One-pot synthesis of 2-phenylimidazo[1,2-α]pyridines from acetophenone, [Bmim]Br3 and 2-aminopyridine under solvent-free conditions

Article abstract of DOI:10.3390/molecules171113368

One-pot synthesis of 2-phenylimidazo[1,2-α]pyridines from acetophenone, [Bmim]Br₃ and 2-aminopyridine under solvent-free conditions in the presence of Na₂CO₃, gave the corresponding 2-phenylimidazo[1,2-α]pyridines in excel

Full text of DOI:10.3390/molecules171113368

Molecules 2012, 17, 13368-13375; doi:10.3390/molecules171113368
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
One-Pot Synthesis of 2-Phenylimidazo[1,2-α]pyridines from
Acetophenone, [Bmim]Br and 2-Aminopyridine under
3
Solvent-Free Conditions
Zhang-Gao Le *, Zong-Bo Xie and Jian-Ping Xu
Department of Applied Chemistry, East China Institute of Technology, Fuzhou 344000, China
*
Author to whom correspondence should be addressed; E-Mail: lezhang_ecit@163.com;
Tel.: +86-794-825-8832; Fax: +86-794-825-6673.
Received: 24 September 2012; in revised form: 24 October 2012 / Accepted: 26 October 2012 /
Published: 9 November 2012
Abstract: One-pot synthesis of 2-phenylimidazo[1,2-α]pyridines from acetophenone,
3 2 3
[Bmim]Br and 2-aminopyridine under solvent-free conditions in the presence of Na CO ,
gave the corresponding 2-phenylimidazo[1,2-α]pyridines in excellent yields ranging
from 72% to 89%.
Keywords: imidazo[1,2-α]pyridine; aromatics; 2-aminopyridine; [Bmim]Br
3
1
. Introduction
Imidazo[1,2-α]pyridines are of interest because of the occurrence of their saturated and partially
saturated derivatives in a variety of biologically active compounds, which have been shown to possess
a broad range of useful pharmacological properties [1], including anti-inflammatory [2,3],
antiprotozoal [4], antiviral [5–7], antiulcer [8,9], antibacterial [10,11], antifungal [12], antiprotozoal [4,13],
antiherpes [14,15] and treatment of hepatitis C [16], and HIV [17], etc. They are also versatile
intermediates for synthetic transformations [18,19].
Various methods have been reported for the synthesis of substituted imidazo[1,2-a]pyridines. The
most important approaches embrace [20]: (1) condensation of 2-aminopyridine with α-halocarbonyl
compounds [21–24], (2) one-pot condensations of isocyanide, aldehydes, and 2-aminopyridines [25–27],
and (3) three-component reactions of 2-aminopyridines, aldehydes, and alkynes [28–30]. Although
new methods are being published continuously, the synthesis of imidazo[1,2-α]pyridines using
2
-aminopyridines with α-haloketones and α-haloaldehydes is still the most popular [31,32]. There are

Molecules 2012, 17
13369
however two intrinsic limitations to this methodology, namely, the small variety of commercially
available α-halocarbonyl compounds and their lachrymatory properties. Generally, α-bromoketones
can be obtained by reaction of ketones with various reagents such as bromine [33], copper (ІІ)
bromide [34], dioxane dibromide [35], polymer-supported pyridinium bromide perbromide [36],
and N-bromosuccinimide [37], etc. All these methods involve the use of expensive reagents and
harmful organic solvents, long reaction times, high temperatures and sometimes only give poor yields,
so we report here a simple, efficient method for a mild one-pot synthesis of 2-phenylimidazo[1,2-
α]pyridines from acetophenone, [Bmim]Br and 2-aminopyridine (Scheme 1).
3
Scheme 1. Synthesis of 2-phenylimidazo[1,2-α]pyridines from acetophenone, [Bmim]Br
3
and 2-aminopyridine.
N
O
R1
NH2
[Bmim]Br3
R2
+
R3
N
R2
Na CO
3
2
R1
N
R3
1
2
3
2
. Results and Discussion
Firstly, we found that the reaction of acetophenone, 1-butyl-3-methylimidazolium tribromide
[Bmim]Br ) and 2-aminopyridine proceeds smoothly in the presence of Na CO at room temperature
(
3
2
3
to form 2-phenylimidazo[1,2-α]pyridine in 82% yield (Table 1, entry 1). In a similar fashion, a variety
of acetophenones reacted smoothly with [Bmim]Br and 2-aminopyridines under these reaction
3
conditions to give the corresponding substituted 2-phenylimidazo[1,2-α]pyridines. The results are
summarized in Table 1.
Table 1. Synthesis of 2-phenylimidazo[1,2-α]pyridines from acetophenone, [Bmim]Br
3
a
and 2-aminopyridine under solvent-free conditions .
1
2
3
b
Entry
R
R
R
Product
3a
Yield (%)
Mp (°C)
136–137
144–145
134–135
164–165
201–202
182
Lit. mp (°C)
136–137 [24]
144–145 [38]
135–136 [24]
165–166 [39]
201 [40]
181–182 [24]
215–216 [41]
159–161 [24]
204–206 [24]
223–224 [38]
234–236 [24]
191–192 [38]
205–207 [24]
171–173 [24]
179–181 [24]
239–240 [24]
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
C
6
H
5
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
82
77
75
89
86
72
87
77
81
80
75
78
77
76
84
81
p-MeC
p-MeOC
p-FC
p-ClC H4
6
H
4
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
6
H
4
6
H
4
6
2,4-Cl
p-BrC
C H
C
2
C
6
H
3
6
H
4
216
6
5
160–161
205–206
224–225
236–237
191–192
206–207
172–173
181–182
140–141
6
H
5
1
1
1
1
1
1
1
0
1
2
3
4
5
6
p-MeC
6
H
4
p-MeOC H4
6
p-FC
p-ClC
C H
6
H
4
6
H
4
Me
Me
Me
6
5
p-MeOC
p-ClC
6 4
H
6
H
4
3p
a
All reaction were run with acetophenone (2 mmol), [Bmim]Br
3
(2 mmol), Na
2
CO
3
(1.1 mmol) and
b
2
-aminopyridine (2.4 mmol) at r. t. Isolated yield.

Molecules 2012, 17
13370
1
All the products gave satisfactory m.p., and H-NMR spectra which were consistent with the
literature data. As can be seen from Table 1, the reaction is general and applicable to acetophenones
bearing various groups such as methyl, methoxy, fluoro, chloro, bromo, etc. (Table 1, entries 1–7). On
the basis of these results, we extended our method to propiophenone. We found that this synthesis can
also be performed in high yield (Table 1, entry 8). The experimental procedure is very simple and
convenient. All of the tested reactions could complete within 40 min.
In order to explore the generality of the method, we conducted experiments with 2-amino-5-
chloropyridine, 2-amino-5-methylpyridine and a variety of acetophenones containing different groups,
such as methyl, methoxy, fluoro, chloro functions, which were also effective and gave the
corresponding phenylimidazo[1,2-α]pyridine derivatives (Table 1, entries 9–16).
The present method has many obvious advantages compared to those reported in the literature,
including higher yields, shorter reaction times, and solvent free conditions, thus being environmentally
more benign. For example, the reactions of acetophenone with 2-aminopyridine by a recently reported
method [20] gave 2-phenylimidazo[1,2-α]pyridine in 55% yield after ten hours at 110 °C, but using the
present method, the same reaction was completed smoothly and gave the product with isolated yields
of 82%. Using Xie’s reported method [39], preparation of 2-(4-fluorophenyl)imidazo[1,2-α]pyridine
and 2-(4-chlorophenyl)imidazo[1,2-α]pyridine by cyclocondensation of 4-fluoroacetophenone, 4-chloro-
acetophenone with [hydroxy(tosyloxy)iodo]benzene and 2-aminopyridine in the ionic liquid (BPyBF )
4
was successful and gave yields 85% and 74%. The same reaction was completed smoothly with the
present method and gave higher yields (89%, 86%).
3. Experimental
3
.1. General
Melting points were determined on a digital melting point apparatus and are not corrected. Nuclear
magnetic resonance spectra were recorded on a Bruker AVANCE DMX 400 spectrometer in CDCl
3
using TMS as an internal standard. The ionic liquid [Bmim]Br was synthesized according to a
3
reported procedure [42]. The other materials are commercially available and were used without
further purification.
3
.2. General Procedure for the Synthesis of 2-phenylimidazo[1,2-α]pyridines
[Bmim]Br
3
(2 mmol) was very slowly added (1 drop per 5 s) to acetophenone (2 mmol) with
CO (1.1 mmol) and
-aminopyridine (2.4 mmol) were added, and the mixture was stirred at room temperature for 40 min.
continuous stirring for 5 min at room temperature (30 °C). Then Na
2
3
2
2
After the reaction completion, the reaction mixture was extracted with Et O, the ethereal layer was
concentrated by rotary evaporator, and the crude product was purified by the preparative thin-layer
chromatography on silica gel using a mixture of petroleum ether and EtOAc as developer to give the
corresponding pure products of 2-phenylimidazo[1,2-α]pyridines.

Molecules 2012, 17
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3
.3. Spectroscopic Data
-Phenylimidazo[1,2-α]pyridine (3a). H-NMR: δ = 6.77–6.79 (t, J = 6.7 Hz, 1 H), 7.16–7.19
1
2
(
m, 1 H), 7.32–7.35 (t, 1 H), 7.43–7.46 (m, 2 H), 7.63–7.65 (d, J = 9.1 Hz, 1 H), 7.86 (s, 1 H), 7.95–7.97
t, 2 H), 8.12 (d, J = 6.8 Hz, 1 H).
(
1
2
1
7
-(4-Methylphenyl)imidazo[1,2-α]pyridine (3b). H-NMR: δ = 2.39 (s, 3 H), 6.77–6.79 (t, J = 6.7 Hz,
H), 7.16–7.18 (t, J = 7.9 Hz, 1 H), 7.24–7.26 (d, J = 8.2 Hz, 2 H), 7.64–7.65 (d, J = 9.1 Hz, 1 H),
.82 (s, 1 H), 7.85–7.87 (d, J = 8.1 Hz, 2 H), 8.11 (d, J = 6.7 Hz, 1 H).
1
2
-(4-Methoxyphenyl)imidazo[1,2-α]pyridine (3c). H-NMR: δ = 3.87 (s, 3 H), 6.74–6.78 (t, J = 6.8 Hz,
1
H), 6.97–6.99 (d, J = 6.8 Hz, 2 H), 7.14–7.17 (t, J = 7.9 Hz, 1 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.78
(s, 1 H), 7.89 (d, J = 6.8 Hz, 2 H), 8.1 (d, J = 6.8 Hz, 1 H).
1
2
-(4-Fluorophenyl)imidazo[1,2-α]pyridine (3d). H-NMR: δ = 6.78–6.81 (t, J = 6.8 Hz, 1 H), 7.11–7.18
(
m, 3 H), 7.62–7.64 (d, J = 9.1 Hz, 1 H), 7.82 (s, 1 H), 7.91–7.95 (m, 2 H), 8.12 (d, J = 6.8 Hz, 1 H).
1
2
-(4-Chlorophenyl)imidazo[1,2-α]pyridine (3e). H-NMR: δ = 6.78–6.81 (t, J = 6.7 Hz, 1 H), 7.18–7.21
(
m, 1 H), 7.39–7.42 (m, 2 H), 7.61–7.64 (d, J = 9.1 Hz, 1 H), 7.84 (s, 1 H), 7.88–7.90 (m, 2 H), 8.12
d, J = 6.8 Hz, 1 H).
(
1
2
-(2,4-Dichlorophenyl)imidazo[1,2-α]pyridine (3f). H-NMR: δ = 6.80 (t, J = 6.8, 1H), 7.17–7.23
(
m, 1 H), 7.36 (dd, J = 2.0, 2.0, 1 H), 7.49-7.50 (m, 1 H), 7.62 (d, J = 9.1, 1 H), 8.14 (d, J = 6.8, 1 H),
8
.26–8.28 (m, 2H).
1
2
-(4-Bromophenyl)imidazo[1,2-α]pyridine (3g). H-NMR: δ = 6.78–6.82 (t, J = 6.7 Hz, 1 H), 7.18–7.21
(
m, 1 H), 7.55–7.57 (m, 2 H), 7.62–7.64 (d, J = 9.1 Hz, 1 H), 7.81 (s, 1 H), 7.83–7.85 (m, 2 H), 8.11
d, J = 6.8 Hz, 1 H).
(
1
3
1
1
-Methyl-2-phenylimidazo[1,2-α]pyridine (3h). H-NMR: δ = 2.64 (s, 3 H), 6.85–6.88 (t, J = 6.8 Hz,
H), 7.16–7.19 (t, J = 7.9 Hz, 1 H), 7.34–7.37 (m, 1 H), 7.45–7.49 (m, 2 H), 6.64–6.67 (d, J = 9.1 Hz,
H), 7.79–7.82 (m, 2 H), 7.91 (d, J = 6.8 Hz, 1 H).
1
6
-Chloro-2-phenylimidazo[1,2-α]pyridine (3i). H-NMR: δ = 7.15 (d, J = 9.4, 1H), 7.34 (d, J = 7.2,
1
H), 7.38-7.51 (m, 2 H), 7.57 (d, J = 9.1, 1 H), 7.82 (s, 1 H), 7.95 (d, J = 7.3, 2 H), 8.16 (s, 1 H).
1
6
-Chloro-2-(4-methylphenyl)imidazo[1,2-α]pyridine (3j). H-NMR: δ = 2.39 (s, 3 H), 7.1(d, J = 9.6 Hz,
1
H), 7.23 (d, J = 7.8, 2 H), 7.54 (d, J = 9.6, 1 H), 7.74(s, 1 H), 7.80 (d, J = 8.1 Hz, 2 H), 8.10 (s, 1 H).
1
6
-Chloro-2-(4-methoxyphenyl)imidazo[1,2-α]pyridine (3k). H-NMR: δ = 3.87 (s, 3 H), 7.00 (dd,
J = 2.0, 2.0, 2 H), 7.13 (dd, J = 2.0, 2.0, 1 H), 7.56 (d, J = 9.54, 1 H), 7.76 (s, 1 H), 7.88 (dd, J = 2.0,
2
.0, 2 H), 8.15-8.16 (m, 1 H).
1
6
-Chloro-2-(4-Fluorophenyl)imidazo[1,2-α]pyridine (3l). H-NMR: δ = 6.91–7.15 (m, 3 H), 7.53 (d,
J = 9.6 Hz, 1 H), 7.71 (s, 1 H), 7.85–7.91 (m, 2 H), 8.10 (dd, J = 2.1, 0.7 Hz, 1 H).

Molecules 2012, 17
13372
1
6
-Chloro-2-(4-chlorophenyl)imidazo[1,2-α]pyridine (3m). H-NMR: δ = 7.15 (dd, J = 2.0, 2.0, 1 H),
7.40–7.42 (m, 2 H), 7.55 (d, J = 9.6, 1 H), 7.76 (s, 1 H), 7.85 (dd, J = 2.0, 2.0, 2 H), 8.13–8.14 (m, 1 H).
1
6
-Methyl-2-phenylimidazo[1,2-α]pyridine (3n). H-NMR: δ = 2.30 (s, 3 H), 7.00 (d, J = 8.8, 1 H),
7
.33 (d, J = 6.4, 1 H), 7.44 (t, J = 6.6, 2 H), 7.53 (d, J = 9.1, 1 H), 7.74 (s, 1 H), 7.83 (s, 1 H), 7.97
(
d, J = 7.1, 2 H).
1
6
6
1
-Methyl-2-(4-methoxyphenyl)imidazo[1,2-α]pyridine (3o). H-NMR: δ = 2.33 (s, 3 H), 3.86 (s, 3 H),
.97 (dd, J = 2.1, 2.1, 1 H), 7.01 (d, J = 1.6, 2 H), 7.51 (d, J = 9.5, 1 H), 7.68 (s, 1 H), 7.87 (d, J = 2.1,
H), 7.89 (d, J = 2.1, 2 H).
1
6
-Methyl-2-(4-chlorophenyl)imidazo[1,2-α]pyridine (3p). H-NMR: δ = 2.34 (s, 3 H), 7.05 (d, J = 9.3,
1
H), 7.39 (d, J = 8.5, 2 H), 7.54 (t, J = 6.0, 1 H), 7.76 (s, 1 H), 7.88 (s, 1 H), 7.90 (d, J = 2.8, 2 H).
4
. Conclusions
In conclusion, we have demonstrated that the synthesis of 2-Phenylimidazo[1,2-α]pyridines from
acetophenone, [Bmim]Br and 2-aminopyridine under solvent-free conditions in the presence of
3
2 3
Na CO , which provides a simple efficient method for the synthesis of 2-phenylimidazo[1,2-
α]pyridines. The present method has many obvious advantages compared to those reported in the
literature, including avoiding to using toxic solvent or catalyst, being environmentally more benign,
the simplicity of the methodology, the ease of product isolation, and the higher yield.
Acknowledgments
This work was financially supported by the Project of NSFC (21262002), and the Science
Foundation of JiangXi Province (2010GZH0003\20113BCB24011), the Science and Technology
Foundation of the Education Department of JiangXi Province (GJJ12370).
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