Microwave-assisted, one-pot three component synthesis of 2-phenyl H-imidazo[1, 2-α]pyridine

Article abstract of DOI:10.1155/2012/198615

A novel synthesis of 2-phenylH-imidazio[1, 2-α] pyridines is described from a one-pot, three-component reaction between pyridine, guanidine (urea or thiourea) and α-bromoketones under microwave irradiation and solvent-free conditions in excellent yields.

Full text of DOI:10.1155/2012/198615

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
http://www.ejchem.net
2012, 9(3), 1047-1052
Microwave-Assisted, One-Pot Three Component
Synthesis of 2-Phenyl H-imidazo[1,2-α]pyridine
KOUROSH MOTEVALLI, ZAHRA YAGHOUBI§, AND ROGHIEH MIRZAZADEH#
 Department of Applied Chemistry, Islamic Azad University, Tehran South Branch, Tehran,
Iran
§ Industrial faculty, Islamic Azad University, Tehran South Branch, Tehran, Iran
# Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran
k_motevalli@azad.ac.ir
Received 5 November 2011; Accepted 7 January 2012
Abstract: A novel synthesis of 2-phenylH-imidazio[1,2-α] pyridines is
described from a one-pot, three-component reaction between pyridine,
guanidine (urea or thiourea) and α-bromoketones under microwave irradiation
and solvent-free conditions in excellent yields.
Keywords: Three-component reaction, Pyridine, Microwave-assisted reaction, Solvent-free.
Introduction
One-pot multicomponent reactions have emerged as an effective tool for atom economic and
benign synthesis by virtue of their convergence, productivity, facile execution, and
generation of highly diverse and complex products from easily available starting materials.1
Green chemistry emphasizes the need for environmentally clean synthesis, which involves
improvement in selectivity, high atom efficiency, elimination of hazardous reagents, and
easy separation with recovery and reuse of reagents.2 In the meantime, the utility of
microwave energy in synthetic organic chemistry has been increasingly recognized as
compared with conventional heating. Reactions promoted by microwave irradiation (MWI)
have shown an environmental friendly nature, greater selectivity, and enhanced reaction rate.
Therefore, the MWI-mediated multicomponent reaction has constituted an especially
attractive synthetic strategy for the rapid and efficient library generation.3

Kourosh Motevalli
1048
Imidazo[1,2-α] pyridines have received considerable interest from the pharmaceutical
industry because of their interesting therapeutic properties,4 including antibacterial,5
antifungal,6 antiviral,7 antiulcer,8 and anti-inflammatory behavior.9 They have also been
characterized as selective cyclin-dependent kinase inhibitors,10 calcium channel blockers,11
β
-amyloid formation inhibitors,12 and benzodiazepine receptor agonists.13 Drug formulations
containing imidazo[1,2-α] pyridines such as alpidem (anxiolytic), zolpidem (hypnotic), and
zolimidine (antiulcer) are currently available (Scheme 1). Different synthetic pathways have
been used to prepare. substituted imidazo[1,2-α] pyridines, either from the imidazole or from
the pyridine nucleus.14 Further, they have been obtained by cyclocondensation of 2-
aminopyridines with substituted phenacylbromides of α-bromoacetophenones in poor
yields.15 2-substituted-imidazo[1,2-α] pyridines have been synthesized by cyclocondensation
of alkynyl(phenyl)iodonium salts with 2-aminopyridine easily in CHCl3 under reflux in the
presence of K2CO3.16 Other methodologies included treating 2-aminopyridines with α-
tosyloxyketones,17 a polymer supported [hydroxy(sulfonyloxy)iodo]benzene with ketones or
alcohols,18 α-diazoketones,19 and propargyl bromide.20 Although these methods are suitable
for certain synthetic conditions sometimes, however, some of these procedures are
associated with one or more disadvantages such as high cost, use of stoichiometric and even
excess amounts of reagents or catalysts, long reaction time, hazardous organic solvents, low
yield, special apparatus and drastic reaction conditions, which leaves scope for further
development of new environmentally clean syntheses. Thus, there is an increasing need for
improved and newer methods of synthesis of imidazo[1,2-α] pyridines.
N
N
N
Me
SO3Me
Cl
N
N
N
Me
C3H7
Cl
C3H7
N
N
O
C3H7
O
C3H7
Zolimidine
Alpidem
Zolpidem
Scheme 1. Biologicaly relevant imidazo[1,2-a]pyridines.
In this Letter, we report a novel and efficient method for the synthesis of 2-phenylH-
imidazo[1,2-α] pyridine 4 via the coupling of pyridine 1, phenacylbromide 2 and guanidine
(urea or thiourea) 3 under microwave irradiation21 (Scheme 2).
Experimental
Chemicals and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and
were used without further purification. Microwave assisted reactions were carried out in
microwave oven (ETHOS 1600, Milestone) with a power of 600 W specially designed for
organic synthesis. Column chromatography were performed on silica Gel (0.015-0.04 mm,
mesh-size 60) and TLC on precoated plastic sheets (25 DCUV-254), respectively. Melting
points were measured on Barnstead Electrothermal melting point apparatus and were not
corrected. IR spectra were measured on aq Shimadzu FT-IR-4300 spectrophotometer as KBr
discs. 1H NMR and 13C NMR spectra were determined in CDCl3 on a Brucker 500
spectrophotometer and chemical shifts were expressed in ppm downfield from
tetramethylsilane.

Microwave-Assisted, One-Pot Three Component Synthesis 1049
General Procedure
A mixture of pyridine (1, 0.16 g, 2 mmol) and phenacylbromide (2, 0.4 g, 2 mmol) was
irradiated with microwaves at 100 °C for 1 min. After nearly complete conversion to N-
Phenacylpyridinium bromides, as was indicated by TLC, guanidine hydrochlolride (3, 0.19
g, 2 mmol) was added to reaction mixture and it was irradiated at 150 °C for a further 2-3
min with a power of 600 W (ETHOS 1600, Milestone). Then the reaction mixture was
cooled to room temperature and the residue was purified by column chromatography (1:2 n-
hexane–EtOAc as eluent, Merck silica gel 60 mesh).
2-Phenylimidazo[1,2-a]pyridine (4a)
White powder; mp 133-134 °C (lit. 131-133)19; νmax (KBr): 2926, 2855, 1741, 1625, 1515,
1465, 1370, 1269, 1205, 1145, 1080, 1032, 690 cm-1; δH (500 MHz, CDCl3): 8.10 (d, J =
6.75 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.85 (s, 1H), 7.64 (d, J = 9.11 Hz, 1H), 7.42 (t, J =
7.31 Hz, 2H), 7.32 (d, J = 7.4 Hz, 1H), 7.19 (t, J = 7.20 Hz, 1H), 6.77 (t, J = 6.75 Hz, 1H);
δc (125 MHz, CDCl3): 145.9, 145.8, 133.9, 128.7, 128, 126.2, 125.7, 124.7, 117.7, 114.4,
108.3.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (4d)
White powder; mp 208-209 (lit. 208) [18]; νmax (KBr): 2920, 1650, 1470, 1370, 1260, 1200,
1085, 1015, 950, 840, 740, 600, 514; cm-1; δH (500 MHz, CDCl3): 8.10 (d, J = 6.78 Hz, 1H),
7.90 (d, J = 8.18 Hz, 2H), 7.84 (s, 1H), 7.60 (d, J = 9.12 Hz, 1H), 7.40 (d, J = 8.18 Hz, 2H),
7.20 (t, J = 7.15 Hz, 1H), 6.78 (t, J = 6.70 Hz, 1H); δc (125 MHz, CDCl3): 145.8, 144.7,
133.7, 132, 129, 127, 125.2, 125, 118, 112.8, 108.2.
Results and Discussion
The applied solvent free reaction proceeds in 3-4 minutes to give products with high yields.
The scope and generality of this procedure is illustrated with respect to various
phenacylbromides and pyridines. The results are presented in Table 1. The structures of the
1
products were established by H NMR, 13C NMR spectroscopy and by comparison of their
spectral data and melting point values with those of the authentic samples reported in the
literature.
O
R
R
N
NH2
NH2
MW 150 0
3-4 min
C
Br
+
Ar
Ar
+
N
N
X
1
2
4
3
X=O, S, NH
Scheme 2
The proposed mechanism of the cyclization step has been outlined in Scheme 3.
Accordinglly, nucleophilic attack of pyridine 1 to phenacyl bromide 2 produces charged
species of 5 that subsequently reacts with urea 3 to produce adduct 6 that undergoes
cyclization by elimination of HBr to produce 7. At the end of process aromatization of
product 4 is obtained by elimination of formamide.

Kourosh Motevalli
1050
Table 1. Synthesis of products 4 under microwave irradiation.
M.P (°C)
Lit mp(°C)
4
a
b
c
d
e
f
Ar
R
X
O
S
Time
(min)
7
Yield
(%)
79
C6H5
H
133-134
131-13319
C6H5
H
9
5
6
7
7
6
8
5
75
80
82
85
80
82
85
85
4-MeOC6H4
4-ClC6H4
2,4-Cl2C6H3
4-FC6H4
4-NO2C6H4
4-MeC6H4
C6H5
H
O
O
S
134-135
208-209
182-184
170-172
267-269
137-138
169-171
133-13417
20818
H
H
181-18222
16924
H
O
O
S
g
h
i
H
26924
H
13723
CH3
O
172-17325,
16324
j
4-ClC6H4
4-ClC6H4
4-BrC6H4
CH3
CH3
CH3
S
O
S
5
8
8
78
85
80
242-244
215-217
240-24223
k
l
216-21725
O
O
Br
O
+
+
N
N
NH2
H2N
Br
3
1
5
2
O
O
NH2
NH2
N
-HCONH2
N
N
-HBr
N
N
N
H
Br
7
4
6
Scheme 3
Conclusion
In conclusion, we have presented a new and efficient one-pot synthesis of the 2-phenyl H-
imidazo[1,2-α]pyridine ring systems in good yields. In addition to its simplicity and solvent
free conditions, this method provides high yields of products making it a useful and

Microwave-Assisted, One-Pot Three Component Synthesis 1051
attractive strategy for the preparation of biologically relevant imidazo[1,2-α]pyridines in a
single step operation.
Acknowledgments
Support of this investigation by the Islamic Azad University Tehran south branch through
grant is gratefully acknowledged.
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Kourosh Motevalli
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