Thermal and microwave-assisted rapid syntheses of substituted imidazo[1,2-a]pyridines under solvent- and catalyst-free conditions

Article abstract of DOI:10.1055/s-0030-1258405

Thermal and microwave-assisted rapid syntheses of highly substituted imidazo[1,2-a]pyridine derivatives by reaction of aminopyridines and -bromo - keto esters under solvent-free conditions are described. Reactions carried out under microwave irradiation give the highest yields of products in reaction times of less than two minutes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258405

PAPER
635
Thermal and Microwave-Assisted Rapid Syntheses of Substituted
Imidazo[1,2-a]pyridines Under Solvent- and Catalyst-Free Conditions
S
ynthesis of Subst
a
itute
d
Imida
u
zo[1, 2-
a
]py
s
ridines hik C. Chunavala, Girdhar Joshi, Eringathodi Suresh, Subbarayappa Adimurthy*
Central Salt and Marine Chemicals Research Institute (CSIR), G. B. Marg, Bhavnagar 364 002, Gujarat, India
Fax +91(278)2567562; E-mail: sadimurthy@yahoo.com
Received 15 November 2010; revised 23 November 2010
Our initial studies focused on the development of an opti-
mum set of reaction conditions for the synthesis of com-
pound 3 from 2-aminopyridine (1) and ethyl 2-bromo-3-
oxobutanoate (2a). Preliminary studies (after screening
Abstract: Thermal and microwave-assisted rapid syntheses of
highly substituted imidazo[1,2-a]pyridine derivatives by reaction of
aminopyridines and a-bromo-b-keto esters under solvent-free con-
ditions are described. Reactions carried out under microwave irra-
diation give the highest yields of products in reaction times of less various solvents including methanol, ethanol, isopropyl
than two minutes.
alcohol, acetonitrile, dichloromethane and 1,2-dichloro-
ethane) revealed that the best yield (87%) of product 3a,
and not the desired naphthyridin-2-ol 3, was obtained un-
der neat conditions at room temperature in 60 minutes. A
similar yield of 3a was achieved within 10 minutes when
the same reaction was carried out at 55 °C.
Key words: aminopyridines, a-bromo-b-keto esters, imidazo[1,2-
a]pyridines, microwave irradiation, solvent-free, thermal
Imidazo[1,2-a]pyridines are an important class of mole-
cules due to their wide spectrum of biological activity and
clinical applications.1 Derivatives of imidazo[1,2-a]pyri-
dine have been shown to act as melatonin receptor
ligands,2 antiviral,3 antiulcer,4 antibacterial5 and antifun-
gal agents,6 an agonist of the benzodiazepine receptor,7 a
calcium channel blocker,8 an inhibitor of b-amyloid for-
mation,9 a ligand for detecting b-amyloid,10 orally active
non-peptide bradykinin B2 receptor antagonists,11a and an
hypnotic agent.11b
OR1
Br
COOR1
R2
O
O
neat
Br
N
R2
+
X
N
NH2
55 °C
N
N
OH
R2
2a
N
3
1
3a
Scheme 1 Reaction of 2-aminopyridine (1) with ethyl 2-bromo-3-
oxobutanoate (2a)
Although a number of methods have been developed for Intrigued by this experimental observation, we decided to
the synthesis of this important framework, most are limit- extend this strategy to the synthesis of substituted imida-
ed to the condensation of a-halocarbonyl compounds with zo[1,2-a]pyridine-3-carboxylates 3b–e using aminopyri-
2-aminopyridines under harsh conditions, or the conden- dine 1 and a-bromo-b-keto esters 2b–e (Figure 1).
sation of substituted imidazoles with unsaturated dicar-
boxylates, or a,b-unsaturated carbonyl compounds.12
Other methods include copper- and palladium-catalyzed
procedures,13and multicomponent reactions.14 Clay- and
alumina-supported, three-component, microwave-assist-
ed reactions for the synthesis of imidazo[1,2-a]pyridines
have been reported.15
O
O
O
O
O
O
OMe
OEt
Ph
O
Br
Br
O
Br
2a
2b
2c
O
O
O
O
OEt
Ph
To the best of our knowledge, there are no methods avail-
able for the rapid synthesis of imidazo[1,2-a] pyridines by
either thermal or microwave reactions. We describe here-
in the unexpected synthesis of ethyl 2-methylimidazo[1,2-
a]pyridine-3-carboxylate (3a), under solvent-free condi-
tions, employing 2-aminopyridine (1) and ethyl 2-bromo-
3-oxobutanoate (2a, R1 = Et, R2 = Me) (Scheme 1). This
reaction was found by chance during our recent investiga-
tions on the synthesis of 3-bromo-4-methyl-1,8-naphthy-
ridin-2-ol (3), which was of interest to us as a ligand and
base for the copper(I)-catalyzed oxidative homocoupling
of terminal alkynes in the presence of an oxidant.16
Br
Br
2d
2e
Figure 1 Structures of a-bromo-b-keto esters 2a–e
The reactions of 2-aminopyridine (1) with a-bromo-b-
keto esters 2b–e were carried out in a similar manner to
that described above to afford alkyl/benzyl 2-alkyl/phe-
nylimidazo[1,2-a]pyridine-3-carboxylates 3b–e. The
yields and reaction times are summarized in Table 1. Eth-
yl 2-bromo-3-oxo-3-phenylpropanoate (2e) gave an 89%
yield of ethyl 2-phenylimidazo[1,2-a]pyridine-3-carbox-
ylate (3e) (Table 1, entry 5). In the present studies, none
of the corresponding 1,8-naphthyridin-2-ols of type 3 was
formed.
SYNTHESIS 2011, No. 4, pp 0635–0641
x
x
.
x
x
.2
0
1
1
Advanced online publication: 12.01.2011
DOI: 10.1055/s-0030-1258405; Art ID: Z27510SS
© Georg Thieme Verlag Stuttgart · New York

636
K. C. Chunavala et al.
PAPER
Table 1 Synthesis of 2-Alkyl- or 2-Phenylimidazo[1,2-a]pyridine-
3-carboxylates 3a–ea
Table 2 Synthesis of Substituted 2-Alkyl- or 2-Phenylimidazo[1,2-
a]pyridine-3-carboxylates 5a–ka
OR1
COOR1
OR1
R3
R5
COOR1
O
O
O
O
R4
R5
R4
R3
neat
N
Br
neat
R2
+
Br
N
+
R2
r.t. to 55 °C
N
r.t. to 55 °C
N
NH2
R2
N
N
NH2
R2
1
2a–e
3a–e
4a–e
2a,b,e
5a–k
Entry
b-Keto ester Time (min) Product
Yield (%)b
Entry
2-
b-Keto
Time
(min)
Product
Yield
(%)b
Aminopyridine ester
1
2
3
4
5
2a
2b
2c
2d
2e
10
10
35
30
25
3a
3b
3c
3d
3e
87
89
84
84
89
1
2
4a
4b
4c
4a
4b
4c
4a
4b
4c
4d
4e
2a
2a
2a
2b
2b
2b
2e
2e
2e
2e
2a
15
15
20
15
15
20
20
20
20
25
30
5a
5b
5c
5d
5e
5f
85
87
84
84
86
86
83
85
85
84
58
3
4
a 2-Aminopyridine (1) (1.0 mmol), b-keto ester 2a–e (1.0 mmol).
5
b Yield of isolated product.
6
7
5g
5h
5i
Using the optimized reaction conditions, substituted 2-
aminopyridines 4a–e (Figure 2) were reacted with a-bro-
mo-b-keto esters 2a,b,e to afford the corresponding 2-
alkyl/phenylimidazo[1,2-a]pyridine-3-carboxylates 5a–
k; the results are summarized in Table 2. In general, the
reactions proceeded smoothly and were complete within
35 minutes giving the products in yields ranging from 80–
89% (apart from imidazo[1,2-a]pyridine 5k which was
obtained in a moderate 58% yield).
8
9
10
11
5j
5k
a Substituted 2-aminopyridine 4a–e (1.0 mmol), b-keto ester 2a,b,e
(1.0 mmol).
b Yield of isolated product.
R3
4a: R3 = Me, R4 = R5 = H
R4
marised in Table 3. Under these conditions the reactions
were very rapid and clean, and the substituted imida-
zo[1,2-a]pyridine products were isolated in 85–95%
yields. The structures of the products prepared under mi-
crowave irradiation conditions were confirmed by com-
4b: R3 = R5 = H, R4 = Me
4c: R3 = R5 = H, R4 = Br
4d: R3 = Me, R4 = Br, R5 = H
4e: R3 = H, R4 = Br, R5 = Me
R5
N
NH2
4a–e
Figure 2 Structures of substituted 2-aminopyridines 4a–e
1
paring their H NMR spectra with those of the same
products prepared via traditional heating (see Tables 1
and 2).
The structure of product 5g was confirmed unambiguous-
ly by single crystal X-ray diffraction (Figure 3).17
OR1
Br
R3
R5
COOR1
R2
O
O
R4
R5
R4
R3
neat
N
+
MW (100 W)
Al2O3
N
N
NH2
R2
Scheme 2 Alumina-supported microwave reaction of 2-aminopyri-
dines with a-bromo-b-keto esters
Figure 3 ORTEP diagram of compound 5g
The advantages of our protocol include the use of com-
mercially available and inexpensive 2-aminopyridines
and a-bromo-b-keto esters, rapid reactions (less than two
minutes using microwave irradiation and less than 35
minutes under thermal heating), mild conditions, a simple
work-up, high yields of products and no contamination
with by-products. The harsh conditions typically em-
ployed for the synthesis of substituted imidazo[1,2-
a]pyridines12c,18 are thus avoided. The present method
does not require the use of expensive or corrosive re-
We also describe herein the microwave-assisted synthesis
of representative substituted imidazo[1,2-a]pyridine-3-
carboxylates under solvent-free conditions (Scheme 2).
The reactions of 2-aminopyridines 1 and 4a–d with a-bro-
mo-b-keto esters 2a,b,e were carried out on neutral alumi-
na (Al2O3) as a solid support under microwave irradiation
(100 W) for 50–90 seconds, with a five-second interval
for every 15 seconds of reaction time. The results are sum-
Synthesis 2011, No. 4, 635–641 © Thieme Stuttgart · New York

PAPER
Syntheses of Substituted Imidazo[1,2-a]pyridines
637
(Scheme 4). As expected the highly reactive C-2 and C-3
carbons of the b-keto ester participated selectively in the
cyclization to give the desired product 7, and not com-
pound 8 which would occur via reaction at carbons C-3
and C-4.
Table 3 Microwave-Assisted Synthesis of Substituted 2-Alkyl- or
2-Phenylimidazo[1,2-a]pyridine-3-carboxylatesa
OR1
R3
R5
COOR1
O
O
R4
R5
R4
R3
neat
Br
N
+
R2
MW (100 W)
Al2O3
N
N
NH2
R2
OEt
COOEt
1,4a–d
2a,b,e
3,5
O
COOEt
neat
N
N
Br
+
X
Entry
2-Amino-
pyridine
b-Keto
ester
Time
(sec)
Product
Yield
(%)b
O
55 °C
N
NH2
N
Br
N
Cl
Cl
7
6
8
1
1
2
3
4
5
6
7
8
1
2e
2a
2b
2e
2e
2a
2b
2e
60
60
50
50
60
70
70
90
3e
5a
5d
5g
5h
5c
5f
95
94
92
95
93
85
92
91
Scheme 4 Reaction of 2-aminopyridine (1) with ester 6
4a
4a
4a
4b
4c
4c
4d
In conclusion, we have developed a convenient, simple
and rapid one-step approach for the direct synthesis of
highly substituted imidazo[1,2-a]pyridine-3-carboxylates
via thermal and microwave-assisted reactions of readily
available 2-aminopyridines and various a-bromo-b-keto
esters, under solvent-free conditions. All the reactions
proceeded efficiently to provide the desired products in
high yields, apart from 5k which was obtained in a mod-
erate 58% yield. This novel route also allows reactive
functionalities to be installed on the imidazole moiety for
the synthesis of promising pharmacophores that are found
in many biologically active compounds.
5j
a 2-Aminopyridine 1,4a–d (1.0 mmol), b-keto ester 2a,b,e (1.0
mmol), MW (100 W).
b Yield of isolated product.
agents, or transition-metal catalysts, and no precautions
need to be taken to exclude moisture.
All commercially available reagents were used without further pu-
rification unless otherwise indicated, and all reactions were carried
out in air without any special precautions. Microwave-assisted reac-
tions were accomplished using a Milstone Start S (Italy) program-
mable microwave oven (model no. Start S; Terminal T260; Line
voltage 230 V; Magnetron SN131528; Frequency 50 Hz). Melting
points were obtained using a Mettler Toledo FP62 melting point ap-
paratus with open capillary tubes and are uncorrected. Column
chromatography was carried out on basic alumina (Sisco Research
Laboratory; 60–325 mesh). Analytical thin layer chromatography
(TLC) was performed on precoated Aluchrosep silica gel 60/UV254
plates. 1H and 13C NMR spectra were recorded at 200 MHz and 50
MHz, respectively, for compounds 3a–e and 500 MHz and 125
MHz, respectively, for compounds 5a–k and 7, using CDCl3 as the
solvent. The 1H and 13C chemical shifts were referenced to the re-
sidual solvent signals at dH 7.26 and dC 77.28 (CDCl3) relative to
TMS as the internal standard. IR spectra were obtained using a
Perkin Elmer GX-2000 FT-IR spectrometer. GC–MS analyses were
recorded using a Shimadzu GCMS-QT2010 with an HP-5 column.
Low-resolution mass spectra (ESI) were recorded in positive mode
using a Waters Micromass Q-ToF instrument. Elemental analyses
were obtained using a Perkin Elmer 2400 Series II CHNS/O analyz-
er.
A possible mechanism for the formation of products 3a–e
and 5a–k is illustrated in Scheme 3. It is rational to as-
sume that intermediate I results from initial reaction of the
2-aminopyridine with a-bromo-b-keto esters 2a–e. Next,
elimination of a molecule of water leads to the more stable
conjugated intermediate II. Finally, intramolecular cy-
clization of II with loss of hydrogen bromide yields the
imidazo[1,2-a]pyridine-3-carboxylates.
R5
R1O
Br
R2
R3
R4
R3
O
O
O
N
H
R4
Br
NH2
+
OH
– H2O
N
N
R2
H
OR1
2a–e
R5
1, 4a–e
I
R5
R1O
Br
R5
O
OR1
R2
R4
R3
O
R4
R3
N
N
– HBr
N
H
R2
N
II
3a–e, 5a–k
Ethyl 2-Methylimidazo[1,2-a]pyridine-3-carboxylate (3a); Typ-
ical Thermal Procedure
Ethyl 2-bromo-3-oxobutanoate (2a) (1.11g, 5.32 mmol) was added
slowly to 2-aminopyridine (1) (500 mg, 5.32 mmol), at r.t. under
stirring. The mixture was heated at 55 °C for 10 min. The reaction
progress was monitored by GC–MS. After completion, the mixture
Scheme 3 A possible mechanism for the formation of products 3a–
e and 5a–k
We also prepared an imidazo[1,2-a]pyridine derivative
possessing a reactive functionality on the imidazole moi- was made basic (pH 8–9) by the addition of sat. aq Na2SO3 soln. The
product was extracted with EtOAc (3 × 10 mL), the combined or-
ganic layers washed with sat. aq Na2SO3 soln (2 × 10 mL) and dried
over anhyd Na2SO4. The solvent was removed under reduced pres-
sure and the crude residue was subjected to column chromatography
over basic Al2O3 (eluent: EtOAc–hexane, 0.5:9.5) to afford pure 3a.
ety. Reaction of 2-aminopyridine (1) with ethyl 2-bromo-
4-chloro-3-oxobutanoate (6) using the above-mentioned
thermal conditions afforded ethyl 2-(chloromethyl)imida-
zo[1,2-a]pyridine-3-carboxylate (7) in 69% isolated yield
Synthesis 2011, No. 4, 635–641 © Thieme Stuttgart · New York

638
K. C. Chunavala et al.
PAPER
White crystalline solid; yield: 965 mg (89%); mp 66–68 °C.
13C NMR (50 MHz, CDCl3): d = 153.0, 147.0, 128.6, 128.0, 127.81,
127.80, 126.9, 116.6, 113.7, 113.0, 66.0, 16.8.
IR (KBr): 3407, 3146, 2996, 1679, 1595, 1490, 1412, 1292, 1222,
1094, 850, 761, 669 cm–1.
ESI-MS: m/z = 267.1 [M + H]+.
1H NMR (200 MHz, CDCl3): d = 9.3 (d, J = 6.8 Hz, 1 H, H-5), 7.6
(d, J = 9.0 Hz, 1 H, H-8), 7.3 (dd, J = 7.4, 7.2 Hz, 1 H, H-7), 6.9 (dd,
J = 6.8, 6.6 Hz, 1 H, H-6), 4.4 (q, J = 7.0 Hz, 2 H), 2.7 (s, 3 H), 1.4
(t, J = 7.0 Hz, 3 H).
Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C,
71.85; H, 5.63; N, 10.59.
Cyclohexyl 2-Methylimidazo[1,2-a]pyridine-3-carboxylate (3d)
Colorless liquid.
13C NMR (50 MHz, CDCl3): d = 161.8, 153.1, 147.2, 128.2, 127.6,
116.9, 113.7, 60.5, 16.8, 14.7.
IR (neat): 3408, 3118, 2933, 2859, 1683, 1499, 1447, 1408, 1336,
1291, 1218, 1091, 916, 764, 657 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.3 (dd, J = 7.1, 7.0 Hz, 1 H, H-
5), 7.6 (d, J = 8.8 Hz, 1 H, H-8), 7.3 (dd, J = 8.9 Hz, 1 H, H-7), 6.9
(dd, J = 6.9, 6.8 Hz, 1 H, H-6), 5.1–5.0 (m, 1 H), 2.7 (s, 3 H, Me-2),
2.0–1.4 (m, 10 H, cyclohexyl).
13C NMR (50 MHz, CDCl3): d = 160.8, 152.4, 146.7, 127.8, 127.2,
116.5, 113.4, 72.4, 31.7, 25.4, 23.5, 16.7.
ESI-MS: m/z = 259.1 [M + H]+.
ESI-MS: m/z = 205.1 [M + H]+.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.73; H, 5.54; N, 13.78.
Ethyl 2-Phenylimidazo[1,2-a]pyridine-3-carboxylate (3e); Typ-
ical Microwave-Assisted Procedure
A mixture of 2-aminopyridine (1) (500 mg, 5.32 mmol) and ethyl 2-
bromo-3-oxo-3-phenylpropanoate (2e) (1.11g, 5.32 mmol) was
mixed thoroughly with neutral Al2O3 (1 g), and then irradiated in a
microwave oven at 100 W for 60 sec with a time interval of 5 sec
after every 15 sec of irradiation. The mixture turned brown, and af-
ter cooling to r.t., the residue was diluted with EtOAc (15 mL) and
made basic (pH 8–9) by addition of sat. aq Na2SO3 soln. The organ-
ic layer was washed with sat. aq Na2SO3 soln (2 × 10 mL) and dried
over anhyd Na2SO4. The solvent was removed under reduced pres-
sure and the crude residue was subjected to column chromatography
over basic Al2O3 (eluent: EtOAc–hexane, 5:95) to afford pure com-
pound 3e.
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C,
70.09; H, 7.07; N, 10.49.
Ethyl 2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylate (5a)
White crystalline solid; mp 64–66 °C.
IR (KBr): 3419, 3075, 2982, 2909, 1685, 1492, 1410, 1316, 1219,
1142, 1096, 1035, 795, 749 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.1 (d, J = 7.0 Hz, 1 H, H-5), 7.3
(s, 1 H, H-7), 6.7 (d, J = 7.0 Hz, 1 H, H-6), 4.4 (q, J = 7.0 Hz, 2 H),
2.6 (s, 3 H, Me-2), 2.4 (s, 3 H, Me-7), 1.4 (t, J = 7.0 Hz, 3 H).
White crystalline solid; yield: 1.349 g (95%); mp 51–53 °C.
13C NMR (125 MHz, CDCl3): d = 161.5, 152.8, 147.3, 138.9, 127.1,
116.1, 115.3, 60.1, 21.3, 16.6, 14.4.
IR (KBr): 3144, 3038, 2979, 1679, 1496, 1475, 1402, 1383, 1334,
1221, 1161, 1047, 840, 755, 700 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.4 (d, J = 6.8 Hz, 1 H, H-5), 7.8–
7.7 (m, 3 H), 7.4–7.3 (m, 4 H), 7.0 (dd, J = 7.2, 6.8 Hz, 1 H, H-6),
4.3 (q, J = 7.2 Hz, 2 H), 1.2 (t, J = 7.2 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 161.1, 153.5, 134.4, 130.1, 128.6,
128.3, 127.8, 127.5, 117.4, 114.0, 60.4, 13.9.
ESI-MS: m/z = 219.1 [M + H]+.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.50; H, 6.45; N, 12.89.
Ethyl 2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylate (5b)
White crystalline solid; mp 65–67 °C.
ESI-MS: m/z = 259.1 [M + H]+.
IR (KBr): 3406, 2987, 2931, 1683, 1539, 1421, 1395, 1244, 1162,
1136, 1087, 816, 770 cm–1.
Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C,
71.70; H, 5.36; N, 10.60.
1H NMR (200 MHz, CDCl3): d = 9.1 (s, 1 H, H-5), 7.5 (d, J = 9.0
Hz, 1 H, H-8), 7.2 (d, J = 9.0 Hz, 1 H, H-7), 4.4 (q, J = 7.2 Hz, 2
H), 2.6 (s, 3 H, Me-2), 2.3 (s, 3 H, Me-6), 1.4 (t, J = 7.2 Hz, 3 H).
Methyl 2-Methylimidazo[1,2-a]pyridine-3-carboxylate (3b)
White crystalline solid; mp 70–72 °C.
13C NMR (125 MHz, CDCl3): d = 162.1, 153.0, 146.4, 131.0, 126.5,
124.0, 116.4, 112.9, 60.8, 19.0, 17.3, 15.1.
IR (KBr): 3389, 2955, 1688, 1495, 1446, 1401, 1330, 1224, 1130,
1093, 804, 762 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.3 (d, J = 7.0 Hz, 1 H, H-5), 7.6
(d, J = 9.0 Hz, 1 H, H-8), 7.4 (dd, J = 7.4, 6.8 Hz, 1 H, H-7), 6.9
(dd, J = 7.0, 6.8 Hz, 1 H, H-6), 3.9 (s, 3 H), 2.7 (s, 3 H, Me-2).
13C NMR (50 MHz, CDCl3): d = 161.6, 152.8, 146.9, 127.8, 127.3,
116.6, 113.4, 50.9, 16.3.
ESI-MS: m/z = 219.1 [M + H]+.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.40; H, 6.68; N, 12.90.
Ethyl 6-Bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate
(5c)
White crystalline solid; mp 120–122 °C.
ESI-MS: m/z = 191.1 [M + H]+.
Anal. Calcd for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C,
62.80; H, 5.42; N, 14.39.
IR (KBr): 3406, 2987, 2931, 1683, 1539, 1421, 1395, 1244, 1162,
1136, 1087, 816, 770 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.1 (s, 1 H, H-5), 7.5 (d, J = 9.0
Hz, 1 H, H-8), 7.2 (d, J = 9.0 Hz, 1 H, H-7), 4.4 (q, J = 7.2 Hz, 2
H), 2.7 (s, 3 H, Me-2), 1.4 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 161.7, 153.5, 145.7, 131.6, 128.7,
117.7, 113.5, 109.2, 61.2, 17.2, 15.1.
Benzyl 2-Methylimidazo[1,2-a]pyridine-3-carboxylate (3c)
White crystalline solid; mp 85–87 °C.
IR (KBr): 3264, 3036, 2932, 2860, 1685, 1498, 1408, 1363, 1215,
1090, 1015, 758, 696 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.3 (d, J = 6.8 Hz, 1 H, H-5), 7.6
(dd, J = 9 Hz, 1 H, H-8), 7.4–7.3 (m, 6 H), 6.9 (dd, J = 6.8, 5.8 Hz,
1 H, H-6), 5.4 (s, 2 H), 2.7 (s, 3 H, Me-2).
ESI-MS: m/z = 283.0 [M + H]+.
Anal. Calcd for C11H11BrN2O2: C, 46.66; H, 3.92; N, 9.89. Found:
C, 46.27; H, 4.09; N, 9.64.
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Syntheses of Substituted Imidazo[1,2-a]pyridines
639
Methyl 2,7-Dimethylimidazo[1,2-a]pyridine-3-carboxylate (5d)
White crystalline solid; mp 118–120 °C.
IR (KBr): 2979, 2925, 1672, 1501, 1387, 1332, 1241, 1167, 1044,
811, 756, 700 cm–1.
IR (KBr): 3130, 3034, 2947, 1686, 1513, 1493, 1466, 1435, 1395,
1267, 1221, 1170, 1138, 1087, 1024, 801, 769, 751 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.10 (d, J = 7.0 Hz, 1 H, H-5), 7.3
(s, 1 H, H-8), 6.8 (d, J = 7.0 Hz, 1 H, H-6), 3.9 (s, 3 H), 2.6 (s, 3 H,
Me-2), 2.4 (s, 3 H, Me-7).
13C NMR (50 MHz, CDCl3): d = 161.8, 153.0, 147.5, 138.9, 127.1,
115.9, 115.4, 50.9, 21.1, 16.3.
1H NMR (200 MHz, CDCl3): d = 9.2 (s, 1 H, H-5), 7.7 (d, J = 3.6
Hz, 2 H), 7.6 (d, J = 9.0 Hz, 1 H, H-8), 7.4 (d, J = 3.4 Hz, 3 H), 7.30
(s, 1 H, H-7), 4.2 (q, J = 7.0 Hz, 2 H), 2.4 (s, 3 H, Me-6), 1.2 (t,
J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 161.1, 146.1, 134.8, 130.6, 130.1,
128.4, 127.4, 126.1, 123.8, 116.7, 60.2, 18.4, 13.9.
ESI-MS: m/z = 281.1 [M + H]+.
ESI-MS: m/z = 205.1 [M + H]+.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.98; H, 5.70; N, 9.83.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.76; H, 6.15; N, 13.43.
Ethyl 6-Bromo-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(5i)
Methyl 2,6-Dimethylimidazo[1,2-a]pyridine-3-carboxylate (5e)
White crystalline solid; mp 132–134 °C.
White crystalline solid; mp 72–74 °C.
IR (KBr): 3132, 3028, 1680, 1486, 1379, 1336, 1212, 1072, 1038,
822, 764 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.6 (dd, J = 1.8 Hz, 1 H, H-5), 7.8–
7.7 (m, 2 H), 7.65 (d, J = 9.4 Hz, 1 H, H-8), 7.60 (d, J = 9.5 Hz, 1
H, H-7), 7.5–7.4 (m, 3 H), 4.3 (q, J = 7.2 Hz, 2 H), 1.2 (t, J = 7.2
Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 161.5, 154.4, 146.1, 134.6, 132.0,
130.8, 129.5, 129.1, 128.3, 118.6, 109.6, 61.4, 14.6.
ESI-MS: m/z = 345.0 [M + H]+.
IR (KBr): 3358, 2930, 1685, 1512, 1449, 1395, 1370, 1271, 1246,
1198, 1163, 1092, 1035, 810, 766 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.1 (s, 1 H, H-5), 7.5 (d, J = 8.4
Hz, 1 H, H-8), 7.2 (d, 1 H, H-7), 3.9 (s, 3 H), 2.6 (s, 3 H, Me-2), 2.3
(s, 3 H, Me-6).
13C NMR (125 MHz, CDCl3): d = 162.6, 153.3, 146.6, 131.2, 126.6,
124.2, 116.5, 112.8, 51.9, 19.0, 17.3.
ESI-MS: m/z = 205.1 [M + H]+.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.50; H, 5.84; N, 13.40.
Anal. Calcd for C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12. Found:
C, 55.74; H, 3.79; N, 8.21.
Methyl 6-Bromo-2-methylimidazo[1,2-a]pyridine-3-carboxy-
late (5f)
White crystalline solid; mp 113–115 °C.
Ethyl 6-Bromo-7-methyl-2-phenylimidazo[1,2-a]pyridine-3-
carboxylate (5j)
White crystalline solid; mp 132–134 °C.
IR (KBr): 3134, 3064, 3001, 2951, 1685, 1517, 1490, 1445, 1391,
1364, 1338, 1286, 1212, 1143, 1165, 1019, 858, 816, 765 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.4 (s, 1 H, H-5), 7.5 (d, J = 9.4
Hz, 1 H, H-8), 7.4 (d, J = 9.6 Hz, 1 H, H-7), 3.9 (s, 3 H), 2.6 (s, 3 H,
Me-2).
13C NMR (125 MHz, CDCl3): d = 162.2, 153.8, 146.0, 131.7, 128.8,
117.8, 113.5, 109.2, 52.2, 17.2.
IR (KBr): 2979, 2925, 1672, 1501, 1387, 1332, 1241, 1167, 1044,
811, 756, 700 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.6 (s, 1 H, H-5), 7.7 (t, J = 3.2
Hz, 2 H), 7.5 (s, 1 H, H-8), 7.4 (d, J = 3.4 Hz, 3 H), 4.3 (q, J = 7.0
Hz, 2 H), 2.5 (s, 3 H, Me-7), 1.2 (t, J = 7.0 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 167.5, 130.1, 128.6, 128.0, 127.4,
126.0, 125.3, 120.3, 116.5, 107.1, 60.4, 22.6, 13.9.
ESI-MS: m/z = 269.0 [M + H]+.
ESI-MS: m/z = 359.0 [M + H]+.
Anal. Calcd for C10H9BrN2O2: C, 44.63; H, 3.37; N, 10.41. Found:
C, 44.32; H, 3.10; N, 10.30.
Anal. Calcd for C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80. Found:
C, 56.45; H, 4.12; N, 8.15.
Ethyl 7-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(5g)
White crystalline solid; mp 88–90 °C.
Ethyl 6-Bromo-2,5-dimethylimidazo[1,2-a]pyridine-3-carboxy-
late (5k)
White crystalline solid; mp 91–93 °C.
IR (KBr): 3431, 3056, 2992, 2915, 1678, 1644, 1486, 1401, 1377,
1224, 1162, 1050, 796, 751, 701 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.2 (d, J = 7.2 Hz, 1 H, H-5), 7.7
(m, 2 H), 7.48 (s, 1 H, H-8), 7.4–7.3 (m, 3 H), 6.8 (d, J = 7.2 Hz, 1
H, H-6), 4.3 (q, J = 7.2 Hz, 2 H), 2.4 (s, 3 H, Me-7), 1.2 (t, J = 7.2
Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 161.1, 147.5, 139.2, 134.0, 130.1,
128.5, 127.4, 116.4, 116.0, 60.3, 21.4, 14.0.
ESI-MS: m/z = 281.1 [M + H]+.
IR (KBr): 3430, 2978, 2927, 1703, 1496, 1407, 1371, 1275, 1200,
1092, 1027, 811, 761, 685 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.5 (d, J = 9.4 Hz, 1 H, H-8), 7.3
(d, J = 9.4 Hz, 1 H, H-7), 4.4 (q, J = 7.2 Hz, 2 H), 2.7 (s, 3 H, Me-
5), 2.6 (s, 3 H, Me-2), 1.4 (t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 160.9, 152.6, 147.0, 136.7, 152.0,
115.8, 114.8, 111.0, 61.1, 22.2, 16.0, 14.5.
ESI-MS: m/z = 297.0 [M + H]+.
Anal. Calcd for C12H13BrN2O2: C, 48.50; H, 4.41; N, 9.43. Found:
C, 48.41; H, 4.11; N, 9.15.
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.56; H, 6.00; N, 10.11.
Ethyl 2-(Chloromethyl)imidazo[1,2-a]pyridine-3-carboxylate
(7)
Brown viscous liquid.
Ethyl 6-Methyl-2-phenylimidazo[1,2-a]pyridine-3-carboxylate
(5h)
White crystalline solid; mp 72–74 °C.
IR (neat): 3433, 2926, 2856, 1734, 1639, 1502, 1463, 1378, 1166,
1083, 1027, 911, 734, 648 cm–1.
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K. C. Chunavala et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 9.3 (d, J = 6.8 Hz, 1 H, H-5), 7.7
(d, J = 9.0 Hz, 1 H, H-8), 7.4 (dd, J = 7.4 Hz, 1 H, H-7), 7.0 (dd,
J = 6.8 Hz, 1 H, H-6), 5.0 (s, 2 H), 4.5 (q, J = 7.0 Hz, 2 H), 1.5 (t,
J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 170.9, 144.9, 128.9, 128.3, 125.7,
117.4, 115.4, 112.5, 61.2, 35.1, 14.4.
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40, 1170. (b) Rewankar, G. R.; Matthews, J. R.; Robins, R.
K. J. Med. Chem. 1975, 18, 1253. (c) Ismail, M. A.; Arafa,
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Boykin, D. W. Bioorg. Med. Chem. 2008, 16, 683.
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Muthas, D.; Nordqvist, A.; Karlen, A.; Larhed, M. Bioorg.
Med. Chem. Lett. 2009, 19, 4790.
ESI-MS: m/z = 276.1 [M + K]– (recorded in negative mode).
(6) (a) Beswick, P. J.; Campbell, I. B.; Naylor, A. WO9631509,
1996; Chem. Abstr. 1997, 126, 8117j. (b) Abignente, E.
Acta Chim. Therap. 1991, 18, 1253. (c) Gudmundsson, K.
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R. J. Med. Chem. 1991, 34, 2060. (b) Trapani, G.; Franco,
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Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found:
C, 54.98; H, 4.28; N, 11.41.
Acknowledgment
We thank Mr. Hitesh, Mr. A. K. Das, Mr. H. Brahmbhatt, Mr. V.
Agrawal and Mr. Viral from our Analytical Division for providing
IR, NMR, and mass spectra and elemental analyses. G.J. and K.C.C.
are grateful to the Council of Scientific & Industrial Research, New
Delhi, India for the awards of Senior Research Fellowship and Ju-
nior Research Fellowship, respectively.
(8) Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.;
Moore, J. B. Jr. J. Med. Chem. 1991, 34, 2060.
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Synthesis 2011, No. 4, 635–641 © Thieme Stuttgart · New York

PAPER
Syntheses of Substituted Imidazo[1,2-a]pyridines
R(int) = 0.0225, data/restraints/parameters: 2813/0/193,
641
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(17) X-ray crystal data for 5g: empirical formula: C17H16N2O2,
formula weight: 280.32, T = 293(2) K, l = 0.71073, crystal
system: monoclinic, space group: P21/c, unit cell
dimensions: a = 11.419(3) Å, b = 14.292(4) Å, c = 9.001(2)
Å, b = 99.912(4)°, V = 1447.1(6) Å3, Z = 4, density
(calcd) = 1.287 mg/m3, absorption coefficient: 0.086 mm–1,
F(000) = 592, crystal size: 0.32 × 0.21 × 12 mm, reflections
collected: 7540, independent reflections: 2813,
goodness-of-fit on F2 = 1.151, final R indices [I ≥ 2s(I)],
R1 = 0.0623, wR2 = 0.1392, R indices (all data):
R1 = 0.0742, wR2 = 0.1456, largest diff. peak and hole:
0.204 and –0.219 eÅ–3. CCDC 793451 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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2941.
Synthesis 2011, No. 4, 635–641 © Thieme Stuttgart · New York