Rapid synthesis of 3-aminoimidazo[1,2-a]pyridines and pyrazines

Article abstract of DOI:10.1080/00397910701862931

p-Toluenesulfonic acid catalyzed the one-pot, three-component synthesis of 3-aminoimidazo[1,2-a]pyridines and pyrazines through a condensation reaction of a 2-aminoazine, an aldehyde, and an isocyanide at room temperature. This methodology affords a number of 3-aminoimidazo[1,2-a]pyridines in reasonable yields and short reaction times without any significant optimization of the reaction conditions. Copyright Taylor & Francis Group, LLC.

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Rapid Synthesis of
3‐Aminoimidazo[1,2‐a]Pyridines and
Pyrazines
Ahmad Shaabani a , Ebrahim Soleimani a , Ali Maleki a & Jafar Moghimi‐Rad a
a Department of Chemistry , Shahid Beheshti University , Tehran, Iran
Published online: 12 Mar 2008.
To cite this article: Ahmad Shaabani , Ebrahim Soleimani , Ali Maleki & Jafar Moghimi‐Rad (2008)
Rapid Synthesis of 3‐Aminoimidazo[1,2‐a]Pyridines and Pyrazines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:7, 1090-1095, DOI:
10.1080/00397910701862931
To link to this article: http://dx.doi.org/10.1080/00397910701862931
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Synthetic Communicationsw, 38: 1090–1095, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701862931
Rapid Synthesis of 3-Aminoimidazo[1,2-a]
Pyridines and Pyrazines
Ahmad Shaabani, Ebrahim Soleimani, Ali Maleki,
and Jafar Moghimi-Rad
Department of Chemistry, Shahid Beheshti University, Tehran, Iran
Abstract: p-Toluenesulfonic acid catalyzed the one-pot, three-component synthesis
of 3-aminoimidazo[1,2-a]pyridines and pyrazines through a condensation reaction
of a 2-aminoazine, an aldehyde, and an isocyanide at room temperature. This
methodology affords a number of 3-aminoimidazo[1,2-a]pyridines in reasonable
yields and short reaction times without any significant optimization of the
reaction conditions.
Keywords: 3-Aminoimidazo[1,2-a]pyridines, 3-aminoimidazo[1,2-a]pyrazines, iso-
cyanide, p-toluenesulfonic acid
INTRODUCTION
Derivatives containing the imidazo[1,2-a]pyridine ring system have been
shown to possess a broad range of useful pharmacological activities,
including antibacterial, antifungal, anthelmintic, antiviral, antiprotozoal,
anti-inflammatory, anticonvulsant, anxiolytic (Alpidem), hypnotic
(Zolpidem), gastrointestinal, antiulcer (Zolmidine), and immunomodulatory
(Kifunensine) activities.[1–4] They have also been shown to be selective
cyclin-dependant kinase inhibitors, g-aminobutyric acid (GABA) and benzo-
diazepine receptor agonists, and bradykinin B2 receptor antagonists.[1–6] The
classical synthesis of imidazo[1,2-a] annulated pyridines, pyrimidines, and
Received in the U.K. May 3, 2007
Address correspondence to Ahmad Shaabani, Department of Chemistry, Shahid
Beheshti University, P. O. Box 19396-4716, Tehran, Iran. E-mail: a-shaabani@cc.
sbu.ac.ir
1090

3-Aminoimidazo[1,2-a]Pyridines and Pyrazines
1091
pyrazines involves the condensation of a-haloketones with 2-aminopyridines,
2-aminopyrimidines, and 2-aminopyrazines, respectively.[7] However, this
approach does not readily lend itself to a diversity-oriented synthesis.
A more versatile approach uses a three-component coupling involving the
condensation of aldehydes, 2-aminopyridine, and isocyanides in the presence
of acid catalysts. This robust approach allows for the preparation of a diverse
range of products. However, it requires long reaction times (20–72 h).[8–11]
The use of an ionic liquid such as 1-butyl-3-methylimidazolium bromide
and a solid acid catalyst such as silica sulfuric acid have been reported for
reducing reaction times.[12]
In connection with our previous work on the synthesis of 3-aminoimi-
dazo[1,2-a]pyridines and pyrazines[12] and our interest in isocyanide-based
multicomponent reactions (MCRs).[13] we report the synthesis of 3-amino-
imidazo[1,2-a]pyridines and pyrazines 4 by three-component condensation
of an 2-aminoazine 1, an aldehyde 2, and an isocyanide 3 in the presence of
catalytic amounts of p-toluenesulfonic acid (PTSA) as an inexpensive
catalyst in excellent yields in methanol at room temperature (Scheme 1).
RESULTS AND DISCUSSION
As indicated in Table 1, the reaction of aldehyde with 2-aminoazine
derivatives and isocyanides afforded 3-aminoimidazo[1,2-a]pyridines and
pyrazines in the presence of PTSA as a promoter in very high yields.
Limitations of this condensation reaction were further explored by
extending the number of reactants. For this purpose, the reactivities of
various aldehydes, constituted of either electron-donor or electron-acceptor
groups, were examined. As indicated in Table 1, the reaction proceeds effi-
ciently in all cases studied.
In conclusion, we have described a novel application of PTSA as a cheap
catalyst for the one-pot preparation of 3-aminoimidazo[1,2-a]pyridines and
pyrazines via condensation of an aldehyde, a 2-aminoazine, and an isocyanide
in quantitative yields at room temperature. The reaction has been shown to
display good functional group tolerance and is high yielding, and product
isolation is very straightforward.
Scheme 1.

1092
A. Shaabani et al.
Table 1. Synthesis of 3-aminoimidazo[1,2-a]pyridines and pyrazines in the presence
of PTSA
Entry
R1
R2
R3
X
Product
Yield (%)
1
2
Me
Br
H
Ph
Ph
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
cyclohexyl
tert-Butyl
CH
CH
CH
CH
N
4a
4b
4c
4d
4e
4f
97
94
94
93
88
92
90
98
91
98
96
86
88
3
Ph
4
H
4-CH3OC6H4
4-CH3OC6H4
3-O2NC6H4
4-ClC6H4
4-CH3C6H4
4-pyridyl
Ph
5
Me
Me
H
6
CH
CH
CH
CH
CH
N
7
4g
4h
4i
8
Me
Me
Me
Br
Me
H
9
10
11
12
13
4j
Ph
4-CH3OC6H4
Ph
tert-Butyl
tert-Butyl
2,6-(Me)2C6H3
4k
4l
N
CH
4m
EXPERIMENTAL
Melting points were measured on an Electrothermal 9200 apparatus. IR
spectra were recorded on a FT-IR 102MB BOMEM apparatus. Mass spectra
were recorded on a Finnigan-Mat 8430 mass spectrometer operating at an ion-
ization potential of 70 eV. 1H and 13C NMR spectra were recorded on a Bruker
1
DRX-300 Avance spectrometer at 300.13 and 75.47 MHz. H and 13C NMR
spectra were obtained on solutions in CDCl3. 2-Aminoazines, isocyanides,
and aldehydes were purchased from Fluka and Merck and used without
purification.
Typical Procedure for Preparation of 4a–m
Catalytic amounts of p-toluenesulfonic acid (0.1 g, 0.52 mmol) were added to
a solution of 2-aminoazine (1.00 mmol), aldehyde 1.20 mmol), and isocyanide
(1.10 mmol) in methanol (4 mL). The resulting mixture was stirred for 2 h at
room temperature. After completion of the reaction, as indicated by thin-layer
chromatography (TLC, ethyl acetate/n-hexane, 2:1), the solid product was
separated by filtration followed by washing the residue with ethyl acetate to
obtain the pure product.
All products (except 4c and 4d) are known compounds,[12] which were
characterized by melting point, IR, 1H and 13C NMR spectral data, and
mass spectroscopy.

3-Aminoimidazo[1,2-a]Pyridines and Pyrazines
1093
Data
N-Cyclohexyl-2-phenylimidazo[1,2-a]pyridin-3-amine (4c). Yellow solid
(0.27 g, 94%); mp 200–202 8C. IR (KBr) cm21: 3250, 2920,1602. MS m/z:
1
291 (Mþ), 259, 158, 76. H NMR (CDCl3) d ¼ 1.15–1.97 (10H, m, 5CH2
of cyclohexyl), 2.94 (1H, m, CH-N of cyclohexyl), 3.76 (1H, brs, NH),
7.06–8.15 (9H, m, H-Ar). 13C NMR (CDCl3) d ¼ 24.7, 25.6, 34.1 (C-
cyclohexyl), 56.8 (CH-N-cyclohexyl), 107.9, 117.7, 123.0, 125.2, 127.0,
127.7, 128.6, 128.6, 133.4, 135.9, 137.5 (C-Ar). Anal. calcd. for C19H21N3:
C, 78.32; H, 7.26; N, 14.42. Found: C, 78.29; H, 7.20; N, 14.35.
N-Cyclohexyl-2-(4-methoxyphenyl)H-imidazo[1,2-a]pyridin-3-amine (4d).
Yellow solid (0.30 g, 93%); mp 152–154 8C. IR (KBr) cm21: 3251, 2925,
1605. MS m/z: 321 (Mþ), 238, 211, 78, 55, 41. 1H NMR (CDCl3) d ¼ 1.17–
1.83 (10H, m, 5CH2 of cyclohexyl), 2.96 (1H, m, CH-N of cyclohexyl), 3.10
(1H, brs, NH), 3.87 (3H, s, OCH3), 7.06–8.15 (8H, m, H-Ar). 13C NMR
(CDCl3) d ¼ 24.8, 25.7, 34.1 (C-cyclohexyl), 55.3 (OCH3), 56.8 (CH-N-cyclo-
hexyl), 111.7, 113.9, 116.8, 122.7, 124.1, 126.6, 128.3, 136.1, 141.2, 159.0 (C-
Ar). Anal. calcd. for C20H23N3O: C, 74.74;H, 7.21; N, 13.07. Found: C, 74.65;
H, 7.15; N, 13.16.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support from the Research Council
of Shahid Beheshti University.
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