Synthesis and characterisation of novel N substituted 2-methylimidazo[1,2a] pyridine-3-carboxamides

Article abstract of DOI:10.3184/174751911X13026260434797

A series of novel N substituted 2-methylimidazo[1,2a]pyridine-3- carboxamides has been synthesised in high yield by a convenient method and characterised by ¹H NMR, MS, IR and elemental analysis.

Full text of DOI:10.3184/174751911X13026260434797

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 243
APRIL, 243–245
Synthesis and characterisation of novel N substituted
2-methylimidazo[1,2a]pyridine-3-carboxamides
Tao Han, Zhichuan Shi, Yongle Peng and Zhigang Zhao*
College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, P. R. China
A series of novel N substituted 2-methylimidazo[1,2a]pyridine-3-carboxamides has been synthesised in high yield by
a convenient method and characterised by 1H NMR, MS, IR and elemental analysis
Keywords: 2-aminopyridine, heterocycle, amide, imidazole[1,2a]pyridine
Nitrogen bridge-head heterocycles containing an imidazole
[1,2a]pyridine ring are a common and important structural
motif in pharmaceutical products, with activities spanning a
diverse range of targets. Several reports in the literature
described the application of these substances as inhibitors of
UV-induced keratinocytic apoptosis1 and as antiviral agents.2
Recently, many reports described this type of compounds as
having potential as inhibitors of the gastric H+/K+-ATPase,3 as
IRAK-4 inhibitors,4 as HIF-1α prolyl hydroxylase inhibitors,5
and with anti-proliferative and DNA-intercalating activity,6
analgesic and anti-inflammatory7, cyclin-dependent kinase
inhibitors8.
Until now, most efforts have been focused on preparing
compounds with different substituents in the 5, 6, 7, 8 positions.
However, to the best of our knowledge, studies on the position
3 have rarely been reported. Prompted by these observations
and in continuation of our research on the preparation of new
heterocyclic compounds with anticipated biological activity, in
the pharmaceutical area, we have synthesised a series of novel
Nsubstituted2-methylimidazo[1,2a]pyridine-3-carboxamides.
The synthetic route is depicted in Scheme 1.
Experimental
Melting points were determined on a micro-melting point apparatus
and the thermometer was uncorrected. Infrared spectra were obtained
on 1700 Perkin-Elmer FTIR using KBr disks. 1H NMR spectra were
recorded on a Brucker 300 MHz spectrometer using CDCl3 as solvent
and TMS as internal standard. Mass spectra were determined on
FinniganLCQDECA instrument. Elemental analysis was performed on a
Carlo-Erba-1106 autoanalyser. All the solvents were purified before
use.
Methyl 2-chloro-3-oxobutanoate (1): Sulfuryl dichloride (0.1 mol)
was added to methyl 3-oxobutanoate (0.1mol) drop wise at 0 °C. After
the addition, the mixture was stirred overnight. The mixture was con-
centrated to dryness to give compound 1, which was used in the next
step without further purification.
Methyl 2-methylimidazo[1,2a]pyridine-3-carboxylate (2): Methyl
2-chloro-3-oxobutanoate 1 and 2-aminopyridine were dissolved in
methanol. The mixture was stirred overnight at room temperature.
The mixture was evaporated to dryness to give a brown oil. The oil
was purified with silica chromatography (ethyl acetate: petroleum
ether = 2:1) to give pure compound 2 as a white solid, yield 88%, m.p.
57–58 °C; IR (KBr) (cm−1): 2955, 1688, 1469, 1222, 761; H NMR
1
(300 MHz, CDCl3) δ: 9.32–9.29 (m, 1H, 5-H), 7.64(d, J = 9.0 Hz, 1H,
8-H), 7.41–7.36 (m, 1H, 7-H), 7.01–6.96 (m, 1H, 6-H), 3.97 (s, 3H,
OCH3), 2.72 (s, 3H, 2-CH3); ESI-MS: 191([M+1]+, 100). Ana1.Calcd
for C10H10N2O2: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.37; H, 5.28;
N, 14.77%.
Result and discussion
2-Methylimidazo[1,2a]pyridine-3-carboxylic acid (3): Compound
2 (10 mmol) was stirred in 10 mL 1 M aqueous sodium hydroxide
for 3 hours. The solution was acidified to deposit a solid, which was
filtered. The solid was dried under vacuum. White solid, m.p. 182–
183 °C, (lit12 185 °C); IR (KBr) (cm−1): 3378, 2967, 1687, 1520, 1446,
1132, 758; 1H NMR (300 MHz, DMSO- d6) δ: 13.50 (br, s, 1H,
COOH), 9.42 (d, 1H, J = 5.1 Hz, 5-H), 7.87–7.79(m, 2H, 8-H and 7-
H), 7.43–7.39(m, 1H, 6-H), 2.69 (s, 3H, CH3). ESI-MS: 175([M-1]+,
100).
Intermediates 1, 2, 3, 4 were prepared according to the literature
methods.9–11 The new intermediate 2-methylimidazo[1,2a]pyri
dine-3-carboxylate 2 was obtained by condensation of methyl
2-chloro-3-oxobutanoate 1 with 2-aminopyridine- in methanol.
At first, we intended to directly synthesise the target compound
5 from 2. However, the reaction required harsh conditions,
a long reaction time and the yield was very low. Consequently
we used the route as shown above. 2-Methylimidazo[1,2a]
pyridine-3-carboxylic acid 3 was obtained by hydrolysing
compound 2 with 1 mol aqueous sodium hydroxide. Com-
pound 3 was refluxed in thionyl chloride for 2 hours and then
the mixture was evaporated to give pure compound 4.
2-Methylimidazo[1,2a]pyridine-3-carbonyl chloride (4): Com-
pound 3 was refluxed in 10mL thionyl chloride for 2 hours. The mix-
ture was evaporated to dryness to give pure compound 4 as a light
brown solid, m.p.140–142 °C; IR (KBr) (cm−1): 2923, 1655, 1493,
1
1452, 1112; H NMR (300 MHz, CDCl3) δ: 9.53 (d, 1H, J = 4.8 Hz,
1
All the compounds 5a–i were confirmed by IR, mass, H
5-H), 8.45(d, 1H, J = 6.0 Hz, 8-H), 8.12(d, 1H, J = 4.8, 6-H), 7.65 (d,
J = 6.0 Hz, 1H, 7-H), 2.69 (s, 3H, CH3). ESI-MS: 195([M+1]+, 100).
Ana1.Calcd for C9H7ClN2O: C, 55.54; H, 3.63; N, 14.39. Found: C,
55.72; H, 3.62; N, 14.42%.
NMR and elemental analysis. Their mass spectra showed the
1
expected molecular ions in high intensity. In the H NMR
spectra, the peaks between 6.5 and 10 ppm were assigned to
the proton in the imidazo [1,2a]pyridine, and a singlet due to
2-CH3 was observed at 2-3 ppm. Compounds (5a, 5d, 5f, 5h)
have the singlet peak in 6–7 ppm due to the CONH. All of
the spectra showed appropriate chemical shifts and coupling
constants for the R group. In IR spectra, the strong bands about
1620 cm−1 indicated the absorption of C=O.
In conclusion, we have synthesised nine new N substituted
2-methylimidazo[1,2a]pyridine-3-carboxamides. The whole
synthetic routes were simple, convenient to use and the final
yields were high. The details of biological activities of 5a–i are
the subject of further examination.
Preparation of 2-methylimidazo[1,2a]pyridine-3-carboxamide 5a–i
Compound 4 was dissolved in dichloromethane and the solution
was added to the solution of the amine (12 mmol) and triethylamine
(15 mmol) in dichloromethane 20 mL. The solution was stirred for
30 min. The mixture was evaporated to dryness and purified by flash
silica chromatography (ethyl acetate: petroleum ether: triethylamine =
1.5:1:1) to give pure 5a–i. The physical and spectroscopic date of
compounds 5a–i are as follows.
N-cyclopropyl-2-methylimidazo[1,2a]pyridine-3-carboxamide
(5a): White solid, yield 83%, m.p.136–137 °C; IR (KBr) (cm−1): 3303,
1622, 1542, 1502, 756; 1H NMR (300 MHz, CDCl3) δ: 9.42–9.39 (m,
1H, 5-H), 7.56 (d, J = 9.0 Hz, 1H, 8-H), 7.34–7.28 (m, 1H, 7-H),
6.92–6.87 (m, 1H, 6-H), 5.94 (s, 1H,CONH), 2.85–2.76 (m, 1H, CH),
2.72 (s, 1H, CH3), 0.67–0.61 (m, 4H, CH2); ESI-MS: 216 ([M+1]+,
100). Ana1.Calcd for C12H13N3O: C, 66.96; H, 6.09; N, 19.52. Found:
C, 70.11; H, 6.07; N, 19.58%.
* Correspondent. E-mail: zzg63129@yahoo.com.cn

244 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 1
N-Diisopropyl-2-methylimidazo[1,2a]pyridine-3-carboxamide
6.98–6.93 (m, 1H, 6-H), 6.12 (s, 1H, CONH), 4.75 (d, J = 5.4 Hz, 2H,
PhCH2), 2.71 (s, 3H, 2-CH3); ESI-MS m/z (%): 266 ([M+1]+, 100).
Ana1. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found:
C, 72.21; H, 5.72; N, 15.81%.
(5b): White solid, yield 85%, m.p.127–129 °C; IR (KBr) (cm−1): 2971,
1
1617, 1547, 1446, 1316, 750. H NMR(300 MHz, CDCl3)δ: 8.12 (d,
J = 6.9 Hz, 1H, 5-H), 7.52 (d, J = 9.0 Hz, 1H, 8-H), 7.20–7.14 (m, 1H,
7-H), 6.80–6.75 (m, 1H, 6-H), 3.87–3.78 (m, 1H, CH), 2.44 (s, 3H,
2-CH3), 1.4 (d, J = 6.6, 12H, CH3); ESI-MS m/z (%): 260 ([M+1]+,
100). Ana1.Calcd for C15H21N3O: C, 69.47; H, 8.16; N, 16.20. Found:
C, 69.87; H, 8.18; N, 16.16%.
N-Benzyl-N-methyl-2-methylimidazo[1,2a]pyridine-3-carbox-
amide (5e): White solid, yield 86%, m.p.155–157 °C; IR (KBr) (cm−1):
1
2935, 1618, 1542, 1438, 756; H NMR (300 MHz, CDCl3) δ: 8.49–
8.46 (m, 1H, 5-H), 7.56–7.58 (d, J = 9.0 Hz, 1H, 8-H), 7.38–7.28 (m,
6H, PhH and 7-H), 6.90–6.85 (m, 1H, 6-H), 3.02 (s, 3H, NCH3), 2.49
(s, 3H, 2-CH3); ESI-MS m/z (%): 280 ([M+1]+, 100). Ana1.Calcd for
C17H17N3O: C, 73.10; H, 6.13; N, 15.04. Found: C, 73.02; H, 6.15; N,
15.07%.
(2-methylimidazo[1,2a]pyridine-3-yl)(piperidin-1-yl)methanone
(5c): White solid, yield 92%. m.p.157–159 °C; IR (KBr) (cm−1): 2988,
1632, 1549, 1392, 760; 1H NMR (300 MHz, CDCl3)δ: 8.51–8.49 (m,
1H, 5-H), 7.77 (d, J = 9.0 Hz, 1H, 8-H), 7.45–7.39 (m, 1H, 7-H),
7.02–6.97 (m, 1H, 6-H), 4.06 (s, 4H, N-CH2), 2.46 (s, 3H, 2-CH3),
1.72–1.64 (m, 6H, CH2); ESI-MS m/z (%): 244 ([M+1]+, 100). Ana1.
Calcd for C14H17N3O: C, 69.11; H, 7.04; N, 17.27. Found: C, 69.01;
H, 7.06; N, 17.25%.
N-Tert-butyl-2-methylimidazo[1,2a]pyridine-3-carboxamide (5f):
White solid, yield 84%, m.p.164–165 °C; IR (KBr) (cm−1): 3238,
1
2974, 1638, 1537, 1453, 1389, 762; H NMR (300 MHz, CDCl3) δ:
9.33–9.30 (m, 1H, 5-H), 7.74–7.71 (d, J = 9.0 Hz, 1H, 8-H), 7.49 (t,
J = 6.9 Hz, 1H, 7-H), 7.07 (t, J = 6.9 Hz, 1H, 6-H), 6.27 (s, 1H,
CONH), 2.76 (s, 3H, 2-CH3), 1.53 (s, 9H, C(CH3)3); ESI-MS m/z (%):
232 ([M+1]+, 100). Anal. Calcd for C13H17N3O: C, 67.51; H, 7.41;
N, 18.17. Found: C, 67.63; H, 7.38, 5; N, 18.15%.
N-Benzyl-2-methylimidazo[1,2a]pyridine-3-carboxamide (5d): White
solid, yield 88%, m.p.151–152 °C; IR (KBr) (cm−1):3272, 2976, 1615,
1
1530, 749; H NMR (300 MHz, CDCl3) δ: 9.48 (d, J = 6.9 Hz, 1H,
5-H), 7.62 (d, J = 9.0 Hz, 1H, 8-H), 7.43–7.30 (m, 6H, PhH and 7-H),

JOURNAL OF CHEMICAL RESEARCH 2011 245
(2-Methylimidazo[1,2a]pyridin-3-yl)(morpholino)methanone (5g):
Received 17 February 2011; accepted 2 April 2011
Paper 1100578 doi: 10.3184/174751911X13026260434797
Published online: 3 May 2011
White solid, yield 92%, m.p.147–148 °C; IR (KBr) (cm−1): 2972,
1
1619, 1523, 1447, 752; H NMR (300 MHz, CDCl3) δ: 8.51 (d, J =
7.7 Hz, 1H, 5-H), 7.56 (d, J = 6.9 Hz, 1H, 8-H), 7.07 (t, J = 6.9 Hz,
1H, 6-H), 6.86 (t, J = 9.0 Hz, 1H, 6-H), 3.76–3.68 (m, 8H, CH2), 2.49
(s, 3H, 2-CH3), ESI-MS m/z (%): 246 ([M+1]+, 100). Ana1.Calcd
for C13H15N3O2: C, 63.66; H, 6.16; N, 17.13. Found: C, 63.55; H, 6.18;
N, 17.16%.
References
1
C.E. Gueiffier, F. Fauvelle, J.C. Debouzy, A. Peinnequin, I. Thery,
V. Dabouis and A. Gueiffier, Eur. J. Pharm. Sci., 2005, 24, 219.
J.M. Chezal, J. Paeshuyse, V. Gaumet, D. Canitrot, A. Maisonial,
C. Lartigue, A. Gueiffier, E. Moreau, J. Teulade, O.R. Chavignon and
J. Neyts, Eur. J. Med. Chem., 2010, 45, 2044.
2
N-Isopropyl-2-methylimidazo[1,2a]pyridine-3-carboxamide (5h):
White solid, yield 82%, m.p.155–156 °C; IR(KBr) (cm−1): 3198, 2972,
1630, 1549, 1466, 761; 1H NMR (300 MHz, CDCl3) δ: 9.38–9.36 (m,
1H, 5-H), 7.54–7.57(d, J = 9.0 Hz, 1H, 8-H), 7.33–7.27 (m, 1H, 7-H),
6.92–6.87 (m, 1H, 6-H), 5.63(d, 1H, J = 6.0 Hz CONH), 4.36–4.29
(m, 1H, CH), 2.68 (s, 3H, 2-CH3), 1.31 (d, J = 6.6 Hz, 6H, CH3); ESI-
MS m/z (%): 218 ([M+1]+, 100). Ana1.Calcd for C12H15N3O: C, 66.34;
H, 6.96; N, 19.34. Found: C, 66.25; H, 6.99; N, 19.36%.
3
4
P.J. Zimmermann, W. Buhr, C. Brehm, A.M. Palmer, M.P. Feth, S.B. Jorg
and W.A. Simon, Bioorg. Med. Chem. Lett., 2007, 17, 5374.
G.M. Buckley, R. Fosbeary, J.L. Fraser, L. Gowers, A.P. Higueruelo,
L.A. James, K. Jenkins, S.R. Mack, T. Morgan, D.M. Parry, W.R. Pitt,
O. Rausch, M.D. Richard and V. Sabin, Bioorg. Med. Chem. Lett., 2008,
18, 3656.
5
6
N.C. Warshakoon, S.D. Wu, A. Boyer, R. Kawamoto, J. Sheville, S.
Renock, K. Xu, M. Pokross, A.G. Evdokimov, R. Walter and M. Mekel,
Bioorg. Med. Chem. Lett., 2006, 16, 5598.
M. Andaloussi, E. Moreau, N. Masurier, J. Lacroix, R.C. Gaudreaultb,
J.M. Chezal a, A.E. Laghdachc, D. Canitrot, E. Debiton, J.C. Teulade and
O. Chavignon, Eur. J. Med. Chem., 2008, 43, 2505.
(2-Methylimidazo[1,2a]pyridin-3-yl)(pyrrolidin-1-yl)methanone
(5i): White solid, yield 94%. m.p.133–135 °C, IR(KBr) (cm−1): 2968,
1
1609, 1533, 1499, 758; H NMR (300 MHz, CDCl3) δ: 8.51 (d, J =
6.9 Hz, 1H, 5-H), 7.54 (d, J = 9.0 Hz, 1H, 8-H), 7.24–7.20 (m, 1H,
7-H), 6.84–6.79 (m, 1H, 6-H), 3.61–3.56 (m, 8H, CH2), 2.50 (s, 3H,
2-CH3); ESI-MS m/z (%): 230 ([M+1]+, 100). Ana1.Calcd for
C13H15N3O: C, 68.10; H, 6.59; N, 18.33. Found: C, 68.23; H, 6.61; N,
18.28%.
7
8
9
R.B. Lacerda, C.K.F. Lima, L.L. Silva, N.C. Romeiro, A.L.P. Miranda,
E.J. Barreiro and C.A.M. Fraga, Bioorg. Med. Chem., 2009, 17, 74.
K.F. Byth, J.D. Culshaw, S. Green, S.E. Oakes and A.P. Thomas, Bioorg.
Med. Chem. Lett., 2004, 14, 2245.
A.F.L. Creemers and J. Lugtenburg, J. Am. Chem. Soc., 2002, 124, 6324.
10 P.C. Lima, M.A. Avery, B.L. Tekwani, H.M. Alves, E.J. Barreiro and
C.A.M. Fraga, IL Farmaco, 2002, 57, 825.
11 E. Abignente, F. Arena, E. Luraschi and C. Saturnino, Il Farmaco, Ed. Sci.,
1985, 41, 119.
12 R. Adams and I. J. Pachter, J. Am. Chem. Soc., 1954, 76, 1845.
We thank the State Administration of Foreign Experts
Affairs of the P.R. China (Project No.2009-15) for the
financial support.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.