Palladium-catalyzed functionalization of 5- and 7-azaindoles

Article abstract of DOI:10.1016/S0040-4039(99)02190-5

Palladium-catalyzed functionalization at the 2-position of various 5- and 7-azaindoles was performed by Suzuki, Heck, and Stille reactions. The 2- substituted azaindoles were obtained with 5% Pd(OAc)₂, LiCl, and KOAc in DMF at 110°C with modera

Full text of DOI:10.1016/S0040-4039(99)02190-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 919–922
Palladium-catalyzed functionalization of 5- and 7-azaindoles
Sung Min Chi,a Joong-Kwon Choi,a Eul Kgun Yum a,∗,† and Dae Yoon Chi b
aBio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusung, Taejeon 305-600,
South Korea
bDepartment of Chemistry, Inha University, Inchon 402-751, South Korea
Received 5 October 1999; revised 15 November 1999; accepted 19 November 1999
Abstract
Palladium-catalyzed functionalization at the 2-position of various 5- and 7-azaindoles was performed by Suzuki,
Heck, and Stille reactions. The 2-substituted azaindoles were obtained with 5% Pd(OAc)2, LiCl, and KOAc in DMF
at 110°C with moderate to high yields. © 2000 Elsevier Science Ltd. All rights reserved.
There has arisen considerable synthetic interest in azaindoles, primarily as bioisosteres for indoles, in
which adoption of an additional nitrogen atom in the aromatic ring confers its own unique properties
to the systems. Azaindoles have been used for various pharmaceutical agents, such as anti-inflammatory
agents,1 anti-psychotic agents,2 etc.3 Since natural azaindoles are relatively scarce, most of the azaindoles
have been prepared traditionally via classical methods such as the Fisher, Madelung, and Reissert
procedures, which, in spite of their synthetic value, generally suffer from harsh reaction conditions
and modest yields.4 Recently, palladium-mediated cyclizations with alkynes have been of great interest
for the preparation of azaindole derivatives5 with modified synthetic procedures for indoles.6 However,
few transition metal mediated functionalization of azaindoles have been described in the literature.7
In particular, reports on the functionalization at the 2-position of 5- and 7-azaindoles are very limited
in the literature.8 Herein, we report the facile functionalization at the 2-position of 5- and 7-azaindole
derivatives, which is based on palladium-mediated coupling reactions.
The 2-iodo-3-substituted azaindoles were obtained by the reaction of 2-trimethylsilyl-3-substituted
azaindoles with ICl at room temperature within 1 h for the palladium-catalyzed functionalization (Eq.
(1)). Heating the reaction mixture5a resulted in some chloride which was unreactive towards further
elaboration.9
∗
†
Corresponding author. E-mail: ekyum@hanbat.chungnam.ac.kr (E. K. Yum)
Present address: Department of Chemistry, Chungnam National University, Taejon 305-764, South Korea.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02190-5
tetl 16118

920
(1)
Initial palladium-catalyzed coupling reactions were performed with various 2-iodo-3-methyl-5-
azaindoles and boric acids, alkenes, and organotin derivatives. The results are summarized in Table 1.
Table 1
Palladium-catalyzed functionalization at the 2-position of 5-azaindoles
The reaction using 2-iodo-3-methyl-5-azaindoles with the phenylboric acid provided 3-methyl-2-
phenyl-5-azaindoles (entries 1–3). The reaction of 2-iodo-3-methyl-1H-5-azaindole provided a trace
amount of 3-methyl-2-phenyl-1H-5-azaindole and most of the starting material was recovered even after
60 h (entry 1). Probably, 1H-azaindole readily forms a complex with the palladium catalyst and the
complex cannot proceed in the catalytic cycle. Also, the reaction of 1-benzyl-2-iodo-5-azaindole required
a longer reaction time for completion compared to the reaction of 2-iodo-1-methyl-5-azaindole (entries 2
and 3). We examined a possible introduction of various phenyl groups at the 2-position of 5-azaindoles,

921
which could not easily be introduced by previous methods (entries 4–8). The Suzuki coupling reactions
proceeded very well with various phenylboric acids, but the reaction with sterically more hindered ortho-
substituted boric acid required a longer reaction time (entries 4 and 5).
Then Stille coupling reactions were also examined to introduce aryl or alkenyl groups at the 2-position
of 5-azaindoles. The reactions provided not only an aromatic group but also an alkenyl group at the 2-
position of 5-azaindoles in moderate yields (entries 9–11). Finally, the Heck reactions were examined
(entries 12–14). The reactions using 1-benzyl-2-iodo-5-azaindole and vinyl olefins provided high yields
of 2-substituted 5-azaindoles with trans:cis isomers in the ratio of 6–10:1.
In order to synthesize pharmaceutically useful 2-substituted 7-azaindole derivatives, the standard
palladium-catalyzed reaction condition was also applied to 2-iodo-3-substituted 7-azaindoles with phe-
nylboric acids, organotins, and olefin derivatives. The results are summarized in Table 2.
Table 2
Palladium-catalyzed functionalization at the 2-position of 3-substituted 7-azaindoles
The reaction using various 2-iodo-7-azaindoles with phenylboric acids provided 2-phenyl-3-
substituted 7-azaindoles in moderate to high yields (entries 1–5). Generally, the Suzuki coupling reaction
of 7-azaindoles provided higher yields of 2-phenyl-7-azaindoles and required shorter reaction times
compared to the reaction of 5-azaindoles. The Stille reaction was also examined (entries 6–10), and
provided various 2-substituted 7-azaindoles in high yields within 8 h (entries 6–9, except for entry 10).
Finally, the Heck reaction was examined with 2-iodo-7-azaindoles and terminal olefins (entries 11–13).
This reaction provided 2-alkyl-7-azaindoles in high yields.
In summary, the functionalizations at the 2-position of 5- and 7-azaindoles were easily performed by

922
palladium-catalyzed Suzuki, Stille, and Heck reactions. This synthetic method is especially useful for the
preparation of various 2-aryl 5- or 7-azaindoles, which cannot be synthesized easily with conventional
synthetic methods.
Acknowledgements
The financial support of the Ministry of Science and Technology is greatly acknowledged.
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