J . Org. Chem. 2002, 67, 2345-2347
2345
Notes
A Gen er a l Meth od for th e P r ep a r a tion of 4-
Sch em e 1
a n d 6-Aza in d oles
Zhongxing Zhang, Zhong Yang, Nicholas A. Meanwell,
J ohn F. Kadow, and Tao Wang*,†
Department of Chemistry, The Bristol-Myers Squibb
Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492
using the protocol originally developed by Bartoli for the
synthesis of indoles.
The Bartoli cyclization (Scheme 1) has been extensively
utilized in the synthesis of indole derivatives from
nitrobenzene derivatives. Due to the close structural
similarity between the indole and azaindole ring systems,
it was anticipated that the Bartoli reaction would provide
a concise, preparative approach to azaindoles. Surpris-
ingly, the reaction of nitropyridines with vinylmagnesium
halides to afford azaindole derivatives appears to be
undocumented.
4
Received December 20, 2001
Abstr a ct: Nitropyridines reacted with an excess of vinyl
Grignard reagent to produce 4- or 6-azaindoles. Improved
yields were obtained when a halogen atom was present at
the position R to the nitrogen atom in the pyridine ring.
To test the feasibility of applying the Bartoli cyclization
strategy to the synthesis of azaindoles, commercially
available 2-methoxy-3-nitropyridine 3a was treated with
3 to 4 equiv of vinylmagnesium bromide in THF at -78
°C. After warming to -20 °C, the reaction mixture was
The azaindole ring system is a structural motif present
in a variety of natural products, pharmaceuticals, and
diverse synthetic intermediates. Investigations into the
1
preparation of this heterocycle can be traced back to
a
1
943.2 To date, the most common methods used for the
4
quenched with 20% aqueous NH Cl to afford a crude
preparation of azaindoles include the Madelung-type
product that appeared surprisingly clean by LC analysis.
Purification via flash chromatography provided a 20%
yield of the desired 7-methoxy-6-azaindole 4a . Although
modest, this yield is comparable to that obtained in the
preparation of indoles.
cyclization,2b a Reissert-type procedure,
2c-e,3a
the Leim-
gruber-Batcho reaction2 and a Lorenz-type cyclization.2g,h
Recently, several groups have described an elegant,
palladium(0)-catalyzed methodology for the construction
of azaindoles starting from acetylenes and iodinated
f,g
Encouraged by this result, the procedure was examined
in the context of a variety of commercially available
nitropyridines, and as summarized in Table 1, reliably
produced either 4- or 6-azaindole derivatives. Generally,
yields were only low to moderate, as is often observed in
the preparation of indoles, but two phenomena are
noteworthy. First, consistent with an observation re-
ported by Dobson and co-workers,4 larger substituents
directly adjacent to the nitro group produced higher
yields of the azaindole products, as demonstrated by
entries 1, 2, 8, and 9 in Table 1. A second observation,
which appears to be unique to azaindole series, is that a
halogen atom at the R- or 4-position of the pyridine ring
is associated with a significantly increased yield of
product. For example, while 4-methyl-3-nitro-pyridine 3f
afforded the corresponding azaindole 4f in 18% yield
3
amino-pyridines. However, due to the limited avail-
ability of appropriately substituted substrates for many
of these procedures, significant effort is required to secure
starting materials for their implementation. Prompted
by a need to synthesize azaindoles from readily available
starting materials, we developed a general and efficient
method for preparing azaindoles from nitropyridines
c
†
This report is dedicated to Professor Gilbert Stork on the occasion
of his 80th birthday.
(1) (a) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck,
A. Tetrahedron Lett. 1996, 37, 3217. (b) Shin-Ya, K.; Kim, J .-S.;
Furihata, K.; Hayakawa, Y.; Seto, H. J . Asian Nat. Prod. Res. 2000,
2
, 121. (c) Nagel, A. A. EP 0870768 Oct 14, 1998. (d) Clark, R. D.;
Clarke, D. E.; Fischer, L. E.; J ahangir, A. US 5,212, 195 May 18, 1993.
e) Cassidy, F.; Hughes, I.; Rahman, S. S.; Hunter, D. J . WO 96/11929
(
April 25, 1996. (f) Desarbre, E.; Coudred, S.; Meheust, C.; Merour, J .-
Y. Tetrahedron 1997, 53, 3637. (g) Dormoy, J .-R.; Heymes, A. Tetra-
hedron 1993, 49, 2885. (h) Gribble, G. W. J . Chem. Soc., Perkin Trans.
(Table 1, entry 6), 2-chloro-4-methyl-3-nitropyridine 3g
1
2000, 1045.
2) (a) Kruber, O. Chem. Ber. 1943, 76, 128. (b) Hands, D.; Bishop,
provided the cognate azaindole 4g in 50% yield (Table 1,
entry 7). Further evidence of this phenomenon can be
found by comparing the matched pairs represented by
entries 4 and 5 and entries 9 and 10.
Although the precise origin of this effect remains to
be elucidated, it may be a consequence of an overall
enhanced electrophilicity of the substrate. Nevertheless,
this observation has practical consequences since the
(
B.; Cameron, M.; Edwards, J . S.; Conttrell, I. F.; Wright, S. H. B. A.
Synthesis 1996, 877. (c) Yakhontov, L. N.; Azimov, V. A.; Lapan, E. I.
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4
3
93. (g) Mahadevan, I.; Rasmussen, M. J . Heterocycl. Chem. 1992, 29,
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Chem. 1965, 30, 2531.
3) (a) Curtis, N. R.; Kulagowski, J . J .; Leeson, P. D.; Ridgill, M. P.;
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999, 9, 585. (b) Park, S. S.; Choi, J .-K.; Yum, E. K.; Ha, D.-C.
(
(4) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozz, R. Tetrahedron
Lett. 1989, 30, 2129. (b) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri,
G.; Petrini, M. J . Chem. Soc., Perkin Trans. 2 1991 657. (c) Dobson,
D.; Todd, A.; Gilmore, J . Synth. Commun. 1991, 21, 611. (d) Dobbs, A.
B.; Voyle, M.; Whittall, N. Synlett. 1999, 1594.
1
Tetrahedron Lett. 1998, 39, 627. (c) Xu, L.; Lewis, I. R.; Davidsen, S.
K.; Summers, J . B. Tetrahedron Lett. 1998, 39, 5159. (d) Ujjainwalla,
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1
0.1021/jo0111614 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/09/2002