An efficient, catalyst- and solvent-free synthesis of imidazo[1,2-a] pyridines and 2,4-disubstituted thiazoles on grinding

Article abstract of DOI:10.3184/030823409X401844

An efficient synthesis of imidazo[1,2-a]pyridines and 2,4-disubstituted thiazoles in excellent yield under catalyst-and solvent-free conditions at room temperature on grinding has been developed. The important features of this method are that it is reasonably fast, very clean, high yielding, simple workup and environmentally benign.

Full text of DOI:10.3184/030823409X401844

84 RESEARCH PAPER
FEBRUARY, 84–86
JOURNAL OF CHEMICAL RESEARCH 2009
An efficient, catalyst- and solvent-free synthesis of
imidazo[1,2-a]pyridines and 2,4-disubstituted thiazoles on grinding
Dongjian Zhua, Jiuxi Chena*, Dengze Wua, Miaochang Liua, Jinchang Dinga,b and Huayue Wua*
aCollege of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, P.R. China
bWenzhou Vocational and Technical College, Wenzhou, 325035, P. R. China
An efficient synthesis of imidazo[1,2-a]pyridines and 2,4-disubstituted thiazoles in excellent yield under catalyst-
and solvent-free conditions at room temperature on grinding 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, 2,4-disubstituted thiazoles, grinding, solvent-free synthesis, catalyst-free synthesis
Imidazo[1,2-a]pyridine derivatives exhibit diverse biological
activities.1,2 The typical procedure for the synthesis of
these compounds involves a condensation reaction of an
synthesis of imidazo[1,2-a]pyridines and 2,4-disubstituted
thiazoles under catalyst- and solvent-free conditions (Schemes 1
and Scheme 2).
D-bromocarbonyl
compound
with
2-aminopyridine
Initially, 1 mmol each of D-bromoacetophenone and
2-aminopyridine as a model reaction were heated at 60°C
in ethanol. After 1 h, only 61% of the desired product of
2-phenylimidazo[1,2-a]pyridine (3a) was obtained. In an
DWWHPSWꢀWRꢀLPSURYHꢀWKHꢀ\LHOGVꢀDQGꢀDFNQRZOHGJLQJꢀWKHꢀEHQH¿WVꢀ
of grinding,27-32 the model reaction was performed under
catalyst- and solvent-free conditions. To keep this method
economical, all the ingredients of the reaction were taken
in a glass mortar, mixed thoroughly and ground well at
room temperature. It was observed that the mixture which
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process of grinding to a light yellow solid mass and thin
layer chromatography (TLC), at this moment, indicated the
conversion to 3a in 90% yield.
A variety of substrates were submitted to this reaction
conditions and the desired products 3 were obtained in
excellent yields (Table 1). It is evident that electron rich and
HOHFWURQꢀ GH¿FLHQWꢀ D-bromoacetophenone reacted smoothly
with 2-aminopyridine and 2-amino-5-methylpyridine to afford
the desired products in excellent yields.
derivatives in neutral,3 weak basic organic solvents at elevated
temperature.4 These compounds were also synthesised by
solid support5 and using catalysts, such as Al2O36 and TiCl4.7
Moreover, the thiazole ring system is also a useful
structural element in medicinal chemistry.8-10 One of the
most common approaches for the synthesis of thiazoles
involves the reaction of readily available D-haloketones with
thioureas/thioamides in the presence of various promoting
agents, such as ammonium 12-molybdophosphate,11
E-cyclodextrin,12,13 iodine,14 [bbim]BF4,15 and with the aid of
microwave.16
,QꢀUHFHQWꢀ\HDUVꢁꢀVLJQL¿FDQWꢀDUWLFOHVꢀKDYHꢀDSSHDUHGꢀUHSRUWLQJꢀ
solid-state reactions by grinding.17-21 Most of these reactions
are carried out at room temperature in absolutely solvent-
free environment using only a mortar and pestle, and
therefore the common merit of these processes is that they are
HI¿FLHQWꢁꢀHFRQRPLFDOꢁꢀDQGꢀHQYLURQPHQWDOO\ꢀIULHQGO\ꢂ
In continuation of our interest in green chemistry,22-26 we
herein developed a green, simple and practical method for the
Table 1 Synthesis of imidazo[1,2-a]pyridinesa
Entry
D-bromoketone
R
Time/min
Product
Yield/%b
1
2
3
4
5
6
C6H5
H
20
10
30
10
20
25
3a
3b
3c
3d
3e
3f
90
95
90
91
94
90
p-OMe–C6H4
p-Cl–C6H4
C6H5
H
H
Me
Me
Me
p-OMe–C6H4
p-Cl–C6H4
aReaction conditions: D–bromoketone (1 mmol) and 2–aminopyridine (1 mmol) on grinding at room temperature.
bIsolated yields.
R
N
O
Grinding, rt
Catalyst- and Solvent-free
Ar
Br +
N
Ar
R
N
NH2
2
1
3
Scheme 1 Synthesis of imidazo[1,2-a]pyridine derivatives from D-bromoacetophenone and 2-aminopyridine on grinding.
S
S
O
Grinding, rt, 5 min
Catalyst- and Solvent-free
R
+
Br
R
NH2
Ar
N
Ar
4
1
5
Scheme 2 Synthesis of 2,4-disubstituted thiazole derivatives from D-bromoacetophenone and thiourea/thioamide on grinding.
* Correspondent. E-mail: hywu3@163.com

JOURNAL OF CHEMICAL RESEARCH 2009 85
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3b): White solid,
m.p. 135–136°C (lit.28 133–134°C); IR Q (cm-1): 2961, 2838, 1612,
1548, 1482, 1371, 1285, 1244, 1175, 1110, 1077, 1030, 924, 838,
743, 631, 536, 446. 1H NMR: G 8.09 (d, J = 6.77 Hz, 1H), 7.89 (dd,
J = 1.95, 1.94 Hz, 2H), 7.77 (s, 1H), 7.61 (d, J = 9.08 Hz, 1H),
7.17–7.15 (m, 1H), 6.97 (dd, J = 1.97, 1.94 Hz, 2H), 6.76 (dd,
J = 0.82, 0.81 Hz, 1H), 3.85 (s, 3H, OCH3). 13C NMR: G 159.6, 145.64,
145.57, 127.3, 126.4, 125.4, 124.5, 117.2, 114.1, 112.3, 107.2, 55.3.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (3c): White solid, m.p.
207–209°C (lit.29 201°C); IR Q (cm-1): 2917, 1632, 1471, 1369,
1250, 1202, 1089, 1009, 933, 830, 742, 598, 510. 1H NMR: G 8.09
(d, J = 6.78 Hz, 1H), 7.87 (d, J = 8.52 Hz, 2H), 7.82 (s, 1H), 7.61 (d,
J = 9.15 Hz, 1H), 7.39 (d, J = 8.52 Hz, 2H), 7.17 (t, J = 7.17 Hz, 1H),
6.77 (t, J = 6.60 Hz, 1H). 13C NMR: G 145.7, 144.6, 133.6, 132.3,
128.9, 127.2, 125.6, 124.9, 117.5, 112.6, 108.2.
6-Methyl-2-phenylimidazo[1,2-a]pyridine (3d): White solid, m.p.
171–173°C (lit.6 172–173°C); IR Q (cm-1): 2921, 1628, 1525, 1471,
1418, 1342, 1259, 1206, 1159, 1079, 846, 805, 768, 715, 685, 571,
506. 1H NMR: G 7.95 (d, J = 7.05 Hz, 2H), 7.83 (s, 1H), 7.73 (s, 1H),
7.53 (d, J = 9.09 Hz, 1H), 7.44 (t, J = 6.63 Hz, 2H), 7.33 (d, J = 6.44
Hz, 1H), 7.00 (d, J = 8.82 Hz, 1H). 13C NMR: G 145.4, 144.7, 133.9,
128.7, 127.84, 127.78, 125.9, 123.3, 122.0, 116.7, 107.9, 18.0.
2-(4-Methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (3e): White
solid, m.p. 179–181°C; IR Q (cm-1): 2926, 1612, 1546, 1483, 1413,
1341, 1301, 1246, 1174, 1103, 1023, 839, 794, 744, 710, 591, 528.
1H NMR: G 7.88 (d, J = 2.26 Hz, 2H), 7.86 (d, J = 2.11 Hz, 1H), 7.68
(s, 1H), 7.51 (d, J = 9.48 Hz, 1H), 7.01 (d, J = 1.57 Hz, 2H), 6.96
(dd, J = 2.10, 2.06 Hz, 1H), 3.85 (s, 3H, OCH3), 2.31 (s, 3H, CH3).
13C NMR: G 159.5, 145.3, 144.6, 127.7, 127.2, 126.6, 123.3, 121.9,
116.5, 114.1, 107.0, 55.3, 18.1. MS-ESI: m/z (%): 239 (100). Anal.
Calcd for C15H14N2O: C, 75.61; H, 5.92. Found: C, 75.66; H, 5.85%.
2-(4-Chlorophenyl)-6-methylimidazo[1,2-a]pyridine (3f): White
solid, m.p. 239–240°C (lit.6 240–242°C); IR Q (cm-1): 2921, 1635,
1540, 1465, 1409, 1257, 1206, 1090, 1010, 944, 835, 803, 734, 511.
1H NMR: G 7.89 (d, J = 2.83 Hz, 2H), 7.88 (s, 1H), 7.75 (s, 1H),
7.54 (t, J = 6.05 Hz, 1H), 7.39 (d, J = 8.53 Hz, 2H), 7.05 (d, J = 9.34
Hz, 1H), 2.33 (s, 3H, CH3). 13C NMR: G 144.8, 144.4, 133.5, 132.5,
128.9, 128.1, 127.1, 123.3, 122.3, 116.8, 107.9, 18.1.
Encouraged by our success, we also investigated the
reaction of D-bromoacetophenone with thiourea/thioamide on
grinding at room temperature under catalyst- and solvent-free
conditions. However, the problem in the grinding reaction
is that the starting materials soon become a tough waxy
substance that is hard to grind. To overcome this, we added
three drops of water to the mixture until the substrates form
a paste-like product that was easily ground. And, the process
gave the corresponding product 4-phenylthiazol-2-amine (5a)
as short as 5 min in 94% yield.
Next, we explored the scope and generality of this present
protocol for the synthesis of various 2,4-disubstituted thiazoles
(Table 2). As expected, a variety of D-bromoacetophenone
bearing either electron-donating (Table 2, entries 9–12)
or electron-withdrawing (Table 2, entries 5–8) groups on
aromatic ring underwent smooth transformation to the
corresponding products 5 in excellent yields when they
reacted with thiourea/thioamide. The substitution group
on the phenyl ring did not make any difference in the
reaction. In all cases, the corresponding products were
afforded as short a reaction time as 5 min in excellent yields.
Moreover, the reaction of D-bromo-4-nitroacetophenone with
thioacetamide and thiobenzamide was conducted successfully
in 88% and 92% yields, respectively (Table 2, entries 13–14).
To the best of our knowledge, it was little reported that a
reaction could be conducted within 5 min; except, Kabalka16
reported microwave promoted synthesis of thiazoles.
Compared to the reaction carried out by microwave irradiation,
this procedure is completely free from organic solvents during
the reaction.
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method for the synthesis of imidazo[1,2-a]pyridine and
2,4-disubstituted thiazole derivatives on grinding at room
temperature under catalyst- and solvent-free conditions.
The mildness of the conversion, experimental simplicity,
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short reaction times, and the easy workup procedure, makes
this procedure attractive to synthesise a variety of these
derivatives.
General procedure for preparation of 5a–n
A mixture of D-bromoketone (1) (1 mmol), thiourea/thioamide (4)
(1 mmol) and three drops of water is ground at room temperature with
a glass pestle in the glass mortar for 5 min. The progress of the reaction
was monitored by TLC. After completion of the reaction, the product
was washed with dehydrated alcohol or ethyl acetate (3ꢀuꢀ10 mL).
The combined organic solvent was removed under vacuum to obtain
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silica gel column chromatography using ethyl acetate–petroleum
ether as eluent to afford the pure product. The physical and spectra
data of the compounds 5a–n are as follows.
Experimental
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All the melting points were uncorrected. 1H NMR and 13C NMR
4-Phenylthiazol-2-amine (5a): White solid, m.p. 150–151°C (Lit.15
150–151°C); IR Q (cm-1): 3432, 2974, 1624, 1524, 1388, 1337, 1045,
670. 1H NMR: G 7.81–7.78 (m, 2H, ArH), 7.42-7.37 (m, 2H, ArH),
7.33–7.28 (m, 1H, ArH), 6.74 (s, 1H, thiazole), 5.05 (br s, 2H, NH2).
13C NMR: G 167.3, 151.3, 134.7, 128.5, 127.7, 126.0, 102.7. MS-EI:
m/z (%): 176 (100), 134 (59), 89 (12).
spectra were measured on
a FT-Bruker AT-300 spectrometer
(1H: 300 MHz, 13C: 75 MHz), using CDCl3 as the solvent with
tetramethylsilane (TMS) as an internal standard at room temperature.
Chemical shifts are given in G relative to TMS, the coupling constants
J are given in Hz. IR spectra was recorded on a AVATAR 370 FI-
IR Spectrophotometer. Mass spectra were measured with Thermo
Finnigan LCQ-Advantage. Elemental analyses were carried out using
a Carlo-Erba EA1112 instrument. Column chromatography was
performed using EM Silica gel 60 (300–400 mesh).
N,4-Diphenylthiazol-2-amine (5b): White solid, m.p. 135–136°C
(Lit.30 135–136°C); IR Q (cm-1): 3432, 2927, 1606, 1562, 1461, 1422,
1310, 692. 1H NMR: G 7.89–7.86 (m, 2H, ArH), 7.60 (s, 1H, ArH),
7.44–7.30 (m, 7H, ArH), 7.10–7.06 (m, 1H, thiazole), 6.84 (br s, 1H,
NH). 13C NMR: G 164.4, 151.3, 140.2, 134.5, 129.3, 128.5, 127.8,
126.0, 122.9, 118.1, 101.7.
General procedure for preparation of 3a–f
A mixture of D-bromoketone (1) (1 mmol), and 2-aminopyridine (2)
(1 mmol) is ground at room temperature with a glass pestle in the
glass mortar. The progress of the reaction was monitored by TLC.
After completion of the reaction, the product was washed with
dehydrated alcohol or ethyl acetate (3ꢀ uꢀ 10 mL). The combined
organic solvent was removed under vacuum to obtain the crude
VROLGꢀSURGXFWꢂꢀ7KHꢀFUXGHꢀSURGXFWꢀZDVꢀIXUWKHUꢀSXUL¿HGꢀE\ꢀVLOLFDꢀJHOꢀ
column chromatography using ethyl acetate–petroleum ether (1:3) as
eluent to afford the pure product. The physical and spectra data of the
compounds 3a–f are as follows.
2-Mmethyl-4-phenylthiazole (5c): White solid, m.p. 67–69°C
(Lit.15 67–68°C); IR Q (cm-1): 3436, 2924, 1640, 1387, 1169, 1028,
676. 1H NMR: G 7.89–7.86 (m, 2H, ArH), 7.42–7.37 (m, 3H, ArH),
7.33–7.27 (m, 1H, ArH), 2.75 (s, 3H, CH3). 13C NMR: G 165.7, 155.1,
134.5, 128.6, 127.8, 126.3, 112.1, 19.2.
2, 4-Diphenylthiazole (5d): White solid, m.p. 90–91°C (Lit.31
91–92°C); IR Q (cm-1): 3435, 2925, 1643, 1519, 1471, 1391, 1058,
673. 1H NMR: G 8.08–8.00 (m, 4H, ArH), 7.49–7.44 (m, 6H, ArH),
7.39–7.37 (m, 1H, thiazole). 13C NMR: G 167.8, 156.3, 134.5, 133.7,
130.0, 128.9, 128.7, 128.2, 126.6, 126.4, 112.6.
2-Phenylimidazo[1,2-a]pyridine (3a): White solid, m.p. 136–
137°C (lit.27 131–133°C); IR Q (cm-1): 2925, 2857, 1738, 1625, 1511,
1460, 1383, 1269, 1201, 1122, 1081, 1040, 744, 688, 458. 1H NMR:
G 8.12 (dd, J = 1.04, 1.03 Hz, 1H), 7.98–7.96 (m, 2H), 7.88 (s, 1H),
7.64 (d, J = 9.14 Hz, 1H), 7.45 (t, J = 7.22 Hz, 2H), 7.35 (d, J = 7.33
Hz, 1H), 7.20–7.17 (m, 1H), 6.79 (d, J = 6.78 Hz, 1H). 13C NMR:
G 145.8, 145.7, 133.8, 128.7, 127.9, 126.0, 125.6, 124.6, 117.5, 112.4,
108.1. MS-ESI: m/z (%): 195 (100).
4-(4-Chlorophenyl)thiazol-2-amine (5e): White solid, m.p.
167–168°C (Lit.15 163–164°C); IR Q (cm-1): 3433, 2924, 1628,
1532, 1466, 1395, 1041, 730. 1H NMR: G 7.74–7.70 (m, 2H, ArH),
7.38–7.33 (m, 2H, ArH), 6.73 (s, 1H, thiazole), 5.07 (br s, 2H, NH2).
13C NMR: G 167.3, 150.2, 133.4, 133.1, 128.8, 127.3, 103.3.
4-(4-Chlorophenyl)-N-phenylthiazol-2-amine (5f): White solid,
m.p. 144–146°C; IR Q (cm-1): 3383, 2974, 1559, 1473, 1399, 1304,

86 JOURNAL OF CHEMICAL RESEARCH 2009
1089, 1053, 834, 691. 1H NMR: G 7.85–7.73 (m, 3H, ArH), 7.33–
7.28 (m, 6H, ArH), 7.08–7.02 (m, 1H, thiazole), 6.77 (br s, 1H, NH).
13C NMR: G 164.8, 150.2, 140.2, 133.6, 133.1, 129.5, 128.8, 127.4,
123.2, 118.4, 102.2. Anal. Calcd for C15H11ClN2S: C, 62.82; H, 3.87.
Found: C, 62.77; H, 3.91%.
4-(4-Chlorophenyl)-2-methylthiazole (5g): White solid, m.p.
118–119°C (Lit.15 111–112°C); IR Q (cm-1): 3442, 1647, 1523, 1391,
1166, 989, 672. 1H NMR: G 7.81 (d, J = 8.63 Hz, 2H, ArH), 7.37
(d, J = 8.63 Hz, 2H, ArH), 7.28 (s, 1H, thiazole), 2.76 (s, 3H, CH3).
13C NMR: G 166.1, 153.9, 133.7, 133.0, 128.9, 127.6, 112.6, 19.3.
MS-EI: m/z (%): 211 (42), 209 (100), 170 (40), 168 (100), 133 (36),
89 (27).
We are grateful to the National Key Technology R&D Program
(No. 2007BAI34B00) and Natural Science Foundation of
=KHQJMLDQJꢀ3URYLQFHꢀꢃ1Rꢂꢀ<ꢄꢅꢆꢅꢇꢅꢈꢉꢀIRUꢀ¿QDQFLDOꢀVXSSRUWꢂ
Received 3 November 2008; accepted 27 November 2008
Paper 08/0279 doi:10.3184/030823409X401844
Published online: 18 February 2009
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4-(4-Chlorophenyl)-2-phenylthiazole (5h): White solid, m.p.
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7.16 (s, 1H, thiazole), 6.93 (d, J = 8.86 Hz, 2H, ArH), 3.83 (s, 3H,
OCH3), 2.75 (s, 3H, CH3). 13C NMR: G 165.6, 159.5, 154.9, 127.59,
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4-(4-Methoxyphenyl)-2-phenylthiazole (5l): White solid, m.p. 127–
129°C (Lit.29 124–125°C); IR Q (cm-1): 3432, 2928, 1608, 1525,
1477, 1248, 1174, 1028, 836, 766, 690. 1H NMR: G 8.05–8.02 (m,
2H, ArH), 7.95–7.92 (m, 2H, ArH), 7.46–7.44 (m, 3H, ArH), 7.34
(s, 1H, thiazole), 6.99–6.96 (m, 2H, ArH), 3.86 (s, 3H, OCH3). 13C
NMR: G 167.7, 159.7, 156.1, 133.8, 130.0, 128.9, 127.8, 127.5,
126.6, 114.1, 110.9, 55.4.
2-Methyl-4-(4-nitrophenyl)thiazole (5m): Yellow solid, m.p. 141–
143°C (Lit.29 136°C); IR Q (cm-1): 3438, 2973, 1640, 1597, 1505,
1335, 1164, 1055, 847, 740, 659. 1H NMR: G 8.28 (d, J = 9.02 Hz,
2H, ArH), 8.05 (m, J = 9.01 Hz, 2H, ArH), 7.54 (s, 1H, thiazole),
2.80 (s, 3H, CH3). 13C NMR: G 166.9, 152.7, 147.2, 140.3, 126.8,
124.2, 116.0, 19.4.
4-(4-Nitrophenyl)-2-phenylthiazole (5n): Yellow solid, m.p. 128–
129°C (Lit.29 122–123°C); IR Q (cm-1): 3434, 2924, 1599, 1510,
1338, 1104, 1054, 844, 734, 685. 1H NMR: G 8.31 (d, J = 8.69 Hz,
2H, ArH), 8.17 (d, J = 8.75 Hz, 2H, ArH), 8.07–8.04 (m, 2H, ArH)
7.69 (s, 1H, thiazole), 7.50–7.48 (m, 3H, ArH). 13C NMR: G 168.8,
153.8, 147.3, 140.3, 133.2, 130.6, 129.1, 127.0, 126.7, 124.2, 116.0.
MS-EI: m/z (%): 282 (100), 252 (63), 236 (22), 149 (32), 89 (28).
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