P2O5 Promoted One-Pot Synthesis of 3-aminoimidazo[1,2-a]pyridines under Solvent-Free Conditions

Article abstract of DOI:10.2174/157017812800167411

A facile, efficient and environment-friendly protocol for the synthesis of 3-aminoimidazo[1,2-a]pyridines has been developed by one-pot condensation of 2-aminopyridine, aromatic aldehyde and alkyl or aryl isocyanide in the presence of P₂O₅

Full text of DOI:10.2174/157017812800167411

198
Letters in Organic Chemistry, 2012, 9, 198-201
P2O5 Promoted One-Pot Synthesis of 3-aminoimidazo[1,2-a]pyridines
under Solvent-Free Conditions
Ebrahim Soleimani*,a, Mojtaba Taranb, Mohsen Zainalia and Shahram Lotfic
aDepartment of Chemistry, Razi University, Kermanshah 67149, Iran
bDepartment of Biology, Razi University, Kermanshah 67149-67346, Iran
cDepartment of Chemistry, Payame Noor University (PNU), Iran
Received September 06, 2011: Revised October 11, 2011: Accepted October 25, 2011
Abstracts: A facile, efficient and environment-friendly protocol for the synthesis of 3-aminoimidazo[1,2-a]pyridines has
been developed by one-pot condensation of 2-aminopyridine, aromatic aldehyde and alkyl or aryl isocyanide in the
presence of P2O5 as catalyst under solvent-free conditions at room temperature. The present approach offers the
advantages of clean reaction, simple methodology, short reaction time, high yield, easy purification, and economic
availability of the catalyst.
Keywords: Imidazo[1,2-a]pyridine, P2O5, 2-Aminopyridine, Isocyanide.
INTRODUCTION
We report the synthesis of 3-aminoimidazo[1,2-a]pyridines 4
by three-component condensation of an 2-aminopridine 1, an
aldehyde 2, and an isocyanide 3 in the presence of catalytic
amounts of P2O5 as an inexpensive catalyst in excellent
yields at room temperature (Scheme 1).
Imidazo[1,2-a]pyridines, an important class of
pharmaceutical compounds exhibit a wide spectrum of
biological activities [1, 2]. The classical synthesis of
imidazo[1,2-a] annulated pyridines, pyrimidines and
pyrazines involves the condensation of ꢀ-haloketones with 2-
aminopyridines, pyrimidines and pyrazines [3, 4]. Being only
a two-component condensation, this reaction is less suitable
for the generation of a large compound library. Recently,
several isocyanide-based multi-component reactions (MCRs)
have been reported for the synthesis of these compounds by
the condensation of an aldehyde, an isocyanide and a 2-
aminopyridine in the presence of a strong protic acid [5, 6]
or Lewis acid [7-10] and montmorillonite K10 [11].
However, these methods show varying degrees of success as
well as limitations such as prolonged reaction times, low
yields, use of toxic solvents, requirement of excess of
reagents/catalysts, laborious work-up procedures, the
requirement of special apparatus, or harsh reaction
conditions. Thus, the development of an alternate milder and
clean procedure is highly demanding for the synthesis of
Imidazo[1,2-a]pyridines, which surpasses those limitations.
The use of phosphorous pentoxide has given many
advantages in organic synthesis. P2O5 is mild and selective
catalyst, easy to handle and readily biodegradable, which has
earlier been used widely in various organic transformations
such as Beckmann rearrangement [12], olefin dimerisation
[13], tetrahydropyranylation of alcohols [14] and formation
of benzoxanthenes [15].
RESULTS AND DISCUSSION
We first investigated the catalytic activities of various
catalysts, which promoted the model reaction of 2-
aminopyridine (1 mmol), benzaldehyde (1 mmol) and
cyclohexyl isocyanide (1 mmol) under solvent-free
condition. In the course of this study, we found that P2O5
was the most effective catalyst producing 3-
aminoimidazo[1,2-a]pyridines in higher yields than other
catalysts, which furnished the product in lower yields. In the
absence of catalyst, the yield of the product was found to be
very low. We also studied the model reaction catalyzed by
P2O5 (10 mol%) at different temperatures. The reaction rate
was unchanged as the reaction temperature was raised. When
it was carried out at room temperature, the maximum yield
was obtained in a short reaction period. To evaluate the
effect of catalyst concentration, the model reaction was
carried out in the presence of different amounts of catalyst
(1, 5, 10 and 15 mol%) at room temperature. The results
showed that 10 mol% of catalyst were sufficient to achieve a
fairly high yield (Table 1).
This encouraged us to study the scope of the reaction
under the optimized reaction parameters in the presence of
10 mol% of catalyst under solvent-free condition at room
temperature. The results of using P2O5 as a catalyst in the
multicomponent reaction of 2-aminopyridnes, aromatic
aldehydes and isocyanides are summarized in Table 2. A
variety of aromatic aldehydes, 2-aminopridine as 2-
aminopyridine, 5-bromo-2-aminopyridine and 5-methyl-2-
aminopyridine with different isocyanides, including
cyaclohexyl isocyanide, tert-butyl isocyanide and 1,1,3,3-
In connection with our previous work on the synthesis of
3-aminoimidazo[1,2-a]pyridines [16-19]and our interest in
isocyanide-based multicomponent reactions (MCRs) [20].
*Address correspondence to this author at the Department of Chemistry,
Razi University, Kermanshah 67149, Iran; Tel/Fax: 0098-831-4274559;
E-mails: e_soleimanirazi@yahoo.com, e-soleimani@razi.ac.ir
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

P2O5 Promoted One-Pot Synthesis of 3-aminoimidazo[1,2-a]pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
199
O
NH2
N
P2O5
H
R3
N
C
+
R2
+
r.t., 1 h
N
N
R2
R1
R1
HN
4
R3
1
2
3
Scheme 1.
Table 1. Optimization Amount of P2O5 Catalyst and Reaction Temperature
NH2
N
CHO
P2O5
1 h
+
+
N
C
N
N
HN
4c
1
2
3
Entry
P2O5 (mol%)
Temperature (˚C)
Yield (%)
1
2
3
4
5
6
7
8
0
25
25
25
25
25
50
70
90
44
50
80
94
95
95
95
94
1
5
10
15
10
10
10
Table 2. Synthesis of 3-aminoimidazo[1,2-a]pyridines in the Presence of P2O5 Under Solvent-Free Condition at Room Temperature
Entry
R1
R2
R3
Product
Yield (%)
1
2
Me
Br
H
H
H
Cy
4a
4b
4c
4d
4e
4f
97
94
94
93
92
90
98
90
96
86
95
90
Cy
3
H
Cy
4
H
4-CH3O
3-NO2
4-Cl
4-CH3
4-CH3
H
Cy
5
Me
Me
Me
Me
Br
Br
Br
H
Cy
6
Cy
Cy
7
4g
4h
4i
8
2,6-(Me)2C6H3
tert-Butyl
9
10
11
12
3-NO2
H
Cy
4j
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
4k
4l
4-CH3
tetramethylbutyl isocyanide were submitted to these reaction
conditions, and the desired products were obtained in good
to excellent yields.
pot condensation of aldehydes, 2-aminopridines and
isocyanides under solvent-free conditions at room
temperature. The main advantages of this method are mild,
clean and solvent-free reaction conditions, good to excellent
yields and an environmentally benign catalyst. This reaction
system not only provides a novel method for the synthesis of
biologically important 3-aminoimidazo[1,2-a]pyridines but
also is an environmentally friendly chemical process and
biodegradable.
CONCLUSION
In conclusion, P2O5 is a highly efficient acid catalyst for
the synthesis of 3-aminoimidazo[1,2-a]pyridines by the one-

200 Letters in Organic Chemistry, 2012, Vol. 9, No. 3
Soleimani et al.
ACKNOWLEDGEMENTS
EXPERIMENTAL SECTION
We gratefully acknowledge financial support from the
Iran National Science Foundation (INSF) and Research
Council of Razi University.
General Procedure for the Synthesis of 3-aminoimidazo
[1,2-a]pyridines 4a-l
To a mixture of 2-aminopyridines (1 mmol), aldehydes (1
mmol) and isocyanides (1 mmol) was added P2O5 (0.1
mmol). The resulting mixture was stirred for 1 h at room
temperature. After completion of the reaction, as indicated
by TLC (ethyl acetate/n-hexane, 2:1), the reaction mixture
was washed with water (2ꢀ10 ml) and the solid residue was
crystallized from ethyl acetate to give pure product.
CONFLICT OF INTEREST
Declared none.
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1
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1
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1
336 (M++1), 335, 278, 222, 197, 92, 78, 57. H NMR (200
[15]
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P2O5 Promoted One-Pot Synthesis of 3-aminoimidazo[1,2-a]pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 3
201
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