Ionic liquid promoted one-pot synthesis of 3-aminoimidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2006.03.011

3-Aminoimidazo[1,2-a]pyridines have been synthesized in good to excellent yields in the presence of the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]Br, the reaction workup is simple and the ionic liquid can be easily separated from the product and reused.

Full text of DOI:10.1016/j.tetlet.2006.03.011

Tetrahedron Letters 47 (2006) 3031–3034
Ionic liquid promoted one-pot synthesis of
3
-aminoimidazo[1,2-a]pyridines
*
Ahmad Shaabani, Ebrahim Soleimani and Ali Maleki
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Received 14 December 2005; revised 18 February 2006; accepted 2 March 2006
Available online 20 March 2006
Abstract—3-Aminoimidazo[1,2-a]pyridines have been synthesized in good to excellent yields in the presence of the ionic liquid
1
-butyl-3-methylimidazolium bromide [bmim]Br, the reaction workup is simple and the ionic liquid can be easily separated from
the product and reused.
2006 Elsevier Ltd. All rights reserved.
ꢀ
Imidazo[1,2-a]pyridines, an important class of phar-
The synthesis of imidazo[1,2-a]pyridines has also been
maceutical compounds exhibit a wide spectrum of
biological activities. As a result, numerous two- and
reported under microwave irradiation in the presence
of a solid acid, montmorillonite K , and Sc(OTf) ,
1
6
10 3
7
three-component approaches for their synthesis have
been reported.
however, special instrumentation is required.
During recent years, ionic liquids have attracted interest
as environmentally benign reagents due to their favor-
able properties and a variety of catalytic reactions have
The classical synthesis of imidazo[1,2-a]pyridines
involves the condensation of a-haloketones with 2-
aminopyridines. Being only a two-component conden-
2
8
been successful using ionic liquids. The solvophobic
sation, this reaction is less suitable for the generation
of a large compound library.
properties of ionic liquids are able to generate an inter-
nal pressure and promote the association of the reac-
tants in a solvent cavity during the activation process
and accelerate a reaction. This property of ionic liquids
is very efficient for MCRs in which the entropy of reac-
tion is decreased in the transition state.
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-aminoazine in the presence of a
3
–5
5
strong protic acid
(AcOH, HClO ) or Lewis acid
During the course of our studies on the development of
new routes for the synthesis of organic compounds using
4
(
Sc(OTf) ). However, these reactions require long times
3
9
for completion and isolation and recovery procedures
are complicated. For example, in the case of Sc(OTf)3,
the reaction mixture was agitated for 72 h at ambient
temperature, then it was allowed slowly to adsorb onto
Dowex 50WX 2–200 strongly acidic cation exchange re-
sin. The resin was washed with MeOH, CH Cl and
ionic liquids and our interest in isocyanide-based
1
0
MCRs,
we developed the synthesis of 3-amino-
imidazo[1,2-a]pyridines via the three-component con-
densation of an aldehyde 1, 2-amino-5-methylpyridine
or 2-amino-5-bromopyridine 2 and isocyanide 3 in 1-but-
yl-3-methylimidazolium bromide ([bmim]Br) at room
temperature (Scheme 1).
2
2
MeOH and finally the product was eluted using 2 M
NH in MeOH and the solvent evaporated.
3
O
NH2
+ R3
N
[
bmim]Br
r.t., 3 h
R1
+
N
C
R1
H
N
R2
N
R2
Keywords: Imidazo[1,2-a]pyridine; Ionic liquid; Isocyanide; Multi-
component reactions; [bmim]Br.
HN
R3
1
2
3
4a-k
0-99%
7
*
Corresponding author. Fax: +98 21 22403041; e-mail: a-shaabani@
cc.sbu.ac.ir
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.011

3032
A. Shaabani et al. / Tetrahedron Letters 47 (2006) 3031–3034
Table 1. Synthesis of 3-aminoimidazo[1,2-a]pyridines in [bmim]Br
1
2
3
Entry
R
R
R
Product
Yield (%)
a
1
2
3
4
5
6
7
8
9
Ph
Ph
Br
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
tert-Butyl
tert-Butyl
tert-Butyl
4a
4b
4c
4d
4e
4f
98 (95, 92, 90, 85)
Me
Me
Me
Me
Me
Br
Me
Me
Me
Me
98
99
92
99
97
99
90
86
72
70
3 6 4
4-CH C H
4-ClC
3-O NC H
4-Pyridyl
Ph
Ph
4-CH
Ph
6 4
H
2
6 4
4g
4h
4i
3
C
6
H
4
4
1
1
0
1
2,6-(Me)
2,6-(Me)
2
C
C
6
H
H
3
3
4j
4k
4-CH
3
C
6
H
2
6
a
The same ionic liquid was used for each of the five runs.
À1
As indicated in Table 1, the reaction of aldehydes with
-amino-5-methylpyridine or 2-amino-5-bromopyridine
cm ): 3250 (NH), 2920, 1602. MS, m/z (%): 372
+
81
+ 79
2
(MH , Br, 28), 370 (MH , Br, 30), 288 (68), 286
and isocyanides afforded 3-aminoimidazo[1,2-a]pyr-
idines in [bmim]Br as a promoter in very high yields.
The structures of the products 4a–k were deduced from
(65), 261 (100), 259 (95), 158 (70), 156 (78), 76 (30).
1
H NMR (300 MHz, CDCl ): dH (ppm) 1.17–1.98
3
(10H, m, 5CH of cyclohexyl), 2.95 (1H, m, CH–N of
2
1
13
their IR, mass, H NMR and C NMR spectra.
cyclohexyl), 3.72 (1H, bs, NH), 7.28–8.32 (8H, m, H-
1
3
Ar). C NMR (75 MHz, CDCl ): dC (ppm) 24.76,
3
To illustrate the need for [bmim]Br, the reaction of
p-methylbenzaldehyde, 2-amino-5-methylpyridine and
cyclohexyl isocyanide was studied in the absence of
25.63, 34.08 (carbons of cyclohexyl), 56.84 (CH–N of
cyclohexyl), 106.87, 117.71, 123.02, 125.23, 127.03,
127.77, 128.62, 128.64, 133.36, 136.89, 139.53 (C-Ar).
[
bmim]Br. The yield of product was only 25% at room
temperature after 12 h. Obviously, [bmim]Br is an
important component of the reaction.
N-Cyclohexyl-6-methyl-2-phenylimidazo[1,2-a]pyridin-
3-amine (4b)—Colorless crystal (0.30 g, 98%): mp 203–
À1
2
06 ꢁC (dec). IR (KBr) (m /cm ): 3195 (NH), 2925,
max
+
+
One of the advantages of ionic liquids is their ability to
function as a recyclable reaction medium. We were able
to separate [bmim]Br from the reaction medium easily
by washing with water and evaporating the solvent
under vacuum, and reuse it for subsequent reactions.
1613. MS, m/z (%): 306 (M +1, 71), 305 (M , 73),
222 (87), 195 (100), 92 (87), 65 (62), 55 (45), 41 (31).
1
H NMR (300 MHz, DMSO-d ): dH (ppm) 1.06–1.74
6
(10H, m, 5CH of cyclohexyl), 2.40 (3H, s, CH ), 2.84
2
3
(1H, m, CH–N of cyclohexyl), 5.16 (1H, bs, NH),
3
7
.36–7.64 (5H, m, H-Ar), 8.10 (2H, d, J = 7.6 Hz,
HH
1
3
In conclusion, we have introduced an efficient and
environmentally friendly approach for the synthesis of
H-Ar), 8.37 (1H, s, H-Ar).
C NMR (75 MHz,
DMSO-d ): dC (ppm) 17.71 (CH ), 24.40, 25.21, 33.18
6
3
3
-aminoimidazo[1,2-a]pyridines via condensation of an
(carbons of cyclohexyl), 56.11 (CH–N of cyclohexyl),
112.95, 115.64, 122.11, 122.01, 126.13, 126.74, 128.37,
128.74, 132.35, 136.82, 145.88 (C-Ar).
aldehyde, 2-amino-5-methylpyridine or 2-amino-5-
bromopyridine and an isocyanide using [bmim]Br in
good to excellent yields at room temperature. To the
best our knowledge, this is the first report on the synthe-
sis of 3-aminoimidazo[1,2-a]pyridines in an ionic liquid
and these new reaction conditions open an important
alternative to the use of volatile organic solvents.
N-Cyclohexyl-6-methyl-2-phenylimidazo[1,2-a]pyridin-
3-amine (4c)—Colorless crystal (0.31 g, 99%): mp 216–
À1
218 ꢁC (dec). IR (KBr) (mmax/cm ): 3225 (NH), 2920,
+
+
1661, 1613. MS, m/z (%): 320 (M +1, 62), 319 (M ,
7
1), 236 (87), 209 (100), 92 (83), 65 (54), 55 (42), 41
1
All the products (except 4h) are new compounds, which
(29). H NMR (300 MHz, DMSO-d ): d (ppm) 1.05–
6 H
1
13
were identified by IR, H NMR and C NMR spectral
data and mass spectroscopy.
1.69 (10H, m, 5CH of cyclohexyl), 2.35 (3H, s, CH ),
2 3
2.42 (3H, s, CH ), 2.83 (1H, m, CH–N of cyclohexyl),
3
5
.20 (1H, bs, NH), 7.34–8.49 (7H, m, H-Ar).
1
3
Typical procedure: preparation of 6-bromo-N-cyclo-
hexyl-2-phenylimidazo[1,2-a]pyridin-3-amine (4a)—To
C NMR (75 MHz, DMSO-d ): dC (ppm) 16.78
6
(CH ), 18.17 (CH ), 24.87, 25.69, 33.61 (carbons of
3
3
a
1
solution of 2-amino-5-bromopyridine (0.17 g,
mmol), benzaldehyde (0.13 g, 1.2 mmol) and cyclo-
cyclohexyl), 56.51 (CH–N of cyclohexyl), 112.55,
122.82, 126.06, 126.34, 127.20, 129.96, 134.17, 134.49,
136.39, 146.29, 153.06 (C-Ar).
hexyl isocyanide (0.12 g, 1.1 mmol) were added
[
bmim]Br11 (0.3 g, 1.4 mmol). The resulting mixture
was stirred for 3 h at room temperature. After comple-
tion of the reaction, as indicated by TLC (ethyl ace-
tate/n-hexane, 2:1), the reaction mixture was washed
with water (2 · 10 ml) and the solid residue was crystal-
lized from ethyl acetate to give 4a as colorless crystals
2-(4-Chlorophenyl)-N-cyclohexyl-6-methylimidazo[1,2-a]-
pyridin-3-amine (4d)—Colorless crystal (0.31 g, 92%): mp
À1
210–212 ꢁC (dec). IR (KBr) (mmax/cm ): 3250 (NH),
+
2920, 1651, 1604. MS, m/z (%): 340 (M +1, 21), 339
+
(M , 50), 256 (87), 209 (67), 92 (100), 65 (48), 55
1
(
0.36 g, 98%): mp 207–208 ꢁC (dec). IR (KBr) (mmax
/
(27), 41 (19). H NMR (300 MHz, CDCl ): d (ppm)
3
H

A. Shaabani et al. / Tetrahedron Letters 47 (2006) 3031–3034
3033
1
1
.16–1.81 (10H, m, 5CH of cyclohexyl), 2.36 (3H, s,
(28), 41 (27). H NMR (300 MHz, DMSO-d ): d
2
6
H
CH ), 2.92 (1H, m, CH–N of cyclohexyl), 3.27 (1H,
(ppm) 0.98 (9H, s, C(CH ) ), 2.33 (3H, s, CH ), 4.69
(1H, bs, NH), 7.13 (2H, d, JHH = 9.2 Hz, H-Ar),
3
3 3 3
3
3
bs, NH), 7.02 (1H, d, J = 9.1 Hz, H-Ar), 7.37 (2H,
HH
3
3
d, J = 8.6 Hz, H-Ar), 7.46 (1H, d, J = 9.2 Hz,
H-Ar), 7.85 (1H, s, H-Ar), 8.02 (2H, d, J = 8.6 Hz,
H-Ar). C NMR (75 MHz, CDCl ): dC (ppm) 18.49
7.25–7.53(4H, m, H-Ar), 7.72 (1H, s, H-Ar), 8.12 (1H,
HH
HH
3
3
13
d, J = 7.5 Hz, H-Ar). C NMR (75 MHz, DMSO-
HH
HH
1
3
d6): dC (ppm) 18.30 (CH ), 30.44 (C(CH ) ), 55.26
3
3
3 3
(
CH ), 24.80, 25.68, 34.13 (carbons of cyclohexyl),
(C(CH ) ), 111.17, 115.93, 121.15, 122.20, 128.16,
3
3 3
5
1
1
6.72 (CH–N of cyclohexyl), 116.20, 120.44, 121.97,
24.72, 128.13, 128.60, 132.17, 133.05, 134.43, 140.12,
47.28 (C-Ar).
128.52, 135.00, 137.14, 139.96, 142.79, 155.33 (C-Ar).
N-tert-Butyl-6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-
amine (4i)—Colorless crystal (0.25 g, 86%): mp 210–
À1
N-Cyclohexyl-6-methyl-2-3-nitrophenylimidazo[1,2-a]-
pyridin-3-amine (4e)—Yellow crystal (0.34 g, 97%): mp
212 ꢁC. IR (KBr) (mmax/cm ): 3230 (NH), 2960, 1663,
+
+
1613. MS, m/z (%): 294 (M +1, 23), 293 (M , 19),
À1
2
2
08–210 ꢁC (dec). IR (KBr) (mmax/cm ): 3240 (NH),
236 (87), 209 (100), 92 (65), 65 (44), 57 (23), 41 (17).
+
1
920, 1609, 1560. MS, m/z (%): 351 (M +1, 13), 350
H NMR (300 MHz, DMSO-d ): dH (ppm) 0.98 (9H,
6
+
(
(
M , 36), 267 (100), 240 (73), 220 (12), 194 (10), 92
73), 65 (25), 55 (31), 41 (12). H NMR (300 MHz,
s, C(CH ) ), 2.33 (3H, s, CH ), 2.37 (3H, s, CH ), 4.70
3
3
3
3
1
3
(1H, bs, NH), 7.25 (2H, d, J = 7.5 Hz, H-Ar), 7.36
HH
3
3
CDCl ): d (ppm) 1.18–1.89 (10H, m, 5CH of cyclo-
hexyl), 2.39 (3H, s, CH ), 2.97 (1H, m, CH–N of cyclo-
hexyl), 3.47 (1H, bs, NH), 7.11 (1H, d, J = 9.2 Hz,
H-Ar), 7.57 (1H, d, J = 9.2 Hz, H-Ar), 7.61 (1H,
dd, J = 8.0 Hz, J = 8.0 Hz, H-Ar), 7.95 (1H, s,
H-Ar), 8.13 (1H, d, J = 8.0 Hz, H-Ar), 8.56 (1H,
d, JHH = 8.0 Hz, H-Ar), 9.05 (1H, s, H-Ar).
(1H, d, JHH = 8.3 Hz, H-Ar), 7.59 (1H, d, JHH =
3
H
2
3
8.3 Hz, H-Ar), 7.97 (2H, d, J = 7.5 Hz, H-Ar), 8.39
(1H, s, H-Ar). C NMR (75 MHz, DMSO-d ): dC
3
HH
3
13
HH
6
3
(ppm) 17.71 (CH ), 20.86 (CH ), 29.84 (C(CH ) ),
HH
3
3
3 3
3
3
55.91 (C(CH3)3), 113.73, 122.32, 122.89, 123.93,
127.73, 128.83, 130.89, 130.95 137.48, 137.96, 146.65
(C-Ar).
HH
HH
3
HH
3
13
C
NMR (75 MHz, CDCl ): d (ppm) 18.45 (CH ), 24.83,
3
C
3
2
5.60, 34.20 (carbons of cyclohexyl), 57.02 (CH–N of
6-Methyl-N-(2,6-dimethylphenyl)-2-phenylimidazo[1,2-
a]pyridin-3-amine (4j)—Colorless crystal (0.23 g, 72%):
cyclohexyl), 116.59, 120.33, 121.28, 121.60, 122.15,
À1
1
1
25.47, 128.40, 129.27, 132.54, 133.49, 135.80, 140.58,
48.35 (C-Ar).
mp 165–168 ꢁC (dec). IR (KBr) (mmax/cm ): 3150
+
(NH), 2750, 1662, 1621. MS, m/z (%): 328 (M +1,
+
1
9), 327 (M , 87), 220 (29), 208 (100), 195 (29), 130
1
N-Cyclohexyl-6-methyl-2-(pyridin-4-yl)imidazo[1,2-a]-
(13), 108 (44), 92 (87), 80 (37), 77 (33), 65 (68). H
pyridin-3-amine (4f)—Yellow crystal (0.30 g, 99%): mp
NMR (300 MHz, DMSO-d ): dH (ppm) 1.86 (6H, s,
6
À1
2
2
35–237 ꢁC (dec). IR (KBr) (mmax/cm ): 3245 (NH),
2CH ), 2.26 (3H, s, CH ), 5.25 (1H, bs, NH), 6.61–
3
3
+
13
920, 1598. MS, m/z (%): 307 (M +1, 27), 306
7.87 (11H, m, H-Ar). C NMR (75 MHz, DMSO-d6):
+
(
M , 52), 223 (78), 196 (54), 92 (100), 65 (60), 55 (35),
dC (ppm) 16.37 (2CH ), 17.82 (CH ), 112.42, 115.78,
3
3
1
4
1
2
1 (31). H NMR (300 MHz, CDCl ): d (ppm) 1.13–
.83 (10H, m, 5CH of cyclohexyl), 2.34 (3H, s, CH ),
120.04, 120.49, 121.15, 121.74, 125.30, 126.57, 127.06,
128.02, 129.31, 135.13, 140.86, 144.85, 153.20 (C-Ar).
3
H
2
3
.95 (1H, m, CH–N of cyclohexyl), 3.20 (1H, bs, NH),
3
7
.01 (1H, d, JHH = 9.2 Hz, H-Ar), 7.45 (1H, d,
6-Methyl-N-(2,6-dimethylphenyl)-2-p-tolylimidazo[1,2-
a]pyridin-3-amine (4k)—Colorless crystal (0.24 g, 70%):
3
JHH = 9.2 Hz, H-Ar), 7.82 (1H, s, H-Ar), 8.00 (2H, d,
JHH = 5.8 Hz, H-Ar), 8.62 (2H, d, J = 5.8 Hz, H-
3
3
À1
+
mp 209–211 ꢁC (dec). IR (KBr) (mmax/cm ): 3150 (NH),
HH
1
3
Ar). C NMR (75 MHz, CDCl ): dC (ppm) 18.46
2750, 1663, 1621. MS, m/z (%): 342 (M +1, 17), 341
3
+
(
CH ), 25.83, 25.61, 34.22 (carbons of cyclohexyl), 57.02
(M , 35), 267 (69), 240 (40), 222 (27), 108 (35), 92
3
1
(
CH–N of cyclohexyl), 116.95, 120.29, 120.99, 122.09,
(100), 80 (21), 65 (58), 55 (37), 41 (20). H NMR
1
26.69, 128.36, 133.02, 140.91, 142.10, 149.60 (C-Ar).
(300 MHz, DMSO-d ): dH (ppm) 1.85 (6H, s, 2CH3),
6
2
.13 (3H, s, CH ), 2.25 (3H, s, CH ), 4.28 (1H, bs,
3 3
1
3
N-tert-Butyl-6-bromo-2-phenylimidazo[1,2-a]pyridin-3-
NH), 6.61–7.79 (10H, m, H-Ar). C NMR (75 MHz,
amine (4g)—Colorless crystal (0.34 g, 99%): mp 206–
DMSO-d ): d (ppm) 16.85 (2CH ), 18.31 (CH ), 18.84
6
C
3
3
À1
81
2
08 ꢁC (dec). IR (KBr) (mmax/c+m ): 3285 (NH), 2955,
(CH ), 113.00, 115.93, 120.53, 121.06, 121.62, 121.84,
3
+
1
619. MS, m/z (%): 346 (MH , Br, 40), 344 (MH ,
125.77, 127.00, 128.84, 129.20, 129.84, 135.40, 141.37,
145.43, 153.65 (C-Ar).
7
9
Br, 42), 289 (85), 287 (100), 261 (90), 259 (90), 158
1
(
75), 156 (73), 76 (59), 57 (25). H NMR (300 MHz,
CDCl ): d (ppm) 1.04 (9H, s, C(CH ) ), 3.37 (1H, bs,
3
H
3 3
1
3
NH), 7.28–8.41 (8H, H-Ar).
C NMR (75 MHz,
Acknowledgements
CDCl ): d (ppm) 30.28 (C(CH ) ), 55.59 (C(CH ) ),
3
C
3 3
3 3
1
1
06.67, 117.69, 123.81, 123.92, 127.87, 127.94, 128.13,
28.41, 134.10, 139.79, 139.98 (C-Ar).
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University.
N-tert-Butyl-6-methyl-2-phenylimidazo[1,2-a]pyridin-3-
amine (4h)—Colorless crystal (0.25 g, 90%): mp 217–
References and notes
À1
2
1
4
20 ꢁC (dec). IR (KBr) (mmax/cm ): 3285 (NH), 2955,
+
+
666, 1599. MS, m/z (%): 280 (M +1, 85), 279 (M ,
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3034
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