One-pot synthesis of 3-aminoimidazo[1,2-a]pyridines catalyzed by heteropolyacids

Article abstract of DOI:10.1002/cjoc.201090070

Condensation of aldehydes, isonitriles and 2-aminopyridines in the presence of H₃PMo₁₂O₄₀ affords different derivatives of 3-aminoimidazo[1,2-a]pyridine in good to excellent yields.

Full text of DOI:10.1002/cjoc.201090070

FULL PAPER
One-pot Synthesis of 3-Aminoimidazo[1,2-a]pyridines
Catalyzed by Heteropolyacids
Oskooie, Hossein A.a
Amini, Maryama
Heravi, Majid M.*,a
Bamoharram, Fatemeh F.b
a Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran, Iran
b Department of Chemistry, School of Sciences, Azad University Khorasan Branch, Mashhad, Iran
Condensation of aldehydes, isonitriles and 2-aminopyridines in the presence of H3PMo12O40 affords different
derivatives of 3-aminoimidazo[1,2-a]pyridine in good to excellent yields.
Keywords 3-aminoimidazo[1,2-a]pyridine, isonitrile, 2-amino-5-bromopyridine, 2-amino-5 methylpyridine, het-
eropolyacid
Introduction
and polluting corrosive liquid acid catalysts by solid
acid catalysts is one of the demands of the societies.
Cleaner technology could be possible by making use of
environmentally friendly catalysts involving the use of
solid acids. Among solid catalysts, heteropolyacids
(HPA) constitute a large class of compounds that are
remarkable owing to their physicochemical properties.
These compounds possess unique properties such as
well-defined structure, Bronsted acidity, possibility to
modify their acid-base and redox properties by changing
their chemical composition (substituted HPA), ability to
accept and release electrons, high proton mobility, en-
vironmental benignity and fewer disposal problems.
Because of their stronger acidity, they generally exhibit
higher catalytic activity than conventional catalysts such
as mineral acids, ion exchange resins, mixed oxides and
zeolites.18
Imidazo[1,2-x]heterocycles are versatile building
blocks drug hunters to search for effective molecular
tools in ‘cell perturbation’ studies quested to discover
new leads for a chemical biologist.1
For instance, imidazo[1,2-a]pyridines have emerged
as versatile drug templates in medicinal chemistry span-
ning applications to anti-inflammatory,2 anti-ulcer, an-
tibacterial agents,3 inhibitors against gastric acid secre-
tion,4 calcium channel blockers5 and sedative-hypnotic
drugs, such as zolpidem (Scheme 1).6 As a result, nu-
merous two- and three-component approaches for their
synthesis have been reported.7-14 The amino group at
position 2 confers special properties to this nucleus,
which has been used to prepare 2-aminoimidazo[1,2-
a]pyridines as anti-rhinovirus agents.15
Scheme 1
Development of methods using HPA as solid and
green catalysts for fine organic synthetic processes re-
lated to fine chemicals, such as flavors, pharmaceuticals
and food additives has been under attention in the last
decade.19
Due to the numerous advantages associated with this
eco-friendly, green and heterogeneous catalyst, HPA
and its salts have been explored as powerful, efficient
and eco-friendly catalysts for organic reactions.20
Herein we reported the synthesis of 3-aminoimi-
dazo[1,2-a]pyridines from reaction of 2-aminoazines,
aldehydes, and isonitriles using a catalytic amount of
HPA (Scheme 2).
Due to these unique pharmacological properties, the
development of synthetic methods, enabling easy access
to these fused heterocycles, is desirable.16 The reaction
of heterocyclic amidines with aldehydes and isonitriles
under acid catalysis conditions was first reported in
1998.17 However, these reactions required long time for
completion and the reaction work-ups were complicated.
This reaction was also performed using a nonpolar sol-
vent, and in the presence of an ionic liquid. Most of the
above mentioned syntheses involve harsh or environ-
mentally hazardous reaction conditions.16
Results and discussion
Recently, we tried synthesis of 3-aminoimidazo-
[1,2-a]pyridines via the three-component condensation
of aldehydes, 2-aminopyridines and isonitriles in the
The replacement of these conventional hazardous
*
E-mail: mmh1331@yahoo.com; Tel.: 00982188041344; Fax: 00982188047861
Received April 14, 2009; revised August 24, 2009; accepted September 14, 2009.
Chin. J. Chem. 2010, 28, 299— 302
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
299

Oskooie et al.
FULL PAPER
Scheme 2
out without any catalyst, when no product was observed
even though the reaction time prolonged. We have re-
cently used heteropolyacids as green and reusable cata-
lyst. The higher activity of HPA than conventional in-
organic and organic acids has been observed.
The performance of HPA has been compared with
other catalysts used in previous procedures (Table 2). As
it can be seen, these heteropolyacids are more effective
than other catalysts,7 being compared economically and
environmentally attractive and effective catalysts for
various reactions and having high capability in practical
uses.23
The efficiency of various heteropolyacids has also
been compared (Table 2). Two types of HPA including
Preyssler, H14[NaP5W30O110] and Keggin, H3[PMo12-
O40], H6 [PMo9V3O40] and H4[PMo9V3O40] were se-
lected as the catalyst for this reaction. The yield of
product decreased in the following order:
presence of heteropolyacid (H3PMo12O40) as a promoter
at room temperature, under solvent free condition
(Scheme 2).
As indicated in Table 1 the reaction of aldehydes
with 2-amino-5-methylpyridine or 2-amino-5-bromo-
pyridine and isonitriles gave quantitative yields.
This MCR reaction presumably proceeds via an in-
termediate imine formed from 2-amino-5-methylpyri-
dine or 2-amino-5-bromopyridine, which is attacked by
an isonitrile to give nitrilium ion21 I, which then
undergoes intramolecular cyclization affording 3-
aminoimidazo[l,2-a]pyridines at room temperature
(Scheme 3).
H [PMo O ] H14 [NaP5W30O110
]
＞
＞
3
12 40
H [PMo V O ] H4[PMo9V3O40]
＞
6
9
3
40
Comparison of H3 [PMo12O40], H14 [NaP5W30O110],
H6[PMo9V3O40] and H4[PMo9V3O40] showed that the
higher activity could be achieved with H3[PMo12O40]. It
is noteworthy to mention that all derivatives were ob-
tained from H3[PMo12O40].
Scheme 3
Reusability of the catalyst
We investigated the reusability and recycling of het-
eropolyacids at the end of reaction. The catalyst could
be recovered by a simple filtration. The recycled cata-
lyst could be washed with methanol and subjected to the
second run of the reaction process. To assure that cata-
lysts were not dissolved in methanol, the catalysts were
weighed after filtration and before reuse for the next run.
The results show that these catalysts are not soluble in
methanol. In Table 3, the comparison of efficiency of
H3PMo12O40 in synthesis of 4a for four times is reported.
As it is shown in this Table the first used recovered
H3PMo12O40 afforded a similar yield to that obtained in
the first run. In the third and fourth runs, the yield was
gradually decreased.
This method not only affords the products in excel-
lent yields but also avoids the problems associated with
previous methods such as cost, hazards and pollution.
We have also studied the effects of various catalysts
in this article. At the first stage, the reaction was carried
Table 1 Synthesis of 3-aminoimidazo[l,2-a]pyridines in the presence of H3PMo12O40
m.p./℃
Entry
R1
Ph
R2
R3
Product
Time/min
Yielda/%
Found
209
180
208
205
208
216
210
218
Reported22
1
2
3
4
5
6
7
8
Br
H
Cyclohexyl
tert-Butyl
4a
4b
4c
4d
4e
4f
20
20
20
15
25
20
20
25
98
91
96
98
90
96
90
90
207—208
New compound
206—208
203—205
208—210
216—218
210—213
217—220
Ph
Ph
Br
tert-Butyl
Ph
Me
Me
Me
Me
Me
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Butyl
3-O2NC6H4
4-CH3C6H4
4-ClC6H4
Ph
4g
4h
a Yields were obtained by GC.
300
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Chin. J. Chem. 2010, 28, 299— 302

One-pot Synthesis of 3-Aminoimidazo[1,2-a]pyridines
Table 2 Effect of catalyst on the synthesis of 4a
500 MHz) δ: 1.08 [s, 9H, C(CH3)3], 3.15 (s, 1H, NH),
6.78—6.82 (m, 1H, H-Ar), 7.15—718 (m, 1H, H-Ar),
7.30—7.37 (m, 1H, H-Ar), 7.45—7.48 (m, 2H, H-Ar),
7.57—7.59 (m, 1H, H-Ar), 7.94—7.95 (m, 2H, Ar-H),
8.26—8.28 (m, 1H, －Ar-H). IR (KBr) v: 3316 (NH),
Entry
Catalyst
H3[PMo12O40]
H14[NaP5W30O110
H6[PMo9V3O40]
H4[PMo9V3O40]
H2SO4/SiO2
H2SO4
Yield/%
98
Solvent Time
1
2
3
4
5
6
7
8
—
—
20 min
3 h
]
75
＋
1
65
—
4 h
2960, 1629, 1612 cm ; MS m/z (%): 266 (M ＋1, 22),
265 (MH＋, 32), 208 (56), 181 (100), 149 (83), 78 (52),
57 (26).
35
—
5 h
55
CH3OH
CH3OH
CH3OH
CH3OH
3 h
N-Cyclohexyl-6-methyl-2-phenylimidazo[1,2-a]pyri-
10
24 h
24 h
5 h
1
din-3-amine (4d): Yield 96%, m.p. 205 ℃ (dec); H
HCl
30
NMR (DMSO-d6, 300 MHz) δ: 1.06—1.74 (m, 10H,
5CH2 of cyclohexyl), 2.40 (s, 3H, CH3), 2.84 [m, 1H,
NCH(CH2)5], 5.16 (s, 1H, NH), 7.36—7.64 (m, 5H,
CH3COOH
36
3
Table 3 Reuse of H3PMo12O40 for synthesis of 4a
H-Ar), 8.10 (d, J＝7.6 Hz, 2H, H-Ar), 8.37 (1H, s,
－1
H-Ar); IR (KBr)＋v: 3195 (NH), 2925, 1613 cm ; MS
Entry
Run
1, 2
3
Yield/%
98
m/z (%): 306 (M ＋1, 71), 305 (M＋, 73), 222 (87), 195
1
2
3
(100), 92 (87), 65 (62), 55 (45), 41 (31).
94
4
90
Conclusion
a Yields were obtained by GC.
In conclusion, we have developed a rapid and effi-
cient method for the synthesis of 3-aminoimidazo[1,2-
a]pyridines using heteropolyacids as heterogeneous
catalyst. This method involves several advantages in-
cluding the simplicity of performance, effortless
work-up, eco-friendly, easily available and easily han-
dled catalyst. Additionally the method does not require
volatile and hazardous organic solvents. High yields of
products and relatively short reaction time are other ad-
vantages of the method.
Experimental
Chemical and apparatus
All the chemicals were obtained from Merck Com-
pany and used as received. Heteropolyacids were pre-
pared according to the literature.19,24-26 All products are
known compounds and were characterized by mp, IR,
1H NMR and GC/MS. Melting points were measured by
using the capillary tube method with an electrothermal
1
9200 apparatus. H NMR spectra were recorded on a
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Chin. J. Chem. 2010, 28, 299— 302