An effective procedure for the preparation of 3-substituted-4- or 6-azaindoles from ortho-methyl nitro pyridines

Article abstract of DOI:10.1016/j.tetlet.2006.06.017

3-Substituted-4- and 6-azaindoles were prepared from ortho-methyl-nitropyridines in a practically convenient, one-pot process based on the Leimgruber-Batcho reaction. The procedure comprises a sequence of (a) condensation of an ortho-methyl-nitropyridine with N,N-dimethylformamide dimethyl acetal; (b) alkylation or acylation of the enamine intermediate; (c) reduction of the nitro group to an aniline with in situ cyclization and elimination of dimethylamine to generate the 3-substituted azaindole heterocycle.

Full text of DOI:10.1016/j.tetlet.2006.06.017

Tetrahedron Letters 47 (2006) 5653–5656
An effective procedure for the preparation of 3-substituted-4-
or 6-azaindoles from ortho-methyl nitro pyridines
Juliang Zhu, Henry Wong, Zhongxing Zhang, Zhiwei Yin, Nicholas A. Meanwell,
John F. Kadow and Tao Wang*
Department of Chemistry, The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford,
CT 06492, United States
Received 16 May 2006; revised 31 May 2006; accepted 2 June 2006
Abstract—3-Substituted-4- and 6-azaindoles were prepared from ortho-methyl-nitropyridines in a practically convenient, one-pot
process based on the Leimgruber–Batcho reaction. The procedure comprises a sequence of (a) condensation of an ortho-methyl-
nitropyridine with N,N-dimethylformamide dimethyl acetal; (b) alkylation or acylation of the enamine intermediate; (c) reduction
of the nitro group to an aniline with in situ cyclization and elimination of dimethylamine to generate the 3-substituted azaindole
heterocycle.
Ó 2006 Elsevier Ltd. All rights reserved.
Derivatives of 3-substituted-4- and 6-azaindole have
been reported to be associated with a range of biological
activities and representative molecules offer potential for
the treatment of infection, inflammation, asthma, pain
and CNS disorders.1 Functionalization at C-3 of indoles
is well documented and many of the synthetic processes
that have been developed rely upon the electron-rich
nature of the enamine-like heterocycle ring.2 However,
when one carbon atom of the benzene ring is replaced
by a nitrogen atom, the direct introduction of substitu-
ents at the C-3 position of azaindoles is considerably
more difficult.3 This is largely due to the reduced reactiv-
ity of the 3-position of azaindoles when compared to
that of indole, a result of the electron deficient nature
of the azaindole heterocycle. As a consequence, general
procedures for the preparation of 3-substituted azain-
doles are relatively sparse in the literature and direct
functionalization at C-3 position of azaindoles is
restricted to Lewis acid-mediated acylation,3,4 halogena-
tion5 and participation in the Mannich reaction.6
dole from the appropriate ortho-methyl nitropyridine.8
In this process, illustrated in Scheme 1, ortho-methyl-
nitropyridines 1a and 1b are first condensed with
DMF-dimethylacetal to produce the enamine intermedi-
ates 2a and 2b. The subsequent reduction of the nitro
group to the aniline is accompanied by in situ cyclization
to afford 6-azaindole 3a or 4-azaindole 3b.
By analogy with the corresponding phenyl derivatives,9
we anticipated that the enamine intermediates 2a and
2b would react with electrophiles to generate the substi-
tuted enamines 4a and 4b (Scheme 1), a process that has
not been reported previously. Reduction of the nitro
group with concomitant cyclization of the aniline and
enamine would then furnish the 3-substituted azaindoles
5a and 5b. In this letter, we demonstrate the reactivity
of the enamine intermediates 2a and 2b towards
electrophiles and describe a practical process that allows
installation of substituents at the C-3 position of 4- and
6-azaindoles.
The two-step Leimgruber–Batcho procedure is a well
established process for synthesizing indoles7 that has
been extended to the preparation of both 4- and 6-azain-
Enamines 2a and 2b were prepared by treating 4- or
2-methyl-3-nitro pyridine with DMF-dimethylacetal or
Bredereck’s reagent at 115 °C. The reactivity of enamine
intermediate 2 towards electrophiles was explored
initially using (E)-N,N-dimethyl-2-(3-nitropyridin-4-
yl)ethenamine (2a) in order to establish the potential
and scope of the reaction. Alkylation of 2a with an alkyl
bromide (e.g., benzyl bromide, 4-phenyl benzyl bromide,
Keywords: 4-Azaindole; 6-Azaindole; Enamine; ortho-Methyl-nitro
pyridine.
*
Corresponding author. Tel.: +1 203 677 6584; fax: +1 203 677
7702; e-mail: wangta@bms.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.017

5654
J. Zhu et al. / Tetrahedron Letters 47 (2006) 5653–5656
H3C
OMe
OMe
N
X
CH3
NO2
X
X
NMe2
[H]
H3C
Y
Y
Y
N
H
NO2
1a: X = C, Y = N
1b: X = N, Y = C
2a: X = C, Y = N
2b: X = N, Y = C
3a: X = C, Y = N
3b: X = N, Y = C
E+
E
E
X
[H]
X
NMe2
Y
N
Y
NO2
H
4a: X = C, Y = N
4b: X = N, Y = C
5a: X = C, Y = N
5b: X = N, Y = C
Scheme 1.
E
E
NMe2
E+
iPr2NEt
dioxane/115oC, 14 h
NMe2
[H]
115 oC, 3 h
N
N
NO2
N
N
H
NO2
2a
4a
5a
Scheme 2.
Table 1.
OMe
E
X
1
N
1)
X
X = C, Y = N
OMe
2) E+, dioxane, iPr2NEt
3) Fe, 1NHCl/MeOH/dioxane
or
Y
Y
X = N, Y = C
N
NO2
H
5
32%
N
69%
N
H
5aa
N
42%
N
H
5ab
N
N
H
5ac
O
CN
CN
N
N
49%
N
30%
N
45%
N
H
H
N
N
H
5ad
5ae
5af
O
N
N
N
47%
N
H
64%
36%
N
5bc
N
H
H
5ba
5bb
allyl bromide, diethylaminoethyl bromide) occurred
readily in the presence of Hunig’s base in dioxane at
115 °C based on LC–MS analysis of the reaction mixture,
as summarized in Scheme 2. Similarly, acylation with ben-

J. Zhu et al. / Tetrahedron Letters 47 (2006) 5653–5656
5655
zoyl chloride and Michael addition to 2-(chloro(phenyl)-
Supplementary data
methylene)malononitrile occurred under the same
conditions. However, mesylation using mesyl chloride
and heteroarylation with 2-chloroquinoxaline were
unsuccessful.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
06.017.
Several reagents and conditions were evaluated in order
to optimize the final reduction–cyclization step to form
the 3-substituted-6-azaindole 5a, as shown in Scheme
2. The reduction of 4aa (E = CH2Ph) was used as the
prototype to examine the potential of zinc or iron as
reductants in a variety of co-solvents that included mix-
tures selected from dioxane, MeOH, EtOH, saturated
aqueous NaHCO3 solution, H2O, 0.1 N and 1 N HCl
solutions and saturated aqueous NH4Cl solution. Based
on this survey, iron was determined to be superior to
zinc and a relatively strong acidic medium (0.1 N HCl
or 1 N HCl aqueous solution) with either MeOH or
EtOH as co-solvent proved beneficial for completing
the transformation. Under these conditions, 4aa (E =
CH2Ph) was completely converted to 5aa (E = CH2Ph).
References and notes
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Encouraged by these results, a one-pot procedure was
developed to prepare 3-substituted-4- or 6-azaindole
derivatives from ortho-methyl nitropyridines, and the
results are summarized in Table 1.10 The appropriate
ortho-methyl nitropyridine was treated with 1,1-
dimethoxy-N,N-dimethylmethanamine at 115 °C to pro-
vide ortho-(N,N-dimethylamino)ethenyl nitropyridines
2a and 2b. Volatile material was removed under vaccum
and the crude enamine 2a and 2b reacted with an elec-
trophile in the presence of N,N-diisopropylethylamine
in dioxane at 115 °C. Excess 1 M aqueous HCl solution,
MeOH and iron were added to the flask and the mixture
heated at 115 °C for 3 h to complete the synthesis by
reducing the nitro group and effecting in situ cyclization
of aniline and enamine to furnish 3-substituted-4- or
6-azaindole 5. This process is operationally simple,
effective and reasonably efficient, offering easy access
to novel 3-substituted-4- and 6-azaindoles with overall
yields of 30–69% for the three steps. This process
provides a convenient means to introduce 3-alkyl moie-
ties at the C-3 position of azaindoles, noteworthy since
the direct alkylation at C-3 of indoles is quite challeng-
ing and this reaction has not been documented with
azaindoles.
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Shih, C.-K.; Crob, P. M. J. Med. Chem. 1997, 40, 2430; (b)
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Frydman, B.; Despuy, M. E.; Rapoport, H. J. Am. Chem.
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In summary, we have reported an experimentally
convenient, one-pot procedure for the preparation of
C-3-substituted-4- and 6-azaindoles starting from the
corresponding ortho-methyl nitro pyridine. C-3 substitu-
ents were installed via reaction of the intermediate
enamine prior to the final reductive cyclization. This
modified Leimgruber–Batcho procedure is attractive
due to the simplicity of the operational procedure, the
mildness of the conditions and the potential applicabil-
ity to other azaindoles.
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Acknowledgements
The authors are very grateful to Dr. Yuping Qiu for
helpful discussions.

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J. Zhu et al. / Tetrahedron Letters 47 (2006) 5653–5656
Fenton, G.; Foster, M.; Harrison, T. K. P.; King, S.; Lai,
10. Typical procedure—Preparation of 3-(4-phenyl)benzyl-6-
azaindole (5ab): 4-Methyl-3-nitropyridine (500 mg, 3.62
mmol) was dissolved in 1,1-dimethoxy-N,N-dimethyl-
methanamine (10 ml) and the reaction mixture heated at
115 °C for 14 h. Volatile material was removed under
vaccum to provide 4-(N,N-dimethylamino)ethenyl-3-nitro-
pyridine which was mixed with 4-bromomethylbiphenyl
(2.69 g, 10.9 mmol) and N,N-diisopropylethylamine (2 ml)
in dioxane (20 ml). The reaction mixture was stirred at
115 °C for 14 h before cooling and adding aqueous 1 N
HCl solution (2 ml), MeOH (5 ml) and iron (2.02 g,
36.2 mmol). The mixture was stirred at 115 °C for 3 h,
cooled and filtered. The filtrate was concentrated under
vaccum and the residue purified by silica gel column
chromatography using CH2Cl2/CH3OH = 9:1 to 4:1 as
eluant to afford 708 mg of product 5ab (69%).
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