Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles

Article abstract of DOI:10.1002/anie.200700804

(Chemical Equation Presented) Changing the rings: A variety of N-fused pyrrolo- and imidazopyridines can be readily formed by a direct Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles, respectively (see scheme). Substituted pyrido

Full text of DOI:10.1002/anie.200700804

Angewandte
Chemie
DOI: 10.1002/anie.200700804
Annulated Heterocycles
Rh-Catalyzed Transannulation of Pyridotriazoles with Alkynes and
Nitriles**
Stepan Chuprakov, Frank W. Hwang, and Vladimir Gevorgyan*
Transition-metal-catalyzed annulations are widely used in the
synthesis of heterocyclic compounds.[1] One of the most
efficient methods for the construction of five-membered
oxygen-containing heterocycles involves the annulation of
diazocarbonyl compounds with alkynes and nitriles. Thus,
Davies et al.[2] and Padwa et al.[3] have employed this
method[4] for the synthesis of furans (X = CH),and Helquist
et al.[5] for the preparation of oxazoles (X = N) [Eq. (1)]. In
contrast,analogous transformations of a-imino diazo com-
pounds,which may lead to the formation of pyrrole and
imidazole rings,are unknown. Herein we report an efficient,
direct,Rh-catalyzed transannulation of pyridotriazoles with
alkynes and nitriles that leads to indolizines (X = CH) and
imidazopyridines (X = N),respectively [Eq. (2)].
amounts of 1. The position of this equilibrium depends on the
temperature and the substitution pattern of the triazole.[9b]
Thus,introduction of a halogen substituent at C7 (R 1 = Cl)
shifts the equilibrium to the left,which has been explained in
terms of nonbonding repulsion between the lone pair of the
halogen and that of the nitrogen in the peri position.[10]
To evaluate the feasibility of using triazoles as precursors
of Rh carbenoids we investigated the reaction of triazoles 3a
and 3b with triethylsilane in the presence of a catalytic
amount of rhodium(II) acetate,which is a method developed
by Doyle and coworkers[11] for the efficient trapping of Rh
carbenoids [Eq. (4)]. Not surprisingly,pyridotriazoles 3a and
3b behave differently under these reaction conditions. Thus,
while the 7-H derivative 3a remains unaffected,the 7-chloro-
substituted compound 3b is smoothly converted into 4,which
À
is the product of carbenoid insertion into the Si H bond.
These experiments clearly indicate that 7-halo-substituted
pyridotriazoles can indeed serve as convenient precursors of
Rh carbenoids.
It has been shown that 2-pyridyl diazo compounds 1[6]
transform into their cyclic triazole form 2[7] upon storage
[Eq. (3)],and it is also known that some of these cyclic
triazoles can still undergo transformations that are character-
istic of diazo compounds.[8] This phenomenon has been
attributed to the closed/open form equilibrium of N-fused
triazoles in solution,[9] which can produce trace to significant
Next,to test our hypothesis regarding the annulation of a-
imino diazo compounds with alkynes to form a pyrrole ring,
we treated triazole 3b with phenylacetylene in the presence of
rhodium(II) acetate. This reaction proceeded smoothly to
produce a mixture of cyclopropene 5 and indolizine 6a with
yields of 68% and 28% of isolated product,respectively
[Eq. (5)]. Surprisingly,cyclopropene 5 does not undergo
further isomerization into indolizine 6a under these reaction
conditions.[12] The ratio of these products remained constant
throughout the course of the reaction,thereby suggesting an
independent path for the formation of 6a.
[*] S. Chuprakov, F. W. Hwang, Prof. V. Gevorgyan
Department of Chemistry
University of Illinois at Chicago
845 West Taylor Street, Chicago, IL 60607 (USA)
Fax: (+1)312-355-0836
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
[**] Financial support from the National Institutes of Health (GM-
64444) is gratefully acknowledged.
We found,however,that the selectivity of the trans-
annulation (6 over 5) could be dramatically improved by using
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 4757 –4759
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Table 2: Rhodium(II)-catalyzed transannulation of triazoles with nitriles.
Entry
R1
R2
Triazole
R3
Product Yield
[%][a]
rhodium(II) heptafluorobutyrate as catalyst.[13] Thus,trans-
1
2
3
4
5
6
7
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
3b
3b
3b
3b
3b
3b
3b
p-Tol
Ph
p-Me(O)CC6H4
7a
7b
7c
7d
7e
7 f
89
83
54
63
75
74
69
annulation of 3b with a series of aryl and alkenyl alkynes[14]
proceeded highly chemoselectively (90:10 to 95:5 vs. cyclo-
propene) to produce indolizines 6[15] in good yields (Table 1).
Electron-rich,electron-deficient,and sterically hindered aryl
alkynes were nearly equally effective in this reaction.
Bn
nPr
cPr
tBu
7g
8
Cl
CO2Me
3b
7h
66
Table 1: Rhodium(II)-catalyzed transannulation of triazole 3b with
alkynes.
9
Cl
Cl
Br
CO2Me
p-CF3C6H4
p-CF3C6H4
3b
3c
3d
3e
CH2SiMe3
Ph
p-Tol
nPr
7i
7j
7k
7l
70
82
73
51
10
11
12
Entry
Alkyne
Product
6a
Yield [%][a]
OMe p-CF3C6H4
1
2
78
80
[a] Yield of isolated product.
6b
3
4
5
6
6c
6d
6e
6 f
73
85
70
65
7
6g
57
[a] Yield of isolated product. Indolizines 6 were accompanied by 5–10%
of the corresponding cyclopropenes 5; these compounds were readily
separable by column chromatography.
Inspired by the successful formation of an N-fused pyrrole
ring from the transannulation of triazoles with alkynes,we
examined the formation of an N-fused imidazole ring in the
reaction of 3 with nitriles and found that pyridotriazoles 3
react smoothly with a variety of aryl,alkyl,and alkenyl
nitriles in the presence of Rh2(OAc)4 (1 mol%) in toluene at
608C (Table 2) to afford N-fused imidazopyridines 7 in
reasonable to high yields.
Both 3-carbomethoxy- (Table 2,entries 1–9) and 3-aryl-
(Table 2,entry 10) pyridotriazoles are equally efficient in this
reaction. Moreover,7-bromo- (Table 2,entry 11) and even 7-
methoxy-substituted (Table 2,entry 12) triazoles proved to be
good substrates for this transannulation reaction.
We propose the following mechanism for this novel Rh-
catalyzed transformation (Scheme 1). First,pyridotriazole 3
undergoes closed/open form equilibrium[9] to produce small
amounts of diazo compound 1 which,upon reaction with
rhodium(II) carboxylate,generates the Rh-carbenoid species
I. A direct nucleophilic attack[18] of alkyne or nitrile 8 on
species I produces ylide species II,according to path A,which
Scheme 1. Plausible mechanisms for the Rh-catalyzed transannulation
of pyridotriazoles with alkynes and nitriles. Y=N, CR’’.
then cyclizes to form 6 or 7 via cyclic zwitterion III.
Alternatively (path B),[2 +2] cycloaddition of I and 8 leads
to metallacyclobutene IV,which can also be formed by
cyclization of II.[19] Rhodacycle IV then undergoes metathesis
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Angewandte
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Belg. 1990, 99,281; c) G. LꢀabbØ,F. Godts,S. Toppet, J. Chem.
to produce Rh carbenoid V which,upon 6 p-electrocyclization
and subsequent reductive elimination,furnishes product 6 or
7. [2+1] Cycloaddition of I with 8 (path C) accounts for the
formation of cyclopropene 5 in the presence of rhodium(II)
acetate [see Eq. (5)]. As discussed above, 5 does not trans-
form into heterocycle 6 under these reaction conditions.[12]
In summary,we have developed an efficient Rh-catalyzed
transannulation of pyridotriazoles for the formation of
pyrrolo- and imidazopyridines,which are important fused
heterocyclic scaffolds.[20] We have also demonstrated that
some of these pyridotriazoles can serve as stable[13] and
convenient[21] precursors of Rh carbenoids.
Soc. Chem. Commun. 1985,589; d) G. LꢀabbØ,I. Luyten,S.
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[10] B. Abarca-Gonzµlez,R. Ballesteros,F. Mojarred,G. Jones,D. J.
Mouat, J. Chem. Soc. Perkin Trans. 1 1987,1865.
[11] V. Bagheri,M. P. Doyle,J. Taunton,E. E. Claxton, J. Org. Chem.
1988, 53,6158.
[12] For a related transformation of 3-carbonyl cyclopropenes into
furans,see refs. [2a] and [3a].
[13] See the Supporting Information for details.
[14] The use of aliphatic alkynes resulted in sluggish and incomplete
reactions.
[15] Halo-substituted N-fused heterocycles can be further function-
alized by cross-coupling reactions.[16] We have also found that the
chloride in 6a can be quantitatively removed by treatment with
PdCl2/HSiEt3.[17]
Received: February 22,2007
Published online: May 11,2007
[16] For a review of coupling reactions of aryl chlorides,see: A. F.
Littke,G. C. Fu, Angew. Chem. 2002, 114,4350; Angew. Chem.
Int. Ed. 2002, 41,4176.
[17] R. Boukherroub,C. Chatgilialoglu,G. Manuel, Organometallics
1996, 15,1508.
[18] A. Padwa,D. J. Austin,A. T. Price,M. A. Semones,M. P. Doyle,
M. N. Protopopova,W. R. Winchester,A. Tran, J. Am. Chem.
Soc. 1993, 115,8669.
Keywords: annulation · nitrogen heterocycles · rhodium ·
synthetic methods · triazoles
.
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Angew. Chem. Int. Ed. 2007, 46, 4757 –4759
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4759