-acetyl-3-methylthio-l,2,4-triazine 5-acetyl-3-methylthio-l,2,4-triazine with cyclic enamines has been indazolo[2,3-a]quinolizine alkaloids <06T5736>. used in the total synthesis of of new indazolo[2,3-a]quinolizine Novel agonist 5HT 5HT1A 1A receptor position emission tomography (PET) ligands derived form vivo <06JMC125; <06JMC125; 1,2,4-triazine-3,5-dione 1,2,4-triazine-3,5-dione 19 have been synthesized and evaluated in vivo 06BMCL2101>. 06BMCL21Ol>.
CH3 I
6.3.1.3 1,3,5-Triazines 1,3,5-Triazines
of an episulfonium ion-mediated ion-mediated cyclotrimerisation previously reported as a The product of 15-membered 1,3,5-triazine <06OBC3120>. <060BC3l20>. The l5-membered ring trilactam has now been shown to be a 1,3,5-triazine tautomerism 2,4-di(benzyloxy)-1,3,5-triazin-6(5H)-one has been tautomerism of of2,4-di(benzyloxy)-1,3,5-triazin-6(5H)-one been studied studied <06MI561>. <06M156l>.
417
Triazines, Triazines, tetrazines tetrazines andfused andfused ring polyaza systems
Theoretical studies on the nonlinear optical properties of octupolar tri-s-triazines have been carried out <06MI808>. The azide-tetrazole isomerism in several polyazido 1,3,5-triazines and diazido-l,2,4,5<06EJI22l0>. tetrazines has been investigated by ab initio quantum chemical methods <06EJI2210>. The tridentate ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine 2,4,6-tri(2-pyridyl)-l,3,5-triazine has continued to be the basis for different complexes, among other with copper <06IC7119>, iron <06MIlI50>, <06MI1150>, manganese, zinc and cadmium <06POL2550>, <06POLl057>. <06POL2550>, and with lanthanoids <06POLl 057>. A novel ligand N,N'di(2-pyridyl)-2,4-diamino-6-phenyl-l,3,5-triazine di(2-pyridyl)-2,4-diamino-6-phenyl-l,3,5-triazine (dpdapt) has been synthesized and its <06POLl95>. reactions with CuCb CuCI2 studied <06POL 195>. A new versatile family of chelating agents based on bis(hydroxyamino)-l,3,5-triazines, bis(hydroxyamino)-1 ,3,5-triazines, BHTS, has been described <06MII285>. <06MI1285>. The synthesis of 2,4,6-trisubstituted-l,3,5-triazines 2,4,6-trisubstituted-l,3,5-triazines has been reviewed <06MI81>. of an activated form of carboxylic acids 20 with zinc dimethyl Reaction of imidodicarbonimidate 21 led to 4,6-dimethoxy-l,3,5-triazines 4,6-dimethoxy-l,3,5-triazines 22 in high yields <06S2845>.
MeO)==NH
o0
R-< R-{
x X
+ +
znEe)=Nj ---------... Zn
N)==N
)=NH
74-95% 74-95%
(0.5 equiv) equiv) (0.5
+ + 1/2 ZnCI ZnCI22 ++ H H20 20
R---~\N~
N~
OMe
MeO MeO
20
OMe OMe
N=
2
21
1,3,5-triazapentadienes have been used as nucleophilic building blocks with different 1,3,5-triazapentadienes electrophilic reagents. In the case of aldehydes, the corresponding 1,2-dihydrotriazines were obtained whereas with ketones, depending on the substitution of the starting compounds, either 1,3,5-triazahexa-l,3,5-trienes 1,3,5-triazahexa-1,3,5-trienes or dihydrotriazines were obtained <06EJ03923>. <06EJO3923>. The dealkylative functionalization of tertiary amines 23 with electron deficient heteroaryl chlorides including triazinyl chloride 24 has been published <06TL2229>. Efficient and practical reaction conditions were determinated for a range of of substrates.
N~N N~ " N
1, ,R 2 R RI..N.R2
~3 R3
+ + PhAN Ph"~N IJ(,CI ~ci
R11 = Me, Me, Et, Et, Bn Bn R 23
24
92-96%
/~ eh
N 25
.R 2 N R3
+
R1CI
Recent applications of 2,4,6-trichloro-l,3,5-triazine 2,4,6-trichloro-l,3,5-triazine and its derivatives in organic synthesis have been reviewed <06T9507>. The selective replacement of of chlorine in cyanuric chloride by the 3,7-dioxa-r-l3,7-dioxa-r-1azabicyclo[3,3,0]oct-5-yl-methoxy group through the Williamson method has been described azabicyclo[3,3,O]oct-5-yl-methoxy <06T73 19>. The reactions of <06T7319>. of cyanuric chloride with some amine nucleophiles have been described under very mild conditions <06H807>. Synthetic strategies to generate 2-aryl- 27, 2-alkyl- 28 and 2-acetylenyl- 29 -substituted 4,6-diamino-l,3,5-triazines from the corresponding 2-chloro compound 26 have been 4,6-diamino-l,3,5-triazines reported <06TL5973>.
418
fa Oliva P. Goya and C. C. G. G. de la
AF
iC N
DME, DME, Pd(PPh Pd(PPh3) 4 3 )4 K K2CO ArB(OH)2,..._ 2C0 33,, ArB(OHh
N
II / .#4..N//J,..R
N~ N .,~ //L...
•
80 "C, oc, 62% 62% 80
HN
N 27
I
3-chloroaniline, 3-chloroaniline, KK2CO 2C0 33 acetone-water acetone-water 40"C, 94%
CI
40 ~ 9 4 ~ . . . . -/ 0 Cl ~ diethyl malonate malonate EtO EtO diethyl NaH •~ N~J'~N Nail N"/ ~Y O"C to 20"C O~176176 .1.\
° ° OEt
26
~
R=N
0 X~/
OEt
N ~ I.i.
Cl" " N " " R CI~N~R
25% 25%
~
y° ° J6 0 0 EtO'~OEt
0
Y
CI/L~N I/L"R
R
EtO
3-chloroaniline 3-chloroaniline K K2C03, ~ 2C0 3 , THF ------..~ 14O/o "'14%
HN~N?-....R HN N R I
i / :~;/
I 28 28
~
CI CI
Ph toluene, toluene, DIPEA DIPEA Cui, Cul, Pd(PPh Pd(PPh3) 4, 3)4, 20 "C, oC, 71% 71% 20
Ph
Ph t~ 3-chloroaniline 3-chloroaniline K K2C03, 2C0 3 , THF
N N Ci Lj.~N ~ . ~i \
33% 330/0
OEt
N Y/ -N N ~ I I ~II
N ~
~.~ v
N I~
HN
R
N
+
R
29
Cl The base and acid hydrolysis of sym-triazine sym-triazine mononitriles has been studied <06CHE642>. The potassium salt of 2-amino-4-methoxy-6-dinitromethylI,3,5-triazines 30 with N204 N20 4 2-amino-4-methoxy-6-dinitromethyl-l,3,5-triazines afforded the nitroformaldoximes 31 and the 1,2,5-oxadiazole N-oxides 32 <06CHEI096> <06CHE1096> <06CHE557>.
R2 .R 1
N
R2 .R 1
N204
R2 .R 1
N
R2 -R 1
N
,~
MeOI~J~LC(NO2)2 K
MeO
N
30
N .(5
MeO
56-67%
OMe
N,O, N+- O_
N,, OH
24-32%
31
32
N-alkyl-2,4-dioxohexahydro-l,3,5-triazines 33 were oxidized easily with oxygen to the N-alkyl-2,4-dioxohexahydro-l,3,5-triazines <06MI85>. corresponding cyanuric acid derivatives 34 <06M 185>.
R
~I O N. O 0yNyO ..N~/N. R/N~N'R R R 33 33
o2 _60-85% 60-85%
R[
O N. O 0yNyO I
R.-N--.[]/N-R R/NyN'R
°340
419
Triazines, Triazines, tetrazines andjitsed and fused ring polyaza systems
The wide spectrum of of potential activity of of 1,3,5-triazines is reflected in the number of publications which have again appeared in 2006. Thus, there have been reports dealing with the in silico discovery of -secretase inhibitors among which s-triazine derivatives were promising lead candidates <06JA5436>. The socalled ADATS, 6-alkylthio-4-[ 1-(2,6-difluorophenyl)-alkyl]-IH-[I,3,5]triazin-2-ones, 1-(2,6-difluorophenyl)-alkyl]- 1H-[1,3,5]triazin-2-ones, have <06Ml1073>, 2,4-diamino- and 2been identifed as novel regulators of cell differentation <06MI1073>, amino-4-alkenyl-l ,3,5-triazines have shown antitumor activity <06EJM219; <06EJM2l9; 06EJM6ll amino-4-alkenyl- 1,3,5-triazines 06EJM611 >. The optimization of triazinyl amines as non-nucleoside inhibitors of HIV-1 HIV-l reverse transcriptase has been published <06BMCL5664>. 1,3,5-Triazin-2,4,6-trione scaffolds have been employed as templates to incorporate the pharmacophore requirements of of cytosolic phospholipase A a substrate mimetics <06BMCL2978>. Screening of a chemical library in a phospholipase Azt~ 2 DNA helicase assay provided the lead for the synthesis of triaminotriazines with antibacterial activity <06BMCL1286>. The synthesis and antibacterial activity of of substituted s-triazines <06EJM1240> and the SAR of novel antibacterial 3,5-diamino-piperidinyl triazines have I>. A series of been described <06BMCL545 <06BMCL5451>. of 2,4,6-trisubstituted triazines has been synthesized and screened for antileishmanial activity <06BMC7706; <06BMC7706; 06EJM106>. 06EJM 106>. The application of cyanuric chloride in different organic reactions has been the subject of of several papers, including a review <06SL2l56>. <06SL2156>. It has been used as a dehydrating agent for the synthesis of isomaleimides <06T937; 06T3557> and for the synthesis of of bicyclic isoxazolines and isoxazoles <06OBC2851>. <060BC285 1>. It has also been employed as catalyst for the synthesis of thiiranes and oxiranes in solvent-free conditions <06TL4775>; together with nBU4NN02 Bu4NNO2 for the converssion of alcohols, thiols and trimethylsilyl ethers to alkyl nitriles <06MI220>; for the synthesis of homoallylic alcohols and amines <06TL9103> and to generate in situ HCI, HC1, used as an efficient catalyst for the solvent-free Hantzsch synthesis of of new dihydropyridines <06S55>. An efficient single-step procedure for the synthesis of 4,6-diarylpyrimidin-2(lH)-ones 4,6-diarylpyrimidin-2(1H)-ones 35 promoted by cyanuric chloride and Zn(OTf)2 or Bi(OTf)3 under solvent-free microwave irradiation conditions has been developed <06H <06HI551>. 1551 >.
Cl CI
o o o Arl.,,~H + Ar2-~CH3 + H2N/[j',.NH2
N~N N .4 N
)lA
Cl . ~ N /N" ~ C ,CI CI Zn(OTf) 22 or Bi(OTfb Bi(OTf)3
microwave 64-94%
O N'~NH Arl -"L~~Ar 2 35
Fluorous 2,4-dichloro-l,3,5-triazines 2,4-dichloro-l,3,5-triazines have been used as nucleophilic scavengers <06MI728> and as amide coupling agents <06MI724>. The preparation of of t-butyl 4,6dimethoxy-I,3,5-triazinylcarbonate dimethoxy-l,3,5-triazinylcarbonate (Boc-DMT) and 9-fluorenylmethyl 4,6-dimethoxy-l,3,5triazinylcarbonate (Fmoc-DMT) and their usefulness as N-protecting reagents for amines has been rerported <06S1931>. The use of of 1,3,5-triazine-based synthons in supramolecular chemistry has been reviewed <06EJI29>. The synthesis of of bis(triazine) molecules capable of acting as synthetic receptors for barbiturate guest molecules has been described <06EJ01444>. <06EJO 1444>. Two series of of triazine-based dendrons were efficiently prepared by a convergent method and their properties studied <06OL1541>. <060L1541>. A practical syntheis of [1,3,5]triazine dendritic molecules on solid supports has been described <06MI2248>.
420
P. Goya G. de la fa Oliva Goya and C. C.G.
A number of tetraazacalix[2]arene[2]triazines tetraazacalix[2]arene[2]triazines bearing substituents on the bridging atoms were synthesized using a fragment coupling strategy <06OL5967>. <060L5967>. Nonmesomorphic as well as mesomorphic V-shaped acids with a structure similar to 2,4,6-triamino-1,3,5-triazine derivative banana liquid crystals, have been complexed to a 2,4,6-triamino-l,3,5-triazine <06JA4487>. <06JA4487>. The organic inclusion compound 2,4,6-tris-(4-bromophenoxy)-l,3,5-triazine 2,4,6-tris-(4-bromophenoxy)-1,3,5-triazine was used to create an ordered arrangement of of endohedral fullerenes in a crystalline host matrix <06CPL327>. chIorosilanes Organic-inorganic hybrid gels based on s-triazine have been prepared from chlorosilanes by exchange reactions <06CC4741>. <06CC4741 >. 1,3,5-Triazines having oligo(1,4-phenylvinylene) chains in the 2-, 4- and 6-positions have been synthesized and exhibit strong push-pull effects <06EJ02609>. <06EJO2609>. The synthesis and crystal structures of di- and triorganotin(IV) derivatives with 6-amino1,3,5-triazine-2,4-dithiol I606>. 1,3,5-triazine-2,4-dithiol have been reported <06JOM 1606>. Self-assembled hexanuclear arene ruthenium metallo-prisms with 2,4,6-tripyridyl-l,3,52,4,6-tripyridyl-1,3,5<06CC4691 >. triazine (ppt) subunits showed unexpected double helical chirality <06CC4691>.
6.3.2
TETRAZINES TETRAZINES
A new electrofluorescent switch was prepared with an electroactive fluorescent tetrazine blend of of polymer electrolyte <06CC3612>. The structure and magnetic properties of the stable oxoverdazyl free radical 6-(4-acetamidophenyl)-1 ,4,5,6-tetrahydro-2,4-dimethyl6-(4-acetamidophenyl)-l,4,5,6-tetrahydro-2,4-dimethyl1,2,4,5-tetrazin-3(2H)-one <06POL2433>. The synthesis and 1,2,4,5-tetrazin-3(2H)-one has been reported <06POL2433>. characterization of two new tetrathiafulvalene (TTF) derivatives bearing pyridine-based substitutents and 1,5'-dimethyl-6-oxoverdazyl radicals have been described <06JOC2750>. <06JOC2750>. New high-nitrogen materials with 3-amino-6-nitroamino-tetrazine 3-amino-6-nitroamino-tetrazine (ANAT) as the anion have been synthesized and their properties studied <06CC4007>. The reaction of 3,6-diaryl-1,2,4,5-tetrazines 3,6-diaryl-l,2,4,5-tetrazines (aryl == phenyl, 2-furyl or 2-thienyl) with 2 equivalents of of Ru(acacMCH Ru(acac)z(CH3CN)2 3CN)z resulted in reductive tetrazine ring opening to yield diruthenium complexes <06IC821>. <06IC821 >. Complexes involving the 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine (bptz) ligand have been obtained <06JA5895; 06MIl498>. 06MI 1498>. of cyanoacetic acid esters with s-triazine monoazides afforded The unusual reaction of derivatives of a novel coupled heterocyclic system: 2-[1,3,5]triazin-2-yl-l,22-[ 1,3,5]triazin-2-yl-1 ,2dihydro[ 1,2,3,4]tetrazine-5-carboxylic acid esters <06CHE965>. dihydro[1,2,3,4]tetrazine-5-carboxylic tetrahydro-1 ,2,4,5-tetrazinan-3-ones have been prepared by the reaction of A series of tetrahydro-l,2,4,5-tetrazinan-3-ones bis(1-methylhydrazide) carbonic acid bis( I-methylhydrazide) with aromatic aldehydes <06JCR(S)515>. <06JCR(S)515>. ,4-dihydroThe synthesis, structure analysis and antitumor activity of 3,6-disubstituted-1 3,6-disubstituted-l,4-dihydro<06BMCL3702>. 1,2,4,5-tetrazine 36 derivatives have been described <06BMCL3702>.
RCN ++ N N2H4x H20 RCN 2 H4 x H2 0
sulfur.
~
EtOH
1R
A NY NH t. I I ....__~
N-N
~ NH ~ ~ R--
R R 32-85% 32-86%
36 36
421
Triazines, polyaza systems Triazines, tetrazines andfused and fused ring polyaza
The inverse electron demand DA reaction of 1,2,4,5-tetrazines has continued to be the most important reaction of this system. of the novel 3-methylsulfinyl-6-methylthio- 37 and 3The cycloaddition reactions of (benzyloxycarbony1)amino-6-methylsulfinyl(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides <0610C <06JOC 185>. OR 11
°0 N-N SCH3H3 H3C-S;--~ r\~F-SC H3C-S-{ 37
37
54-96% R R 54-96%
\
N-R22 N-R
+ +
N-N °O___//N-N H3C-S-{ rNHCbz
\)---NHCbz N=N 38 38
H3C-S----~
N=N
39
=
~
O ~
R
==
N-N
H3 H3C-~S ~;/ S ~C H3C-S~SCH3
R R22 R
N=N
II
O ~
=•)R ===<
N-N
H3C-S~NHCbz H3C-S~NHCbZ
R
R 34-83% 34-83% 40 4O
The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazines 3,6-di(pyridin-2-yl)-l,2,4,5-tetrazines to give the corresponding di(pyridin-2-yl) pyridazines was considerably accelerated under microwave assisted conditions <06JOC4903>. <0610C4903>. The [4+2] cycloaddition of of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate dimethyl-l,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene N,O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S 1513>.
jEWG C,O2Me EtO NH2 ~2Me~ ,~~ ~.__~--'3~ NY ~ 12-98% NI I /
NyN
H2N
=N
C,O2Me
~
$::WG I
N N"
NH
Me02C MeO2C, Zn/AcOH Zn/AcOH ~
•
2
CO2MeNH2
C0 2Me
42
CO2Me C,O2Me C02Me~ 93% ~ ~ ~X;Me 41 93% 41 N N rNH NH22 N C0 CO2Me 2Me
43
...-:
/ ~ NH NH22 Me02C MeO2C 44 Me02C MeO2,~ N
Zn/AcOH Zn/AcOH v ~
87% 87%
;rEWG
H N ~ EwG
HN
~N HN)--~NH2
HNy( ...-: NH 2 Me02C MeO2C
45
45
Other examples of the use of of 1,2,4,5-tetrazine derivatives in [4+2] [4+2] cycladditions have been reported <06T8169; 06E103358>. 06EJO3358>. Conformationally restricted 6-isoxazol-5-yl-6,7-dihydo-5H-[ 1,2]diazocin-4-ones were 6-isoxazol-5-yl-6,7-dihydo-5H-[1,2]diazocin-4-ones synthesized from 1,2,4,5-tetrazines and isoxazolylcyclobutanone <061OC2480>. <06JOC2480>. The reaction of of thietan-3-one 46 with 1,2,4,5-tetrazines 47 gave 4H-pyrazolo[5,1c]thiazines 48 via a rare anti-Michael addition <06TL7893>.
422
P. Goya Goya and CG. C.G. de la Oliva
Ph Ph
Ar
r
N~N
ROH
S S~
NyN N.,~N
KOH KOH
46 46
Ar 47 47
Ph--)j0 + +
II
I
Ph~
Y - t'-.::r
Ph ~IPh"
~
/ L
~ -..... ~ N-N/, "r S,,._~N / Ar
::::-...
~
S"-{N
Ar
Ar
A r J Ar
52-56% 52-56% 48 48
The hetaryl displacement in 3,6-disubstituted 1,2,4,5-tetrazines with anhydro bases of Nmethylquinaldiniums has been described <06MI99>.
6.3.3
FUSED FUSED [6]+[5] POLYAZA POLYAZA SYSTEMS SYSTEMS
6.3.3.1 Triazino Triazino and tetrazino [6+5] fused systems
The synthesis and biological activity, as vascular endothelial growth factor (VEGF) pyrrolo[2,1:f][1,2,4]triazine derivatives have been inhibitors, of of a series of substituted pyrrolo[2,1-J][1,2,4]triazine reported <06JMC2143>. Novel synthetic routes for the preparation of of previously inaccesible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines pyrazolo[I,5-d][1,2,4]triazines have been described and their affinity for benzodiazepine binding site studied <06BMCL3550; 06BMCL872>. the GABA GABAA A [ 1,2,4]triazines, [ 1,2,4]triazin8-ones imidazo[2, l,2-b] [1 ,2,4]triazines, imidazo[ 11,2-d] ,2-d] [1 ,2,4]triazin-8-ones and imidazo[2,1Imidazo[ 11,2-b] j] [1,2,4]triazin-8-ones J][ 1,2,4]triazin-8-ones have also been synthesized as agonists of the GABA GABAA benzodiazepine A <06JMCI235; 06BMCLl477; receptor <06JMC1235; 06BMCL1477; 06BMCLl582>. 06BMCL1582>. The synthesis, crystal structure and anticancer activity of derivatives of ethyl and methyl (tetrahydroimidazo[2,I-c][1,2,4]triazin-3-yl) (tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl) formate and acetate have been reported <06EJM539; 06EJMI373>. 06EJM1373>. pyrazolo[4,3-e][1,2,4]triazine 4,3-e][ 1,2,4]triazine 52-53 family of natural products, The synthesis of the pyrazolo[ fluvine A, pseudoiodinine and nostocine A have been reported <06JA5646>.
H2N.N..H
H
NTO
[PhCH2NMe3]+CI~'~- NZ ~.-N//',,.CO2Et MeCN,A
E
N-N H
EtOH,A ~
002
49
i. CF3CO2H CH2Cl2 ii. KOH, KOH,MeOH MeOH
B~
'oc
ILN~CO2Et 47% 50
.Nx_..~H H, .N HH TMSCHN2 N'N~N TMSCHN ~,,, N / ~ N + WN"X{, z ~0., ~I/NI'NH N NH - - - -....~ II + llN/O I. N N~'~ MeOHMeCN MeOH:MeCN OMe 4:9 18% 35% 4:9 35% 0O 18% OMe /0
51
52 Identical to fluvial fluviol A and narmethylpseudaiadinine normethylpseudoiodinine
Me Me I
WNyN, N"N'r~N' I~N~NH llN~NH 4% 4% 0O 53 Identical to nastacine nostocine A
Pyrazolo[4,3-e][ 1,2,4]triazine derivatives have been prepared from oximes of of 5-aryl- and Pyrazolo[4,3-e][1,2,4]triazine 5-formyl-I,2,4-triazines pyrazolo[5, l-c][ 1,2,4]triazines incorporating an 5-formyl- 1,2,4-triazines <06MIl91>. <06MI 191 >. Novel pyrazolo[5,1-c][ N-(2-oxoethyl)phthalimide moiety have been reported <06JCR(S)6>.
423
Triazines, Triazines, tetrazines tetrazines andfUsed andfused ring polyaza systems
,2,4-triazolo[3,4:f][1 ,2,4]triazin-8(7H)-one The synthesis and structures of of 6-amino-l 6-amino-l,2,4-triazolo[3,4-J][1,2,4]triazin-8(7H)-one <06MI169; 06MI444> and of of dihydrotetrazolo[5,I-c][1,2,4]triazines dihydrotetrazolo[5,1-c][1,2,4]triazines have been derivatives <06MIl69; described <06H1595>. <06HI595>. Pyrazolo[I,5-a][1,3,5]triazines 58 were obtained by an efficient one-step reaction from Pyrazolo[1,5-a][1,3,5]triazines iminodithiocarbonates iminodithiocarbonates 54 and pyrazole 55, or by an alternative two-step reaction form the aroyl isothiocyanates 56 and pyrazole 55 <06TL5441 <06TL5441>. >.
O
SEt
HN,"N~__Me Ar ...JJ...N//[~.SEt + H2N~..L.~/~- ~ DMF,A 54
Ar
55
f'l?
Me Me
NI~ HN hHN 0
Ar"[J"N-C- =S + 56
H~"
H2N 55 55
Me
H L1 Ar"vN NH A ~ A r I1~ ---..... II N~I,~NH MeCN 0 MeCN O SS
II
70-96% 70-96%
i.NaH,EtBr EtBr LNaH, DMF, Itrt DMF, iLDMF~
EtS 58
~ 75-90%
57
1,2,4-triazolo[ 1,5-a][ 1,3,5]triazines (5-azapurines) The synthesis and biological activity of 1,2,4-triazolo[I,5-a][1,3,5]triazines has been reviewed <06HI723>. <06H 1723>. Novel three-component reactions of thiazole Schiff bases, ammonium acetate and aromatic aldehydes under solvent-free microwave irradiation conditions yielded diastereoselectively thiazolo-s-triazines <06GC455>. 2-amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one and its Aminomethylation of 2-amino-5,5-bis(hydroxymethyl)-l,3-thiazol-4(5H)-one spiro analogs gave the corresponding [1 ,3]thiazolo[3,2-a][ 1,3,5]triazine derivatives [1,3]thiazolo[3,2-a][1,3,5]triazine <06CHE1086>. <06CHE 1086>. Condensed tetrazolo[1,5-a][1,3,5]triazin-7-ones tetrazolo[ 1,5-a][ 1,3,5]triazin-7-ones have been prepared from the corresponding 4-azido-l ,3,5-triazines <06CHE 1051>. 4-azido- 1,3,5-triazines 1051 >.
6.3.3.2 Purines Purines and related structures structures The number of publications under this heading is considerable, even through purine nucleosides and related structures have not been included. A general and efficient solid-phase synthesis of N-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase <06TL8897>.
P. Gaya Goya and CG. C.G. de la Oliva
424
H S'~N ~Ar ~,,,, N~/NH2
~L~N
..
ArNCS, ArNOS'DMF DMF~-~
N" R2 CHzCl CH2Cl2, 80 ~ z, 80°C microwave microwave
.RI
DIC, DIC, CHzCl CH2Cl2z
,~N~/NH ~
L~ N
H
RI
R2
DMF, EtOH, EtOH, DMF, 25 ~ 25°C
N" H
60
..
59
~...N / ~ N ~L~N
R1
Ar x.~N'H TFA, CH3ON N R2 25 ~ ,v-
61
,,,/~.....--N Ar A N-:J-~ N ~NH ~>--N'H Jt ~N
HN
HN R1 R1
N
Ar
N
R2 R Z
55-81% 55-81% 62
A regiospecific strategy to N-7-substituted purines 65 and its application to a library of of 2,6,8-trisubstituted purines has been reported. The three-step synthetic strategy involves cyclization reactions of suitably substituted pyrimidines 63 with either a carboxylic acid or an aldehyde <06JC041O>. <06JCO410>.
SAr H H SAr
. . ~ N'RI N~N'R1
R
)l~ N
NH2 NHz
63 63
RZCOzH
SAr SAr
..
/j~T~N//X~
R2CO2H ~
2 or R CHO R2CHO
R1 R1
3 4 ii. R R3R4NH ii. R NH
64 64
33-90% 33-90%
61-95% 61-95%
..
mCPBA R2Z i.imCPBA. ~
/~"N ~ ' ' ' ' ~.I
;f):N}-R R N N N R
R _R44 R33, -R
)l\~' ~ N
RI
ANN ~-...::::::/ I / / X N -
R R
Rz2 }-R N
N
65 65
A practical synthesis of 2-arylamino-6-alkylaminopurines from 2,6-dichloropurine 2,6-dichloropurine by base-assisted substitution of the 6-chloro substituent with cyclobutylamine followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in the intermediate <06OPRD799>. purine with an aromatic amine has been published <060PRD799>. Suzuki-type Pd(O) Pd(0) coupling reactions have been used for the synthesis of 2-arylpurines <06BMCL3144>. A microwave-assisted method to prepare novel 8-mercapto-3-methyl-7-alkyl xanthines 68 has been reported. Compared to conventional synthetic routes, the new method has significantly shortened synthetic steps and reaction time <06TL775>. 0O
q"' ~ B r
oO
[NH NH2z CH CH33
66
RNH RNH2z
..
..~,.__
microwave, 120~ 10 10 min min 120°C, 71-81% 71-81%
~x"HR
oO
NHR
EtOC(O)SK EtOC(O)SK
.. ~
DMF, [NH NHz2 microwave, microwave, 120 °C, ~ 10 10 DMF, min 120 min CH CH33 73-97% 73-97% 67
O
R
qN~SH .~I~//X__
SH
oO
N N
CH33 CH 68
DirectC-Harylationofpurinesinposition Direct C-H arylation ofpurines in position 8 by diverse aryl iodides has been achieved with Pd catalysis in the presence of CuI and CS2C03. Cs2CO3. The methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reactions
425
Triazines, Triazines, tetrazines tetrazines andfused andfused ring polyaza systems
<060L5389>. Treatment of NaH followed by alkyl iodides <06OL5389>. of 6-(heteroaryl)purines 69 with Nail <06JOC8901 >. gave regiospecific N9 alkylation derivatives 70 <06JOC8901>.
N-X N-X
N-X
dl \L R-.-J!...~ \N" -H
R
~:
1 NJl N~
Y Y
N
69 69
N H H
R
N
H
Y
N
N,
i. NaH, DMF 1 ii. ii. RRll1
83-97%
83-97%
70 70
R1
The selective magnesiation of of chloro-iodo purines which represents an efficient approach to new purine derivatives has been published. Both 6-chloro-2-iodo-purine 71 and 2-chloro-6I1Mg exchange reaction with i-PrMgCI -80°C, iodo-purine 72 undergo a selective I/Mg i-PrMgC1 at at-80 ~ thus, 6chloro-2-(phenylhydroxymethyl)-purine 73 and 2-chloro-6-(phenylhydroxymethyl)-purine 74 were synthesized. However, the reaction course at 0 °C ~ was different. Magnesiation of 6chloro-2-iodo-purine 71 proceeded with the migration of magnesium to the 8 position of the purine nucleus. In the case of 2-chloro-6-iodo-purine 72, substitution of iodine by an alkyl group from the Grignard reagent together with a CI/Mg C1/Mg exchange reaction took place. Finally, the reaction with aldehydes afforded the corresponding alcohols 6-chloro-8(phenylhydroxymethyl)-purine 75 and 6-alkyl-2-(phenylhydroxymethyl)-purine 76 <060Ll291>. <06OL 1291 >.
Cl
Cl
CI
Cl
CI
~N
DoC TH ~ H OH RNI.~N~N N / ~ N/XN ---'~ FRICHo_8O ~ TH ," ~NN/~N N//L" \7 ii.,.iPrMgC,. FRIcHoOoC ~ N ~1~ / ~ NN N~xR
Rl
I
)l ~ ~
OH OH
'N
~
R 73 73 R
i. iPrMgCI, THF
i. iPrMgCI, THF ~ ii.,./PrMgC,. -80°C
Ii. R1 CHO
ii.R1 CHO
48-85%
48-85%
R 71 71
47%
47%
I i. iPrMgCI, THF ~N i. R 1MgCI , THF ~ -80°C ~I, ~ ~ -80°C to 0 °C .. 1 Ii. CI/'--N"'-': ~ ii. R CHO ii. R2 CHO ii. 50% 72 R 54-68%
THF i / - ~ N~> ~ i. iPrMgCl, N -80~176 ~ -80 ~ .A. .I-.NJ RIcHo Cl N R2CHO CI N//L'N 72 R 54-68% 74 R 50%
t
N
75 75
~ R R
R1
OH
R1
N
N3--Nj R2 76 R
The cyclization and rearrangement products from the coupling reactions between terminal O-ethynyl(hydroxymethyl)benzene and 6-halopurines have been described <06T6121>. <06T6121 >. In a report dealing with the synthesis and anticancer activity of (6'-substituted)-7- and 9(2,3-dihydro-5H-l ,4-benzodioxepin-3-yl)purines, transformations of (2,3-dihydro-5H- 1,4-benzodioxepin-3-yl)purines, of N9'-alkyl-6'-halopurines have been described <06TlI724>. <06T11724>. Several reports have dealt with biological properties of purine derivatives: a general review <06BMC3987>; 2-arylpurines as CdK inhibitors <06BMCL3144>; 2,6-disubstituted and 2,6,8-trisubstituted purines as adenosine receptor antagonists <06JMC2861>; 2,8,9trisubstituted purines as TNF-a. TNF-c~ inhibitors <06BMCL4360>; 6-substituted purines as antileishmanial agents <06EJMl>; <06EJM 1>; purine derivatives incorporating metal chelating ligands as my HIV integrase inhibitors <06BMC5742> and purine-based derivatives as inhibitors of the heat schock protein 90 <06JMC381; 06JMC817; 06JMC5352>.
426 426
P. Gaya fa Oliva Goya and e.G. C.G. de la
Several papers dealing with xanthine-based compounds as adenosine A receptor antagonists have been published: published: 1,3,81,3,8- and 9-substituted 9-deazaxanthines as human A AZB 2B adenosine receptor antagonists <06JMC282>; 1,3-dipropyl-8-( l-heteroarylmethyl-1H1,3-dipropyl-8-(1-heteroarylmethyl-lHA2B pyrazol-4-yl)xanthine derivatives as high affinity and selective A 2B adenosine receptor substituted xanthines as adenosine A~ Al receptor antagonists <06BMCL302>; norbornyllactone norbomyllactone substituted 1-(2-hydroxy-3-phenoxypropyl)]xanthines as AI antagonists <06BMC3654>; 1- and 3-[ 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines A1 and imidazoline derivatives as potent A2 adenosine receptor antagonists <06BMC2697>; tricyclic imidazoline A2 Al receptor antagonists <06JMC7l32> and selective selective adenosine A1 <06JMC7132> and tricyclic arylo-, imidazo-, A2A receptor pyrimido- and diazepinopurinediones diazepinopurinediones with affinity for the adenosine AZA <06BMC7258>. A convenient regioselective one-pot approach to pyrazolo[1,5-a]- and imidazolo[1,2~,~-unsaturated imines 77, a]pyrimidine derivatives 79 from aminoheterocycles 78 and a,~-unsaturated situ, has been described <06TL26 11>. generated in situ, <06TL2611 >.
ArlCN
Etop o EtO"~ ~
NH
N
F ;r21 RNH2 Ar2~,r~N~ . , , 78 ~-~
Arl.~( D Ar2CHO 0,-"I~QOEt ~L Ar 1L Et
NH
77 77
J
52_76O/o
R
~N '~ Ar ~ 79 79
Microwave-assisted regiospecific shyntesis shyntesis of 2-trifluoromethyl-7-trihalomethylated 2-trifluoromethyl-7-trihalomethylated pyrazolo[1,5-a]pyrimidines has been reported <06MI358>. A one-step synthesis of pyrazolo[1,5-a]pyrimidine via an intermolecular aza-Witting reaction has been achieved <06JHC523>. The synthesis pyrazolo[3,4-djpyrimidine derivatives and their activity as potent synthesis of new pyrazolo[3,4-d]pyrimidine antiproliferative and proapoptopic agents has been reported <06JMC <06JMCI549>. 1549>. of antimicrobial pyrazolo[3,4-djpyrimidines containing 8A series pyrazolo[3,4-d]pyrimidines (trifluoromethyl)quinoline have 5-amino- 1-[8(trifluoromethyl)quinoline been synthesized from 5-amino-l-[8(trifluoromethyl)quinolin-4-yl]-lH-pyrazole-4-carboxylate (trifluoromethyl)quinolin-4-yl]- 1H-pyrazole-4-carboxylate and 4-carbonitrile <06BMC2040>. A test library with three novel p38a p38ct inhibitory activity has been prepared, among them pyrazolo[3,4-d]pyrimidine and pyrazolo[3,4-b]pyrazine with potent in vivo vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-d]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide Friedl~.nder has been reported <06JHCl169>. A facile synthesis of pyrazolo[3,4-djpyrimidines pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-djpyrimidin-4-one pyrimido[4,5-d]pyrimidin-4-one derivatives has been published <06SC2963>. Pyrazolo[4,3-djpyrimidines Pyrazolo[4,3-d]pyrimidines have been prepared as inhibitors inhibitors of coagulation factor Xa <06BMCL73l>, <06BMCL5176; 06BMCL3755>, as cannabinoid receptor CB CB1I antagonists <06BMCL731>, as selective PDE5 PDE s inhibitors inhibitors <06JMC3581> and as analogues of myoseverin with antiproliferative <06EJM1405>. antiproliferative activity <06EJM 1405>. Yriazolino[4,3-a]pyrimidines, pyrazolo[3,4-d]pyridazines and isozazolo[3,4-djpyridazines isozazolo[3,4-d]pyridazines 4,3-a ]pyrimidines, pyrazolo[3,4-djpyridazines Triazolino[ have been synthesized from hydrazonoyl chlorides chlorides <06SC97>. A novel tricyclic piperidine-fused pyrazolo[1,5-a]pyrimidin-7-(4H)-one has been synthesized with regioselective formation of the tricyclic core structure <06MI7l5>. <06MI715>.
427
Triazines, tetrazines tetrazines and fused ring polyaza systems Triazines, andfused
6.3.4
FUSED [6]+[6] POLYAZA POLYAZA SYSTEMS SYSTEMS
Molecular orbital calculations have been used to analyze the stabilities of dihydropterins <06H1705>. The photochemistry of of 6-(hydromethyl)pterin in aqueous solution has been investigated <06HCAI090>. <06HCA 1090>. A new synthesis of pterins based on the acylation of of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero DA cycloaddition and cleavage of N-D bond has been reported <06HCAI140>. of the N--O <06HCA1140>. Several new substituted pterins have been obtained in an efficient one-pot procedure using N ,N'N,N'dimethyldichloromethyleniminium chloride (phosgeniminium chloride) and a suitable pyrazine <06H933>. Pteridines have been prepared in good yields from 6-amino-5-nitrosouracils with Meldrum's acid in the presence of piperidine as catalyst under thermolytic conditions <06SC3085>. Novel 6-formylpterin derivatives have been synthesized and their neuroprotective effects studied <060BCI811>. <06OBC 1811>. The synthesis of 4-trifluoromethylpyrimido[4,5-c]pyridazin-5,7-diones from 6hydrazinouracils and 1,1, 1,1,1-trifluoropropane-2,3-dione I-trifluoropropane-2,3-dione monohydrates has been reported <06H1875>. Novel pyrimido[4,5-c]pyridazines have been synthesized and investigated as inhibitors oflymphocyte of lymphocyte specific kinase <06BMCL4257; 06H2037>. 4,5-c ]pyridazin-5,7-diones 80 with Reaction of of 3-alkylamino-6,8-dimethylpyrimido[ 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazin-5,7-diones cyclohexyl and cycloheptylamines afforded novel cycloalkano bis(pyrrolo[2,3c]pyrimido[5,4-e]pyridazines 81 <06T652>. NH2
Me.N N".
ci
)n
- 1,2 ,2 n=
I
Me 80 80
O
O
M~ N
Me/N
O N-Me
..
AgPY2M O4 AgPY2 Mnn04 6-13% 6-13%
Me N O
N"N 31""N/"~-NN "3L"N" N I
I
R
R 81
Electron-rich 6-[(dimethyl(amino)methylene)amino uracil 82 underwent [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides to afford novel pyrimido[4,5-d]pyrimidine derivatives 83-84 after elimination of dimethylamine from the (1: I) cycloadducts and oxidative aromatization. This one-pot procedure yielded (1:1) excellent yields when carried out in the solid state and under microwave irradiation <06BMCL3537>.
428
and C.G. C. G. de la fa Oliva P. Goya and
OEt x
yOEt
O~,.OEt o
~
o O
0
Me, M e . . N~ ~
~
/
I
ArNH2
H
AL1 microwave microwave 83-95% 83-95%
~ J~~-~-.~ ~,~ O-~~ N.Me A microwave o ~ ~ ~microwave
Me Me
Me Me
82 82
Ar ~
00,~Et
Ar N,Ar
Me'N
A
I J
O"~NLN/'~J 0 ~ N Me Me 83 ~
y A [
0 O Ar Me.. N.JJ.,..~ N.. Ph Me'N N,Ph
J O~,. 0 ~ L N ~N
,N,p o~N "Pnn O 80-90%
Me 84 84
of p38 MAP kinase inhibitors, inhibitors, a series of of 3,4-dihydropyrimido[4,53,4-dihydropyrimido[4,5Within an SAR study of d]pyrimidin-2-ones 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones were d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones prepared <06BMCL4400>. <06BMCL4400>. Coordination frameworks of pyridazino[4,5-d]pyridazine have revealed a pronounced of pyridazino[4,5-d]pyridazine ability for anion 1t <06CC4808>. n interactions <06CC4808>. In a report dealing with novel classes of of GABA GABAA benzodiazepine binding site A receptor benzodiazepine Wadsworth-Emmons ligands, pyrazino[2,3-d]pyridazines were prepared using an aza Wadsworth-Emmons pyridazino[4,5-c]pyridazine cyclization as the key step <06TL2257>. The formation of of pyridazino[4,5-c]pyridazine 4-phenyl-I,2,4-triazoline-3,5-dione to crossderivatives upon [4+2] cycloaddition of of 4-phenyl-l,2,4-triazoline-3,5-dione <06JHCII15>. conjugated monoferrocenyltrienes has been reported <06JHC 1115>.
6.3.5
MISCELLANEOUS MISCELLANEOUS
Pyrimido[3',2':4,5]thieno[3,2-d]pyrimidinones Pyrimido[3',2':4,5]thieno[3,2-d]pyrimidinones reacted with hydrazonoyl halides in dioxane and triethylamine to give the corresponding tetracyclic fused tetrazines <06JHC935>. The electrochemical oxidation of catechols in the presence of 6-methyl-l,2,4-triazin-3thion-5-one and 4-amino-6-methyl-I,2,4-triazin-3-thion-5-one 4-amino-6-methyl-l,2,4-triazin-3-thion-5-one as nucleophiles in aqueous solutions provided an efficient electrosynthesis of thiazolo[3,2-b] [1,2,4]triazin-7-one and thiazolo[3,2-b][1,2,4]triazin-7-one 1,2,4-triazino[3,4-b] 1,3,4-thiadiazine derivatives respectively <06TLl713> <06TL 1713> <06TL8553>. Isoindolo[2,I-c]benzo[I,2,4]triazines Isoindolo[2,1-c]benzo[1,2,4]triazines 85 have been described as a new ring system with antiproliferative activity <06BMC343>.
O
R1 H H H2N
O
~ ..~ R3 NaHSO3 R4 40-95%
CN a 4
NaNO2
N H2N
.,
R3
R2
R1
AcOH 84-98%
0 .4 N-N
R2
R1
85
Structurally related sets of triazinoquinoline, triazinoisoquinoline and pyridotriazine derivatives have been synthesized and their binding to benzodiazepine receptors studied <06EJM445>. Pyridazino[3',4' :3,4]pyrazolo[5, l-c]-1 ,2,4-triazines have been prepared and Pyridazino[3',4':3,4]pyrazolo[5,1-c]-l,2,4-triazines their antimicrobial activity evaluated <06PS809> <06PS2505>.
Triazines, tetrazines andfused systerns and fused ring polyaza systems
429 429
of tetracyclic 1,2,3An efficient one-pot synthesis An efficient one-pot synthesis of tetracyclic 1,2,3fused triazine[4",5":4',5']thieno[3',2':4,5]thieno[3,2-dj-1 ,2,3-triazines has described triazine[4",5":4',5']thieno[3',2':4,5]thieno[3,2-d]- 1,2,3-triazines has been described been <06JHC1051>. <06JHC 1051 >. pyrazolo[4,3-e][11,2,4]triazolo[ ,2,4]triazolo[ 1,5I,5The synthesis synthesis and biological studies studies of of a new new series of of pyrazolo[4,3-e][ c]pyrimidines as antagonists antagonists of of the human human A A33 adenosine adenosine receptor receptor have been reported reported have been c]pyrimidines <06JMCl720>. <06JMC 1720>. The solid phase phase parallel synthesis of of tetrahydroimidazo[1,2-a][1,3,5]triazepin-2-thiones tetrahydroimidazo[ 1,2-a][ 1,3,5]triazepin-2-thiones The 2-imines has been reported starting from resin-bound peptides <06JC0127>. <06JCO127>. and 2-imines been reported resin-bound peptides Pyrazo1o[ with potent potent and selective phosphodiesterase phosphodiesterase Pyrazolo[ 1',5': 1,6]pyrimido[4,5-djpyridazinones 1,6]pyrimido[4,5-d]pyridazinones with 5 (PDE inhibitory activity have been been described (PDEs) described <06JMC5363> <06JMC5363> s) inhibitory
6.3.6
REFERENCES REFERENCES
<06BMC343> <06BMC2040> <06BMC2697>
<06BMC3654> <06BMC3987> <06BMC5742> <06BMC7258>
<06BMC7706> <06BMCL262>
<06BMCL302> <06BMCL73I> <06BMCL731>
<06BMCL872>
<06BMCLl286> <06BMCL1286> <06BMCLl477> <06BMCL1477>
<06BMCL 1582> <06BMCL1582> <06BMCL2101>
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<06CHE1051> <06CHE I051 > <06CHE I086> <06CHE1086> <06CHE I096> <06CHE1096> <06CPL327> <06EJI29> <06EJ122 10> <06EJI2210> <06EJM 1> <06EJMI>
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P. Goya and C. G. de la fa Oliva C.G.
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Triazines. Triazines, tetrazines andfused and fused ring polyaza systerns systems
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<06JMC5363> <06JMC5363> <06JMC7132> <06JMC7132> <06JOCI85> <06JOC 185> <06JOC2480> <06JOC2750> <06JOC4578> <06JOC4903> <06JOC5679>
G. de la fa Oliva P. Goya and C. C.G.
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Triazines, tetrazines and andfused fused ring polyaza systems
<06JOC8272> <06JOC8901> <06JOMI606> <06JOM 1606>
<06JST83> <06JST87> <06JSTl23> <06JST123> <06MI85> <06M 185> <06MI67> <06MI81> <06MI99>
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<06OBC 1811> <060BCI811> <060BC285I> <06OBC2851 > <060BC3120> <06OBC3120> <060Ll291> <06OL1291> <060Ll541> <06OL 1541> <060L5389> <06OL5389> <060L5967> <06OL5967> <060M2972> <06OM2972> <060PRD799> <06OPRD799> <06POLl95> <06POL 195>
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<06T937> <06TI182> <06T 1182> <06T3557> <06T3557> <06T5736> <06T5736> <06T6121> <06T6121> <06T6214> <06T6214> <06T7319> <06T7319> <06T8169> <06T9507> <06T11724> <06T 11724> <06TA2617> <06TL775> <06TL869> <06TLI713> <06TL 1713> <06TLI721> <06TL 1721> <06TL2229> <06TL2257> <06TL2611> <06TL2611 > <06TL3865> <06TL4775>
G. de la Oliva P. Goya and C. C.G.
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436
Chapter 6.4 Six-membered ring systems: systems" with 0 and/or S atoms
Unfortunately, due to unforeseen and unfortunate circumstances, the regular chapter on 'Six-membered ring systems: with 0O and/or S atoms' does not appear in this volume. We apologise for this omission. We anticipate that PHC 20 will include a double chapter on this of 2006 and 2007. area, covering the literature of
437
Chapter 7
Seven-membered rings John B. Bremner Department of of Chemistry, Chemistry, University University of of Wollongong, Wollongong, Wollongong, NSW 2522, AUSTRALIA [email protected] jo hn_b remne r@ uow. edu. au Samosorn Siritron Samosom Department ofChemistry, Department of Chemistry, Faculty ofScience, of Science, Srinakharinwirot University, University, Bangkok 10110, THAiLAND THAILAND [email protected] siritron @swu.ac.th
7.1
INTRODUCTION INTRODUCTION
The chemistry and biological activities of seven-membered heterocyclic systems continued to command significant attention in 2006. In this chapter both fused and non-fused heterocycles are O, and S as the heteroatoms in the seven-membered ring addressed with an emphasis on N, 0, components. Reviews which include some treatment of these heterocyclic derivatives have been published covering ring-closing metathesis of heteroatom substituted dienes <06H(70)70S>, <06H(70)705>, and a review of the pyrrolo[1,2-a]azepine-based pyrrolo[ 1,2-a]azepine-based Stemona alkaloids <06MI99>. A detailed review on synthetic approaches to oxepines has also been published <06T930l>. <06T9301>.
7.2
7.2.1
SEVEN-MEMBERED HETEROATOM SEVEN-MEMBERED SYSTEMS SYSTEMS CONTAINING CONTAINING ONE ONE HETEROATOM
Azepines derivatives Azepines and derivatives
Detailed computational studies have been reported on S-azatropolone 5-azatropolone and IH-azepine-4,S1H-azepine-4,5<06JPC(A)1600>. dione and related isoelectronic homologues and isomers <06JPC(A) 1600>. A novel electrophilic reaction of the 2-methoxyazepinium ion 2, formed in situ from 1 on treatment with TiC1 TiCla,was ,was observed in the presence of benzene to give 3, 4 and 5. The kinetics of 4 (kl, 1<" kz, k3) the isomerisation (k!, kJ ) of the 4H-azepine 3 to 8 via 6 and 7 were also reported <06EJO3803>. <06EJ03803>.
438
J.B. Bremner and S. Samosorn
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OMe
NOMe
OMe OMe
NOMe OMe
7
6
3
"N
P
8
Satake et et al. reported further detailed studies on the chemistry of 2H-azepines 2H-azepines highlighting a propylthio shift on [1,5] sigmatropic hydrogen shift and also an unusual (1,5] [1,5] sigmatropic propylthio measurements were consistent with a heating 9 to afford 10 and 11 respectively; kinetic measurements <06OL5469>. concerted process for the propylthio shift <060L5469>. R R
R R
R R
Q--"-- b
/. pHr ~ ~ ONOMe Me PrS
+
Qspr
A =_ PrS P r S~. ~NOMe O/ .M e +
/.
11 11
10
9
R == t-Bu t-Bu a: R b: Me b: R= R=Me
~~ oNOMe SMP:
Access to the 4,4'-disubstituted 4,4"-disubstituted azepine derivatives 14 was achieved in good yield by ring closing metathesis on the dienes 12 using the Grubbs II catalyst 18; the diene precursors 12 could be made in racemic o~,~'-disubstituted lactone precursors racemic or optically enriched form from a,a'-disubstituted precursors <06S1437>. Removal of of the N-protecting group and reduction of the double bond in 13 by <06S1437>. hydrogenation then resulted in the azepanes 14.
~ -CBz R2~N-CBZ R1
(i)
=
(ii)
-CBz CN-CBZ
R2'" R RI1
,. R~,C N HH R2'" R '~11 14 14
13
12
R11 R Me a: Me b: b: Ph Ph
R22 R H H Me Me
75% 75% 83% 83%
R11 R a: Me Me b: b: Ph Ph
R22 R H H Me Me
100% 100% 90% 90%
Reagents: N"v reflux, reflux, 82°C,S H"2, 50 psi, Reagents: (i), (i), CICH,CH,CI, C1CH2CH2CI,Grubbs Grubbs II Ru cat., cat., N 82 ~ 5 h; (ii), (ii), Pd/C, H psi, AcOH, AcOH, 20°C, 20 ~ overnight. overnight.
439 439
Seven-membered rings
The power of ring closing metathesis for seven-membered ring synthesis continued to be realised as exemplified by the preparation of the tetrahydroazepines 16 (X = CH,) CH2) or 2azepinones 16 (X = CO) from the appropriately substituted precursors 15. Yields were generally good to high (particularly with Grubbs II ruthenium catalyst 18). However, as noted in other reactions of this type, amine functionality (15a, R 1' == Bn, R2= R' = H, X = CH,) CH2) compromised the metathesis process, and a very low yield of 16 was obtained with Grubbs I catalyst 17 and no 1); starting material 15 was reproduct at all with the second generation Grubbs catalyst (Table I); isolated in both cases <06Tl777>. <06T1777>.
R1
RI 11
M~rO
I
(i) (i)
Me
MeO~_~
oO
R2
\R2 R2
16
15
~~9NP--
P(CYh P(CY)3 CI\ I CI-.... RU~
Ru~/ RU~
CI/ I Ph Ci/~u=~ph
CI/ CI/I
P(CYh P(CY)3 17
I
Ph Ph
P(CYh P(CY)3 18
Reagents: Reagents: (i), (i), Grubbs Grubbs I or II cat., cat., DCM, DCM, 40°C. 40 ~
Table 1 I Table Substrate
R 11
R R'2
X
15a 15b
Bn Bn
H H
CH 2 CH, C=O
Grubbs I cat. 16 yield (%) 8 88
Grubbs II cat. 16 yield (%) 0 90
Inclusion of the amide in oxazolidinone functionality can be used to overcome diene statial disposition issues, for example in the conversion of 19 into 20; yields of 20 were generally high (Table 2). Ring opening of the oxazolidine moiety with or without loss of the mandelic acid moiety then afforded the corresponding azepin-2-ones <06TL3625>. <06TL3625>.
TBSO. ~ ~ / / " TBSO~ O"><'N~
o
N~
4RR
PI~
Ph'..~kO0 :: 19
.,-
5 mol% mol% Grubbs Grubbs cat. cat.
CH2CI 2 (abt 10 -2 M)
Reagents: cat. (5 mol %), M). Reagents: (i), (i), Grubbs Grubbs cat. (5 mol %), DCM DCM (ca 10 10.22 M).
TBSO TBSO
Ph,,, Ph'''~O ~/'~
~
#, R
O o 20
440
J.B. Bremner and S. Samosorn
Table Table 2 19 19a 19b 19b
Catalyst 17 18
R H i-Bu
20, Yield (%) 20a, 91 20a,91 20b, 78
Other N-substituted and reduced 2-azepinone derivatives 22 can also be accessed in high precursors 21 using Grubbs II catalyst 18. A yields (Table 3) by ring closing metathesis on the precursors variety of N-heteroaryl substitutent substitutent groups were tolerated in this reaction <06TL3295>. <06TL3295>.
(o •
o
R11 ,R
~H~R' N~~~--R3 BocH
~N0 ~~I~,R 2
Grubbscat. cat. Grubbs
.R2 R2
#
----
R2 22
21 Table 3 Table R' .\~/
R'2 R H
R 33 H
/~..~
H
H
10
88
-I-/-- ~
H
H
10
92
Y)j Iii ~r-Q
-~
rO
R1
BocHN~/~N 'R1 3 I ? R R3
Grubbs II cat. (mol%) 5
Yield (%) 90
-
of the azepinones 24 has been developed based on ring closing A compact synthesis of a-amino enones 23 <06H(67)549>. <06H(67)549>. High yields of products were metathesis reactions of the a-amino R ~ = Me, R' R 2 = Boc). The obtained (for example, 24, R = H, R R'2 = Boc, 90%) from (23, R =H, R' R 2 = (2-Pyr)SO,) (2-Pyr)SO2) was converted into a cathepsin K inhibitor. azepinone derivative 24 (R = H, R'
R~ /~'J"N P
0)
(i)
" O
,
R1
23
RVO ~o
R
, p P
24 24
Reagents: (2.5-5 mol%), Reagents: (i), (i), Grubbs Grubbs II cat. cat. (2.5-5 mol%), DeM, DCM, heat, heat, 12 12 h. h.
Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiationlithiation - addition methodology has been described to provide access to the (Ar I = p-BrPh, p-BrPh, Ar = p-MeOPh)); p-MeOPh»; these were then converted into 27 via 26, azepine precursors 25 (Ar' via 28 and 29 <06JA2178>. and subsequently to the further substituted azepan-2-ones 30 via <06JA2178>.
441
Seven-membered rings
CH 3
H3C,,,~ 3 Ar
'r):'"
H3C,, ~
H3C~" "':: ,Ar ~ ~.Ar
(i)
(i)
N'Boc "Boc
COzEt CO2Et
,.
H,C"i
3
~.Ar
(ii)
Ar" ~ - "Boc Ar~~ Boc
,. Oj j, -~C H OH3 '
o
o0 / "NH NH
N
I Ar Ar
Ii
25
~H3 .CH3
Ar Ar (ii)
26 Ar
27
(iii) 1(iii)
Ph
.CH3
ArH2C"
Ph Ph
CH3
__
(v) (,j
.CH3 ~H3
A
CH '3 CH
<
0 Ph
(iv) ''V'
o(3// ,~r ~ Ar
oO" ~'~
O" ~
.CH3 CH '
Ar Ar ~ ~ 29 28 Reagents: (i), DCM, 83%; HC! (aq.), Pd(OH)" EtOH, EtOH, benzene, benzene, 96%, Reagents: (i), Me]AI, Me3A1,p-anisidine, p-anisidine, DCM, 83%; (ii), (ii), HC1 (aq.), CHCI" CHC13,86%; 86%; (iii), (iii), H" 1-I2,Pd(OH)2, 96%, dr = 94:6; LOA. b. p-BrC6H4CH2Br, p-BrC 6H,CH,Br, THF, H,O, 62%, 94:6; (iv), (iv), a. a. LDA. THF, 94%, 94%, dr = 98:2; 98:2; (v), (v), CAN, CAN, MeCN, MeCN, I-I20, 62%, dr = >99:1. >99:1. ~ 30
As part of of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted 3,6-disubstituted tetrahydro-1H-azepines, tetrahydro-1H-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported <06JOM5406>. <06JOM5406>. Boc Boc
Boc Boc
II
II
N
MeO, Meo~'~
(i) (i)
1 ~OTBS OTBS
,
MeoJN Me
!J0
0
31
j
~---OTB$ ~OTBS 32
Reagents: (i), II cat., Reagents: (i), Grubbs Grubbs 11 cat., 2.5 mol%, mol%, 90%. 90%.
The synthesis of the N-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs Grubbs I ruthenium catalyst. This azepine of a number number was an important precursor for the preparation, preparation, via epoxidation of the double bond, of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. <06JMC 1597>. of 7-methylazepanone
~
Me
NCbz NCbz
~ 33
Me
(i)
NCbz CNCbZ 34
Reagents: (i), Grubbs Grubbs I cat., cat., DCM. Reagents: (i), DCM. A two-carbon two-carbon ring expansion expansion reaction of of 5-membered cyclic enamines gave 6,7-dihydro-1H6,7-dihydro-1Hazepines on reaction with dimethyl acetylenedicarboxylate <06ZN(B)385>. <06ZN(B)385>.
442
J.B. Bremner and S. Samosorn
The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation Iring cyclisation/ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield <06T7455>.
OH OH
N3v~z O O N'~O
(i) (i)
H Fhl~o
9
Ho-CiL
o• O
Ho HO He
°X
35 Reagents: (i), (i), 10% 10% Pd/C, Pd/C, HCO,NH" HCO2NH4, EtOAc. Reagents: EtOAc.
7.2.2
0/\-
36
Fused azepines azepines and derivatives derivatives
A palladium-catalysed intramolecular hydroamidation (using 39 as the catalyst) with the amido alkyne 37 proceeded regioselectively in the presence of base (KOH or NaOEt) to provide access to the 3-benzazepin-2-one 38. This reaction can also accommodate other alkynes <06TL381l>. <06TL3811 >.
~ N-Me ~-Me
(i)
o
o
NHMe
37
38,82%; 38, 82%; KOH 80%; 80%;NaOEt NaOEt
Reagents: (i), Pd(PPh 3 ),(OAc),239, 39, base, base, DMF, DMF, 60 °e, Reagents: (i), Pd(PPh3)2(OAc) ~ 16 16 h.
C02Me
Me
,Et /CO2Me
40
H"
A
,,,( )~§ B
74% Me02C
~
H 41
,C02M~
'XN.Et
443
Seven-membered rings
Reduced fused azepines (e.g. 40) have been used in a new ring expansion strategy to afford fused hexahydroazoninoindoles (e.g. 41) from reaction with methyl propiolate propiolate in methanol to give the ylide intermediate A which then ring expanded via the methanol stabilised stabilised intermediate intermediate B to give 41 <06Tl239>. <06T1239>. The imidazo-benzazepine imidazo-benzazepine 43 was prepared in moderate yield by a combination combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a <06TL3225>. microwave-promoted intramolecular intramolecular Heck reaction <06TL3225>.
": C 5:
T01 C I [ ~ S OS02 2T~ CN
~ B r Br
(X [
..-:;;
+ +
H2N ' ' ~ v / ~ H2N~
+
CHO CHO
-~
Ph
~N~
N=!
~ PhjNF
(ii) (ii)
..-:;; B Br
(i)
[":: ..-:;;
42
Ph
N=! N=/
43 Reagents: Pd(OAc)"2, P(o-tolyl)" NEt"3, 125°C, microwave, 66%. Reagents: (i), (i), K,CO" K2CO3, DMF, DMF, 60%; 60%; (ii), (ii), Pd(OAc) P(o-tolyl)3, CH,CN, CH3CN,NEt 125 ~ 1I h, microwave, 66%.
intramolecular nitrone 1,3-dipolar An intramolecular 1,3-dipolar cycloaddition reaction to give 46 from 45 followed by IH-Ireductive N-O bond cleavage afforded a stereoselective synthesis of the tetrahydro 1H-1benzazepines 47; the nitrone precursors 44 were prepared in tum turn by a Claisen rearrangement from an N-allylamine N-allylamine <06SL2275>. <06SL2275>.
(i), (ii)
R2
44
v
,.
R2
-R 1 45
.H R
R (iii)
R..
a R
46 46
R2 R
R1
R1
47 47
R2
b
c
R
R11
R2 2
H CH OH 33 CI Cl
H H H
H H H
R1
Reagents: mol), Na2WO4.2H20 Na,WO,2H,Q (4-6 mol%), to -5 °C, Reagents: (i), (i), 30% 30% H,Q, H202 (3-4 mol), mol%), acetone-H,Q acetone-H20 (9:1vjv), (9:iv/v), 25°C 25 ~ to-5 ~ 40-50 h, then H,Q with CH,Cl,; toluene, reflux, mol), 80% AcOH (excess), then H20 and and extraction extraction with CH2C12;(ii), (ii), toluene, reflux, 3-4 h; (iii), (iii), Zn (6 mol), 80% AcOH (excess), 80-85 80-85 °C, ~ 2-5 h, 25°C then 5% NH.oH solution 25 ~ then 5% NH4OH solution and extraction extraction with with EtOAc. EtOAc.
444
J.B. Bremner and S. Samosorn
Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to via 49 and 50, into the chiral provide access to the amino ester 48 which could then be converted, via <060L2667>. substituted 1-benzazepine l-benzazepine derivative 51 <06OL2667>.
0 (i)
(iii) (ii), (iii~
49 49
48 48
°
H2Ph CH 2 Ph
HN•. C & N
~I
,,'Ph ,, ,Ph
"':
"CH2Ph
(iv)
N H~ , , ,
(iv)
"'Ph "Ph
I~
"
,Ph "Ph
//
50 51 Reagents: (i), A1Et 94%" (ii), (ii), n-BuLi; (iii), PhCH PhCH2Br, 79%; (iv), (iv), BH 91%. Reagents: (i), AlEt"3, 94%; n-BuLi; (iii), BH"3, 91 %. 2Br, 79%;
Acid catalysed rearrangement of the tetrahydro I-benzazepine 1-benzazepine sulfonamides 52 gave the 9substituted sulfone derivatives 53 plus, in the case of 52b, 52b, the 7-substituted 7-substituted isomeric derivative <06SC355>. 54 <06SC355>.
"'cO I
O:S=O
"~O
"W "'CO o_-,:o
a ~
52 52
= =
lil
+
.
NO2 12.,, 54
H
54
53 53
= =
a: R 11 = H; R R 22 = H H a: R
= =
= =
a: R 11 = H; H R R 22 = H H a: R
b: R R11 = H; H; R R22 = N0 NO2 b: R R11= H; H; R R22 = N0 NO2 b: b: 2 2 Reagents: (i), S0 at 105 DC for 20 min then pour over ice. Reagents: (i), 98% H H2SO 4 105 ~ for min then pour over ice. 2 4 A compact approach to the 1-phosphonylated 2-benzazepine 56 was achieved based on a ringl-phosphonylated 2-benzazepine closing metathesis reaction on 55 using Grubbs II catalyst catalyst <06SL2771>. <06SL2771>.
445
Seven-membered rings
Ph
~J1
~ t
""
~
'0 06
(i)
(
t ~o/ ~ N ' BN-S n n P(O)(OMe)2 P(O)(OMeh
N
(MeOh(O)P (MeO)2(O)P
55
n
'Sn
56
Reagents: N"v Grubbs Reagents: (i), (i), DCM, DCM, styrene styrene (5 (5 eq.), eq.), ,4 , 4 h, N Grubbs II cat. cat. (10 mol%), mol%), 78%. 78%.
Poly(ethylene glycol) (PEG) was used as a soluble polymeric support in the efficient 2-benzazepine S8 58 via a phosphine-free preparation of the 2-benzazepine phosphine-free palladium-catalysed Heck reaction from S7 57 <06Tl0456>. <06T10456>. COOMe COOMe
(i) (i)
~.~hN~cOOM R
e
C(} @ t
57
""
o
N
-...0
N
ph Ph
'R R
58
R R == PEG-N-(CH2kSi(Meh-CH2CH2S02-~ PEG-N-(CH2)4-Si(Me)2-CH2CH2SO 2~ I
II
Ts T8 Reagents: (i), (i), Pd(OAc) K~CO3, PEG-3400-0H, PEG-3400-OH, 80°C, 80 ~ 12 12 h, 100%. 100%. Reagents: Pd(OAc)"v K,CO" 59 (TT= tris(tetrachlorobenzenediolato)phosphate(V» tris(tetrachlorobenzenediolato)phosphate(V)) and The binaphthyl azepinium salt S9 corresponding corresponding azepine 60 were developed as effective catalysts for the enantioselective enantioselective unfunctionalised alkenes, with enantiomeric excesses up to 87% <06TA2334>. epoxidation epoxidation of unfunctionalised <06TA2334>.
(
..~
TT-
59
7.2.3 7.2.3
60
Oxepines Oxepines and fused derivatives derivatives
oxepin-2-one 61, a mimic of The single crystal X-ray structure of the enantiopure tetrahydro oxepin-2-one steroidal androgens, has been reported <06ZN(B) 111>. Ill>. A new procedure has been described for expoxidation of strained fused the synthesis of substituted furano-fused oxepines based on expoxidation cyclobutenes followed by thermal rearrangement <060L5l83>. <06OL5183>.
446
J.B. Bremner and S. Samosorn
£!pO Me.
.,,,.....~O
Oo~O
o
Me 61
A new and useful route to the 3-benzoxepin-2-one 64 involved coupling of the Fischer 65 to the epoxy phenylacetylene 62 to give 64 (46%) via via 63. An epoxyvinylcarbene carbene 6S complex is proposed for the initiation of the reaction followed by CO insertion and cyclisation <06H(67)233>.
MeO /r
-~7
MeO MeO
40o o
/(~Me
CCc
63
62
(:
64
Cr(CO)s C.r(CO)5
II )l
Reagents: Me Me/~'OMe 65, dioxane, dioxane, reflux, Reagents: OMe 65, reflux, 24 h.
palladium-catalysed ortho-alkylation/intramolecular A tandem palladium-catalysed o r t h o - a l k y l a t i o n / i n t r a m o l e c u l a r Heck reaction coupling 1-benzoxepines 67 from the sequence was used effectively to access in fair yields the tetrahydro I-benzoxepines iodoaryl precursor 66 and the appropriate alkyl bromide. The norbomene plays a relay role in the <06JOC4937> proposed reaction cycle <06JOC4937>
\ 6C)
C o zEt /CO2Et
(i)
I"'" ~
66
o
67
a: a: RR = (CHzhCI, (CH2)3Cl,47% 47% b: b: RR = (CHzhCOOEt, (CH2)3COOEt,45% 45% c: c: RR = (CHzhPh, (CH2)3Ph,45% 45% Reagents: (i), Pd(OAc),2 (10 mo!%), P(2-furyl)3 P(2-furyl)3 (20 mol%), norbornene norbomene (4 Reagents: (i), Pd(OAc) (10 mol%), (20 mol%), (4 eq.), eq.), CS,CO, Cs2CO3(2 (2 eq.), eq.), R(CH2)3Br R(CH2)3Br(6 (6 eq.), eq.), CH,CN, CH3CN, 80°C, 80 ~ 16 16 h.
A new BF -induced stereospecific rearrangement of the epoxy ethers 68 gave the enantiopure BF3-induced 3 tetrahydro 2-benzoxepin-4-ols 69a,b in generally good yields <06JOC1537>. The enantiomerically enriched compounds 69c,d were also produced.
447
Seven-membered rings rings
oO O
~r
-''OcH3 (i)
R.~~ '
OCH3
H O ~ o M e OMe ~
_OMe
g R
68
69 a: R= H a:R=H b: b: RR = CF CF33 c: c: R=CI R=CI d: d: RR = Ph Ph
Reagents: (i), DCM, -78 DC, Reagents: (i), BFJ.OEt, BF3.OEt2(0.3 (0.3 eg.), eq.), DCM,-78 ~ 15 15 min. min.
Ring-closing metathesis has been used effectively to prepare the pyrido[3,2-b]oxepine pyrido[3,2-b]oxepine <06TL6235>. precursor 70 <06TL6235>. derivative 71 in good yield from the pyridyl diene precursor
o
~ CO N
(i)
---=
70 Reagents: (i), toluene, 70 70°C, %. Reagents: (i), Grubbs Grubbs II cat. cat. (10 mol%), mol%), toluene, ~ 16 16 h, 71 71%.
71
The oxepine-fused beta-carboline 73 was synthesized in good yield (71 %) from the diene (71%) precursor 72 using ring-closing metathesis and Grubbs I catalyst <06TL6895>.
~ ~
II~ ~N
b
H
72
(i)
O~
I
._.._.
73
Reagents: mol%), DCM, DCM, rt, ct, 24 Reagents: (i), (i), Grubbs Grubbs I cat. cat. (5 (5 mol%), 24 h.
The synthesis of the fungal natural product ulocladol (from the marine fungus Ulocladium Ulocladium botrytis) was achieved by three routes, including a two-step sequence involving ring enlargement botrytis) of the 6-membered ring lactone in 74 to the 7-membered ring system in ulocladol 77. Treatment of 74 with methanol in the presence of base give 76 (via 75 and the oxy anion A) in 82% yield; <06H(69)217>. hydrogenolysis to remove the benzyl groups then gave 77 in 63% yield <06H(69)217>.
448
J.B. Bremner and S. Samosorn
OH ~OMe
F
~~::: lJyr'
M,O. MeO..~\ y
I
(i)
T "oB.
i
1_
BnO BnO
-
OMe
OMe ~/OM e
OMe
HO
MeO OBn ~eO "U'OBn
MeO .. I'v'eO ,'-'::
OBn OBn 0O
74 74
OH OH
co ~ " ~
OBn
OBno
_
75 HO HO
76
m
BnO BnO
OMe
HO ,,~..~/OMe
(ii) (ii)
OMe
HO MeO MeO
MeO MeO OH O
BnO (~/k~,,,OOe
77 77
A
, Pd/C, AcOEt, 63%. Reagents: (i), Reagents: (i), K,CO K2COJ3,, MeOH, MeOH, reflux, reflux, 82%; 82%; (ii), (ii), H2, 2 Pd/C, AcOEt, 63%.
A palladium-catalysed palladium-catalysed carbometallation-alkyne carbometallation-alkyne cross coupling cascade process has been reported for the stereo- and regio-controlled regio-controlled synthesis of dibenzoxepines dibenzoxepines with substituted substituted exocyclic alkene functionality <060Ll68S>. <06OL 1685>.
7.2.4 Thiepines and fused derivatives A review covering homologation of heterocycles via lithiation-based lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications applications to 2,7-dihydro 2,7-dihydro benzothiepine benzothiepine derivatives <06AHC13S>. <06AHC 135>. A neat synthesis of the chiral 10, Il-dibenzo[b,j]thiepine 79 from the chiral precursor 10,11-dibenzo[b,f]thiepine precursor 78 has been described. Cyclisation of the lithiated intermediate was mediated via reaction with sulfur bis(imidazole) 18>. bis(imidazole) <060BC22 <06OBC2218>.
BrO [~OMe
MeO
OMe
(i), (ii) (ii) (i),
Br 78 78
N-0N~"-NIS~N,,% W S'N 0 N Reagents: \d Reagents: (i), (i), t-BuLi; t-BuLi; (ii), (ii), \d
79
449
Seven-membered Seven-membered rings
7.3 7.3.1 7.3.1
SEVEN-MEMBERED SEVEN-MEMBERED SYSTEMS CONTAINING CONTAINING TWO TWO HETEROATOMS HETEROATOMS Diazepines and and fused fused derivatives derivatives Diazepines
Although highly reactive, 2H-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4H-l ,3-diazepines 86. Reaction of 80 with difluorocarbene in the presence 3-fluoro-4H- 1,3-diazepines of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction; the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines <06TL639>. 1,3-diazepines
lAr-t"b 11~r..~~r(~!00 Ar O l ~ OC"O . :;-- Ar F
:cF2, [ 80
JHO
~o
81
Ar~___~ ? F2]
84
(i)
0
82
F
--~
0O-..J II J
0 83
:;-0O-..Z/' II
>-F ~N Ar?N~F1 Et3N Ar,(NN' Ar~N~F ArAr~N,. ~y Ar 86. Fj a:a: ArAr = Ph (41%) 85 85 b:ArAr==4-CLC6H s 4(18%) b:
Ph (41%) 4-CIC H4 (18%)
Reagents" (i), (i), CF,Br" CF2Br2,active active Pb, Pb, Bu4NBr, CH2C12,40-43 40-43 DC, ~ 66 h Reagents: Bu 4NBr, furfural, furfural, CH,Cl"
The 1,4-diazepane 87 has been used as a neutral 6-electron ligand for the support of cationic Group 3 metal (Sc,Y) alkyl catalysts <06CC3320>. Me I
N Me 87
Me2
I
Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation; the Si-TrisAmine® Si-TrisAmine | was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining <06MCL3777>.
450 450
J.B. Bremner Bremner and and S. Samosorn
Cl
..s~O o-"
R;
R1
88
R1
89
R1 a: a"
90
R2
3,4-Cl 3,4-CI2 5-Br-2-thienyl 64% z 5-Br-2-thienyl 3-F 4-CI-Ph 82% 4-CI-Ph
b:
Reagents: (i), NH,NH,2(4 eg.), R'SO,C1, PS-DMAP, Reagents: (i), NH2NH eq.), i-PrOH, i-PrOH, 75°C, 75 ~ 16 16 h; (ii), (ii), R2SO2C1, PS-DMAP, DCM, DCM, rt, 16 16 h; (iii), (iii), Si-TrisAmine Si-TrisAmine
In an extension of of previous work on conjugated of the conjugated enamine carbonyl derivatives, reaction of pyrazolone 91 with N,N'-disubstituted N,N-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3-d][l,2]diazepine-8-carboxylates 92 in good yields. While the exact hexahydropyrazolo[4,3-d][1,2]diazepine-8-carboxylates mechanism for the formation of 92 is not known, Michael-type addition known, one possibility, namely a Michael-type mechanism of the alcohol to a pre-formed pyrazolo-diazepine, pyrazolo-diazepine, was excluded <06T8l26>. <06T8126>. Ph
~:N
B-
(i)
(i)
"e2NMOOOEt ~
MezN ~ MezN
R 2 0 , , , / ~ ,C~~,Et ~ N RZO'~tX~
H H _COOEt
I
o
COOEt
RLN a 1-N
,
R1N
~
I - ] NN-Ph -Ph
R1
O
0 92 92
91 91
--R-1--R-z- - -
R1
R2
-a-'. a: --,-.,.--------:...,,---=~ Me Me 74%
b: b: c:
Me Me
Et 81% n-Pr 85%
Reagents: reflux. Reagents: (i), (i), R'NHNHR', R'OH, R2OH, reflux.
An elegant two-step solution-phase solution-phase methodology was developed for the synthesis of of the 4 benzodiazepine-2,5-diones (93 ; e.g. R' R ~= PhCH" PhCH 2, R R 5 = Me, 32%). 32%). benzodiazepine-2,5-diones (93; R22 = Me, R R33 = Me, R4 = H, R' The first step was a Ugi four-component reaction followed in the second step by a palladiumpalladiumintramolecular N-arylation reaction. This methodology has considerable scope for mediated intramolecular <06TL3423>. further application in heterocyclic synthesis <06TL3423>.
O R1-NH2 + R 2 L R 3
+ R5-NC
(•
(i), (i), Ugi 4 component reaction reaction
4-
,,/,,~,~COOH R4~B
r
(ii), (ii), [PdJ, [Pd], N-arylation N-arylation
,R1 ....-'~..~/'~ N R2 R 4 ~ R 3
F~5
-O
93
Microwave-promoted Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. under Regioselective N4-aminoethylation of the 1,4-benzodiazepin-2-one 1,4-benzodiazepin-2-one 94 was observed under DMF/K2C0 33 to afford, for example, 96a and 96b 96b in 64% and 67% yield microwave conditions in DMF/K2CO respectively (Table 4). In contrast, the thermal reaction at 80 DC ~ in DMF DMF with K,CO K2CO 3J as base gave the Nl-aminoethylation Nl-aminoethylation products (95a, 65%) These results were 65%) and (95b, 76%). These
451
Seven-membered rings
rationalised using computer-based calculations of the N Nl1 versus N4 alkylation reaction profiles. Microwave irradiation is suggested to facilitate anion production due to a higher change in dipole moment along the deprotonation pathway with a small preference for the N4 anion D over AlB, A/B, although the latter is of lower energy, and fast alkylation then proceeds via E or C <06TL3357>. K+ K +
H
"'" C( N
0 O
N)'''CH3 , ,CH3
/./
NH
Route A A Route
-
~
{
C(N--/(O I
O- K§
N~
, 3 )"'CH
/./
,,C
NH
A
94 94
B
~
+ K2CO3
RCI RCI
CI 1)CI 5- K+ K+ |
,|
R : 1)-
"'" C(
R
0
,
O
N)"'CH3 'CH 3
/./
NH
C
H
O
Route Route B
'OH3
95
H
{C(J~~H'}, ,CH3
O
N [ ~ ~ . ' ~N i~CH3
K+
9
o
L
E
+ K2CO3
'"CI 5-K
l H
0
~ N " 'CH3 96 96
R
Table 4 a b
R (CH,),NCH,CH, (CH3)2NCH2CH2
NCH2CH2
Conditions I(,C0 3,DMF, K2C03, DMF, 80°C, 80 ~ 6 h I(,C0 ,DMF, K2C03, 3 DMF, 80 ~ 7 h 80°C,
Product (%) 95a (65%) 95b (76%)
Conditions K,C0 ,DMF, K2C03, 3 DMF, MW,90s MW, 90 s I(,C0 ,DMF, K2C03, 3 DMF, MW, 90 s MW,90s
Product (%) 96a (64%) 96b (67%)
Reagents and methods for the synthesis of 1,5-benzodiazepine derivatives from 0ophenylenediamine and carbonyl compounds have attracted an unusually high degree of interest in 2006. Illustrative of this, the condensation of two mol tool equivalents of acetone with 0ophenylenediamine 97 was reported <06TL3135> on simple grinding of the components in the presence of an organic acid catalyst at room temperature resulting in 98. The yields of 98 were
452
Bremner and and S. Samosorn Samosorn J.B. Bremner
dependent upon the acid used, but with trimesic acid (5 mol%) a 97% yield of of 98 was obtained obtained dependent grinding for 10 minutes. Picric acid also gave a high yield of of 98 but but use of of this latter acid after grinding should NOT NOT be recommended in view of of the potential potential hazards. Single crystal X-ray data on the of 98 were also reported <06TL3135>. <06TL3135>. trimesic acid and picric acid salts of organic acid
+ v
2(CH3)2CO
~. rt, grinding
"NH2
98
97
1,5-benzodiazepine A range of other catalysts and conditions for similar cyclisations to the 1,5-benzodiazepine <06TL8523>, ultrasound and APPTS <06TL8133>, [BPy]HSO [BPy]HS044 system have included NBS <06TL8523>, <06SC1661>, Mg(C104) Mg(Cl04 ),2 <06SC1645>, <06SCI645>, ZnC12 ZnCl, <06H(68)1017>, <06H(68)1017>, CAN acidic ionic liquid <06SC1661>, <06SLl009>, (NH4)H2PW,2040 (NH4 )H,PW 120 4o <06SC3797>, <06SC3797>, YbC13 YbCl 3 <06SC457>, and solvent-free conditions at <06SL1009>, pH 7 <06SC817>. An intramolecular Pictet-Spengler type cyclisation in the intermediates 100, readily prepared tum from 99, gave the new dihydropyrimido[4,5-b][1,4]benzodiazepines dihydropyrimido[4,5-b][1,4]benzodiazepines 101. in turn 101. Yields were generally good to excellent (101, R' = = H, R' R 2= = Pr, 65%) <06T2563>. a2 CI
CI H R1
CI
H
+H +
R2 R1
-H O CH 3 99
7.3.2 7.3.2
H3C
101
100
Dioxepines, Dioxepines, dithiepines dithiepines and fused derivatives derivatives
In the continuing search for new antimalarial agents, a number of spiroperoxy compounds incorporating a dihydro-2,3-benzodioxepine moiety were designed and synthesised. For example, the spiroperoxy derivative 108 was made from 102 via via oxidation and the Wittig product 103. 103. Deallylation of 103 then gave a mixture of 104, 105 and 106, and finally peroxidation gave 107 and subsequent cyclisation through an intramolecular Michael-type addition reaction afforded 108 <06T7699>.
~ ~ o
~6H 102 0H OH
~CQ: ~.~o
(i), (ii)
-
"::
1-&
OH
103 0H OH 103
-
(iii) (iii)
453 453
Seven-membered rings
~ HO o
I '-':: ~
104
~+~ MeO ,.,
+
+ 4-
0
I GOzEt Et
GOzEt
105
uYt0J ~_'C~ HO. 0
-
(iv)
HO O
U
(v)
0
107
I GOzEt
106
cg 108
GOzEt
GOzEt
(COCI,), DMSO, NEt3; NEt,; (ii), Ph3P=CHCO2Et, Ph,P=CHCO,Et, rt, rI, 12 h, 85% from from 102; (iii), PdC12, PdCI" MeOH, rt, rI, 24 h, then Reagents: (i), (COCI2), rI, 22 h, 71% 71 % from from 103; (v), HNEt HNEt"2, CF3CH2OH, CF,CH,OH, rt, rI, 19 h, 59%. 60 ~cC, 4 h; (iv), UHP, p-TsOH, DME, rt,
Lewis 1,3-dioxepines 109 gave the trisubstituted Lewis acid mediated mediated [1,3] rearrangement rearrangement of of the 1,3-dioxepines trisubstituted tetrahydrofurans 110 110 in high high yields and with with generally high diastereoselectivities. diastereoselectivities. The The Lewis Lewis tetrahydrofurans acids used included included TiCl,(i-PrO), TBSOTf <06CC3119>. <06CC3ll9>. acids used TiC12(i-PrO) 2 and TBSOTf
R2
(i)
,CHO
R2' ' C 2 R 1 109
110
Reagents: (i), Lewis Lewis acid, acid, DCM, DCM, -78 cC. Reagents: ~
7.3.3
Miscellaneous Miscellaneous derivatives derivatives with two heteroatoms heteroatoms
Ring expansion expansion based on the Baeyer-Villiger Baeyer-Villiger reaction continued continued to be a valuable methodology for preparing preparing 1,3-oxazepinones, 1,3-oxazepinones, as exemplified exemplified by the reaction reaction of 111 with m-CPBA m-CPBA giving 112 in high yield; none of the isomeric 1,4-oxazepan-2-one 1,4-oxazepan-2-one derivative was observed consistent consistent with some directive influence influence by the nitrogen <06TL6389>. <06TL6389>.
CfO N I
+s
Ts
111
0
..
m-GPBA m - C P B A,,..._ 89%
(50
O
+s I
Ts
112
454
J.B. Bremner and S. Samosorn
Treatment of 112 with an arylmagnesium bromide, followed by dehydration provided access to the substituted alkenes, e.g., 113a l13a and 113b, l13b, in moderate yields <06TL6389>. <06TL6389>. Ar
0
c)
~N ~ O
(i), (ii)
(i), (ii)
,..
t A Ar r
T8
NH I T8
109
110
\
Ar =Ph, 60% 110 a:a:Ar=Ph, 60%
109
b: Ar = p-MeOC p-MeOC6H4, 6 H4 , 43%
Reagents: ArMgBr; (ii), BF)-OEt,.2. Reagents: (i), (i), ArMgBr; (ii), BF3-OEt
Ring-closing metathesis on the dienes 116 and 117 with Grubbs ruthenium catalyst II 18 afforded the 7-membered precursor 116 was 7-membered ring sulfones 118 and 119 respectively. The diene precursor accessed from reaction of the sulfonyl chloride 115 with 3-buten-I-ol114 3-buten-1-ol 114 <06T9017>. <06T9017>. O2
CI'S~ cl'S"~ 115
115 + + H O . ~
HO~
oo\ \ / /0o
00 %,9
-
(i)
~~ 0 "s
(I)
"
116 116
~1(v) (v) 00 0~ `2
o
(ii), (iii)
(ii), (iii)
-
"
~'(H' ~11-~7~ ~-_ 117
~1(iv) (Iv) 00 0,,9 ~~ " c . a3 o.s.~r~
OCH
118 119 118 119 , 0 °c, Reagents: Et)N, CH,CI (ii), n-BuLi, THF, -78°C; (iii), Mel, 64%; (iv), Grubbs catalyst (5 mol%), Reagents: (i), (i), Et3N, CH2C12, ~ rt; (ii), n-BuLi, THF, -78 ~ (iii), MeI, 64%; (iv), Grubbs catalyst II (5 mol%), 2 , 70°C, 100%. C,H" C6H6,70°C, 70 ~ 60%; 60%; (v), (v), Grubbs Grubbs catalyst catalyst II (5 (5 mol%), mol%), C,H C6H6, 100%. 6 70 ~
The Pd-based methodology described by Ma Ma et et at. al. has scope for the synthesis of fused 1,3oxazepines <06T9002>. <06T9002>. Considerable value would be added to this methodology if it could be 1,3-benzazepine system, perhaps via via alternative methods for adapted to the simpler 1,3-benzazepine carbinolamine carbinolamine precursor precursor generation. A modified four-component Ugi reaction was used to synthesise a variety of heterocyclic ring fused (ring A) 1,4-oxazepine derivatives 123. For example, starting from 120 O-alkylation gave 121 and then 122 after ester hydrolysis; reaction of 122 with amines and isonitriles isonitriles on heating <06TL2659>. Other fused rings A included thiophene and thiazole afforded 123 in low yields <06TL2659>. rings.
Seven-membered rings
G(O'R OH
r 0 O
(i)
O..R
120, R=CH33 Ring A:
~ltN~' N'H
CH 3 CH3
N CH 3
0o
O-'R R
0:}~
o o.,
(ii) (ii)
~O
0 o
Ring A:
455 455
C
(iii) (iii) L
0
O0 121, 121, R=CH R=CH 3, 70% 3 , 70% 122 R=H, 122, R=H, 60% 60%
' 1
R
123,25% 123, 25%
R11 = m-CI-PhCH22 R R2 = = PhCH2 PhCH 2
Reagents: (i), CH3COCH2C1, CH,COCH,CI, I~CO K,CO"3, 18-crown-6, 18-crown-6, CH3CN CH,CN or Nail, NaH, DMF; DMF; (ii), (ii), R'-NH R'-NH"2, R2-NC, R'-NC, MeOH, MeOH, 50 50°C, Reagents: ~ 3-8 h; NaOH, EtOH, EtOH, H20. H20. (iii), 5% NaOH,
example of of a multicomponent multicomponent synthesis, synthesis, dihydrobenz[f][ dihydrobenz[f] [1,4]oxazepin-5-ones were In a further example 1,4]oxazepin-5-ones were prepared in good yields in two two steps steps by combining combining an initial three-component three-component Ugi condensation condensation prepared 3 1 2 with a subsequent subsequent Mitsunobu Mitsunobu cyclisation cyclisation to give (124; (124; e.g. R ' == H, R2= R = i-Pr, R R3== cyclohexyl, cyclohexyl, 65%) <06OBC4236>. <060BC4236>. 65%)
R1
/I O
124
CH-CONHR3 ' R2
l,l-dioxides 126 were prepared in fair yields (e.g. 126, R = The 1,2-benzothiazepine 1,2-benzothiazepine 1,1-dioxides = H, Ar = = p-CIC 6H4 , 52%) by a Heck coupling on the precursors precursors 125, which were obtained in turn tum from an p-C1C6H4, Baylis-Hillman reaction involving the appropriate sulfonamide, aza Baylis-Hillman sulfonamide, aldehyde, and methyl reactants <06TL8591>. <06TL8591>. acrylate reactants
O O
Ar/jj''H
H2N..~O
(i) (i)
Br --'J~'-/~v
o
(ii) (ii)
/ [O[ ~ O ,Ar . .,S..~O~/--R .,~ "
eO
0
H 125
Br
O~// ~S--NS H- NH
cct
R-l.. R ~
'~
126 126
---=
Ar Ar
COOMe COOMe
Reagents: (i), (i), Ti(i-PrO)4' Ti(i-PrO)4, 2-hydroxyquinuc1idine, 2-hydroxyquinuclidine, molecular molecular sieves, sieves, i-PrOH; i-PrOH; (ii), (ii), Pd(OAc)" Pd(OAc)2, P(o-tolyl)" P(o-tolyl)3, NEt" NEt 3, THF, THF, Reagents: 160°C, 160 ~ I1 h, h, microwave microwave
The first observation of the uncommon phenomenon of desmotropy in seven-membered heterocycles was reported for the prototropic annular tautomers 128 and 129. These dihydro-4,1benzothiazepines, which were prepared (via the non-isolated intermediates 130 and 131 from the fused azetidinone 127 on treatment with NaOEt), could be isolated in pure form by column
456
Bremner and S. Samosom J.B. Bremner Samosorn
chromatography. chromatography. However, they equilibrated equilibrated in solution (acidic chloroform) to give a 3:1 ratio of <06TL5665>. 128 and 129, as monitored by NMR NMR spectroscopy <06TL5665>.
O lAN~"~, '
NaOEt, EtOH, ~ S ? c"o~o E t rt, 15min + ~ ..~ S COOEt COOEt CC>COOEt + C(~: ,. ~ -.N~
[ ~ N sS @ 0 ( " ....
NaOEt, EtOH, rt, 15 min
'"CI
127 127
~ /_
H
°
1282 8 0 1
~ S +
1/
129
CI-
..
130 130
131 131
A number of heteroaryl-fused 3-oxo-l,4-thiazepine-5-carboxamides, 3-oxo-l,4-thiazepine-5-carboxamides, for example the indolefused derivatives 133, have been accessed using a modification of of the four-component Ugi condensation. In the case of 133, the starting point was the indolic acid 132. The yields of 133 1 R'== i-Pr, R2= <06JOC2811>. were moderate to good (for example, R R'= EtO-(CH2) EtO-(CH')3'3, 66%) <06JOC281l>. R11 R
" co-
R~2HNOCNyo
CHO
~
I
::/""1 ~ S) ~"%./~N ~ N S
/--COOH (i), (i), (ii) (ii) (COOH
/:/
' sS N ,
- - - -"
,
Me
Me
132 132
133 133
, MeOH, Reagents: MeOH, rt, 10 Reagents: (i), (i), R'NH RINH2, 10 min.; min.; (ii), (ii), R'NC, R2NC,MeOH, MeOH, 50°C, 50 ~ 2-3 h. 2
The unexpected 1,5-benzothiazepine 1,5-benzothiazepine derivatives 135, with an exocyclic substituted double 51%) bond at the 4-position, were obtained in moderate yields (e.g. 135, R = 4-Me, 51 %) on reaction of 134 with the aminothiol 136 in acetic acid. The structure of the products products was confirmed by detailed 1D and 2D NMR experiments <06H(68) 1319>.
"cc cc SH
N°YO
n
~~ H ° 0 H 134 134
/./
NH2
NH 2
136 136
9
[~
AcOH
AcOH
135 135
S~
S
~N ~
R
HO~o~
°
457 457
Seven-membered rings
A further neat example of multicomponent multicomponent reactions in heterocyclic synthesis was reported by al. <06AG(E)7793>. <06AG(E)7793>. They prepared the furan-fused 1,4-thiazepine Ma et at. l,4-thiazepine 140 in good yield using the three components 137, 137, 138, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised.
°OOil
:r~>
Ph
Sr- Et
Br Et 137 137
::r~PhPh
iO2Me (i) (')
)l
+
,
Ph yS.~Ph
COzMe
[I C
~]~~/~
+
Ph
III
°
N ~ EI~ ~ \C02Me COzMe Me02C
C02Me 139 139 COzMe
138 138
Et ..--: MeOzC
140 140 Reagents: (i), i-Pr,NEt, i-Pr2NEt, DCM, 78%.
7.4
7.4.1
SEVEN·MEMBERED SEVEN-MEMBERED HETEROATOMS HETEROATOMS
SYSTEMS
CONTAINING CONTAINING
THREE
OR
MORE
Systems with N, Sand/or S and/or 0 O
gr
o,,o 0" //0
HN-'S--NH
HN/S'NH
(i)
Y
0')<'0
141 O~<~O /-
141
1l (ii)
142
I (iii)
(ii)
Br
Br
o,,o ~o,/o~
°0° °0° 144 144
°XO 1
R
R
o,,o ~o,/o~
Br
Palladium-catalyzed Palladium-catalyzed amidationreactions reactions amidation MW,15-60 15-60min min MW, deprotection deprotection
0
Z
,0
143 143 R R
o,,o o,/o~
N-'S-N'~
HO OH OH
vOO
145 145
146 146
HO
HO OH OH
HO
Reagents: (i), AgO AgO"2, 2-bromobenzyl bromide, DCM, 100 cC, K,CO], 2-bromobenzyl ~ 60 min, microwave; (ii), K2CO3, bromide,DMF, bromide, DMF, 100 cC, ~ 16 h, 99%; 99%" (iii), K,CO K2COJ3,, benzyl bromide, DMF, 100 CC, ~ I1 h, 98%; (iv), Pd(dba)" Pd(dba)2, Xantphos, CS,CO], Cs2CO3, amide, NMP, dioxane, 160 cC, ~ 15 min, microwave.
458
J.B. Bremner and S. Samosorn
An expeditious route to the cyclic sulfamide sulfamide HIV-l HIV-1 protease protease inhibitors of type 145 and and 146 (tetrahydro-l,2,7-thiadiazepine (tetrahydro-l,2,7-thiadiazepine l,l-dioxide 1,1-dioxide derivatives) from 141 and and 142 palladium-catalysed amidation reactions. These reactions of 144 and were hinges on palladium-catalysed and 143 were microwave promoted promoted and and provided, provided, after removal of the cyclic ketal protecting group, protecting group, moderate to good yields of (145, NHCOCH 22-moderate (145, 57%) and (146,66%) (146, 66%) for example example with R = - NHCOCH 2-naphthyl <06T4671>. A number of [1,2,3]-oxathiazepane [1,2,3]-oxathiazepane 2,2-dioxides have been prepared in good yields by regioselective regioselective nucleophilic ring opening of aziridino[l,2,3]oxathiazinane aziridino[1,2,3]oxathiazinane dioxide precursors <06T11331>. <06Tl1331>. A light-induced ring expansion of the tetrazolo-uracil tetrazolo-uracil147 147 afforded ready access to the ring expanded 5H-l,3,5-triazepine-2,4-dione 5H-1,3,5-triazepine-2,4-dione nucleoside derivative 148 in 80% yield <06JOC1742>.
°O)-NH ~--NH\
N-N N-N
II/ N
) N I [ O 0N 0
o~ Ac AcO
hv >> 290 290 nm nm hv
HN HN
O~N
J
q~
H20' CH CH3CN 3CN H20,
~bAC OAc
0
Ac
ACOJ-{OAC
OAc
147
148
The chiral 1,3,5-triazepane-2,6-dione 1,3,5-triazepane-2,6-dione 149 and its ring fused analogue 150 have been shown to form H-bonded helical molecular tapes with P chirality on self assembly in the solid state. state. With aromatic-aromatic ring interactions resulting in hollow 149, this self assembly proceeds through aromatic-aromatic tubular structures <06CC4069>.
O ° HN/~NH
O ° HN)lNH HN~LNH
HN)lNH
M~lkl-~ cH2Ph ~N~CH2Ph O Me
°
149
~ / ~ cH2Ph ~N~CH2Ph
PhCH20/ PhCH20
°
-" N O 150
Resin bound dipeptides have been used in the parallel synthesis of 3,4,7-trisubstituted 3,4,7-trisubstituted 4,5,8,9tetrahydro-3H-imidazo[1,2-a][1 ,3,5]triazepine-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3HN-alky1-4,5,7,8-tetrahydro-3Htetrahydro-3H-imidazo[ 1,2-a][ 1,3,5]triazepine-2(7H)-thiones imidazo[I,2-a][1,3,5]triazepin-2-amines imidazo[ 1,2-a][ 1,3,5]triazepin-2-amines by ring construction methodology <06JCOl27>. <06JCO 127>. 1,2-dihydro-3H-1,3,4-benzotriazepines has The single crystal X-ray structures of three new 1,2-dihydro-3H-l,3,4-benzotriazepines been reported <06CHE907>. A compact synthesis of dihydro-l,2,4-benzotriazepin-5-ones has also been described <06M1349>. In connection with studies on antimalarial compounds, simpler mimics of artemisinin based 152, on substituted 1,2,4-trioxepanes were examined. Examples include the 1,2,4-trioxepanes 152, 153 and 154, 154, with the seven-membered seven-membered ring being made by acid catalysed condensation of the appropriate ketone with the hydroxy hydroperoxide 151. 151. Unfortunately the 1,2,5-trioxepanes vitro (up to 1000 were not active as antimalarials in vitro 1000 nM) probably due to their resistance to Fe(II)-mediated degradation <06BMCL6124>. Fe(II)-mediated <06BMCL6124>.
459
Seven-membered rings Seven-membered
a1
a1
o=(
ArS\pOH
ArS___N o ' O ' ~
R2
~OH ~ "OH
(i)
151
R1 a: (CH (CH2) Z)44
R2
152 152 a: 72% b: 76% b:76% c:82% c: 82%
Ar p-CIC6 H44 p-ClC6H p-CIC 6 H4 p-CIC6H4
(CH (CH2) Z)44
jIn)
b: (CH (CH (CH2)5 (CH2)5 Z)5 Z)5 c: Adamantylidene Adamantylidene p-CIC6H4 p-CIC sH4
(ii)
0 o IIII
R1 O
H
..O
(iii)
R2
"~~/~o
"
R2
/'X_,, ~
_
R11
o~O'-L' R2Z o ~~
ArS~/ ~"R Ars~b ~~_/0 153 153
154 a: a : 887% 7% 154 b: 83% b:83% c: 89% c:89%
a: a : 887% 7% b:83% b: 83% c:89% c: 89%
Reagents: ketone, p-toluenesulfonic p-toluenesulfonic acid; Reagents: (i) ketone, acid; (ii) (ii) m-CPBA m-CPBA(1.0 (1.0 eq.), eq.), DCM, DCM, rt, 6 h; h; (iii) (iii) 2,6-lutidine 2,6-1utidine(4.2 (4.2 eq.), eq.), trifluoroacetic trifluoroacetic acid acid anhydride anhydride(3.8 (3.8 eq.), eq.), acetonitrile, acetonitrile,rt.
The chemistry of pentathiepins has been extended to the pyrrolo-fused derivative 155. Reaction of 155 with dimethyl acetylenedicarboxylate (DMAD) and triphenylphosphine at room temperature gave the fused 1,4-dithiin derivative 156 in high yield <060L4529>. <06OL4529>. It is probable that the triphenylphosphine removes three sulfur atoms from 155 to give a dipolar reactive intermediate for a cycloaddition with DMAD DMAD to afford 156.
U) S-S
N
M~ M~
(i)
S-S
Md 155 155
156
Reagents: (i), DMAD, PPPh DCM, rt, , DCM, Reagents: (i), DMAD, P h 3, rt, I1 h, 80%. 80%. J
7.5
SEVEN-MEMBERED SYSTEMS SYSTEMS OF OF PHARMACOLOGICAL PHARMACOLOGICAL SIGNIFICANCE SIGNIFICANCE SEVEN-MEMBERED
Pharmacologically active compounds incorporating 7-membered heterocyclic components continue to flourish. Examples include the designed enhancement of pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione 1,4-benzodiazepine-2,5-dione antagonists 157 of the Hdm2-p53 protein-protein interaction <06MCL33l0>, <06MCL3310>, the synthesis of enantiomerically pure 1,4-benzodiazepine-2,5-diones 1,4-benzodiazepine-2,5-diones and their assessment as Hdm2 antagonists <06BMCL3ll5>, <06BMCL3115>, l,4-benzodiazepines 1,4-benzodiazepines as inhibitors of respiratory syncytial virus <06JMC231l>, <06JMC2311>, benzodiazepinone-based benzodiazepinone-based cysteine protease inhibitors of type 158 as potential antimalarial compounds <06JMC3064>, <06JMC3064>, methyl substituted azepan-3ones as cathepsin K inhibitors <06JMC1597>, <06JMC1597>, novel inhibitors of the epidermal growth factor
460
J.B. Bremner Samosorn Bremner and and S. Samosorn
receptor tyrosine kinase based on pyrimido[ pyrimido[4,5-b]-l,4-benzoxazepines 4,5-b ]-1 ,4-benzoxazepines (and the corresponding fused thiazepines and diazepines) <06BMCL5102>, and xantheno[9,I-cd] xantheno[9,1-cd] azepines as analogues of clavizepine <06JOC3963>. benzo[b]azepin-2-one and -2,5-diones have been assessed as selective dopamine Reduced benzo[b]azepin-2-one D3-receptor antagonists <06BMCL658>, and 2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones 2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones have moderate herbicidal activity <06JHCI275>. <06JHC1275>. Other compounds of interest include dibenzo[b,j][I,4]oxazepines dibenzo[b,f][1,4]oxazepines for assessing aspects of the histamine H4 receptor site <06JMC4512>, benzodiazepine-based -tum -turn mimetics with moderate affinity for the AT2 receptor and in one case high affinity for the ATl AT1 receptor <06JMC6133>, T-cell selective cytotoxic 1,4-benzodiazepine-2,5-diones <06BMCL2423>, achiral 1,3,4-benzotriazepines 1,3,4-benzotriazepines as selective (over CCKI CCK1 receptors) CCK2 receptor antagonists <06JMC2253>, and 1,51,5benzodiazepines containing a benzophenone moiety as photoaffinity probes for labelling within the membrane-spanning domain of the cholecystokinin receptor <06JMC850>. Further examples include antibody-directed enzyme prodrug therapy (ADEPT) based on pyrrolo[2,1-c][1,4]benzodiazepine pyrrolo[2,I-c][I,4]benzodiazepine prodrugs <06BMCL252>, novel, orally active vasopressin V2 receptor agonists based on 5,Il-dihydropyrido[2,3-b][I,5]benzodiazepines 5,11-dihydropyrido[2,3-b][1,5]benzodiazepines <06BMCL954>, and 5H-1,4-benzodioxepin-3-yl uracil and purine derivatives as anticancer agents <06Tl <06Tl1724>. 1724>. 5H-l,4-benzodioxepin-3-yl Interest continues in the design and pharmacological evaluation of dual functional agents and in 4,1this context molecular docking and QSAR studies have been described on a number of 4, 1benzoxazepinone derivatives as inhibitors of both wild type and mutant (K103N) HIV-I HIV-1 reverse transcriptases <06MI281>. Pyrrolo-l,5-benzoxazepines, which are potent apoptosis inducers in a number of chemotherapy-resistant human cancer cell lines, have been shown to target tubulin and in one case (PBOX-6) was shown not to bind to the vinblastine or colchicine binding sites <06MI60>. A significant advance in selective 5-HTlA 5-HT1A receptor agonists with neuroprotective effects has been detailed <06BMC1978>; <06BMCI978>; these compounds are 1,4-benzoxazepine derivatives. A series of moderately potent thiazepines as inhibitors of interleukin-I interleukin-1 converting enzyme has been described <06BMCL4728>, while a new class of antileukemic agents based on pyrrolo[I,2pyrrolo[1,2b][I,2,5]benzothiazepines b][ 1,2,5]benzothiazepines have been reported <06JMC5840>. Cl
I
Ph~
0
0
HO
ArHNCO2~~-~oN~'~L" N~ O Cl HO2CH2CH2CH2CH2C
O 157
158 158
Using representative 1,3,5-triazepane-2,6-diones, an interesting protein data mining study based on high-throughput docking identified and verified secreted phospholipase A2 as the target for these diones. These diones can be viewed as conformationally restrained dipeptide mimetics <06JMC6768>, and in another significant paper they have been reported as having inhibitory Pyrrolo[2, I-b][ 1,4]benzodiazepine-azepane activity on the liver stage of malaria <06CEJ8498>. Pyrrolo[2,1-b][1,4]benzodiazepine-azepane
461
Seven-membered Seven-membered rings
159) have been synthesised and their DNA-binding conjugates (e.g. 159) DNA-binding properties assessed <06BMCL 1160>. <06BMCLl160>. OH
Me O. /{,. _
HO
MeO 159
7.6
"~~ 0
FUTURE F U T U R E DIRECTIONS DIRECTIONS
The The scope for further developments in the chemistry of of seven-membered heterocyclic systems considerable, particularly particularly with respect to multi-heteroatom component New synthetic is considerable, component systems. New methods are needed for these systems and ring-fused derivatives. The demand for such systems methods is likely to be largely driven by the search for structurally novel drug leads.
7.7
REFERENCES REFERENCES
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06BMCL3777 06BMCL4728
06BMCL5102
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462 06BMCL6124 06CC3119 06CC3119 06CC3320 06CC4069 06CC4069
06CEJ8498 06CEJ8498
06CHE907 06EJ03803 06EJO3803 06H(67)233 06H(67)233 06H(67)549 06H(67)549 06H(68) 1017 06H(68)1319 06H(68)1319 06H(69)217 06H(69)217 06H(70)705 06H(70)705 06JA2178 06JA2178 06JC0127 06JCO 127 06JHC 1275 06JHC1275 06JMC850 06JMC1597 06JMC 1597
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06JOC1537 06JOC1537 06JOC1742 06JOC 1742 06JOC2811 06JOC3963 06JOC4937 06JOM5406 06JOM5406
J.B. Bremner Brernner and S. Sarnosorn Samosorn
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Seven-membered Seven-membered rings
06JPC(A) 1600 1600 06JPC(A) 06M 1349 06M1349 06MI60 06MI60 06MI99 06MI281 06MI281
06OBC2218 060BC22 I8 06OBC4236 060BC4236 06OL2667 060L2667 06OL4529 060L4529 06OL5183 060L5183 06OL5469 060L5469 06OL 16185 060Ll6185 06S1437 06SC355 06SC457 06SC803 06SC817 06SC 1645 06SCI645 06SC 1661 06SCI661 06SL 1009 06SLl009 06SL2275 06SL2771 06SL277I 06T1777 06T2563 06T4671 06T467I 06T7455 06T7699 06T8126 06T8126 06T9002 06T9017 06T9301 06T10456 06TI0456
06T11331 06TI1331 06T 11724 06T11724 06T12392 06T12392 06TA2334 06TA2334 06TL639 06TL639 06TL2649 06TL2649 06TL3135 06TL3135 06TL3225 06TL3225 06TL3295 06TL3295 06TL3357 06TL3357 06TL3423 06TL3423 06TL3625 06TL3625 06TL3811
463
R.L. Redington, J.J. Phys. Phys. Chem. Chem. A 2006, 110, 110, 1600. 1600. R.L. N.L N.I. Hindawi, J.A. J.A. Zahra, M.M. EI-Abadelah, B.A. Abu Abu Thaher, K.-P. K.-P. Zeller, Zeller, Monatsh. Chem. Chem. 137, 1349. 1349. 2006, 137, J.M. J.M. Mulligan, L.M. L.M. Greene, Greene, S. S. Cloonan, Cloonan, M.M. McGee, V. V. annis, Onnis, G. G. Campiani, e. C. Fattorusso, M. M. Lawler, D.e. D.C. Williams, Williams, D.M. D.M. Zisterer, Mol. Mol. Pharmacol. 2006, 70,60. 70, 60. Lawler, H. H. Greger, Greger, Planta Medica Medica 2006,72,99. 2006, 72, 99. Z. Zhang, M. Zheng, L. L. Du, J. Shen, X. X. Luo, W. Zhu, H. Jiang, J. Comput. Aided Mol. Des. 2006, 20, 281. 20,281. P. Wyatt, A. Hudson, J. J. Charmant, A.G. Orpen, H. H. Phetmung, Org. Org. Biomol. Chem. Chem. 2006,4,2218. 2006, 4, 2218. L. L. Banfi, Banff, A.B.G. Guanti, P. P. Lecinska, R. R. Riva, Org. Org. Biomol. Chem., 2006, 4, 4236. Y.S. Park, E.K. Yum, A. Basu, P. P. Beak, Org. Org. Lett. 2006, 8, 2667. S.A. S.A. Amelichev, L.S. Konstantinova, N.V. Obruchnikova, O.A. Rakitin, e.W. C.W. Rees, Org. Org. Lett. 2006, 8, 4529. 2006,8,4529. AJ. A.J. Leyhane, K.L. K.L. Snapper, Org. Org. Lett. 2006, 8, 5183. K. Satake, H. Okamoto, M. Kimura, Org. Org. Lett. 2006, 8,5469. 8, 5469. Y. Kubota, K. H. Yu, R.N. R.N. Richey, M.W. Carson, MJ. M.J. Coghlan, Org. Org. Lett. 2006, 8, 1685. 1685. L. Delhaye, A. A. Merschaert, K. K. Diker, LN. I.N. Houpis, Synthesis 2006, 1437. 1437. H. H. Ren, M. Zanger, J. Mckee, Synth. Commun. 2006,36,355. 2006, 36, 355. F. Xu, Z. Zhou, Q. Q. Shen, Synth. Commun. 2006,36,457. 2006, 36, 457. J. Wu, F. B. Ganai, S. Kumar, e. C. Andotra, K. Kapoor, Synth. Commun. 2006,36,803. 2006, 36, 803. M. Kidwai, P. Mothsra, Synth. Commun. 2006,36,817. 2006, 36, 817. Z.-H. Zhang, S.-T. Yang, J. Lin, Synth. Commun. 2006,36, 2006, 36, 1645. 1645. Y. Du, F. Tian, W. Zhao, Synth. Communya Lakshmi, R.B.N. Prasad, N. Lingaiah, P.S. Sai 2006, 36, 3797. Prasad, Synth. Commun. 2006,36,3797. 1009. R. Varala, R. Enugala, S. Nuvula, S.R. Adapa, Synlett 2006, 1009. S.L. Gomez Ayala, E. Stashenko, A. Palma, A. Bahsas, J.M. Amaro-Luis, Synlett 2006, 2275. N. Dieltiens, e.V. C.V. Stevens, Synlett 2006, 2771. S. Brass, H.-D. Gerber, S. Dorr, WE W.E. Diederich, Tetrahedron, 2006, 62, 1777. X. Che, L. Zheng, Q. Dang, X. Bai, Tetrahedron 2006, 62, 2563. H. Gold, A. Ax, L. Vrang, B. Samuelsson, A. Karlen, A. Hallberg, M. Larhed, Tetrahedron 2006, 62, 4671. 62,4671. L. Gireaud, L. Chaveriat, 1. I. Stasik, A. Wadouachi, D. Beaupere, Beaupbre, Tetrahedron 2006, 62, 7455. H.-X. Jin, Q. Zhang, H.-S. Kim, Y. Wataya, H.-H. Liu, Y. Wu, Tetrahedron 2006, 62, 7699. D. Bevk, U. Groselj, A. Meden, J. Svete, B. Stanovnik, Stanovnik, Tetrahedron 2006, 62, 8126. e. C. Ma, S.-J. Liu, L. Xin, J. R. Falck, D.-S. Shin, Tetrahedron 2006, 62, 9002. A. Le Flohic, C. Meyer, J. Cossy, Tetrahedron 2006, 62, 9017. N.L. Snyder, H.M. Haines, M.W. Peczuh, Tetrahedron 2006, 62, 9301. Yadav-Bhatnagar, J. Martinez, F. Lamaty, Tetrahedron P. Ribiere, V. Declerck, Y. Nedellec, N. Yadav-Bhatnagar, 2006, 62, 10456. Guthikonda, P.M. Wehn, B.J. BJ. Caliando, Caliando, J. Du Bois, Tetrahedron 2006, 62.11331. 62. 11331. K. Guthikonda, M.e. Nunez, M.G. Pavani, M. Diaz-Gavilan, F. Rodriguez-Serrano, J.A. Gomez-Vidal, J.A. M.C. 2006,62,11724. Marchal, A. Aranega, M.A. Gallo, A. Espinosa, J.M. Campos, Tetrahedron 2006, 62, 11724. L.G. Voskressensky, S.V. Akbulatov, T.N. Borisova, A.V. Varlamov, Tetrahedron 2006, 62, 12392. J. Vachon, C. Lauper, K. Ditrich, J. Lacour, Tetrahedron: Tetrahedron: Asymmetry 2006, 17, 2334. 2006,17,2334. 2006,47,639. M.S. Novikov, A.A. Amer, A.F. Khlebnikov, Tetrahedron Lett. 2006, 47, 639. I1yin, V.Z. Parchinski, Parchinski, J.N. Peregudova, Peregudova, A.S. Trifilenkov, Trifilenkov, E. B. Poutsykina, S.E. Tkachenko, Tkachenko, A.P. Ilyin, D.V. Kravchenko, 47, 2649. Kravchenko, A.V. Ivachtchenko, Ivachtchenko, Tetrahedron Lett. 2006, 2006,47,2649. Thakuria, A. Pramanik, Pramanik, B.M. Borah, G. Das, Tetrahedron Lett. 2006, 2006,47,3135. H. Thakuria, 47, 3135. X. Beebe, V. Gracias, S.W. Djuric, 47, 3225. Djuric, Tetrahedron Lett. 2006, 2006,47,3225. 2006,47,3295. G. Liu, W.-Y. Tai, Y.-L. Li, F.-J. Nan, Tetrahedron Lett. 2006, 47, 3295. 2006,47,3357. J.K. Mishra, J.S. Rao, G.N. Sastry, G. Panda, Tetrahedron Lett. 2006, 47, 3357. e. Kalinski, M. Umkehrer, Umkehrer, G. Ross, J. Kolb, C. e. Burdack, Burdack, W. Hiller, Tetrahedron Lett. 2006, 2006,47, C. 47, 3423. A. Kamimura, K. Tanaka, 47, 3625. Tanaka, T. Hayashi, Y. Omata, Ornata, Tetrahedron Lett. 2006, 2006,47,3625. Stephenson, D. Mitchell, Mitchell, Tetrahedron Lett. 2006, 2006,47,3811. Y. Yu, G.A. Stephenson, 47, 3811.
464 06TL5665 06TL6235 06TL6389 06TL6895 06TL8133 06TL8523 06TL859I 06TL8591 06ZN(B) 06ZN(B)I1II 11 06ZN(B)385
J.B. Bremner and S. Samosorn
P. Csomos, L. Fodor, J. Sinkkonen, K. Pihlaja, G. Bernath, Tetrahedron Lett. 2006,47,5665. 2006, 47, 5665. E. Banaszak, C. Comoy, Y. Fort, Tetrahedron Lett. 2006, 2006,47,6235. 47, 6235. M.-Y. Chang, S.Y. Wang, c.-L. 2006,47,6389. S.-Y. C.-L. Pai, Tetrahedron Lett. 2006, 47, 6389. S.K. Chattopadhyay, S.P. S.P. Roy, D. Ghosh, G. Biswas, Tetrahedron Lett. 2006,47,6895. 2006, 47, 6895. K.P. Guzen, R. Cella, Celia, H.A. H.A. Stefani, Tetrahedron Lett. 2006,47,8133. 2006, 47, 8133. S.V. More, C.-F. Yao, Tetrahedron Lett. 2006,47,8523. 2006, 47, 8523. C.-W. Kuo, S.V. A. Vasudevan, P-S. 2006,47,8591. P-S. Tseng, S.W. S.W. Djuric, Tetrahedron Lett. 2006, 47, 8591. B. Kluess, W. Kreiser, T. Sukri, W. Poll, H. Wunderlich, Z. Z Naturforsch. Teil B, 2006, 2006, 61, 111. G. Maas, R. Reinhard, H.-G. H.-G. Herz, Z. Naturforsch. Teil B, 2006,61,385. 2006, 61,385.
465
Chapter 8
Eight-membered and larger rings George R. Newkome The University Akron, Ohio University ofAkron, of Akron, Akron, Ohio USA USA [email protected] [email protected]
8.1
INTRODUCTION
Numerous reviews as well as perspectives, feature feature articles, articles, tutorials, tutorials, and mini-reviews have appeared throughout 2006 2006 that are of particular interest interest to the macroheterocyclic enthusiast and those delving into into supramolecular chemistry at the macromolecular macromolecular level, level, as nanoconstructs: switchable well as those studying nanoconstructs: switchable rotaxanes <06CSR361>; cyclodextrin rotaxanes and polyrotaxanes <06CR782>; <06CR782>; novel multiple rotaxanes and catenanes <06CC294l>; <06CC2941>; molecular machines via catenanes and rotaxanes <06ICC1063>; <06ICC1063>; hosts for organometallic complexes <06CR767>; <06CR767>; amino acid supramolecular cyclodextrin hosts derived macrocycles <06ACIE1364>; self-organization of disc-shaped molecules <06CR2527>; luminescent <06CSR83>; palladacycles that are more than precatalysts <06CR2527>; sensors <05T855 1>; from sub-phthalocyanines to sub-porphyrins sensors and switches switches <05T8551>; <06ACIE2834>; porphyrin-fullerene systems with rotaxane and catenane architectures <06CRC862>; anion<06CRC892>; macromolecular malonates for fullerene fullerene encapsulation <06CRC862>; templated assembly of interpenetrated and interlocked macromolecules <06CC2105>; <06CC2105>; labeling labeling monoclonal antibodies antibodies with macrocyclic radiolabelled complexes <06CC2105, 06DT36l7>; 06DT3617>; artificial nanomachines, based on interlocked entities entities <06CSRI135>; <06CSRl135>; ligand design in multimetallic architectures <05ACR243>; metal-mediated multiporphyrin assemblies <06ACR84l>; <06ACR841>; self-assembled nanostructures inspired inspired by photosynthesis <06JOC505l>; the dynamics and stereochemistry of interlocked materials <05CCCCI493, <06JOC5051>; <05CCCC1493, 05CEJ4655>; 05CEJ4655>; core-modified porphyrins, as platforms for organometallic chemistry 1319>; heteroporphyrins and <05CCR2510>; metallation of expanded porphyrins <06EJOC <06EJOC1319>; porphyrincalix[4]arenes <05RJOC787>; superphanes to their analogues <06CCR468>; porphyrincalix[4]arenes beltenes <06PAC699>; phenylaza- and benzoazacrowns <05RCR46l>; <05RCR461>; macrocyclization via templation <05TCC67>; design of molecular switches switches and sensors sensors <05TCC99>; H-bondedassembly of synthetic molecular motors and machines <05TCC133>; <05TCCI33>; H-bond-mediated H-bond-mediated template synthesis synthesis of rotaxane, catenanes, and knotanes <05TCCI4l>; <05TCC141>; N-confused porphyrins <06PAC29>; microwave irradiation in ring construction <05RCR969, 04MI01>; molecular knots <05TCC261>; <05TCC26 1>; amide- and urea-type gelators with tailored properties <05TCC203>; marine polycyclic ether <05TCR4314>; resorcarenes <05COC337, 05COCI167>; 05COC 1167>; chelates, pincers, as well as spirocycles <05JOMC5485>; macrocyclization by loops and belts <06CR5274>; ring-closing metathesis <06ACIE6086>; molecular loops
G.R. Newkome G.R. Newkome
466
<06CR5291>; thiacalixarenes <06CR529 1>; sugar-derived crown ethers <06COC643>; and synthetic routes to porphyrins possessing fused rings <06T10039>. <06T1 0039>. As always, because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings have been reviewed; in general, lactones, lactams, of some articles and cyclic imides have been excluded. In view of the delayed availability of appearing in previous years, several have been incorporated, where appropriate. I apologize in advance that it is impossible to do justice, justice, to this topic and the numerous researchers that have elegantly contributed to the field, in the allotted twenty pages.
8.2
CARBON-OXYGEN CARBON-OXYGEN RINGS
The coupling of 1,3-difluoronitrobenzene K2C03 1,3-difluoronitrobenzene with resorcinol promoted by Cui CuI with K2CO3 in pyridine under high dilution conditions gave the hexameric product 1 in 25% yield along with the smaller [2+2] [2+2] cyclophane <06EJOCI109>. <06EJOCll09>. Similarly, nucleophilic aromatic substitution of 1,5-difluoro-2,4-dinitrobenzene 1,5-difluoro-2,4-dinitrobenzene with 2-propylresorcinol in either Et3N/MeCN syn/anti mixture of conformers of of the cyclic tetramer and cyclic hexamer or CsF/DMF gave a syn/anti <06TL4041>. The 3,3',4,4'-tetranitrodibenzo-24/30-crown-8/10 3,3',4,4'-tetranitrodibenzo-24/30-crown-8/10 ethers have been made and shown to form organogels with chloroalkanes at 3% w/v <060L1371>. <06OL1371>. The treatment of 4hydroxybenzaldehyde with triethylene glycol in the presence of of K K2CO3 2C0 3 in refluxing MeCN bis-aldehyde, which was transformed to the bis( bis(ethynyl)ketone gave the desired bis-aldehyde, ethynyl)ketone intermediate in 84% overall yield, then upon treatment with the known 3-methoxyphenylenaminone under high dilution conditions, macrocyclization to generate 2 was accomplished <05T5363>. The treatment of poly[diphenyl-co-methyl(bromopropyl)]silane poly[diphenyl-co-methyl(bromopropyl)]silane with (4-hydroxyphenylazo)dibenzo-18-crown-6 azo)dibenzo-18-crown-6 under the traditional Williamson conditions generated the poly[diphenyl-co-methyl(propyloxyphenyl-azodibenzo-18-crown-6]silane, as a brown solid poly[diphenyl-co-methyl(propyloxyphenyl-azodibenzo-18-crown-6]silane, <06CC788>. <06CC788>. The reversible acid-catalyzed transacetalation of the cyclophane formal 3 has been ring-fusion/ring-fission process to generate a mixture of polymer cyclic shown to undergo a ring-fusionlring-fission formaldehyde acetals by means of <06CEJ8566>. The stepwise of oxonium ion intermediates <06CEJ8566>.
O~NO0~ 0~0~0~0 0/'-..0/'-..0/'-..0
I~
2
~
growth of oligo(p-phenylene oxide)s and cyclization via the Ullmann coupling reaction using di(4-iodophenyl) ether and CuIlN,N-dimethylglycine CuI/N,N-dimethylglycine gave the cyclic oligo(p-phenylene oxide)s <06JOC8614>. <06JOC86 14>. The cross-cyclocondensation of of ethereal-linked a,w-diynes t~,o~-diynes and Rh(I)/Hg-BINAP catalyst gave the [7]dimethyl acetylenedicarboxylate in the presence of of a Rh(I)/Hs-BINAP [21]-polyethereal cyclophanes in good yields <06EJOC3575>. Novel, linear, soluble highmolecular weight, film-forming polymers and copolymers possessing main-chain crown ether
Eight-membered and larger Eight-membered largerrings rings
467
units has been prepared via electrophilic aromatic units alternating with aliphatic (C (C10-C16) IO -C I6 ) units <06M4696>. Various (a)chiral substitution, followed by reduction of the carbonyl moieties moieties <06M4696>. macrocyclic oligo-malonates were synthesized in a simple simple one-step process via condensation of malonyl dichloride with a,co-diols t~,co-diols <06EJOC2296>. Treatment of salicylaldehyde with base in EtOH, followed by the introduction introduction of 1,4-dibromobutane 1,4-dibromobutane gave (96%) (96%) (CH2CH20C6H4CHO)2, (CHzCHzOC6H4CHO)2, which was subjected subjected to an intramolecular McMurry coupling to generate (95%) the macrocyclic stilbene that when treated with Br2 stilbene that Br2 followed by dehydrobromination gave (90%) the desired macrocyclic alkyne 4 <06JOC6124>. A novel triptycene-based bis( bis(crown ether) was synthesized in 46% yield from from a known crown ether) tetrahydroxy-triptycene tetrahydroxy-triptycene derivative with 1,2-bis[2-[2-(2-tosylethoxy)ethoxy]ethoxy]benzene 1,2-bis[2-[2-(2-tosylethoxy)ethoxy]ethoxy]benzene Cs2CO3 in DMF at 100°C; 100 ~ this this rigid bis-host can accommodate dibenzylammonium with CS2C03 stable clip-shaped complexes with bis[2]pseudorotaxane as well as stable salts to generate a bis[2]pseudorotaxane paraquat derivatives and ammonium salts salts <060Ll069, <06OL1069, 06CEJ4594, 060L211, 06OL211, 06JOC4509, 060Ll859>. 06OL1859>. The triply crowned 1,3,5-tris(arylalkynyl)mesitylene 1,3,5-tris(arylalkynyl)mesitylene was prepared by the treatment of triiodomesitylene with 4'-ethynylbenzo-18-crown 4'-ethynylbenzo-18-crown ether using Sonogashira coupling conditions <06EJOC516>. The ethynyl derivative of a nickel nickel octaethylporphyrin was coupled with a cone cone crown conditions to give a diphenolic diphenolic intermediate, calixarene under either Sonogashira or Negishi conditions which was alkylated to give the desired Pacman-like conformationally frozen cone cone bisporphyrin 5 in 55% yield <06JA3488>. <06JA3488>. The 1,3-di(2-pyridinylmethyloxy)-p-tert-butyl1,3-di(2-pyridinylmethyloxy)-p-tert-butyldihomooxacalix[4]arene-crown-6 (6) was synthesized by the reaction of the corresponding dihomooxacalix[4]arene-crown-6
\O
~
_
B
u
O
~
f ~.
.~ .
.N - - ~
t-Bu
(/ ~
,od2 ~ /,
~Bu
x
X
6'
'
~Bu
= = (CH2CH20)4CH2CH2 (CH2CH20)4CH2CH2
EtO2C.11./J.....~~O. ~L!.~'~CO2Et
=
H2C--~~--~ o r C H 33 R - H or H 1 C - o orCH dihomooxacalix[4]arene-crown-6 NaH in dry DMF dihomooxacalix[4]arene-crown-6 with 2-(chloromethyl)pyridine'HCl 2-(chloromethyl)pyridine.HC1 with Nail 65 ~ for 48h <06T3081>. at 65°C <06T3081>. A complete set of partially O-methylated products of p-tertbutyltetrahomodioxacalix[4]arene butyltetrahomodioxacalix[4]arene has been prepared, thus permitting the tailoring of the
468
G.R. Newkome G.R. Newkome
cavity for better guest encapsulation <06JOC504>. Refluxing ethyl 3,5-di(hydroxymethyl)-4hydroxybenzoate in xylene afforded the known hexahomotrioxacalix[3]arene (48%) and the unknown octahomotetraoxacalix[4]arene (7, 9%) <06JOC4509>. The acid-catalyzed condensation of furan and pentafluorobenzaldehyde gave very low yields of the 30n and 40n expanded porphyrinoids, in which the furan rings were inverted in an alternating fashion and displayed non-twisted conformations <06015541>. <06015541 >. A methanofullerene derivative possessing an ammonium subunit has been prepared and subsequently shown to form a supramolecular complex with a porphyrin-crown ether <06T1979>. The synthesis and study of these fullerene-containing supramolecular conjugate <06Tl979>. photoactive devices have also been reported <06CRC 1022>. I022>.
8.3
CARBON-NITROGEN C A R B O N - N I T R O G E N RINGS RINGS
A series of expanded porphyrins possessing meso-trifluoromethyl meso-trifluoromethyl moieties, such as Nfused [24]penta-, [28]hexa-, [32]hepta-, [48]deca-, and [56]dodecaphyrins, were prepared by the acid-catalyzed, one-pot condensation of 2-(2,2,2-trifluoro-l-hydroxyethyl)pyrrole 2-(2,2,2-trifluoro-I-hydroxyethyl)pyrrole <06CEJ4909>. The acid-catalyzed condensation of a pyrrole bisacrylaldehyde bisacrylaldehyde with a tripyrrane then oxidation with FeC!) 1. 1.3), which displayed a strong FeCI3 gave a [22]porphyrin-(3. [22]porphyrin-(3.1.1.3), diamagnetic current in the NMR as well as a red shifted porphyrin-like UV-vis spectra <060L5113>. The 1,3-dipolar cyc1oaddition <06OL5113>. cycloaddition of expanded porphyrins e.g., the mesooctakis(pentafluorophenyl)[36]octaphyrins-( 1.1.1.1.1.1.1.1) with an azomethine ylide regiooctakis(pentafluorophenyl)[36]octaphyrins-(1.1.1.1.1.1.1.1) and stereoselectively generated mono- and bis-pyrrolidine-fused bis-pyrrolidine-fused octaphyrins <060LlI69>. <06OL 1169>. A series of of related expanded (4 to 44 pyrrole units) isocorroles was prepared in ca. 50% yields bis(azafulvene) derivative of gem-dimethyldipyrrylmethane by treatment of the bis(azafulvene) gem-dimethyldipyrrylmethane with 2,2'bipyrrole under neutral conditions and without a catalyst <06TLl817>. <06TL1817>. Treatment of of 4hydroxyisophthaldehyde with excess C C6HsMgBr 6H sMgBr generated a carbinol that was subsequently condensed with pyrrole and aromatic aldehydes in the presence of BF BF3"Et20, 3·Et1 0, followed by oxidation with DDQ to afford new tetraarylcarbaporphyrinoids in 10-24% yield <060L5263>. The synthesis of novel [1,2,3]triazolo[4,5-b]porphyrin, from p-nitro-meso<06OL5263>. [3-nitro-mesoNaN3 in DMF, and its use in the creation of tetraarylporphyrins with NaN3 of dimeric and pentameric porphyrins have been reported <06ACIE5487>. The Suzuki coupling of bromoporphyrins, derived from 5, I0, 15,20-tetraphenylporphyrin, with 2-allyl-4,4,5,5-tetramethyl-l,3,25,10,15,20-tetraphenylporphyrin, dioxaborolane was conducted in toluene at 100°C 100 ~ under an inert gas with anhydrous K K2CO3 1C03 to give polyallylporphyrins in acceptable yields <06CC3900>. Improved methodology for of the N-alkylation of N-confused porphyrins has appeared <06JOC811>. A different type of 6,11,16,21-tetra-3-aza-m-benziporphyrin confused system recently appeared in which 6, II, 16,21-tetra-3-aza-m-benziporphyrin (8), an analog of 5,10, 15,20-tetraarylporphyrin in which one of the pyrrole moieties was replaced by 5,10,15,20-tetraarylporphyrin a pyridine ring pointing outwards, linked at the P,pt-positions, ]3,]3'-positions, was formed by condensation of of 3,5-bis[phenyl(2-pyrrolyl)methyl]pyridine, 3,5-bis[phenyl(2-pyrrolyl)methyl]pyridine, pyrrole, and p-tolualdehyde catalyzed by F F3CCO2H 3CC01H <05EJOC5039>. The synthesis of 6-methyl-2,6, 10-[ II ]-12,25-phenanthrolinophane possessing a 1,10I, I06-methyl-2,6,10-[ll]-12,25-phenanthrolinophane phenanthroline ring with a 2,9-polyaza-bridge has been reported and characterized <06DT4000>. The use of water-soluble pyridinophanes for the two-centered phase-transfer catalysis of N-alkylation of indoles, imidazoles, benzimidazoles, and benzotriazoles has appeared <06S654>. Macrocyc1es Macrocycles possessing 3-8 and 10 subunits of N-(p-tolyl)aminopyridine, e.g., the aryl-substituted azacalix[n](2,6)pyridines (9), by a Cu- and Pt-catalyzed of 2,6aryl amination have been formed <05SL263>; also see <06OL4895>. <060L4895>. The reaction of dibromopyridine with N,N'-di(3-aminopropyl)ethylenediamine N,N-di(3-aminopropyl)ethylenediamine with Pd(dba)z/BINAP Pd(dba)l/BINAP and NaO-tBu gave the desired polyazamacrocyc1e polyazamacrocycle 10 in 24% yield <06SL87>; related 14-
469
Eight-membered and larger larger rings 3 CH 3
=
HN"~NH
3) (n = 3)
CH 3 9
10
membered tetraazamacrocycles possessing a pyridine subunit have also appeared <06DT4124>. The reaction of N-(3-chloromethyl-5-methylpyrazolyl)-4-methylpyrazolylmethane with 3-aminopropanol gave a tetrapyrazolic intermediate, intermediate, which with 1,21,2conditions gave the target macrocycle 11 <06T9153>. dibromoethane under high dilution conditions Various bridged nicotinates 12 possessing a [n ](2,5)pyridinophane subunits (n =- 8-14) were [n](2,5)pyridinophane prepared by a different sequence sequence of events, specifically the reaction of methyl propiolate with a series offormyl-substituted interesting dynamic of formyl-substituted (vinylimino)phosphoranes (vinylimino)phosphoranes <06T4128>. An interesting combinatorial library of macrocyclic oligoimines, starting with enantiopure transcyclohexane-l,2-diamine and 2,6-diformylpyridine, has appeared and these imines were subsequently reduced with borohydride to give the corresponding chiral polyamines in overall high yield and purity <06CC2224>. Although lactams are generally not considered in this review, the formation of bowl-shaped cyclic trimers 13 of aromatic amides was reported to occur in high yields by the condensation of meta-substituted meta-substituted 3-(alkylamino)benzoic acid using dichlorotriphenylphosphorane dichlorotriphenylphosphorane <06TL413>. A series of simple chiral polyazamacrocycles with 12-, 12-, 18-,24-,27-, 18-, 24-, 27-, and 36-membered rings were easily synthesized using (S)-a-phenylethylamine, as the chiral source, and 2,6-bis(chloromethyl)pyridine 2,6-bis(chloromethyl)pyridine <06TL2371>. Trianglamines, a family of macrocyclic heterophanes, have been synthesized through a [3+3] [3+3] cyclocondensation of (R,R)-1,2-diaminocyclohexane (R,R)-l,2-diaminocyclohexane with terephthaldehyde, followed by borohydride reduction and N-alkylation <06CEJ1807>. <06CEJl807>. The reaction of cyclam 25°C with 1,2-di(3-bromoprop-2-ynyl)benzene l,2-di(3-bromoprop-2-ynyl)benzene and K K2CO3 ~ for 12h gave a mixture ZC0 3 in DMF at 25 of the mono- and desired bis-eneyne bis-eneyne 14 <06TLlI7>. <06TL117>. The improved synthesis of the 1,4,7, lO, 13,16,21 ,24-octaazabicyclo[8.8.8]hexacosane (a 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane simple peraza[2.2.2]cryptand) was prepared in 70% yield via a two-step one-pot process by tris(2-aminoethyl)amine with glyoxal in isopropanol at at-78 ~ the initial condensation of tris(2-aminoethyl)amine -78°C, followed by a Na/liquid NH3 NH 3 reduction <06S759>. <06S759>. The equilibrium and rearrangements associated with the two-step synthesis of l,4,7,lO-tetraazacyclododecane 1,4,7,10-tetraazacyclododecane from triethylenetetraamine, glyoxal, and diethyl oxalate have been considered <62T6855>. A 0-tetraazacyclododecane-4,7, lO-triacetic-lnovel bifunctional octa-coordinate ligand, 1,4,7,1 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1{methyl[4-aminophenyl)methyl]phosphinic <050BCI12>. N{methyl[4-aminophenyl)methyl]phosphinic acid]}, has been reported <05OBCl12>. Substituted Substituted diaza[l2]annulenes diaza[12]annulenes have been prepared via a one-pot procedure with N-(2,4dinitrophenyl)pyridinium chloride chloride with aryl and alkyl amines in 40-80% yield <060L4279>. <06OL4279>. l,5-diazacyclooctane subunits coupled with two ethylene Macrocycles possessing two 1,5-diazacyclooctane II-tetraazabridges gave rise to the highly topologically constrained 1,4,8, 1,4,8,11-tetraaza48 tricyclo[9.3.3.3 • ]eicosane <06ICCl80>. tricyclo[9.3.3.34'8]eicosane <06ICC180>. The novel [2]rotaxanes [2]rotaxanes possessing a tetracationic cyclophane, i.e., cyclobis(paraquat-4,4-biphenylene), cyclobis(paraquat-4,4-biphenylene), and a lumpy molecular thread that incorporated a photoactive diary1cycloheptatriene diarylcycloheptatriene and photo-active aryl subunits subunits have been created in ca. 30% yields via simply coupling the two halves <06EJOC378>.
470
C.R. G.R. Newkome
HC3C~ H3[NjN~ ,.CN.H CcN, N/~N ~OH 3
h ~'N~'J'N/;
N~OH
) r ~N
NN"
N"
-
-
~ruCOzMe O2Me
\
I,tf,
(eH,)"]
H3C H3C11 O\~ /CH3 H3C~N~v "N H3C
H3C
11
12
°PN/ H'C~
CH3
r VrNJ) I
13 0 8.4
CHa 6H 3
14
CARBON-SULFUR RINGS CARBON-SULFUR
A novel set of fully conjugated giant macrocyclic oligothiophenes containing 601t, 60n, 9011:, 90n, 120n, 15011:, 150n, and 18011: 180n "frames" possessing butyl-substituents has been synthesized by means 12011:, of of either a Sonogashira or McMurry coupling procedure; the 60-18011: 60-180n macrocycles possess 1.8-6 nm inner cavities and 3.3-7.5 nm outer molecular diameters <06JA16740>. <06JAI6740>. Related cyclic oligothiophenes (CnT, n=6-30, even only) in syn- and anti-conformations have been theoretically studied at the B3LYP/6-31 B3LYP/6-31G(d) G(d) level <06JOC2972>. The homocoupling of of the Lipshutz cuprates [ArzCu(CN)Lb] [ArzCu(CN)Li2] (hetero)aryl halides by electron-transfer oxidation of with organic electron-acceptors has been demonstrated, for example, when bis(3-bromo-2thienyl)methane was treated with two equivalents of BuLi, followed by euCN CuCN and Et3N, Et3N, followed by oxidation with 1A-benzoquinone, 1,4-benzoquinone, the desired 10<06JOC611O>; the membered ring was generated <06JOC6110>; related bis(3-bromo-2-thienyl)dimethylsilane bis(3-bromo-2-thienyl)dimethylsilane gave the silicon-bridged 10-membered cyclophane. Under high-dilution conditions, the treatment of disodium I,2-dicyanoethene-1 ,2-dithiolate with 1,2-dicyanoethene-l,2-dithiolate either 1,8-dichloro-3,6-dithiaoctane or 1,9-dichlorothe 3,7-dithianonane gave corresponding S maleonitrile-tetrathiacrown ethers [mn12S4 [mnl2S4 or mn13S4; X-ray data confirmed the structures mnl3S4; the 15 and it was further shown that mn 12S4 is the first mnl2S4 preorganized tetradentate thiacrown ether that forms sandwich complexes with the coordination number eight [with silver(I)] <06EJIC2377>. The O-alkylation of5,11,17,23of 5,11,17,23tetra-tert-butyl-2,8,14,20-tetrathia-calix[4] arene-25,26,27,28-tetraol with bromomethyl tetra-tert-butyl-2,8, 14,20-tetrathia-calix[4]arene-25,26,27,28-tetraol 11,17 ,23-tetra-tert-butyl-25,27-bis[(ethoxycarbonyl)acetate gave rise (47%) to the distal-5, distal-5,11,17,23-tetra-tert-butyl-25,27-bis[(ethoxycarbonyl)Cs2CO3 methoxy]-26,28-dihydroxy-2,8,14,20-tetracalix[4]arene, which upon treatment with CS ZC03 in THF, followed by 2-(chloromethyl)pyridine'HCl 2-(chloromethyl)pyridine.HC1 gave (61%) 5,11,17,23-tetra-tert-butyl(ethoxycarbonyl)methoxy ]-26,28-bis[ (2-pyridinylmethyl)oxy]-2,8,14,20-tetra25,27-bis[ 25,27-bis[(ethoxycarbonyl)methoxy]-26,28-bis[(2-pyridinylmethyl)oxy]-2,8,14,20-tetrathiacalix-[4]arene possessing an 1,3-altemate 1,3-alternate configuration <06JIPMC31>. The first p-tert-butylhexahomotrithiacalix[3]arene (15) by means of a synthesis of the C C3-symmetrical 3-symmetrical p-tert-butylhexahomotrithiacalix[3]arene 2,6-bis(chloromethyl)-p-tert-butylphenol with single-pot procedure by the treatment of of 2,6-bis(chloromethyl)-p-tert-butylphenol Na zS'9H zO under high dilution conditions; other hexahomotrithiacalix[3]arenes were NazS-9H20
A ;:OHO:O),
~S4
Eight-membered and rings Eight-membered and larger larger rings
471
synthesized via a convergent process by a [2+ 1] cyclization from mono- and [2+1] bis(chloromethyl)phenol components <06JIPMC253>. Using macrocyclization conditions, bis(chloromethyl)phenol e.g., rapidly stirred suspension of of CS Cs2CO3 2C03 in DMF in the concentration range of 50-100 mmol/L at 65-100 DC, ~ macrocycles [20]aneS6(OH)6, [20]aneS6(OH)6, [13]aneS4(OH), [13]aneSa(OH), [26]aneSg(OH)2, [26]aneS8(OH)2, and [32]aneSg(OHh [32]aneS8(OH)2 have been prepared via the reaction of of 1,3-dichloro-2-hydroxypropane with the appropriate dithiol <06P599>.
8.5
CARBON-OXYGEN/CARBON-NITROGEN RINGS CARBON-OXYGEN/CARBON-NITROGEN
A chiral [4]pseudocatenane 16 was synthesized from chiral triptycene-based tris(crown ether) and three equivalents of bis[p-(but-3-enyloxy)benzyl]ammonium bis[P-(but-3-enyloxy)benzyl]ammonium salt in CH CH2C12 2Ch in the presence of Grubbs II catalyst, followed by reduction <06CEJ5603>. Several novel were of calix[4]arenocrowns prepared by a simple one-pot reaction calix[4]monohydroquinone diacetate with bis-tosylates, e.g. 1,4-bis[2-(2-(2-(2-tosyloxy1,4-bis[2-(2-(2-(2-tosyloxyethoxy)ethoxy)ethoxy)ethoxy)benzene, in dry MeCN in the presence of NaOH; the selfcalix[4]areno[2]catenanes with a dicationic salt and p-bis(bromomethyl)p-bis(bromomethyl)assembly into calix[4]areno[2]catenanes benzene was also demonstrated <06TL6012>.
foo,
o
3PF -
o/
o o..
8.6
CARBON-NITROGEN-OXYGEN CARBON-NITROGEN-OXYGEN RINGS
A new synthesis of 1,7-bridged cyclens has appeared by reacting bis(2-formylbis(2-formylphenyl)ether or 1,8-diformyldibenzofuran with cyclen under reductive amination conditions, e.g., in the presence of of2.8 DC 2.8 equimolar amounts ofNaBH(OAc)3 of NaBH(OAc)3 in 1,2-dichloroethane at 25 ~ <06CC5054>. New dioxadiaza-, trioxadiaza-, and hexaaza-macrocycles possessing the rigid dibenzofuran group have been prepared from 1,8-diformylbenzofuran and appropriate a,ffior,co-
472
G.R. Newkome Newkome G.R.
O,O'-bis(2diamine, followed by reduction <06T8550>. The treatment of O,0'-bis(2formylphenyl)triethylene glycol with diethyl ketone in the presence of ammonium acetate gave the PEG-bridged 2,6-di(2-oxaphenyl)-3,5-piperidin-4-one in reasonable yield <06CHCI25>. <06CHC125>. A variety of macrocyclic phenanthrolines were synthesized from 2,9-bis(4hydroxyphenyl)-l, 1O-phenanthroline and numerous 11,3-bis(co-bromoalkoxy)benzenes ,3-bis(co-bromoalkoxy)benzenes (alkyl hydroxyphenyl)-l,10-phenanthroline = C6-C16) C6-C16) were used and under specific reaction conditions [K [K2CO3 DMSO/H20 20 (99:1) at 2C03 in DMSO/H 65 DC ~ for 4 h], the ClO C10 connectors were favored <06JOC7477>. The resultant Cu(I)phenanthroline (with C C10 tris(4-biphenyl)methyl-(CHz)6OC6H4C-CH lO linkages) complex with tris(4-biphenyl)methyl-(CH2)60C6H4C=CH generated the [2]rotaxane in 72% yield and thus it was catalyzed by the macrocyclic Cu(I) <06OL5133>. reagent <060L5I33>. The route to oligomeric corroles has been reported in which a monomeric meso-free oxacorrole was treated with AgOTf, instead of the usual AgPF AgPF6, 6, the dimer was isolated in ca. 90% yield; this coupling was first observed during an attempt to metallate the oxacorrole with a silver salt <06CEJl05>. <06CEJ105>. An alternative to forming the meso-meso linkages was reported for the coupling in the related family of22n of 22~ smaragdyrins using the AgPF AgPF66 (3.7-19.3% yield of dimer); however with n-BuLi, the yield was shown to be 10-30% <06CC4584>. Two-photon absorption cross-section values for a series of 22n 22~ smaragdyrins possessing phenylacetylenylphenyl- and [(phenylacetylenyl)phenylacetylenyl]phenyl- with meso-links as well as their Rh(I) complexes have been reported <060L629>. <06OL629>. Substituted oxacalix[m]arene[n]pyrimidines have been prepared by SNAr SNAr conditions on 4,6dihalopyrimidines; however depending on the reaction conditions, either a mixture of oxacalix[m]arenes (m == 4-12) was obtained or m == 4 could be selectively synthesized in high <06OL4161 >. Oxacalix[2]arene[2]hetarenes Oxacalix[2]arene[2]hetarenes were formed by the cyclooligomerization yield <060L416I>. of henoIs with meta-dichlorinated azaheterocycles in a single step <060L2755>. of meta-dip meta-diphenols <06OL2755>. -
-
o O
/
~N H2N~NH 2
o N~/~N
~
O~O
PhOCH2COCI '
DCM, 78 ~
,O,
"~N~N
o,
17
19
.
~ ~o~o OH gHO0'rf\
18
20
Method 10N HCI, Method a: 10N HCI, H20, H20. A L'>
•
Method b: LiOH, LiOH. H202, H20 2 • 0 O°C Method ~
O ~,1
27%
0 OH HO,~,~O o o 0 H N~NH 00 HN~NH
O ~,1
O
~ 7
0
o
0
V
0 '----./
21 ~ I
""
Method b: 74% 74% Method
OH
gHO0 0'rf\
OH
HO~I.0
O'J::HN~NH
a
'0
7
Methoda: M'lhod " 86% B<>%
H
0 '----./
""
~ O ~ 2 0 22 ~ I ""
V
M-~thoda: Method a: 90O/o 90% Method b: 74% Method
473
Eight-membered and larger larger rings
The synthesis of macrocyclic chiral aminoacids was demonstrated by the initial conversion ofa of a bis-aldehyde 17 with 1,3-diaminopropane 1,3-diaminopropane to give the corresponding bis-imine NEt3 gave an ca. equal mixture of 18, which with phenoxyacetyl chloride in the presence of of NEt3 of bis-~-lactams bis-~-lactams 19 and 20 that can lastly be ring-opened to afford the desired chiral macrocycles 21 and 22 <06JOC8787>. <06JOC8787>. Norephedrine and (IR,2S)-ephedrine (1R,2S)-ephedrine were initially transformed into the mono-N-protected intermediate, which was then reacted with BrCH BrCH2CN, 2CN, SOCI2, followed by small PEG reagents, mesylation, followed by sequential treatment with SOCb, deprotection of of the N-cyanomethyl group, and lastly intramolecular alkylation gives easy access to chiral azacrown ethers <06TL4817>. A chiral N-containing calix[4]arene bearing the chiral 1,2-diphenyl-l,2-oxyamino 1,2-diphenyl-l,2-oxyamino moiety on the lower rim showed excellent molecular recognition between the mandelic acid enantiomers <06TL6357>. A series of chiral C2C2symmetric 2,2'-bipyridine-containing crown ethers has been reported for the enantiomeric recognition of amino acid derivatives <05T7924>. An aqueous solution of equimolar 0-phenanthroline-2,9-dialdehyde, quantities of 2-[2-(2-aminoethoxy)ethoxy]ethylamine, 1,1 1,10-phenanthroline-2,9-dialdehyde, and Cu(I) gave rise to a dimeric, helical macrocycle in quantitative yield <06CEJ4069>; by alteration of of the components, catenanes could be isolated. A new type of of molecular motor 7](2,6)pyridinocyclophanes, possessing embedded 1,3-dioxanes was demonstrated for [7. [7.7](2,6)pyridinocyclophanes, within the bridges; the rotation of of the central pyridine ring was controlled by the bridge composition and that molecular motion was stopped by the addition of CF3S03Ag CF3SO3Ag <060L2619>. <06OL2619>.
2PF6 -
O~
RO
OR
24
25
=
benzyl or or methyl methyl R = benzyl
Novel bipyridinocrownophanes bipyridinocrownophanes 23 possessing two bipyridine moieties were easily prepared by an intramolecular [2+2] photocycloaddition of of a linear bis(vinylbipyridine derivative <06T8550>. The synthesis of a tris( crown formazan) from hexakistris(crown (actamidophenoxymethyl)benzene has been reported <06TL1303>. <06TLl303>. The 19-membered azoand azoxy-crown ethers have been created by the reductive macrocyclization of of the corresponding bis(nitrophenoxy)oxaalkanes bis(nitrophenoxy)oxaalkanes <06Tl49>. <06T149>. Other new azobenzocrown ethers of of different sizes and substitution patterns have also been synthesized <05T10738>. <05Tl 0738>. A series of redox-active Wurster's crownophanes were prepared via a macrocyclization process involving N,N'-dimethyl-p-phenylenediamine N,N-dimethyl-p-phenylenediamine an various tosylated glycols <05Tl2350>. <05T12350>. A novel 2,3,6,7,10,11-hexaphenyl1,4,5,8,9,12example of bis-macrocycle of 2,3,6,7,10,II-hexaphenyl-l,4,5,8,9,12hexaazatriphenylene (24) prepared from a linear tris-benzil system connected by PEG linkages has appeared <060L1311>. <06OL1311>. In the process of making complexes composed of macrocyclic molecular clips, e.g., 25, the C,N,O-macrocycles were generated from 1,2-bis[2(4-(4-pyridinyl)phenylmethoxy)ethoxy]ethane and a,a'-dibromo-p-xylene with added KPF KPF6 6 <06CEJ865>. Treatment of of diaza-18-crown-6 with a 5,15-o-diamido picket- or a 5,15-
474
G.R. Newkome
diaminophenyl-porphyrin led to the formation of three new macromolecule, specifically a cryptand, a bis-, and a tris-macrocycle tris-macrocycle <06T3056>. 8.7
CARBON-NITROGEN-SULFUR RINGS
I] strategy starting from A series of porphyrinoids has been synthesized by the [3+ [3+1] tripyrrane analogues (26) with the desired thiophenediol 27 to give 28 and 29; interestingly, when macrocyde macrocycle 28 was treated with alkoxide in EtOH, conversion to 29 was observed along with decomposition <06OL3355>. <060L3355>. The synthesis and characterization of a coremodified [26]hexaphyrins(1. [26]hexaphyrins(1.1.1.1.0.0) 1.1. 1.0.0) and the related 54n-modified dodecaphyrin have been reported <06OL4847>. <060L4847>. Dithiaethyneazuliporphyrin (30), the first contracted carba[3+1] 1,4-bis[5-(phenyl-hydroxyI] strategy using 1,4-bis[5-(phenyl-hydroxyporphyrinoid, has been prepared by a [3+ methyl)thien-2-yl]-1,4-diphenyl-2-butyne and azulene <06CC3346>.
EtO2% . . ~
jC O2Et
HO
OH
P-TO~~:-TOI -Tol
COzEt "1" EtO2C"~NH NHN~ "CO2Et + p-Tol~ P
1)TFA,
NH4C'
2) DDQ v
2)DDQ
27 26
EtO2C CO2Et ~EtO2C
EtO2C
CO2Et CO2Et
CO2Et
EtOzC
EtO2C~
EtOzC
-+ .
.
.
.
.
.
.
EtO-, Eto-, EtOH
.
~,,.S ~...~~ p-Tol" ~
EtOH
"p-Tol
p-mol" ~
28 28
29
"p-mol
A simple, nearly quantitative route for the detosylation of mixed azathiacrown ethers using sodium amalgam has appeared <06S756>. The incorporation of a 2,2'-bisethereal
o
--
hv
~ 0 CH2CI2 0
~~--
0 0
30 30
32 s-s s--s 32
azobenzene moiety into a 19-membered ring 31 has been reported starting from the 2,2-bishydroxyazobenzene in six-steps; this effort was developed to create a commercial 2,2-bishydroxyazobenzene
Eight-membered and larger larger rings rings Eight-membered
475
novel photo-triggering device involving the EE to Z isomerism <06CC3818>. The proof-ofof a tripyridinylthioethereal macrocycle macrocyc1e 32 has appeared appeared showing the high degree of of structure of structure molecular distortion <06AC(E)o4952>. <06AC(E)o4952>. The use of of 1,9-dithia-5,13-diazacyclohexadecane 1,9-dithia-5,13-diazacyc1ohexadecane in molecular cyc1am and aza-18-crown-6 has given rise to a new conjunction with orthogonally protected cyclam macrocyc1e incorporating N4-, N4 -, N2S2-, NzSz-, and NO6-donor N06-donor sites; sites; the authors also heterotopic macrocycle cyc1am and the 1,9-dithia-5,13-diazacyclohexadecane 1,9-dithia-5,13-diazacyc1ohexadecane into a cofacial ligand incorporated cyclam of 1,4,10,13-tetrathia-7,16-diazacyclooctadecane 1,4,10,13-tetrathia-7,16-diazacyc1ooctadecane with <06T4173>. The N-functionalization of KzCOJ and K! KI has been reported 2-chloro-N-pyren-1-yl-acetamide in MeCN with K2CO3 2-chloro-N-pyren-l-yl-acetamide 1,4,7-trithia-11-azacyc1otetradecane has been prepared (62%) from N,N<06TL497>. The 1,4,7-trithia-11-azacyclotetradecane bis(3-chloropropyl)amine and 2,2'-thiobis(ethanethiol), 2,2'-thiobis(ethanethiol), subsequent treatment with 9bis(3-chloropropyl)amine (chloromethyl)anthracene generated the desired N-alkylated product (73%) <06EJIC2997>. of a rhodium(II)-catalyzed double Stevens rearrangement has been applied The novel use of of sulfur-containing heterophane 33 then to the desulfurized cyclophane cyc10phane 34 to the conversion of of these <060L25 11>; this procedure complements the well-known ring-contraction of <06OL2511>; thiaheterophanes. thiaheterophanes. A novel zig-zag polymer has been reported that possesses of the pyridinophane unit dithia[3.3](2,6)pyridinophane moieties; the incorporated syn-form of readily complexes palladium to generate a polymeric complex that can catalyze the Heck <060Ll029>. coupling reaction <06OL 1029>.
Q
Q
N N (NyN\ (Et~J3P /,/N..~ N..,~ (EtO)3P hv E,,,~"~~
/,/N.~N.~ E/L[..e S D O S ,~ SS 0O SS E~# Rh2OAc4E'~~~L~/~: R\_ Xylenes, EA E~E A 33 R R R
k
8.8
E,j~\);N\E,~EE E~E
34
R R
34
CARBON-PHOSPHORUS-OXYGEN C A R B O N - P H O S P H O R U S - O X Y G E N RINGS RINGS
Treatment of (S,S)-bis(2-hydroxypropyl)phenylphosphine (S,S)-bis(2-hydroxypropyl)phenylphosphine oxide with initially base followed by CI(CHz)zO(CHz)zOTf CI(CHz)20(CHz)zOTf gave the dichloride intermediate, which with base and either catechol or tosyl amine in DMF and elevated (150 0c) ~ temperatures generated the 0-aza-18-crown-6-ether in macrocyc1ic macrocyclic phosphane oxide 35 in 15% yield or the 1-phospha-1 1-phospha-10-aza-18-crown-6-ether 44% yield <06EJOC154>. <06EJOC 154>. 8.9
CARBONC A R B O N - PHOSPHORUS-SULFUR PHOSPHORUS-SULFUR RINGS RINGS
A new 2,2'-bipyridine containing phosphadithiamacrocycle 36 has been synthesized (10%) by the treatment of 6,6'-bis(bromomethyl)-2,2'-bipyridine 6,6'-bis(bromomethyl)-2,2'-bipyridine and dilithium 3-phenyl-3phosphapenta-1,5-dithiolate; phosphapenta-l,5-dithiolate; conversion to the corresponding P-oxide was readily obtained by its simple oxidation in an open atmosphere <06P801>. The synthesis of calix[1]phosphole[1]thiophene[2]pyrrole (37) was generated in low overall yield by the treatment of 2,5-bis(1-hydroxy-1-methylethyl)phosphole 2,5-bis(1-hydroxy-l-methylethyl)phosphole P-sulfide with boron trifluoride 2,5-bis[(pyrrole-2-yl)methyl]phosphole intermediate etherate in pyrrole to generate the (}4~4-2,5-bis[(pyrrole-2-yl)methyl]phosphole 1-hydroxy-1-methylethyl)<06JA 11760>, which was similarly condensed with 2,5-bis( <06JAl1760>, 2,5-bis(1-hydroxy-l-methylethyl)thiophene to give the desired macrocyc1e macrocycle 37 <060M3105>. <06OM3105>. The corresponding calix[l]calix[1]phosphole[ 1] furan[2]pyrrole was prepared by the substitution of 2,5-bzs( 1-hydroxy-1phosphole[1]furan[2]pyrrole 2,5-bis(1-hydroxy-1methylethyl)furan in the last step <060M3105> <06OM3105> or with 2,5-bis[hydroxy(phenyl)methyl]2,5-bis[hydroxy(phenyl)methyl]-
476
G.R. G.R. Newkome Newkome
thiophene to create a P-containing hybrid porphyrin, which exhibited high aromaticity, as an 18rt-electron system <060L57 <06OL5713>. 181t-electron 13>.
\"r01 [":: < O~ /-N
Ph<
0
O~
;-0"-.J0~
':?
~
)
N )-Ph
I
35
8.10
S, S
36
37
CARBON-SULFUR-OXYGEN RINGS CARBON-SULFUR-OXYGEN
~.-...o/----No/..~ 10~01
R~[~S SJ(S svS R XS 1>=<1 R R / - ~S ~ - SSS-\SSI
ST~::~S S/(SC S~JScl0HH2'
SX S
I>=<~
S S s~S" I
lO 21
S SCH "S~sc10H21 10 21
~o."--,,P---../
R R = SCH SCH2CH2S 2 CH 2 S or SCH SCH33
38
Il-dithiacyclotridecan-9-01 and 1,4,7New procedures to the formation of 1,4-dioxa-7, 1,4-dioxa-7,11-dithiacyclotridecan-9-ol trioxa-10,14-dithiacyclohexadecaen-12-ol 0, 14-dithiacyclohexadecaen-12-01 utilized 2,3-dibromopropanol with either trioxa-l (CH (CHzOCHzCHzSH)2 O(CHzCHzOCHzCHzSH)2 LizCO3 20CH 2CH 2SH)2 or O(CH 2CH 20CH 2CH2SH)2 with Li 2C03 in aqueous EtOH; the procedure was shown to proceed via an oxirane intermediate <06CHC206>. The convenient tridecan-9-01 to the 1,4-dioxa-7,11-dithiacyclotridecan-9-one I,4-dioxa-7, I I-dithiacyclotridecan-9-one was oxidation of the above tridecan-9-ol accomplished by a Swem Swern oxidation at low (-70°C) (-70 ~ temperatures; the alkylation and acylation of the ring alcohol moieties were also reported therein. therein. A new amphiphilic bis-tetrathiafulvalene bis-tetrathiafulvalene annulated macrocycle 38 that can form redoxactive organogels as well as electrically active nanostructures, e.g., nanowires and sizecontrollable nanodots, has been reported <05ACIE7283>. Thiones that incorporate two different poly(ethylene glycol) chains were prepared from bis(tetraethylammonium)bis(1,3bis(tetraethylammonium)bis(l,3dithiole-2-thione-4,5-dithiol)zincate and subsequent tosylation, followed by reaction with ptert-butylcaIix[ 4]arene to generate 39 <06CEJ1906>. <06CEJI906>. This thioxo reagent did not couple tert-butylcalix[4]arene upon reaction with triethyl phosphite, but upon conversion [Hg(OAc)l, [Hg(OAc)2, CHCb CHC13 and AcOH] of the thioxo moiety to the oxo analog, which was successfully transformed to the desired TTF of the remaining phenolic positions. derivative 40; the final step was the alkylation of 8.11
CARBON-NITROGEN-SULFUR-OXYGEN CARBON-NITROGEN-SULFUR-OXYGEN RINGS RINGS
of bis-N,N'-(2-(2-(2-(2-thioacetylethoxy)ethoxy)ethylbis-N,N-(2-(2-(2-(2-thioacetylethoxy)ethoxy)ethylThe dynamic self-assembly of via 7t-rt 1t-1t attraction and disulfide bonds led to the formation of of perylenetetracarboxylic diimide via of a threading process a cyclic perylene dimer as well as the related catenane composed of of the N-azo-coupled NO2S2 N0 2S2 macrocycle 41 was accomplished <06JAI 1150>. The formation of <06JA11150>. of N, N,N-phenyldiethanolamine by the treatment of Ar-phenyldiethanolamine with tosyl chloride, followed by thiourea and then bicarbonate to give 2,2'-(phenylazanediyl)diethanethiol, which with 1,2-bis[21,2-bis[2<060Ll641>. (chloromethyl)phenoxy]ethane generated the desired macrocycle in 48% yield <06OL 1641>. Lastly, treatment of of this macrocycle with diazonium salt of of 4-nitroaniline 4-nitroaniline gave 41 in 88%
477
and larger rings rings Eight-membered and
Bu' But
tBu
tBu tBu
~ But
~
tBu tBu
tBu
1) 1) CHCI CHCI3a,, AcOH, Hg(OAch
AcOH,
Cs~,CH~Cm=~I S~/
~a~
o) H~/OAc/~ •
2) P(OEth, '"
OTs
o,s--~ - ~
~o)~jo..,)
(n = 0 or 1)
~:( s.~s
39
S
~~,o~o~o~
~o~o~o~ '~u
~u~-~OH~ o o ~-~~ E3u,.~O~_._/ ,~-~ 40 SU'
o o H~ L-~ .~_/ ~_jO~~tg 'S u U
2 yield; this functionalized N0 NO2S2 Hg +2 2S2 macrocycle was shown to a chromoionophore with Hg+ selectivity.
41 8.12 8.12
CARBON-SILICON/SELENIUM/TELLURIUM RINGS CARBON-SILICON/SELENIUM/TELLURIUM
l2-membered ring heterocycles An interesting synthesis of of numerous (>40) 4- to 12-membered containing different combinations combinations of of Group 14 and 16 elements [Si, [Si, Sn, S, Se, and Te] has a,w-dihalides utilized gem-dialkylsilyl gem-dialkylstannyl moieties in been reported from ~,co-dihalides gem-dialkylsilyl and gem-dialkylstannyl <06JA14949>; oxidation of of mixed SeSe, rings with the precursors <06JA14949>; S(Se, Te)/Si eight-membered tings NOPF 6 or Br2 gave the corresponding dications or a bicyclic dibromide. NOPF6
8.13
CARBON-METAL CARBON-METAL RINGS RINGS
The expeditious expeditious stepwise directed assembly of of large homochiral metallocycles with up to 6,6'-bis(alkynyl)-1,1'-binaphthalene bridging ligands and 38 trans-Pt(PEt3)2 trans-Pt(PEt3)2 centers as 38 6,6'-bis(alkynyl)-l,l'-binaphthalene <06JAl1286>. well as possessing cavities as large as 22 nm in diameter has been reported <06JA11286>. {AU2[Il(C=C)2Py]h, of3,5-diethynylpyridine [AuCl(SMe2)] and NEt3 gave {Auz[Ia(C-C)zPy]}2, The reaction of 3,5-diethynylpyridine with [AuCI(SMe2)] which with monodentates monodentates or 1,6-bis(diphenylphosphino)hexane 1,6-bis(diphenylphosphino)hexane gave the neutral complexes of of the general formula {(AuL)z[~t(C-C)zPy]} {(AuLMIl(C=C)2Py]) <0405707>. <0405707>.
478 8.14
G.R. Newkome G.R. Newkome
CARBON-NITROGEN-METAL CARBON-NITROGEN-METAL RINGS
The treatment of dendritic ligands possessing directed pyridine end-groups with diplatinum acceptors both possessing a 120 0~ angles lead to the self-assembled hexameric <06JAlO014>. The reaction of a series of di-directed core (42) of a metallodendritic family <06JA10014>. 3,6-bis[trans-Pt(PEt3)z(NO3)]phenanthrene and related metal-terminated accepters, based on 3,6-bis[trans-Pt(PEt3h(N03)]phenanthrene extended counterparts with a tridirectional tetrahedral donor [tris(4-pyridinylethynyl[tris(4-pyridinylethynylM3L2 trigonal-bipyramidal cages;<06JOC9464> phenylene)ethane] gave three-dimensional M3L2 <060L399 I, 06JOC4155>. The very unique self-assembly ofa for related systems, also see <06OL3991, of a I-perfluoroalkyl-2,6-di(4-diethynylpyridine) Pd(N0 3)2 gave a well-confined molecular1-perfluoroalkyl-2,6-di(4-diethynylpyridine) with Pd(NO3)2 <06MI1273>. The scale fluorous "droplet" and has been considered a "inverse dendrimer" <06MIl273>. self-complementary assembly of metallomacrocycles has been accomplished by the mixing of equimolar amounts of N,N'-bis(pyridin-4-yl)pyridine-2,6-dicarboxyamide, N,N-bis(pyridin-4-yl)pyridine-2,6-dicarboxyamide, [RuCb(PPh [RuClz(PPh3)2] 3 )2] and 11,3-bis(diphenylphosphino)propane ,3-bis(diphenylphosphino)propane <06ACIE4290>. Treatment of four equivalents of N,N',N"-tris(3-pyridinyl)-l,3,5-benzenetricarboxamide N,N ,N'-tris(3-pyridinyl)-1 ,3,5-benzenetricarboxamide with three equivalents of Pd(NO3)2 Pd(N0 3)2 in DMSO gave a quantitative yield of a single self-assembled cage, <[Pd <[Pd6L8](NO3)12 >, assigned 6Lg](N03 )12>, by a single crystal structure <06JA3530>. As a continued effort to prepared hexameric systems based on the self-assembly of directed bis-terpyridine monomers, several interesting in families, e.g. 43, of iron and ruthenium connectivity have appeared <06DMP413, 06DT3518>. But in the assembly process, the creation of a three-step procedure to the novel first nondendritic fractal 44 entitled the "Sierpinski hexagonal gasket" was reported <06M1l782>. <06MI1782>. O(Gn) Et3P
O PEt3 "Pt.
.Pt"
"",,~
N
o
o N ~'
N ~'
%N--.PEt3 Et3P N.~JJn = 0_ - 3 yr...~ .~.Pt" Et3P ~ PEt3
42
8.15
o
~
O = Fe", X = PF6 or Zn"' X = BF4- ~
N~~N~ N
43
"~NN~I iN
9
CARBON-OXYGEN-NITROGEN-METAL RINGS C A R B O N - O X Y G E N - N I T R O G E N - M E T A L RINGS
The treatment of triazacyclononane with TsO(CH2)20C6H40(CH2)20CH2-bpy TsO(CH2)2OC6H40(CH2)2OCH2-bpy gave (40%) the desired tris-armed macrocycle, which with Fe(II) gave the red crystalline tricyclic <06TL3541>. pseudocryptand 45 <06TL3541 >. The selective formation of a homo- or hetero-cavitand cage of two molecules of tetra(4-pyridinyl)-, tetrakis( 4-cyanophenyl)-, or tetrakis(4tetrakis(4-cyanophenyl)-, Pd(dppp)(OTf)2 or Pt(dppp)(OTf)2 ptedppp)(OTf)2 has pyridinylethynyl)cavitands with four molecules of Pd(dppp)(OTf)2 <06JA1531>. been reported <06JA 1531 >.
479 479
Eight-membered Eight-membered and and larger larger rings rings
84 PF6" II a4PF,'
=Ru"
44 44
8.16
O = Rull •$ - =Fe~J Fe"
CARBON-SILICON/GERMANIUM-NITROGEN-METAL RINGS CARBON-SILICON/GERMANIUM-NITROGEN-METAL RINGS
The self-assembly of -gennane with of di[4-(5-pyrimidyl)phenyl]dimethylsilane and and-germane (ethylenediamine)palladium dinitrate in an 1:2 ratio generated a new octahedral supramolecule containing group 14 elements <06ICC50>. supramolecule 8.17
CARBON-PHOSPHORUS-OXYGEN-METAL CARBON-PHOSPHORUS-OXYGEN-METAL RINGS RINGS
To a solution of CH 2Ch, a THF solution of of [Cu(MeCN)4]PF66 in CH2C12, of either [Rh(CO)z(Cl)h [Rh(CO)2(C1)]2 or [Cu(MeCN)4]PF [5, l5-bis[4-(2-diphenylphosphanylethoxy)phenyl]-1 O,20-bis(mesityl) porphyrinato]zinc(II) porphyrinato]zinc(II) [5,15-bis[4-(2-diphenylphosphanylethoxy)phenyl]-10,20-bis(mesityl) or 92%) the desired [LRhCl(CO)h or [LCu(MeCN)z(PF (L) was added to give (94 or [LRhCI(CO)]2 or [LCu(MeCN)z(PF6)]2 6)h macrocycles 46 46 or or 47, respectively <06JA16286>. <06JA16286>. M s M e• •
/
12+ /)7.'.L~~ ~ ---12+
_ ¥
Ph2P
I
L'--M--L I Ph2PN___
"
~'!/
ON
e ~r-~XP~Ph2 Ph2 I
M M e• s•
L-M-L. L--M--L, rI
~:T~~~Ph2 M e s
\
~C~
PPh2
~"
0/--/
M e• s, M
l , L = CO, L' = CI46 M == Rh Rh~, 46 L = CO, L'= CI-
47 M M == Cu CUi, L' = CH3CN, CH 3CN, X X==PF PF647 I, LL == L'= 68.18 8.18 04MI01 04MIOI
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Newkorne G.R. Newkome
05ACIE7283 05ACIE7283
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Eight-membered and larger rings
06CEJ4069 06CEJ4594 06CEJ4909 06CEJ5603 06CEJ8566 06CHCI25 06CHC125 06CHC206 06COC643 06CR767 06CR782 06CR2527 06CR5274 06CR5291 06CRC862 06CRC1022 06CRCI022
06CSR83 06CSR36I 06CSR361 06CSRI135 06CSR1135 06DMP413 06DMP4l3 06DT3518 06DT3617 06DT4000 06DT4124 06EJIC2377 06EJIC2997 06EJOCI54 06EJOC 154 06EJOC378
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Eight-membered and larger rings
06P599
06TL4041
Water, J.M.Vere, J.M.Vere, A.J.Blake, W.L.Driessen, M.W.Glenny, L.G.A.van de Water, AJ.Blake, C.Wilson, W.L.Driessen, 2006, 25, 599. J.Reedijk, M.SchrOder, M.Schriider, Polyhedron 2006, 2006, 25, 25,801. V.Muns, R.Kivek~is, R.Kivekas, R.Sillanpaa, L.Escriche, J.Casab6, V.Muns, R.Sillanp~i~i,Polyhedron 2006, 801. 2006, 78, 29. H.Maeda, H.Furuta, Pure Appl. Chern. Chem. 2006, R.Gleiter, B.Hellbach, B.Hellbach, S.Gath, S.Gath, RJ.Schaller, R.J.Schaller, Pure Appl. Chern. Chem. 2006, 2006, 78, 78, 699. 699. 2006, 654. MDhanasekaran, Synthesis 2006, P.Rajakumar, M.Dhanasekaran, 2006, 756. P.B.Forshee, J.W.Sibert, Synthesis 2006, M.Y.Redko, R.Huang, J.L.Dye, J.L.Dye, J.EJackson, J.E.Jackson, Synthesis 2006,759. 2006, 759. I.P.Beletskaya, A.D.Averin, M.V.Serebryakova, I.P.Beletskaya, AD.Averin, N.A.Pleshkova, A.A.Borisenko, M.V.Serebryakova, F.Denat, R.Guilard, F.Denat, R.Guilard, Synlett 2006,87. 2006, 87. A.M.Skwierawska, J.F.Biernat, V.c.Kravtsov, V.C.Kravtsov, Tetrahedron 2006, 149. A.M.Skwierawska, J.F.Biernat, 2006, 62, 149. N.Solladi6, T.M.F.Duarte, J.N.Solladie, M.E.Walther, H.Herschbach, H.Herschbach, E.Leize, E.Leize, A.V.Dorsselaer, A.V.Dorsselaer, T.M.F.Duarte, F.Nierengarten, F.Nierengarten, Tetrahedron 2006,62,1979. 2006, 62, 1979. G.Charalambidis, M.di Vaira, A.G.Coutsolelos, A.G.Coutsolelos, Z.Halime, M.Lachkar, N.Matsouki, G.Charalambidis, M.di Vaira, B.Boitrel, Tetrahedron 2006, 2006, 62, 3056. 3056. 2006, 62, 3081. P.M.Marcos, P.M.Marcos, J.R.Ascenso, Tetrahedron 2006, 3081. N.Kanomata, S.Yamada, S.Yamada, T.Ohhama, T.Ohhama, A.Fusano, A.Fusano, Y.Ochiai, J.Oikawa, M.Yamaguchi, M.Yamaguchi, F.Sudo, Tetrahedron 2006,62,4128. 2006, 62, 4128. J.D.Chartres, L.F.Lindoy, L.F.Lindoy, G.V.Meehan, G.V.Meehan, Tetrahedron 2006,62,4173. 2006, 62, 4173. M.Argese, M.Brocchetta, M.Brocchetta, M.De 2006, MDe Miranda, P.Paoli, F.Perego, P.Rossi, P.Rossi, Tetrahedron 2006, 61,6855. 61, 6855. V.Felix, Tetrahedron 2006,62, F.Li, R.Delgado, R.Delgado, A.Coelho, A.Coelho, M.G.B.Drew, M.G.B.Drew, V.F61ix, 2006, 62, 8550. 8550. S.Radi, A.Yahyi, A.Yahyi, A.Ramdelkrim, I.Zidane, B.Hacht, Tetrahedron 2006, 9153. 2006, 62, 9153. S.Radi, S.Fox, R.W.Boyle, R.W.Boyle, Tetrahedron 2006, 10039. 2006, 62, 10039. S.Fox, M.Kar, A.Basak, A.Basak, M.Bhattachaejee, M.Bhattachaejee, Tetrahedron Lett. 2006, 2006, 47, 4 7, 117. 117. H.Takayanagi, F.Imabeppu, K.Katagiri, H.Masu, T.Kato, M.Tominaga, B.Therrien, H.Takayanagi, E.Kaji, K.Yamaguchi, 2006, 47, 413. K.Yamaguchi, H.Kagechika, I.Azumaya, Tetrahedron Lett. 2006,47,413. S.H.Kim, K.C.Song, S.Ahn, S.Ahn, Y.S.Kang, Y.S.Kang, S.-K.Chang, S.-K.Chang, Tetrahedron Lett. 2006, 47, 497. S.H.Kim, 2006,47, 47, 1303. 1303. 2006,47, A.H.M.Elwahy, A.A.Abbas, Tetrahedron Lett. 2006, A.Ysukajima, J.Watanabe, Tetrahedron Lett. 2006,47,1817. 2006, 47, 1817. J.Setsune, A.Tsukajima, J.Xiao, X.shen, 2006,47,2371-2375. L.Ai, J.Xiao, X.Shen, C.Zhang, C.Zhang, Tetrahedron Lett. 2006, 47, 2371-2375. T.Nabeshima, T.Nabeshima, Y.Tanaka, T.Saiki, T.Saiki, S.Akine, S.Akine, C.1keda, C.Ikeda, S.Sato, S.Sato, Tetrahedron Lett. 2006,47, 2006, 47, 3541. K.Kobayashi, Tetrahedron Lett. H.Konishi, K.Tanaka, Y.Teshima, T.Mita, O.Morikawa, O.Morikawa, K.Kobayashi,
06TL4817 06TL48 I7 06TL6012 06TL6357
2006,47,4041. 2006, 47, 4041. M.Toumi, Tetrahedron Lett. 2006, 2006,47,4817. F.Couty, G.Evano, G.Evano, L.Menguy, L.Menguy, V.Steimetz, V.Steimetz, M.Toumi, 47, 4817. L.-G.Lu, G.-K.Li, 2006,47,6021. G.-K.Li, X.-X.Peng, X.-X.Peng, C.-F.Chen, C.-F.Chen, Z.-T.Huang, Tetrahedron Lett. 2006, 47, 6021. X.-X.Liu, Y.-S.Zheng, 2006,47, Y.-S.Zheng, Tetrahedron Lett. 2006, 47, 6357. 6357.
06P801 06P801 06PAC29 06PAC699 06S654 06S756 06S759 06SL87 06T149 06Tl49 06T1979 06Tl979 06T3056 06T3081 06T4128 06T4173 06T6855 06T8550 06T9153 06T10039 06Tl0039 06TL 117 06TLI17 06TL413 06TL497 06TL1303 06TLl817 06TL 1817 06TL237I 06TL2371 06TL3541 06TL354I
483
484 INDEX N-Acetylneuraminic acid, 295 Adenosine-N-oxides, 310 Aerothionin, 294 B2, 181 Aflatoxin B 2, 181 Alkylidenedithiolanes, 202 191 3-Alkylidenetetrahydrofurans, 191 191 2-Alkylidenetetrahydrofurans, 191 2-Amino- 1,3,4-oxadiazoles, 2-Amino-l ,3,4-oxadiazoles, 309 4-Amino-5-nitrosopyrimidines, 427 4-Amino-5-nitrosopyrimidines,427 2-Aminofuran, 179 6-Aminopenicillanate, 100 4-Aminoquinolines, 288 Amphidinolide, 103 Antimalarial agents, 452 4-Aryl-3,3-difluoro-13-1actams, 93 4-Aryl-3,3-difluoro-~-lactams, trans-2-Aryl-3-chloro-~3-1actams,93 trans-2-Aryl-3-chloro-~-lactams, 3-Aryl-furans, 184 3-Aryl-furans,184 N-Arylhexahydropyrimidines, N-Arylhexahydropyrimidines 94 10-Aza-9-thiaphenanthrenes, 27 7-Azabicyclo[4.2.1 ]nonene ]nonene, 95 7-Azabicyclo[4.2.1 Azacalix[n](2,6)pyridines, 468 1-Azafenestrane, 94 l-Azafenestrane, 7-Azaindoles, 160 Azapalladabicyclo[3.2.1 ]octanes, 105 Azapalladabicyclo[3.2.1 5-Azapurines, 423 5-Azapurines,423 1,3-Azasiletane, 104 1,3-Azasiletane, 5-Azatropolone, 437 5-Azatropolone,437 2-Azatryptophans, 212 2-Azatryptophans,212 Azepanes, 438 Azepanes,438 1H-Azepine-4,5-dione, 437 IH-Azepine-4,5-dione,437 Azepinones, 308, 308,439,440 439, 440 Azetidin-2,3-diones, as synthonS, 97 Azetidin-2-thione, 95 Azetidin-2-ones, 96, 97 Azetidin-3-ones, 93, 94 L-2-Azetidinecarboxylic acid, 92 Azetidines, spirocyclic, spirocyclic, 94 4-Azido4-Azido-l1,3,5-triazines, ,3,5-triazines, 423 Aziridino[ 1,2,3]oxathiazinane 1,2,3 ]oxathiazinane dioxide, dioxide ' 458 2H-Azirines, 449 2H-Azirines,449 Azocinones. Azocinones. 308 Bacteriochlorin, 45, 46 Bengazole A, 302 Benz[/][ Benz[f][l1,4]oxazepin-5-ones, ,4]oxazepin-5-ones, 455
3-Benzazepin-2-one,442 3-Benzazepin-2-one, 442 2-Benzazepine, I-phosphonylated, 1-phosphonylated, 444 I-Benzazepine.444 1-Benzazepine. 444 Benzazulene, 289 Benzimidazo[I,2-a]quinolines Benzimidazo[ 1,2-a]quinolines, 225 1,3-Benzimidazoles,223 ' 1,3-Benzimidazoles, 223 1,2-Benzisoxazoles, 1,2-Benzisoxazoles, 290 B.enzo[ b]benzo[2,3-dJthiophen-6,9Benzo[b]benzo[2,3-d]thiophen-6,9dlOnes, diones, 114 Benzo[ b]furan-2-aldehyde, 198 Benzo[b]furan-2-aldehyde, b ]furan-3-one, 197 Benzo[ Benzo[b]furan-3-one, Benzo[b]furans, 195, 195, 196 Benzo[b]thiophenes, 114, 114, 118, 118, 119, 119, 126 Benzo[c][1,2]thiazines,21 Benzo[c][ 1,2]thiazines, 21 Benzo[c]carbazoles, 160 Benzo[c]pyrroles,147 Benzo[c]pyrroles, 147 Benzo[c]selenophenes, 127 Benzo[c]tellurophenes, 127 IH-Benzo[dJazepines,333 1H-Benzo[d]azepines, 333 Benzo[ b]furoisocoumarins 196 Benzo[b]furoisocoumarins, Benzo[dJthiazoles, Benzo[d]thiazoles, 250, 260, 261 2H-Benzo[e]indazoles,226 2H-Benzo[e]indazoles, 226 2H-Benzo[g]indazoles,226 2H-Benzo [g] indazoles, 226 Benzocispentacin, 98 1,4-Benzodiazepin-2-one, 450 1,5-Benzodiazepine, 1,5-Benzodiazepine, 451 1,5-Benzodiazepine. 1,5-Benzodiazepine. 452 1,4-Benzodiazepine-2,5-diones, 450, 450 460 ' 460 1,4-Benzodiazepines,459 1,4-Benzodiazepines, 459 Benzodioxoles, 278 Benzodithiole, 280 Benzofurans, aromaticity, 198 N-oxides 294 Benzonitrile N-oxides, Benzoporphyrins. 44 ' 1,2-Benzothiazepine I-dioxides, 455 1,2-Benzothiazepine 1, 1,1-dioxides, 1,5-Benzothiazepine, 1,5-Benzothiazepine, 456 4, I-Benzothiazepines, 98 4,1-Benzothiazepines, 2,I-Benzothiazines, 1 2,1-Benzothiazines, Benzothieno[2,3-b]benzothiophenes Benzothieno[2,3-b]benzothiophenes, ' 125 Benzothieno[3,2-b]benzothiophenes Benzothieno[3,2-b]benzothiophenes, ' 122 Benzothiepine, 448 3H-l1,3,4-Benzotriazepines, ,3,4-Benzotriazepines, 458 3H1,3,4-Benzotriazepines, 460 1,3,4-Benzotriazepines, 1,4-Benzoxazepine, 460 1,4-Benzoxazepine,
485
Index
2-Benzoxepin-4-ols,446 2-Benzoxepin-4-ols, 446 3-(Benzyloxycarbonyl)amino-6methylsulfinyl-l ,2,4,5-tetrazine, 421 methylsulfinyl- 1,2,4,5-tetrazine, 9,9'-Binaphtha[2, 9,9 '-B inaphtha [2,1I-b -b]furanyl-8,8'-diol, ]furanyl- 8,8 '-diol, 198 Binaphthyl azepinium salt, 445 Biosynthesis of marine oxazoles, 298 Bipinnatin J, 179 4,4'-Bipyrazole, 179 Bis(pyrrolo[2,3-c]pyrimido[5,4e]pyridazines,427 e]pyridazines, 427 Bis[ 1I]benzothieno[2,3-c:3',2']benzothieno [2,3-c: 3',2'i][I,IO]phenanthrolines, i][ 1,10]phenanthrolines, 120 Bisnaphthohexaphyrin, 48 2,2'-Bithiophenes, 118, 118, 119, 119, 123, 123, 124 Brevione B, 192 3-Bromofuran, 179 Bromo-y-hydroxybutenolides, 179 C C6o, 48-51 6o ,48-51 Calafianin, 294 Calafianin, Calix[1 Calix[ 1]phosphole[1 ]phosphole [ 1]furan[2]pyrroles, ]furan[2]pyrroles, 475 1]phosphole [ I]thiophene[2]pyrrol 1]thiophene [2]pyrrol Calix[ I]phosphole[ es, 475 es,475 Calix[4]arenes, 292, 425, 476 292,425,476 Calix[4]areno[2]catenanes, 471 Calix[4]arenocrowns,471 Calix[4]arenocrowns, 471 Carbapenems, 100 Cathepsin K, 440, 459 Cephalosporin, 100 Chartellines, Chartellines, 98 Chemiluminescence, 101, 101, 102 58.63 Chlorins, 44, 45, 58. 63 3-Chloro-4-iodofurans, 185 Chlorophyll a, 44 Cholecystokinin, 460 Cladiella-6, II-dien-3-ol, 190 Cladiella-6,11-dien-3-ol, Colchicines,460 Colchicines, 460 Combretastatin A-4, 96 Confused isoquinoporphyrin, 48 Cornforth rearrangement, 300 Corrole,49 Corrole, 49 Cyclodextrin, 292 Cyclohepta[d]thiazole, 260 Cyclohepta[dlthiazole,260 4H-Cyclopenta[2,I-b:3,4-b1dithiophen4H-Cyclopenta[2,1 -b :3,4-b ] dithiophen4-ones, 120 b]pyrroles, 144 Cyclopenta[ Cyclopenta[b]pyrroles, Cyclopenta[c]thiophenes, 124
Cyclopenta[dl-2-( IH)pyrimidinones, Cyclopenta[d]-2-(1H)pyrimidinones, 364 Cyclopenta[d]thiazole, 260 Cyclopenta[dlthiazole, 5H-Cyclopentapyrazines, 223 Cyclotetrasilene, 104 Cytoxazene, 309 1,3-DC, regioselectivity, 291 Deacetoxyalcyonin acetate, 190 Decaturin D, 192 191 Descurainin, 191 5-Dethia-5-oxa-cephams, 99 N ,N'-Di(2-pyridyl)-2,4-diamino-6N,N'Di(2-pyridyl)-2,4-diamino-6phenyl-I ,3,5-triazine, 417 phenyl- 1,3,5-triazine, 3,6-Di(pyridin-2-yl)-1 ,2,4,5-tetrazines, 3,6-Di(pyridin-2-yl)- 1,2,4,5-tetrazines, 421 Dialuminacyclobutene, 106 2,8-Diamino purines, 423 4,6-Diamino-l ,3,5-triazines, 417 4,6-Diamino- 1,3,5-triazines, Diaza[ 12]annulenes, 469 Diaza[12]annulenes,469 Diazetidines, Diazetidines, 387 A2-1,2-Diazetines, 95 ~2-1,2-Diazetines, Diazido-l ,2,4,5-tetrazines, 417 Diazido- 1,2,4,5-tetrazines, Diazirine, 278 5H-[1,2]Diazocin-4-ones,290 5H-[ 1,2]Diazocin-4-ones, 290 Diazonamide A, 302 10,II-Dibenzo[b,j]thiepine,448 10,11-Dibenzo[b,J]thiepine, 448 5,5-dioxides, 5 Dibenzo[c,e][1,2]thiazine 5,5-dioxides, 6HDibenzo[c, e] 6H-Dibenzo[c, e][[1,2]thiazines, 1,2]thiazines, 9 7H-Dibenzo[d,j][ 7H-Dibenzo[d,J] [1,3]thiazepines, 1,3]thiazepines, 27 Dibenzofurans, 193 Dibenzothiophenes, 121 121 Dibenzoxepines, 448 Dibenzoxepines,448 Dichloroketene. 279 3,3-Difluoroazetidinone,95 3,3-Difluoroazetidinone, 95 Difuranylmethane, 184 6,7-Dihydro-lH-azepines 6,7-Dihydro- 1H-azepines on, 441 2,5-Dihydro-2,5-dimethoxyfuran, 179 2,3-Dihydrobenzo[b]furans,193 2,3-Dihydrobenzo[b]furans, 193 Dihydrobenzo[c]furans, 180 5,6-Dihydrobenzo [h]quinazolines, h]quinazolines, 362 5,6-Dihydrobenzo[ 2,3-Dihydrofuran, 181, 181, 192 2,3-Dihydrofuran,, 181 2,3-Dihydrofuran" 181 2,5-Dihydrofurans, 182 4,5-Dihydroisoxazoles, 289 5,6-Dihydropyrazin-2( 1H)-ones, 99 5,6-Dihydropyrazin-2(1H)-ones, N ,N'-Dimethyldichloromethyleniminium N,N'-Dimethyldichloromethyleniminium chloride, 427 6-Dinitromethyl-l ,3,5-triazines, 418 6-Dinitromethyl- 1,3,5-triazines,
486
Index
I,4-Dioxaspiro[4.5]decane, 1,4-Dioxaspiro [4.5]decane, 97 1,7-Dioxaspiro[4.5]decanes, 188 1,7-Dioxaspiro[4.5]decanes,188 I,3-Dioxepines, 453 1,3-Dioxepines, Dioxetanone, 102 2,4-Dioxohexahydro-1,3,5-triazines, 2,4-Diox0hexahydro- 1,3,5-triazines, 418 Dioxolanones, 278 1,3-Dioxolium-4-olates, 97 2,5-Diphenylfurans, 179 2,3-Diphenyltetrahydrofurans, 2,3-Diphenyltetrahydrofurans, 188 Dipyrido[ 1,2-a:2',3'-djimidazoles, 1,2-a:2',3'-d]imidazoles, 225 Dipyrrylmethane,53 Dipyrrylmethane, 53 [1,3,2,4]Diselenadiphosphetane, [ 1,3,2,4]Diselenadiphosphetane, 105 1,2-Diselenolane, 203 Dithia[3.3 ](2,6)pyridinophanes, 475 Dithia[3.3](2,6)pyridinophanes,475 1,9-Dithia-5, 13-diazacyclohexadecanes, 1,9-Dithia- 5,13-diazacyclohexadecanes, 475 7,11-Dithiaazasteroids, 23 Dithiadiselenafulvalene, Dithiadiselenafulvalene, 201 Dithieno[3,2-b:2',3'-djphospholes, 122 Dithieno[3,2-b:2',3'-d]phospholes, 1,3-Dithiolane-2,4,5-trithione, 1,3-Dithiolane-2,4,5-trithione, 280 1,2-Dithiole-3-thiones, 203 Divinyldioxolanones, Divinyldioxolanones, 278 Docetaxel, 101 Dpdapt,417 Dpdapt, 417 Episulfonium ion, 416 C-Ethoxycarbonyl nitrene, 295 FAAH,302 FAAH, 302 Fatty acid amide hydrolase. 302 Ferrocenyl dioxolane, 278 3-Fluoro-4H- 1,3-diazepines, 3-Fluoro-4H-I ,3-diazepines, 449 3-Fluoroazetidines,93 3-Fluoroazetidines, 93 Fluoroazetidinium hydrochloride, 92 Fluorous 1,3,5-triazines, 419 Fluvine A, 422 3-Forrnytetrahydrofuran, 3-Formytetrahydrofuran, 182 Fucosidase inhibitor, 294 Fullerene. 49, 292 Furan natural products, 176, 176, 177 Furan, cyclopropanation, 180 Furano-l,4-thiazepine, Furano1,4-thiazepine, 457 Furano-oxepines,445 Furano-oxepines, 445 Furanotetrahydroquinolines, 181 Furanotetrahydroquinolines, Furans froim allenes, 187 Furans from alkynyl cyclopropyl ketones, 186 Furans from alkynyllithiums, 187 Furans from allenones, 186
Furans from enynones, 186 Furans, with SF SFs, 5, 184 Furfural, 449 Furo[2,3-b]furan, 197 Furo[2,3-b]pyrans, 183 Furo[2,3-b]pyridine-4(1H)-one, 194 Furo[2,3-b]pyridine-4(1H)-one, Furo[2,3-djpyrimidines,370 Furo [2,3-d]pyrimidines, 370 Furo[2,3-h]chromen-2-one, Furo[2,3-h]chromen-2-one, 193 Furo[3,2-e][ Furo [3,2-e] [ 1,2,4]triazolo[ 1,2,4]triazolo [ 1,5c]pyrimidines, 233 Furo[3,4-c]coumarins, 188 2-Furylzinc chloride, 184 Galanthamine, 198 Galectins, 291 Glycoproteins, 306 Glycosaminoglycans, 306 D-Gulonolactam,442 D-Gulonolactam, 442 Haloetherification, 188 Heliannuls, 195 1,4,5,8,9,12-Hexaazatriphenylenes,473 1,4,5,8,9,12-Hexaazatriphenylenes, 473 Hexahydroazoninoindoles, 443 Hexaphyrin, 48 [26]Hexaphyrins(1.l.1.l.0.0),474 [26]Hexaphyrins(1.1.1.1.0.0), 474 4-(3-Hydroxyalkyl)pyrimidine, 182 3H-Imidazo [1,2-a][1,3,5]triazepin-21,2-a] [ 1,3,5 ]triazepin-23H-Imidazo[ amines, 458 amines,458 Imidazo[ 1,2-a]pyrazines, 371, 371,373 Imidazo[1,2-a]pyrazines, 373 Imidazo[1,2-a]pyridines, 226 Imidazo[ 1,2-a]pyridines, 225, 225,226 Imidazo[1,2-a]pyrimidines, Imidazo[ 1,2-a]pyrimidines, 222, 225, 362 Imidazo[ 1,2-a]pyrimidinium salts, 220 3H-Imidazo[ I,2-a][1 ,3,5]triazepine3H-Imidazo [ 1,2-a] [ 1,3,5 ]triazepine2(7H)-thiones,458 2(7H)-thiones, 458 Imidazo[ 1,2-b] [ 1,2,4]triazines, 422 Imidazo[l ,2-b ][1,2,4]triazines, Imidazo[ 11,2-b] [ 1,2,4]triazoles, 233 ,2-b] [1,2,4]triazoles, 6H- Imidazo Imidazo[[ 11,2-b ,2-b ]-1 ,2,4-triazol-6-ones, ]- 1,2,4-triazol-6-ones, 232 Imidazo[ ,2-b ]pyrazole, 218 Imidazo[l1,2-b]pyrazole, Imidazo[ [ 1,2,4]triazin-8-ones, Imidazo[l1,2-d] ,2-dj[1 ,2,4]triazin-8-ones, 422 ,5-a]pyridines, 225, 226 Imidazo[ 11,5-a]pyridines, 225,226 ,2,4]triazin-8-ones, 422 Imidazo[2, 1:f][1 l-J][ 1,2,4]triazin-8-ones, Imidazo[4,5:f][1, 10]phenanthrolines, Imidazo [4,5-J] [ 1,10]phenanthrolines, 121 5H-Imidazo[5,1-a]isoindoles,225 5H-Imidazo[5,1-a]isoindoles, 225 Imidazo-benzazepine,443 Imidazo-benzazepine, 443 Imidazoporphyrin-C 6o , 56 Imidazoporphyrin-C60, Indazolo[2,3-a]quinolizine, Indazolo[2,3-a]quinolizine, 416 Indeno[1,2-b]thiophenes,l13 Indeno[ 1,2-b]thiophenes, 113 Indeno[1,2-djpyrimidinones,364 Indeno[ 1,2-d]pyrimidinones, 364
487
Index
Indeno[[ 11,2-e]pyrrolo ,2-e]pyrrolo[[11,2-a]isoindoles, ,2-a]isoindoles, Indeno 364 ,2-e]pyrrolo[[ 1,2Indeno[ Indeno [11,2-e]pyrrolo aa]pyrimidinones, ]pyrimidinones, 364 Indolizines, 322 Inthomycin B, 302 5-Iodoisoxazolines,291 5-Iodoisoxazolines, 291 Isatin,51 Isatin, 51 Isobacteriochlorins, 58, 59 Isoindolo[2, ]benzo[ 1,2,4]triazines, Isoindolo [2,1l-c -c]benzo[ 1,2,4]triazines, 427 Isoxazole-5-carboxylates, 290 4-Isoxazolecarbaldehyde, 289 Isoxazolo[4,3-c] [2,11]benzothiazines, ]benzothiazines, 23 Isoxazolo[4,3-c] [2, Isoxazolo[3,4-djpyridazines, Isoxazolo [3,4-d]pyridazines, 426 IIH-Isoxazolo[ 4,5-c ]thiopyrano[3,25H, 11H-Isoxazolo[4,5-c]thiopyrano[3,2c][2,1 ]benzothiazines, 24 c] [2, 1]benzothiazines, Isoxazolylcyclobutanones,290 Isoxazolylcyclobutanones, 290 ]3-1actone, 103 Lactacystin 13-lactone, [3-Lactamase. 98 13-Lactamase. ]3-Lactams, 93 13-Lactams,93 [3-Lactams, 95, 96 13-Lactams, Lactonamycin, 190 Manzamine A, 177 Melanostatin, 98 3-Mercapto-l ,2,4-triazines, 415 3-Mercapto- 1,2,4-triazines, Metabotropic glutamate receptor. 301 2-Methoxyazepinium ion, 437 2-Methoxyfurans, 180 3-Methylenetetrahydrofurans, 192 N-Methylglycine, 49 N-Methylglycine,49 3-Methylsulfinyl-6-methylthio-l,2,4,53-Methylsulfinyl-6-methylthio- 1,2,4,5tetrazine, 421 Molybdenacyclobutanes, 106 Myoseverin,426 Myoseverin, 426 Naphtha[2,3-b]furan, 194 Naphthacene, 49 Naphtho[2, Naphtho [2,1I-b -b ]]furo[3,2-djpyrimidines, furo [3,2-d] pyrimidine s, 364 Naphtho[2,3-b]furans, Naphtho[2,3-b ]furans, 198 Naphtho[ a]carbazoles, 160 Naphtho[a]carbazoles, Naphthohexaphyrin, 48 Naphthoporphyrins. 45, 46 291, 292 Nitrile oxide 1,3-DC, 1,3-DC, 65, 291,292 4-Nitroisoxazoles, 290 3-Nitroisoxazolines, 293 Nitrone 1,3-DC 1,3-DC reactions, 296, 443 Norbornadiene, Norbomadiene, 65
Nostocine A, 422 Octaphyrin, 61 Ophirin B, 190 7-Oxabenzo-norbomadienes, 182 7-Oxabicyclo[2.2.1 ]hept-5-ene, ]hept-5-ene, 99 7-0xabicyclo[2.2.1 Oxacalix[2]arene[2]hetarenes,472 Oxacalix [2]arene[2]hetarenes, 472 Oxacillin, Oxacillin, 100 1,2,4-0xadiazoles, 1,2,4-Oxadiazoles, 394 7-Oxa-norbomadienes, 7-Oxa-norbornadienes, 182 1,3-0xasiletane, 1,3-Oxasiletane, 104 [ 1,2,3]Oxathiazepane [1,2,3 ]Oxathiazepane 2,2-dioxides, 2,2-dioxides, 458 1,3-0xathiolanones, 1,3-Oxathiolanones, 202 Oxazaborolidine, 102 1,4-0xazepan-2-one, 1,4-Oxazepan-2-one, 453 1,4-Oxazepine, 454 1,4-0xazepine, 1,3-Oxazepines, 454 1,3-0xazepines,454 1,2-0xazetidines, 1,2-Oxazetidines, 78 Oxazole-4-carboxaldehyde. 301 Oxazole-4-carboxamides,300 Oxazole-4-carboxamides, 300 5-0xazoleacetates,299 5-Oxazoleacetates, 299 Oxazole-containing peptides, peptides, 300 Oxazolidine, 439 Oxazolidine,439 Oxazolidinone, 307, 308, 439 Oxazoline ligands, enantiopure, enantiopure, 305-307 Oxazolo[3,2-a ]pyrimidin-5-ones, 366 Oxazolo[3,2-a]pyrimidin-5-ones, Oxazolo[3,2-a ]pyrimidin-7-ones, 366 Oxazolo [3,2-a]pyrimidin-7-ones, Oxazolomycin, 103 Oxepane, 207 Oxepines 437 Oxepino 13-carboline, ]3-carboline, 447 Oxiranes, 419 6-0xo[ 6-Oxo [1,2,4]triazin-l-yl-alaninamides, 1,2,4]triazin- 1-yl-alaninamides, 415 4-0xoazetidine. 4-Oxoazetidine. 95 Ozonide, 203 Paclitaxel, 100 Paclitaxel, [2.2]Paracyclophanes, [2.2]Paracyclophanes, 305 Patemo-Biichi reaction, 101 Patem6-Bfichi Pentathiepins, 459 Penicillin V, 100 Pentacene, 48 (Pentafluorophenyl)porphyrin, tetrakis, 46,49, 61 46,49,61 Pentamethylferrocene, 305 [1,2,3 ,4,5]Pentathienopino[6,7[ 1,2,3,4,5 ]Pentathienopino [6,7bb]pyrroles, ]pyrroles, 147 Peraza[2.2.2]cryptands, 469
488
Index Index
Phorboxazole B, 302 Phosgeniminium chloride, 427 I-Phospha-l-aza-18-crown-6-ethers, 1-Phospha1-aza- 18-crown-6-ethers, 475 Phosphaalkenes, 106 Phosphaalkenes, PhosphapaIIadacycIe, 105 Phosphapalladacycle, 1,3-Phosphasiletane, 104 Phosphazenes, 105 Photochromism, 198 Photodynamic therapy, 64 PHOX ligands, 305 Phthalocyanin, 201 Phytochlorin-C 60 diad, 53 Phytochlorin-C60 Phytochlorin-C 60 " 55 Phytochlorin-C60,, TM, 300 Pirate TM' PolyantheIIin A, 190 Polyanthellin Porphyrin-a-dione, 65 Porphyrin-c~-dione, N-(Porphyrin-2-ylmethyl)glycine, 57 Porphyrincalix[4]arenes,465 Porphyrincalix[4] arenes, 465 Porphyrinic azomethine ylides, 55 Porphyrinic nitrile oxides, 57 Porphyrinic pyridinium ylides, 57 Positron emission tomography, 416 Propargylic dithioacetals, 188 Protoporphyrin IX, 44 Pseudomonic acid, 300 Pseudouridines, 290 Pterins,427 Pterins, 427 Purines, magnesiation, 425 PxycaIix[4]arene,292 Pxycalix[4]arene, 292 Pybox,305 Pybox, 305 Pyrano[2,3-c]pyrazol-6-ones, 218 IH,6H- Pyrano[2,3-c]pyrazol-6-ones, 1H,6H-Pyrano[2,3-c]pyrazol-6-ones, 218 Pyrano[2,3-c]pyridazines, 356 ,2-c]quinolin-2,5(6H)-diones, Pyrano[3 Pyrano[3,2-c]quinolin-2,5(6H)-diones, 329 Pyrazin-2-ones, 385 ,2-a]indoles, 371 Pyrazino[ 11,2-a]indoles, 2( 1H)-Pyrazinones, 371 2(1H)-Pyrazinones, IH,5H-Pyrazolo[1 ,2-a][1 ,2,4]triazoles, 1H,5H-Pyrazolo [ 1,2-a] [ 1,2,4]triazoles, 233 Pyrazolo[1 Pyrazolo[ 1',5': 1,6]pyrimido[4,51,6]pyrimido [4,5d]pyridazinones, 357,428 357, 428 Pyrazolo[I,5-a][1 ,3,5]triazines, 423 Pyrazolo [ 1,5-a] [ 1,3,5]triazines, Pyrazolo[ 11,5-a]pyrimidin-7-(4H)-one, ,5-a]pyrimidin-7-(4H)-one, 426 Pyrazolo[ 11,5-a]pyrimidine, ,5-a]pyrimidine, 218, 361, 362,364,369,426 362, 364, 369,426
Pyrazolo[ 1,5-d] [[1,2,4]triazines, 1,2,4]triazines, 422 Pyrazolo[3,4-b]pyridines, 218 Pyrazolo [3 ,4Pyrazolo[3,4c][ c] [11,5,2]diazaphosphinines, ,5,2]diazaphosphinines, 218 Pyrazolo[3,4-c] 1,2-thiazines, 20 Pyrazolo [3,4-c] 1,2-thiazines, Pyrazolo[3,4-c]pyridazines, 357 1IH-Pyrazolo[3,4-d]pyridazine-3,6H- Pyrazo lo[ 3,4-d] pyridazine- 3,6diones, 218 diones,218 Pyrazolo[3,4-d]pyridazines, 357 Pyrazolo[3,4-d]pyridazines,357 Pyrazolo [3,4-d]pyridazines, 426 Pyrazolo[3,4-d]pyridazines, Pyrazolo [3,4-d]pyrimidine, 426 Pyrazolo[3,4-d]pyrimidine, Pyrazolo [3,4-d]pyrimidine, 426 Pyrazolo[3,4-d]pyrimidine, Pyrazolo[3,4-d]pyrimidine, 364, 368, 426 Pyrazolo[4',3':5,6]thiopyranol[4,3b]quinolines, 214 b]quinoIines,214 3H-Pyrazolo[4,3-c]thiopyrano[3,2c][2,1 ]benzothiazines, 24 Pyrazolo[4,3-d][ 1,2]diazepine-8carboxylates, 450 Pyrazolo [4,3-d]pyrimidin-7-ones, 364 Pyrazolo[4,3-d]pyrimidin-7-ones, Pyrazolo [4,3-d]pyrimidines, 426 Pyrazolo[4,3-d]pyrimidines, Pyrazolo[4,3-e][1,2,4]triazine,422 Pyrazolo[4,3-e] [ 1,2,4]triazine, 422 Pyrazolo [ 1,2,4]triazolo [ 1,5Pyrazolo[[4,3-e] 4,3-e] [1,2,4]triazolo[1 ,5c]pyrimidines, 353,368,428 c)pyrimidines, 353, 368, 428 Pyrazolo 4,3-e]pyrrolo[[ 11,2-a]pyrazines, ,2-a]pyrazines, Pyrazolo[[4,3-e]pyrrolo 374 Pyrazolo[5, -c) 1,2,4-thiadiazines, 20 Pyrazolo[5,1l-c] Pyrazolones, 414 Pyridazin-3-ones, 385 Pyridazin-4-ones, 386 Pyridazine-3,6-diones, 388 Pyridazino [3,4-a]carbazoles, 355 Pyridazino[3,4-a]carbazoles, Pyridazino [3,4-b]indoles, 388 Pyridazino[3,4-b]indoles, Pyridazino [3 ',4': 3,4]pyrazolo [5,1l-c]-c]Pyridazino[3' ,4':3,4]pyrazolo[5, 1,2,4-triazines, 427 I,2,4-triazines, Pyridazino [4',3': 4,5 ]thieno [3,2-d] 1,2,3Pyridazino[4',3':4,5]thieno[3,2-d] triazines, 355 triazines,355 Pyridazino [4,5-b] [ 1,8 ]naphthyridinPyridazino[4,5-b][1 ,8]naphthyridin6(7H)-ones, 355 Pyridazino [4,5-c]pyridazine, 428 Pyridazino[4,5-c]pyridazine, Pyridazino [4,5-d]pyridazine, 428 Pyridazino[4,5-d]pyridazine, 3H-Pyridazino[5,4,3-k/]acridin-3-ones, 3HPyridazino[5,4,3-kl]acridin-3-ones, 356 [7.7](2,6)Pyridinocyclophanes, 473 [n](2,5)Pyridinophanes, [n ](2,5)Pyridinophanes, 469 Pyrido [ 1',2': 1,5]pyrazolo[3,41,5]pyrazolo [3,4Pyrido[1 d]pyrimidines, 369 Pyrido[2,3-b][ 1,5]benzodiazepines, 460 Pyrido[2,3-b]pyrazines, Pyrido[2,3-b ]pyrazines, 372 Pyrido [4,3-d]pyrimidin-2-ones, 428 Pyrido[4,3-d]pyrimidin-2-ones,428
489
Index Index
IH- Pyrido[2,3-dJpyrimidin-4-ones, 361 1H-Pyrido[2,3-d]pyrimidin-4-ones, Pyrido[2,3-dJpyrimidin-7-ones, 361 Pyrido[2,3-d]pyrimidin-7-ones, Pyrido[2,3-dJpyrimidines, 365,368 365, 368 Pyrido[2,3-d]pyrimidines, Pyrido[3",2" :4',5']thieno[3',2':4,5]pyrimi Pyrido[3",2":4',5']thieno[3',2':4,5]pyrimi 1,6-a]benzimidazoles, 363 do[ 1,6-a]benzimidazoles, Pyrido[3',2':4,5]thieno[3,2dJpyrimidines, 363 d]pyrimidines, Pyrido[3',2':5,6]thiopyrano[4,3c]pyridazin-3(2H,5H)-ones, 355 Pyrido[3,2-b]oxepine,447 Pyrido[3,2-b]oxepine, 447 ,2,4]triazolo[4,3Pyrido[3,2-e] [11,2,4]triazolo[4,3Pyrido[3,2-e][ a ]pyrazines, 371 a]pyrazines, 4,3,2-mn ]pyrrolo[3,2, Pyrido[[4,3,2-mn] Pyrido pyrrolo [3,2,1I-de ]acridines, 163 de]acridines, Pyrido[4,3-b ]pyrimidines, 365 Pyrido[4,3-b]pyrimidines, Pyridotriazine, 427 Pyrimidin-2( 1H)-ones, 385,395, 385, 395,419 Pyrimidin-2(1H)-ones, 419 Pyrimidin-4-ones, 385 Pyrimidine-5-carbaldehyde, 290 Pyrimido[3',2':4,5]thieno[3,2Pyrimi do [3',2':4,5 ]thi eno [3,2dJpyrimidinones, d]pyrimidinones, 428 Pyrimido[4',5':4,5]thieno[2,3c]pyridazines,356 c]pyridazines, 356 Pyrimido[[4,5-b 4,5-b]][[1,4]benzodiazepines. Pyrimido 1,4]benzodiazepine s. 452,460 452,460 Pyrimido[4,5-b ]-11,4-diazepines, ,4-diazepines, 460 Pyrimido[4,5-b]Pyrimido[4,5-b ]-11,4-thiazepines, ,4-thiazepines, 460 Pyrimido[4,5-b]Pyrimido[4,5-c]pyridazin-5,7-diones, Pyrimido[4,5-c]pyridazin-5,7-diones, 353,427 353,427 Pyrimido[ 4,5-c ]pyridazines, 356, 427 Pyrimido[4,5-c]pyridazines, Pyrimido[4,5-dJpyrimidin-2-ones,427, Pyrimido[4,5-d]pyrimidin-2-ones, 427, 428 Pyrimido[4,5-dJpyrimidines, Pyrimido [4,5-d]pyrimidines, 365 Pyrimidopyrido[4',3':4,5]thieno[2,3d]pyrimidines, 361 Pyrroline N-oxides, 296 Pyrrolo[1,2-a]azepine,437 Pyrrolo[ 1,2-a]azepine, 437 Pyrrolo[ 11,2-b] ,2-b][[1,2,5]benzothiazepines, 460 Pyrrolo[ 11,2-b]pyridazines, ,2-b]pyridazines, 141 141 Pyrrolo[1 ,2-b]pyridazines, 355 Pyrrolo[ 1,2-b]pyridazines, 4H-Pyrrolo[ 4H-Pyrrolo [1,2-c][ 1,2-c] [1,2,3]triazoles, 1,2,3]triazoles, 230 Pyrrolo[2,I-a]isoquinolines, Pyrrolo[2,1-a]isoquinolines, 141, 141, 147 Pyrrolo[2, Pyrrolo [2,1I-b][ -b] [1,4]benzodiazepineazepane,460 azepane, 460 Pyrrolo[2, I-b]thiazoles, 141 Pyrrolo[2,1-b]thiazoles, 141 Pyrrolo[2,1-c][1 ,4]benzodiazepine, 460 Pyrrolo[2, l-c] [ 1,4]benzodiazepine, Pyrrolo[2,1:f][1 ,2,4]triazine, 422 Pyrrolo[2, l-J][ 1,2,4]triazine, Pyrrolo[2,3-b]indol-2-ones, 153 Pyrrolo[2,3-b]indoles, 157
3H-Pyrrolo [2,3-d]pyrimidin-2(7H)-ones, 3H- Pyrrolo[2,3-dJpyrimidin-2(7H)-ones, 369 Pyrrolo [2,3-d]pyrimidine-2,4-diones, Pyrrolo[2,3-dJpyrimidine-2,4-diones, 364 Pyrrolo[2,3-d]pyrimidines, 363,369, 363, 369, 370 Pyrrolo[3,2,1-hi]indazoles, Pyrrolo[3,2,I-hi]indazoles, 158 Pyrrolo[3,2-d]pyrimidines, Pyrrolo[3,2-dJpyrimidines, 361 PyrroloPyrrolo-l1,5-benzoxazepines, ,5-benzoxazepines, 460 Pyrroloporphyrins, 51 Pyrrolylthieno [2,3-d]pyrimidines, 360 Pyrrolylthieno[2,3-dJpyrimidines, Quinuclidines, 308 Rasfonin, 179 Rhazinilam, 103 Ring closing metathesis, sevenmembered rings, 438 Salinosporamide A, 103 Sapphyrin, 49 1,3-Selenazolidin-4-ones, 273 1,3-Selenazolidines, 273 Silyl nitronate, 293 Silylisoxazoles, 288 Silylmethylisoxazoles, 288 Silylmethylpyrazoles. 288 Silylpyrazoles, 288 Singlet oxygen, 101, 101, 102, 102, 179 SIPHOX, 305 SIPHOX,305 Spirobutenolide, 178 3-Spirocyclopropanated 2-azetidinones, 99 5-Spirocyclopropane isoxazolidines, 295 3-Spirocyclopropane monobactams, 296 3-Spirocyclopropane ~-lactam, 295 Spiroisoxazolines, 294 Spironucleosides, 104 Spiro-13-1actams, 99 Spiro-~-lactams, Stemona alkaloids, 437 N-Sulfinylimines, 279 [3-Sultams, 295 ~-Sultams, TADDOL, 195 TADDOL,195 101 Taxol, 101 Telomestatin, 301 Telomestatin,301 Tetraarylporphyrins, 45, 46 Tetraazabacteriochlorin, 49 Tetraazabacteriochlorin,49 Yetraazacalix[2] arene[2]triazines, 420 Tetraazacalix[2]arene[2]triazines,420 1,4,7,10-Tetraazacyclododecanes, 469 Tetraazaporphine, 49 Tetraazaporphine,49 1,2,4,5-Tetrazine-3,6-dicarboxylate, 421
490
Index
1,4,8,11Tetraazatricyclo[9.3.3.34'8]eicosanes, 03 408]eicosanes, Tetraazatricyclo[90303 469 189-191 Tetrahydrofuran synthesis, 189-191 183 Tetrahydrofuranyl oxonium ions, 183 Yetrahydroimidazo[ 1,21,2Tetrahydroimidazo[ aa][1,3,5]triazepin-2-thiones, ][1 ,3,5]triazepin-2-thiones, 428 Tetrahydrolipstatin, 103 Tetrahydroquinolines, 326 201I Tetraselenafulvalene, 20 201I Tetrathiafulvalene, 20 1,2,4,5-Tetrazin-3(2H)-one, 420 1,2,4,5-Tetrazin-3(2H)-one, [ 1,2,3,4]Tetrazine-5-carboxylic acid, [1,2,3,4]Tetrazine-5-carboxylic 410 1,2,4,5-Tetrazines, 387 1,2,4,5-Tetrazines, inverse electron demand DA reactions, 421 Yetrazolo [ 1,5-a] [ 1,3,5]triazin-7-ones, ,5-a][1 ,3,5]triazin-7-ones, Tetrazolo[1 234, 423 234,423 Yetrazolo[ 11,5-a]quinoxalines, Tetrazolo[ ,5-a]quinoxalines, 234 Yetrazolo[5, l-c][ 1,2,4]triazines, 423 Tetrazolo[5,I-c][1,2,4]triazines,423 Tetrazolo-uracil, 458 Tetrazolo-uracil,458 1,3,4-Thiadiazoles, 271 1,3,4-Thiadiazoles, 1,2,4-Thiadiazoles, 271 1,2,4-Thiadiazoles, 7H- 1,3,4-Yhiadiazolo [3,2-a]pyrimidin7H-l ,3,4-Thiadiazolo[3,2-a]pyrimidin7-ones, 360 7-ones,360 1,3-Thiasiletane, 104 1,3-Thiasiletane, 1,4-Thiazepine-5-carboxamides, 456 1,3-Thiazepines, 253 1,3-Thiazepines,253 1,1,-dioxides, 103,295 ,-dioxides, 103, 295 1,2-Thiazetidine 1,1 1,2-Thiazetidine 1-oxide, 1,2-Thiazetidine I-oxide, 104 1,2-Thiazinylium salts, 28 1,2-Thiazinylium Thiazolino[3,2-c]pyrimidine-5,7-diones, Thiazolino[3,2-c]pyrimidine-5,7-diones, 369 [ 1,3 ]Thiazolo [3,2-a] [ 1,3,5]triazine, 1,3,5]triazine, 423 [1 ,3]Thiazolo[3,2-a][ 5H-Thiazolo[3,2-a]pyridine-5-ones, 5HThiazolo[3,2-a]pyridine-5-ones, 246 Thiazolo [5,4-d]pyrimidines, 362 Thiazolo[5,4-d]pyrimidines,362 Thieno[2,3-b]pyridines, 114, 127 Thieno[2,3-b]pyridines, 114, Thieno[2,3-b]pyrroles, Thieno[2,3-b]pyrroles, 126 Thieno[2,3-b]thiophenes, 120, 126 Thieno[2,3-b]thiophenes, 119, 120, Yhieno[2,3-c]furans, Thieno[2,3-c]furans, 120 Yhieno[2,3-c]pyridazines, Thieno[2,3-c]pyridazines, 356 Yhieno [2,3-d] [4,5-d]dipyrimidines, 360 Thieno[2,3-d][4,5-d]dipyrimidines, Yhieno [2,3 -d]pyrimi din-4( 1H)one s, 370 Thieno[2,3-d]pyrimidin-4( 1H)-ones, Yhieno [2,3-e] [[1,2,4]triazolo[1,51,2,4]triazolo [ 1,5Thieno[2,3-e] c]pyrimidin-5 (6H)-ones, 363 c]pyrimidin-5(6H)-ones,363 Thieno[3,2-b]pyridines, Thieno[3,2-b]pyridines, 113 Thieno[3,2-c] Thieno[3 ,2-c][[ 1~,4,2]thiazines, A4,2]thiazines, 22 Yhieno[3,4-b]thiophenes, Thieno[3,4-b]thiophenes, 125 1H-Thieno[3,4-c][ IH- Thieno[3,4-c][ 1,2]thiazines, 1,2]thiazines, 21
Thietan-3-one, 104 Thiiranes, 419 Thiiranethione, 280 Thiocarbonyl ylides, 280 2H,6HThiopyrano[3,22H,6H-Thiopyrano[3,2c][2,I]benzothiazines,23 c][2,1 ]benzothiazines, 23 3-Thioxo-I ,2,4-triazin-5(4H)-ones, 416 3-Thioxo- 1,2,4-triazin-5(4H)-ones, NTosyl-3-halo-3-butenylamineso 93 N-Tosyl-3-halo-3-butenylamines. Traversianal, 181 181 Triazacyclononanes,478 Triazacyclononanes, 478 4,7a, 4,7 a, 12b-Triazadibenzo[e.g]azulene12b-Yriazadibenzo [e,g] azulene1,3,8-triones, 357 1,3,5-Triazapentadienes, 417 1,3,5-Triazepane-2,6-dione, 458, 460 5H-l ,3,5-Triazepine-2,4-dione, 458 5H- 1,3,5-Triazepine-2,4-dione, H-[ 1,3,5]Triazin-2-ones, 419 11H-[ 1,2,4-Triazin-3-thion-5-one, 415, 427 415,427 1,2,4-Triazin-5(4H)-oneso 1,2,4-Triazin-5(4H)-ones. 416 1,2,4-Triazine 1,2,4-Triazine 4-oxideo 4-oxide. 416 1,2,3Triazine[4",5":4',5']thieno[3',2':4,5]thien Yriazine[4",5":4',5']thieno[3',2':4,5]thien o[3,2-d]-1,2,3-triazines, o[3,2-d]- 1,2,3-triazines, 428 1,2,4-Triazine-3,5(2H, 1,2,4-Triazine-3,5 (2H, 4H)-diones, 416 [1,2,4]Triazine-3-thione, [ 1,2,4]Triazine-3-thione, 415 1,2,4-Triazines, 1,2,4-Triazines, 316 Triazinoisoquinoline, 427 Triazinoquinoline,427 Triazinoquinoline, 427 1,2,4-Triazoles, 387 1,2,4-Triazoline-3,5-dione, 1,2,4-Triazoline-3,5-dione, 428 ,2,4]Triazolo[4,3-a]pyrazines, 374 [[11,2,4]Yriazolo[4,3-a]pyrazines, Triazolino[4,3-a]pyrimidines, 364, 426 Triazolino[4,3-a]pyrimidines, Triazolium salts, 289 ,5-a][1 ,3,5]triazines, 1,2,4-Triazolo[1 1,2,4-Yriazolo [ 1,5-a] [ 1,3,5]triazines, 423 [1,2,4]Triazolo[1 ,5-a]pyrazines, 374 [ 1,2,4]Yriazolo[ 1,5-a]pyrazines, [1 ,2,3]Triazolo[ ,5-a]pyridines, 230 [ 1,2,3 ]Triazolo[ 11,5-a]pyridines, ,5-a]pyrimidines, 368 [1,2,4]Triazolo[1 [ 1,2,4]Triazolo[ 1,5-a]pyrimidines, ,5-c]pyrimidin-5[1,2,4]Triazolo[1 [ 1,2,4]Triazolo[ 1,5-c]pyrimidin-5amines,368 amines, 368 1,2,4-Triazolo[3,4:fl[1 ,2,4]triazin1,2,4-Yriazolo [3,4-J] [ 1,2,4]triazin8(7H)-one,423 8(7H)-one, 423 -a]pyridines, 233 [[1,2,4]Triazolor4,3 1,2,4]Yriazolo[4,3-a]pyridines, 4,3-a]pyrimidin-7-ones, 1,2,4-Triazolo[[4,3-a]pyrimidin-7-ones, 1,2,4-Triazolo 359 1,2,4-Triazolo[4,3-a ]quinoxalines, 233 1,2,4-Triazolo[4,3-a]quinoxalines, 1,2,4-Triazolo[4,3-b ]pyridazines, 232, 1,2,4-Triazolo[4,3-b]pyridazines, 354 1,2,4-Triazolo[[4,5-a]pyrimidin-5-ones, 4,5-a]pyrimidin-5-ones, 1,2,4-Triazolo 361
Index
[1,2,3]Triazolo[ 4,5-b ]porphyrins, 468 [ 1,2,3]Triazolo [4,5-b]porphyrins, 1H-I ,2,3-Triazolo[4,5-c ]pyridines, 230 1H- 1,2,3-Triazolo[4,5-c]pyridines, 1,2,3-Triazolo[4,5-dj-1 ,2,4-triazolo[[ I,51,2,3-Triazolo [4,5-d]- 1,2,4-triazolo 1,5aa]pyrimidin-9-ones, ]pyrimidin-9-ones, 230 7H- 1,2,3-Triazolo [4,5-d]pyrimidin-77H-I ,2,3-Triazolo[4,5-djpyrimidin-7ones, 360 [4,5-d]pyrimidin-777HH-11,2,3-Triazolo ,2,3-Triazolo[4,5-djpyrimidin-7ones, 364 3H-1 ,2,3-Triazolo[4,5-djpyrimidines, 3H- 1,2,3-Triazolo [4,5-d]pyrimidines, 230 1,2,3-Triazolo[4,5-d]pyrimidines, 367 1,2,3-Triazolo[4,5-djpyrimidines, 2,4,6-Trichloro-I ,3,5-triazine, 4417 I7 2,4,6-Trichloro- 1,3,5-triazine, 4-Trifloyloxazoles, 301 2-Trimethylsilyloxyfuran, 178 1,3,6-Trioxa-7-azacyclopenta[cdjindene, 1,3,6-Yrioxa-7-azacyclopenta[cd]indene, 191 1,2,4-Trioxepanes, 458 Triphenylporphyrin, 54, 64 Tripodal oxazolines, 304 Tripyrrane, 59 1,4,7-Trithia-II-azacyclotetradecanes, 1,4,7-Trithia- 11-azacyclotetradecanes, 475 1,2,3-Trithiolane. 1,2,3-Trithiolane. 203 TTF,201 TTF, 201 UlocIadoi. 447 Ulocladol. Uracil, 427 Uracyl-5-carbaldehyde, 290 Valilactone, 103 (S)-Valinol, 303 (S)-Valinol,303 Vinblastine, 460 Vinylporphyrins, 44 Vinylporphyrins,44 Williamson ether synthesis, 189 Woollins' reagentm 105 Woollins'reagentm Xanthine, 426 (S)-Xyl-BINAP,199 (S)-Xyl-BINAP, 199 Xyloketal A, 182 Zinc porphyrin, 292 3-Zinciobenzo[b]furans, 3-Zinciobenzo[b ]furans, 195
491
