Solvent- and catalyst-free synthesis of imidazo[1,2-a]pyridines under microwave irradiation

Article abstract of DOI:10.3184/174751916X14683327937934

A facile solvent- and catalyst-free method for the synthesis of a series of imidazo[1,2-a]pyridines in good to excellent yields by the condensation of 2-aminopyridines with α-bromoketones under microwave irradiation has been developed. The important featu

Full text of DOI:10.3184/174751916X14683327937934

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 SEPTEMBER, 529–531
RESEARCH PAPER 529
Solvent- and catalyst-free synthesis of imidazo[1,2-a]pyridines under
microwave irradiation
a,b
c
c
c
b,c
b
Dulin Kong , Xianghui Wang , Zaifeng Shi , Mingshu Wu , Qiang Lin * and Xin Wang
ªSchool of Pharmaceutical Sciences, Hainan Medical University, Haikou 571199, Hainan Province, P.R. China
b
Key Laboratory of Soft Chemistry and Functional Materials, Nanjing University of Science and Technology, Ministry of Education, Nanjing 210094, P.R. China
Key Laboratory of Tropical Medicinal Plant Chemistry of the Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University,
c
Haikou 571158, P.R. China
A facile solvent- and catalyst-free method for the synthesis of a series of imidazo[1,2-a]pyridines in good to excellent yields by the
condensation of 2-aminopyridines with α-bromoketones under microwave irradiation has been developed. The important features of this
method are that it is reasonably fast, very clean, high yielding, simple workup and environmentally benign.
Keywords: imidazo[1,2-a]pyridines, microwave irradiation, catalyst-free
Imidazo[1,2-a]pyridines have attracted significant interest
among the medicinal chemistry community because of their
promising and diverse bioactivity, which includes antiviral,
included treating 2-aminopyridines with α-haloketones in polar
27
organic solvents. However, in spite of their potential utility,
many of these reported methods suffer from drawbacks such as
harsh reaction conditions, waste of solvents and catalyst which
have to be recovered, treated and disposed. Therefore, it is still
necessary to develop a more efficient method, particularly
considering today’s environmental concerns combined with
economic aspects. Microwave assisted organic reactions using
dry media have attracted much interest because of the simplicity
in operation, greater selectivity and rapid synthesis of a variety
1–3
4
5
6
7
antiulcer,
antibacterial,
anticancer,
antifungal,
and
8
antituberculosis properties. This class of compounds has also
been described as cyclin-dependent kinase (CDK) inhibitors,
calcium channel blockers, and GABA receptor modulators.
9
10
11
A
Importantly, some synthetic drugs that contain this
imidazo[1,2-a]pyridine have been commercialised such as the
1
2
13
14
sedative Zolpidem, the anxiolytic Alpidem or Saridipem,
2
8
of heterocyclic compounds. We describe a focused microwave
assisted solvent and catalyst-free method for the synthesis of
imidazo[1,2-a]pyridines from different 2-aminopyridines with
various α-bromoketones (Scheme 1).
15
and the heart-failure drug Olprione (Fig. 1).
The typical procedure for the synthesis of these compounds
involves a condensation reaction of an α-bromocarbonyl
compound with 2-aminopyridine derivatives in neutral, weak
1
6–24
basic organic solvents at elevated temperature.
compounds were also synthesised by using solid support
These
Results and discussion
We initially chose the reaction of α-bromoacetophenone
2
5
26
catalysts such as Al O and TiCl4. Other methods have
(1 mmol) with 2-aminopyridine (1 mmol) in ethanol under
2
3,
catalyst-free conditions at 65 °C as a model reaction (Table 1,
entry 2). To optimise the reaction, several solvents and thermal or
microwave heating conditions were investigated for the reaction
of 2-aminopyridine with α-bromoacetophenone. Among the
solvent mediated reactions, water was found to be suitable
under microwave irradiation and gave 2-phenylimidazo[1,2-a]
pyridine in 82% yield. To our delight, microwave irradiation at
N
N
Cl
Me
N
N
Cl
Me
O
O
n-Pr
n-Pr
Me
Me
65 °C (100 W) of the neat reagents gave 2-phenylimidazo[1,2-a]
Alpidem
Zolpidem
pyridine in 90% yield (Table 1, entry 4). It was observed that
the mixture was initially in the solid state, and then turned to a
liquid during the process of stirring, and then finally solidified
to a light yellow solid mass.
With the best reaction condition in hand, the scope and
limitation of the reaction were examined (Table 2). As
expected, the reaction proceeded smoothly with yields ranging
from good to excellent and tolerated various functional groups
such as fluoro, chloro, methyl and methoxy groups. As shown
in Table 2, the α-bromoacetophenone with electron-rich
N
Me
HN
N
O
N
Me
N
N
NC
O
n-Pr
Saripidem
Olprinone
Fig. 1 The drugs containing imidazo[1,2-a]pyridine unit.
O
R1
N
Br
N
R2
R1
Catalyst- and solvent-free
NH2
+
o
N
MW, 65 C
R2
Scheme 1 Synthesis of imidazo[1,2-a]pyridine derivatives from α-2-aminopyridine.
*
Correspondent. E-mail: linqianggroup@163.com

530 JOURNAL OF CHEMICAL RESEARCH 2016
a
Table 1 Optimisation of the reaction conditions
Table 2 Synthesis of imidazo[1,2-a]pyridinepyrazoles under microwave
irradiation
a
O
N
Br
N
R
Catalyst- and solvent-free
O
N
N
NH2
+
R
Catalyst- and solvent-free
MW, 65 o
N
NH2
+
Br
Ar
C
Ar
MW, 65 o
N
C
a
b
1
2
3
Entry Solvent
Conditions
Thermal
Thermal
Thermal
MWI
MWI
MWI
MWI
Time/min
Yields/%
51
b
Entry
R
Ar
Time/min Product Yields/%
1
2
3
4
5
6
7
Toluene
C H OH
Neat
Neat
CCl4
8
8
60
15
8
1
2
3
4
5
6
7
8
9
H
H
H
H
4-Me
4-Me
4-Me
4-Me
5-Cl
5-Me
C6H
15
20
8
20
20
18
20
18
20
15
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
85
90
86
85
83
86
84
85
86
58
80
90
57
77
73
5
2
5
4-CN–C6H
4
4-CH O–C H
2-F–C6H
4
3
6
4
4
C6H
5
Water
THF
8
8
4-CH O–C H
3
6
a
4-CN–C6H4
2-F–C6H4
C6H5
Reaction conditions: All microwave and thermal reactions performed at 65 °C. These
microwave reactions performed at 100 W and 1 bar pressure.
b
Isolated yields after purification.
10
C6H5
3j
a
Reaction conditions: All microwave reactions performed at 100 W, 65 °C and 1 bar
functionality as well as electron-poor functionality underwent
the condensation reaction with 2-amino-4-methylpyridine,
pressure.
Isolated yields after purification.
b
2
2
-amino-5-methylpyridine, 2-amino-5-chloropyridine and
-aminopyridine equally well to afford the corresponding
products in good to excellent yields.
(
400 MHz, CDCl ): δ 8.09 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H),
3
Conclusion
7.88 (s, 1H), 7.64 (d, J = 8 Hz, 2H), 7.59 (d, J = 9.2 Hz, 1 H), 7.18 (t,
J = 7.2 Hz, 1H), 6.78 (t, J = 6.4 Hz, 1H); C NMR (100 MHz, CDCl ):
δ 145.8, 143.5, 138.2, 132.5, 126.3, 125.8, 125.5, 119.1, 117.7, 113.1,
1
13
In summary, we have described a simple, highly efficient, and
facile procedure for the synthesis of imidazo[1,2-a]pyridine
derivatives from the readily available starting materials.
To the best of our knowledge, this is the first report of a
solvent- and catalyst-free synthesis of imidazo[1,2-a]pyridines
under microwave irradiation. The procedure offers simple
experimental procedure, short reaction time, low cost, efficient
yield and mild reaction conditions, which makes this method
a useful and attractive strategy in view of its economic and
environmental advantages.
3
10.9, 109.6.
2
-(4-Methoxyphenyl)H-imidazo[1,2-a]pyridine (3c): White solid,
2
2
–1
m.p. 136–137 °C (lit. 133–134 °C); IR (cm ): n 2988, 1607, 1547,
1
4
479, 1365, 1281, 1242, 1172, 1107, 1025, 924, 836, 741, 629, 531,
1
41. H NMR (400 MHz, CDCl ): δ 7.94 (d, J = 6.8 Hz, 1H), 7.82 (d,
3
J = 8.4 Hz, 2H), 7.63 (s, 1H), 7.54 (d, J = 9.2 Hz, 1H), 7.06 (t, J = 7.6
Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.63 (t, J = 6.8 Hz, 1H), 3.77 (s, 3H);
13
C NMR (100 MHz, CDCl ): δ 159.5, 145.6, 145.5, 127.2, 126.5, 125.5,
3
1
24.4, 117.1, 114.1, 112.1, 107.3, 55.3.
2
-(2-Fluorophenyl)imidazo[1,2-a]pyridine (3d): White solid;
Experimental
All compounds were fully characterised by spectroscopic data.
The NMR spectra were recorded on Brucker 400 and 500 NMR
instrument, chemical shifts (δ) are expressed in ppm, and
values are given in Hz, and CDCl was used as the solvent. The
2
9
–1
m.p. 114–115 °C (lit. 112–113 °C); IR (cm ): n 3046, 1625, 1580,
542, 1479, 1361, 1248, 1204, 1067, 937, 824, 744, 517, 470. H NMR
500 MHz, CDCl ): δ 8.35–8.38 (m, 1H), 8.12 (d, J = 6.5 Hz, 1H),
.05 (d, J = 4.0 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.27–7.32 (m, 2H),
1
1
(
8
3
J
13
3
7.13–7.19 (m, 2H), 6.77 (t, J = 7.0 Hz, 1H). C NMR (125 MHz,
microwave assisted reactions have been carried out in a Biotage
Initiator instrument. The reactions were monitored by thin layer
chromatography (TLC) using silica gel GF254. The melting points
were determined on an XT-4A melting point apparatus and are
uncorrected. All chemicals and solvents were used as received without
further purification unless otherwise stated. Column chromatography
was performed on silica gel (200–300 mesh). Elemental analyses were
performed on a Yanagimoto MT3CHN recorder.
CDCl ): δ 161.4, 159.4, 145.0, 139.3, 129.1, 129.0, 128.9, 125.8, 125.0,
3
1
24.6, 121.7, 121.6, 117.5, 115.8, 115.6, 112.5, 112.3, 112.1.
-Methyl-2-phenylimidazo[1,2-a]pyridine (3e): White solid, m.p.
162–164 °C (lit.30 162–164 °C); IR (cm–
): n 3067, 1639, 1503, 1434,
1360, 1241, 1151, 1059, 1023, 922, 862, 779, 713, 599, 496. H NMR
7
1
1
(500 MHz, CDCl ): δ 7.91–7.93 (m, 3H), 7.72 (d, J = 2.5 Hz, 1H), 7.41
3
(t, J = 7.5 Hz, 2H), 7.35 (s, 1H), 7.28–731 (m, 1H), 6.54–6.56 (m, 1H),
13
2.36 (s, 3H). C NMR (125 MHz, CDCl ): δ 146.2, 145.6, 135.6, 134.0,
3
A vial containing a mixture of 2-aminopyridine (1) (1 mmol), and
α-bromoketone (2) (1 mmol) was placed in a microwave synthesiser.
The vial was subjected to microwave irradiation programmed at 65 °C,
128.8, 127.9, 126.0, 124.9, 115.9, 115.1, 107.6, 21.5.
2-(4-Methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (3f): White
3
1
–1
solid, m.p. 157–159 °C (lit. 160 °C); IR (cm ): n 2905, 1640, 1605,
120 W and 1 bar pressure. After 15–20 min of irradiation, the mixture
1481, 1445, 1364, 1300, 1243, 1169, 1017, 828, 780, 741, 706, 594, 523,
436. H NMR (400 MHz, CDCl ): δ 7.82–7.87 (m, 3H), 7.59 (s, 1H),
7.32 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 6.8 Hz, 1 H), 3.80 (s,
3H), 2.33 (s, 3H); C NMR (100 MHz, CDCl ): δ 159.4, 146.0, 145.4,
135.3, 127.1, 126.7, 124.6, 115.6, 114.7, 114.0, 106.6, 55.3, 21.3.
1
was cooled to room temperature. The crude product (3) was subjected
to column chromatography on alumina (solvent: dichloromethane) to
obtain the pure products.
3
13
3
2
-Phenylimidazo[1,2-a]pyridine (3a): White solid, m.p. 135–136 °C
2
2
–1
(
lit. 131–133 °C); IR (cm ): n 3126, 3066, 1629, 1472, 1363, 1268,
200, 1139, 1073, 1023, 920, 742, 500. H NMR (500 MHz, CDCl ): δ
.05–8.06 (m, 1H), 7.98–7.95 (d, J = 8 Hz, 2H), 7.81 (s, 1H), 7.61 (d, J =
Hz, 1H), 7.42 (t, J = 8 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.11–7.15 (m,
4-(7-Methylimidazo[1,2-a]pyridin-2-yl)benzonitrile (3g): White
1
23
–1
1
8
9
1
solid, m.p. 201–202 °C (lit. 201–203 °C); IR (cm ): 3036, 2215, 1640,
1603, 1476, 1411, 1369, 1250, 1166, 1108, 849, 801, 742, 703, 550, 428.
3
1
H NMR (400 MHz, CDCl ): δ 7.95 (t, J = 8.4 Hz, 3H), 7.79 (s, 1H),
3
13
H), 6.71–6.74 (m, 1H). C NMR (125 MHz, CDCl ): δ 145.9, 146.8,
7.63 (d, J = 8.4 Hz, 2H), 7.33 (s, 1H), 6.60–6.62 (m, 1 H), 2.37 (s, 3H);
3
13
133.9, 128.8, 128.1, 126.1, 125.7, 124.7, 117.6, 112.5, 108.2.
C NMR (100 MHz, CDCl ): δ 146.4, 143.3, 138.5, 136.5, 132.4, 126.2,
3
4
-(H-imidazo[1,2-a]pyridin-2-yl)benzonitrile (3b): White solid,
124.9, 119.1, 116.0, 115.7, 110.7, 109.0, 21.4.
2
3
–1
m.p. 209–210 °C (lit. 210–211 °C); IR (cm ): n 3039, 2214, 1601,
596, 1473, 1410, 1364, 1179, 842, 756, 707, 550, 433. H NMR
2-(2-Fluorophenyl)-7-methylimidazo[1,2-a]pyridine (3h): White
1
–1
1
solid, m.p. 118–120 °C; IR (cm ): n 3441, 2915, 1642, 1475, 1434,

JOURNAL OF CHEMICAL RESEARCH 2016 531
1
1
363, 1308, 1203, 1066, 1025, 772, 704, 596, 470. H NMR (500 MHz,
6
A.T. Baviskar, C. Madaan, R. Preet, P. Mohapatra, V. Jain, A. Agarwal,
S.K. Guchhait, C.N. Kundu, U.C. Banerjee and P.V. Bharatam, J. Med.
Chem., 2011, 54, 5013.
CDCl ): δ 8.35–8.38 (m, 1H), 7.96 (t, J = 7 Hz, 2H), 7.39 (s, 1H),
.27–7.31 (m, 2H), 7.13–7.17 (m, 1H), 6.58 (d, J = 6.5 Hz, 1H), 2.39 (s,
H). C NMR (125 MHz, CDCl ): δ 161.3, 159.3, 145.4, 138.9, 135.9,
28.8, 125.0, 124.5, 121.9, 121.8, 115.8, 115.6, 115.1, 111.7, 111.6, 21.5.
Anal. calcd for C H FN : C, 74.32; H, 4.90; N, 12.38; found: C, 74.50;
H, 4.72; N, 12.64%.
-Chloro-2-phenylimidazo[1,2-a]pyridine (3i): White solid, m.p.
3
7
3
1
13
7
8
Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med. Chem., 1991,
3
2
6, 13.
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11
2
2
013, 4, 110.
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9
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32
–1
2
1
05–206 °C (lit. 205–207 °C); IR (cm ): n 3128, 3033, 1922, 1762,
1
660, 1504, 1427, 1329, 1269, 1202, 1068, 931, 805, 711, 500. H NMR
(
1
1
1
500 MHz, CDCl ): δ 8.14 (d, J = 1 Hz, 1H), 7.91–7.93 (m, 2H), 7.80 (s,
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3
H), 7.56 (d, J = 9.5 Hz, 1H), 7.43 (t, J = 8 Hz, 2H), 7.34 (t, J = 7.5 Hz,
13
H), 7.12 (dd, J = 2, 9.5 Hz, 1H). C NMR (125 MHz, CDCl ): δ 146.9,
3
44.1, 133.4, 128.9, 128.4, 126.1, 123.4, 120.6, 117.9, 108.6.
1
1
2
3
K.J. Holm and K.L. Goa, Drugs, 2000, 59, 865.
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6
-Methyl-2-phenylimidazo[1,2-a]pyridine (3j): Yellow solid, m.p.
2
4
-1
1
1
72–173 °C (lit. 171–173 °C); IR (cm ): n 3035, 1645, 1603, 1511,
449, 1339, 1257, 1205, 1160, 1073, 1028, 909, 804, 712, 502. H NMR
1
14
D.J. Sanger, Behav. Pharmacol., 1995, 6, 116.
(
500 MHz, CDCl ): δ 7.90–7.92 (m, 2H), 7.78 (s, 1H), 7.67 (s, 1H), 7.49
3
15 K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki, Cardiovasc. Drug Rev.,
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2002, 20, 163.
13
6
.96 (dd, J = 1.5, 9 Hz, 1H), 2.24 (s, 3H). C NMR (125 MHz, CDCl ):
16 S. Sharma, B. Saha, D. Sawant and B. Kundu, J. Comb. Chem., 2007, 9,
3
δ 145.5, 144.8, 134.0, 128.8, 127.9, 128.0, 126.0, 123.4, 122.1, 116.8,
08.0, 18.1.
783.
17
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1
1
8
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We are thankful for the financial support from the Natural
Science Foundation of Hainan Province of China (no. 20162033)
and the Cultivation Research Foundation of Hainan Medical
University (HY2015-02).
19
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Electronic Supplementary Information
2
2
2
3
Spectroscopic data for 3 are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 7 June 2016; accepted 17 June 2016
Paper 1604134 doi: 10.3184/174751916X14683327937934
Published online: 24 August 2016
24 D. Zhu, J. Chen, D. Wu, M. Liu, J. Ding and H. Wu, J. Chem. Res., 2009,
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