Convenient two-step one-pot synthesis of 3-substituted imidazo[1,2-a]pyridines and imidazo[1,2-b]pyridazines

Article abstract of DOI:10.1007/s12039-018-1462-z

Abstract: A convenient and novel two-step one-pot method for the synthesis of 3-substituted imidazo[1,2-a]pyridines and 3-substituted imidazo[1,2-b]pyridazines was developed through the reaction of heterocyclic amines and N,?N-dimethylformamide dimethyl a

Full text of DOI:10.1007/s12039-018-1462-z

J. Chem. Sci. (2018) 130:55
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-018-1462-z
REGULAR ARTICLE
Convenient two-step one-pot synthesis of 3-substituted
imidazo[1,2-a]pyridines and imidazo[1,2-b]pyridazines
HONGLI FAN∗ and FENGHAI LI
School of Chemistry and Chemical Engineering, Heze University, 2269 Daxue Road, Heze 274000, Shandong,
China
E-mail: fanhl2007@163.com
MS received 4 January 2018; revised 9 April 2018; accepted 10 April 2018
Abstract. A convenient and novel two-step one-pot method for the synthesis of 3-substituted imidazo[1,2-
a]pyridines and 3-substituted imidazo[1,2-b]pyridazines was developed through the reaction of heterocyclic
amines and N, N-dimethylformamide dimethyl acetate with active electrophiles RCH2Br (R = CO2Et, CN,
COPh, 4’-MeO-PhCO and 4’-F-PhCO). This protocol provides a simple and practical approach to 3-substituted
fused imidazo-heterocyclic compounds in moderate to high yields.
Keywords. Imidazo[1, 2-a]pyridine; imidazo[1, 2-b]pyridazine; heterocyclic amine; active electrophiles.
1. Introduction
anditsderivativeswerereactedwithDMF-DMA(N, N-
dimethylformamide dimethyl acetate) to produce the
corresponding intermediates in near quantitative yields,
which were subsequently condensed with active elec-
trophiles, such as ethyl bromoacetate, bromoacetoni-
trile, 2-bromoacetophenone, 2-bromo-4’-methoxyacet-
ophenone or 2-bromo-4’-fluoroacetophenone in the
same flask without isolation to afford the desired 3-
substituted imidazo[1,2-a]pyridines.
Imidazo[1,2-a]pyridines exhibit diverse biological
properties such as anticonvulsant,1 antimicrobial,2 anti-
viral,3 antiparasitic,4 anti-inflammatory,5 antitubercu-
losis6 and inhibitory effects on DNA oxidation and
quenching radicals.7 They are also ligands for major
inhibitory neurotransmitter receptors.8 Consequently,
many useful synthetic methods have been reported in
the literature. Generally, such nitro-containing fused
heterocycles are prepared through the condensation of
heterocyclic amines with α-haloketones in the pres-
ence of an inorganic base at high temperatures.9 This
method also produces 2-substituted products. Recently,
some novel synthetic approaches have been developed
to construct 3-substituted imidazo[1,2-a]pyridines.10
Although a number of investigations have been car-
ried out, developing a convenient and library-friendly
method is still desirable in hit-to-lead drug discov-
ery, which requires quick follow-up to construct 3-
substituted imidazo[1,2-a]pyridines from readily acces-
sible starting materials in a single operation under
mild conditions. Herein, we report a two-step one-pot
2. Experimental
2.1 Materials and physical measurements
All 2-aminopyridines 1a–1f, 6-chloropyridazin-3-amine 6
and active electrophiles 3a–3e were purchased from Nan-
jing Chemical Reagent Co., Ltd., (Nanjing, China, Purity
more than 97%), all reagents and solvents were used as
received. Column chromatography was performed using sil-
icagel (200–300mesh). Nuclear MagneticResonance(NMR)
spectra were recorded on a Varian 400 MHz spectrometer
◦
(1H: 400 MHz, 13C: 100 MHz) at 25 C, using CDCl3 or
DMSO-d6 as the solvent. Chemical shifts (δ ppm) are reported
approach to the synthesis of 3-substituted imidazo[1,2- with respect to tetramethylsilane (TMS) as an internal stan-
dard. Mass spectra were recorded using the Electrospray
a]pyridines. Commercially available 2-aminopyridine
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-018-1462-z) contains
supplementary material, which is available to authorized users.

55 Page 2 of 8
J. Chem. Sci. (2018) 130:55
Ionization Method (ESI) on Agilent mass spectrometers (d, JC−F = 237.3 Hz), 145.85, 141.95 (d, JC−F = 2.5 Hz),
(G1969A LC/MSD TOF and 6545 Q-TOF LC/MS). Melt- 119.18 (d, JC−F = 25.1 Hz), 118.11 (d, JC−F = 8.9 Hz),
ing points were measured on a WRS-1 apparatus and are 114.96 (d, JC−F = 42.6 Hz), 109.99, 60.67, 14.39. HRMS-
uncorrected.
ESI: Calcd. for C10H10FN2O2(M + H)+: 209.0721, Found:
209.0713.
2.2.1e Iimidazo[1,2-a]pyridine-3-carbonitrile 4e:14 Wh-
2.2 Synthesis of 3-substituted
imidazo[1,2-a]pyridines 4a-4n and 5a-5f
◦
1
ite solid; M.p.: 160 C. H NMR (δ, ppm in CDCl3, 400
MHz): 7.15 (t, J = 7.2 Hz, 1H); 7.50 (t, J = 7.2 Hz, 1H);
7.81 (d, J = 9.2 Hz, 1H); 8.20 (s, 1H); 8.40 (d J = 9.2 Hz,
1H). 13C NMR (δ, ppm in CDCl3, 100 MHz): 147.20, 142.47,
128.32, 125.66, 118.69, 115+.09, 111.13, 98.20. HRMS-ESI:
Calcd. for C8H6N3(M + H) : 144.0556, Found: 144.0550.
2.2.1f (Imidazo[1,2-a]pyridin-3-yl)phenylmethanone 4f:
2.2a Typical procedure for preparation of 4a–4h (4a
as an example):: A solution of 0.094 g 2-aminopyridine
(1a, 1 mmol) and 0.24 g DMF-DMA (2 mmol) in 2 mL DMF
◦
was stirred at 65 C for 2 h. Then, 0.126 g NaHCO3 (1.5
mmol) and 0.217 g ethyl bromoacetate (3a, 1.3 mmol) were
added sequentially. The mixture was stirred at 85 ◦C. After the
reactionwascompletedasmonitoredbythinlayerchromatog-
raphy (TLC), it was diluted with 20 mL water and extracted
with EtOAc (3 × 20 mL). The combined organic extract was
washed with water and brine, dried over anhydrous Na2SO4
and concentrated under reduced pressure. The crude prod-
uct was purified by silica gel column chromatography (ethyl
acetate/hexane, 1:6) to afford pure product 4a.
10b
◦
1
White solid; M.p.: 110–111 C. H NMR (δ, ppm in
DMSO-d6, 400 MHz): 7.33 (t, J = 7.4 Hz, 1H); 7.57 (t,
J = 7.6 Hz, 2H); 7.68 (m, 2H); 7.87 (t, J = 7.4 Hz, 3H); 8.24
(s, 1H); 9.63 (d, J = 7.2Hz, 1H). 13C NMR (δ, ppm in CDCl3,
100 MHz): 184.82, 149.05, 145.63, 139.24, 132.04, 129.45,
128.88, 128.83, 128.59, 123.52, 117.+73, 115.15. HRMS-
ESI: Calcd. for C14H11N2O (M + H) : 223.0866, Found:
223.0856.
2.2.1g (Imidazo[1,2-a]pyridin-3-yl)(4’-methoxyphenyl)
methanone 4g:10b White solid; M.p.: 113–114 ◦C. 1H NMR
(δ, ppm in CDCl3, 400 MHz): 3.91 (s, 3H, CH3); 7.03 (d, J =
8.8 Hz, 2H, ArH); 7.26 (t, J = 7.2 Hz, 1H, ArH); 7.67 (t, J =
8.4 Hz, 1H, ArH); 7.89 (d J = 8.8 Hz, 2H, ArH); 7.99 (d, J =
9.2 Hz, 1H, ArH); 8.25 (s, 1H, ArH); 9.71 (d, J = 6.8 Hz,
1H, ArH). 13C NMR (δ, ppm in CDCl3, 100 MHz): 183.40,
163.45, 146.53, 140.41, 131.20, 131.01, 130.94, 129.04,
123.21, 116.63, 116.15, 114.14, 55.61. HRMS-ESI: Calcd.
for C15H13N2O2(M + H)+: 253.0972, Found: 253.0947.
2.2.1h (4’-Fluorophenyl)(imidazo[1,2-a]pyridin-3-yl)me-
2.2.1a Ethyl imidazo[1,2-a]pyridine-3-carboxylate 4a:11
◦
1
White solid; M.p.: 50–51 C. H NMR (δ, ppm in CDCl3,
400MHz): 1.43 (t, J = 7.2 Hz, 3H, CH3); 4.42 (q, J =
7.2Hz, 2H, CH2); 7.05 (t, J = 6.8 Hz, 1H, ArH); 7.42 (t, J =
8.4 Hz, 1H, ArH); 7.74 (d, J = 8.8 Hz, 1H, ArH); 8.31 (s, 1H,
ArH); 9.31 (d, J = 6.8Hz, 1H, ArH). 13C NMR (δ, ppm in
CDCl3, 100 MHz): 180.58, 148.35, 141.42, 127.59, 127.39,
117.79, 115.77, 114.14, 60.38, 14.41. HRMS-ESI: Calcd. for
C10H11N2O2(M + H)+: 191.0815, Found: 191.0811.
2.2.1b Ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxy-
late 4b:10b Light brown solid; M.p.: 109–110 C. 1H NMR
◦
◦
1
thanone 4h:10b White solid; M.p.: 132–133 C. H NMR
(δ, ppm in CDCl3, 400 MHz): 7.16–7.26 (m, 3H); 7.60 (t,
J = 7.8 Hz, 1H); 7.83(d J = 8.8 Hz, 1H); 7.90–7.95 (m, 2H);
8.21 (s, 1H); 9.73 (d, J = 6.8 Hz, 1H). 13C NMR (δ, ppm in
DMSO-d6, 100MHz):182.32; 164.37(d, JC−F = 198.6Hz);
148.54; 145.36; 135.31; 131.56 (d, JC−F = 7.2 Hz); 130.17;
128.45; 122.81; 117.52; 115.76 (d, JC−F = 17.4Hz); 115.74.
HRMS-ESI: Calcd. for C14H10FN2O (M + H)+: 241.0772,
Found: 241.0757.
(δ, ppm in CDCl3, 400 MHz): 1.42 (t, J = 7.2 Hz, 3H, CH3);
4.42 (q, J = 7.2 Hz, 2H, CH2); 7.50 (dd, J1 = 9.2 Hz,
J2 = 1.8 Hz, 1H, ArH); 7.64 (d, J = 9.6 Hz, 1H, ArH);
8.29 (s, 1H, ArH); 9.51 (d, J = 2.0 Hz, 1H, ArH). 13C
NMR (δ, ppm in CDCl3, 100 MHz): 160.34, 146.73, 141.49,
130.92, 127.83, 118.35, 116.12, 109.22, 60.74, 14.39. HRMS-
ESI: Calcd. for C10H10BrN2O2(M + H)+: 268.9920, Found:
268.9915.
2.2.1c Ethyl 6-chloroimidazo[1,2-a]pyridine-3-carboxy-
late 4c:12 White solid; M.p.: 92 C. H NMR (δ, ppm in
◦
1
CDCl3, 400 MHz): 1.44 (t, J = 7.2 Hz, 3H, CH3); 4.44 2.2b Typical procedure for preparation of 4i–4n (4i as
(q, J = 7.2 Hz, 2H, CH2); 7.41 (dd, J1 = 9.6 Hz, J2
=
anexample): Asolutionof0.173g2-amino-5-bromopyridi
2.0 Hz, 1H, ArH); 7.70 (d, J = 9.6 Hz, 1H, ArH); 8.30 (s, ne (1b, 1 mmol) and 0.24 g DMF-DMA (2 mmol) in 2 mL
1H, ArH); 9.41 (d, J = 2.4 Hz, 1H, ArH). 13C NMR (δ, DMF was stirred at 65 C for 3 h. Then, 0.126 g NaHCO3
◦
ppm in CDCl3, 100 MHz): 160.33, 146.62, 141.69, 128.76, (1.5 mmol), 0.033 g KI (0.2 mmol) and 0.156 g bromoace-
125.67, 122.64, 118.05, 116.25, 60.72, 14.39. HRMS-ESI: tonitrile (3b, 1.3 mmol) were added sequentially. The mixture
◦
Calcd. for C10H10ClN2O2(M + H)+: 225.0425, Found: 225. was stirred at 85 C. After the reaction was completed as
0417.
monitored by TLC, it was diluted with 20 mL water and
2.2.1d Ethyl 6-fluoroimidazo[1,2-◦a]pyridine-3-carboxy- extracted with CHCl3 (3 × 20 mL). The combined organic
1
late 4d:13 White solid; M.p.: 52–53 C. H NMR (δ, ppm extract was washed with water, dried over anhydrous Na2SO4
in CDCl3, 400 MHz): 1.42 (t, J = 7.2 Hz, 3H, CH3); 4.42 (q, and concentrated under reduced pressure. The crude product
J = 7.2 Hz, 2H, CH2); 7.34 (td, J1 = 8.8 Hz, J2 = 2.4 Hz, was purified by silica gel column chromatography (chloro-
1H, ArH); 7.71 (dd, J1 = 9.6 Hz, J2 = 4.8Hz, 1H, ArH); form/hexane, 3:1) to afford pure product 4i.
8.30 (s, 1H, ArH); 9.28 (dd, J1 = 4.0 Hz, J2 = 2.4 Hz, 1H,
ArH). 13C NMR (δ, ppm in CDCl3, 100 MHz): 160.42, 154.06
2.2.2a 6-Bromoimidazo[1,2-a]pyridine-3-carbonitrile 4i:
White solid; M.p.: 194–196 C. H NMR (δ, ppm in
10d
◦
1

J. Chem. Sci. (2018) 130:55
Page 3 of 8 55
◦
CDCl3, 400 MHz): 7.47 (dd, J1 = 9.8 Hz, J2 = 2.0 Hz, 1H); 2 mL DMF was stirred at 65 C for 2 h. Then, 0.252 g
7.74 (d, J = 9.6 Hz, 1H); 8.17 (s, 1H); 8.42 (d, J = 2.4 Hz, NaHCO3 (3 mmol) and 0.417 g ethyl bromoacetate (3a, 2.5
1H). 13C NMR (δ, ppm in CDCl3, 100 MHz): 145.85, 142.66, mmol) were added sequentially. The mixture was stirred at
◦
132.00, 125.81, 119.20, 110.52, 110.08, 98.54. HRMS-ESI: 85 C. After the reaction was completed as monitored by
Calcd. for C8H5BrN3(M+H)+: 221.9661, Found: 221.9652. thin layer chromatography (TLC), it was diluted with 20 mL
2.2.2b 6-Chloroimidazo[1,2-a]pyridine-3-carbonitrile 4j: water and extracted with CHCl3 (3 × 30 mL). The combined
15 Light yellow solid; M.p.: 195–198 ◦C. 1H NMR (δ, ppm in organic extract was washed with water, dried over anhydrous
CDCl3, 400 MHz): 7.53 (dd, J1 = 9.6 Hz, J2 = 1.8 Hz, Na2SO4 and concentrated under reduced pressure. The crude
1H); 7.68 (d, J = 9.6Hz, 1H); 8.15 (s, 1H); 8.52 (d, product was purified by silica gel column chromatography
J = 1.6 Hz, 1H). 13C NMR (δ, ppm in CDCl3, 100 MHz): (chloroform/hexane, 1:1) to afford pure product
145.66, 142.77, 132.00, 129.90, 123.64, 119.20, 118.9+6, 5a.
110.45, 109.99. HRMS-ESI: Calcd. for C8H5ClN3(M+H) :
2.2.3a Ethyl 8-(2-ethoxy-2-oxoethoxy)H-imidazo[1,2-a]
pyridine-3-carboxylate 5a: White solid, M.p.: 93–95 ◦C. 1H
178.0167, Found: 178.0158.
2.2.2c 6-fluoroimidazo[1,2-a]pyridine-3-carbonitrile 4k:
NMR (δ, ppm in CDCl3, 400 MHz): 1.29 (t, J = 7.2 Hz, 3H,
16
White solid; M.p.: 173–176 ◦C. 1H NMR (δ, ppm in
CH3), 1.43 (t, J = 7.2 Hz, 3H, CH3), 4.28 (q, J = 7.2 Hz,
DMSO-d6, 400 MHz): 7.70 (td, J1 = 10.0 Hz, J2 = 2.0 Hz,
1H); 7.92 (dd, J1 = 9.8 Hz, J2 = 5.2 Hz, 1H); 8.48 (s,
1H); 8.98 (t, J = 3.0 Hz, 1H). 13C NMR (δ, ppm in CDCl3,
100 MHz): 154.50 (d, JC−F = 241.6 Hz), 144.79, 143.02
(d, JC−F = 2.4 Hz), 120.43 (d, JC−F = 25.1 Hz), 119.23
(d, JC−F = 8.9 Hz), 112.99 (d, JC−F = 41.2 Hz), 110.53,
99.61. HRMS-ESI: Calcd. for C8H5FN3(M+H)+: 162.0462,
Found: 162.0459.
2H, CH2), 4.42 (q, J = 7.2 Hz, 2H, CH2), 4.98 (s, 2H, CH2),
6.72 (d, J = 7.6 Hz, 1H, ArH), 6.93 (t, J = 7.4 Hz, 1H, ArH),
8.26 (s, 1H, ArH), 9.00 (d, J = 6.8 Hz, 1H, ArH). 13C NMR
(δ, ppm in CDCl3, 100 MHz): 168.11, 160.57, 147.02, 142.34,
140.37, 121.44, 116.87, 113.88, 107.16, 66.28, 61.51, 60.5+1,
14.40, 14.11. HRMS-ESI: Calcd. for C14H17N2O5 (M+H) :
293.1132, Found: 293.1123.
2.2.3b 8-(Cyanomethoxy)H-imidazo[1,2-a]pyridine-3-ca
rbonitrile 5b: Light brown solid; M.p.: 229–230 ◦C. 1H NMR
(δ, ppm in DMSO-d6, 400 MHz): 5.47 (s, 2H, CH2), 7.23 (m,
2H, ArH), 8.39 (d, J = 5.2 Hz, 1H, ArH), 8.43 (s, 1H, ArH).
13C NMR (δ, ppm in DMSO-d6, 100 MHz): 145.96, 142.68,
140.85, 121.56, 116.40, 115.42, 111.67, 109.08,+99.22, 54.99.
HRMS-ESI: Calcd.. for C10H7N4O (M + H) : 199.0614,
Found: 199.0608.
2.2.3c 2-(3-BenzoylH-imidazo[1,2-a]pyridin-8-yloxy)-1-
phenylethanone 5c: White solid, M.p.: 209–211 ◦C. 1H NMR
(δ, ppm in DMSO-d6, 400 MHz): 5.97 (s, 2H, CH2), 7.20 (m,
2H, ArH), 7.60 (t, J = 7.6 Hz, 4H, ArH), 7.71 (m, 2H,
ArH), 7.90 (d, J = 7.2 Hz, 2H, ArH), 8.06 (d, J = 7.6 Hz,
2H, ArH), 8.19 (s, 1H, ArH), 9.28 (d, J = 6.8 Hz, 1H,
ArH). 13C NMR (δ, ppm in DMSO-d6, 100 MHz): 194.19,
184.39, 147.38, 144.49, 142.71, 139.16, 134.54, 134.44,
132.64, 129.35, 129.16, 128.36, 124.11, 121.53, 116.12,
109.65, 71.45. HRMS-ESI: Calcd. for C22H17N2O3(M +
H)+: 357.1234, Found: 357.1225.
2.2.2d (6-Bromoimidazo[1,2-a]pyridin-◦3-yl)phenylmetha
1
none 4l:10b White solid; M.p.: 143–145 C. H NMR (δ,
ppm in CDCl3, 400 MHz): 7.57 (t, J = 7.6 Hz, 2H);
7.67 (t, J = 7.2 Hz, 1H); 7.79–7.86 (m, 4H); 8.25 (s,
1H); 9.70 (s, 1H). 13C NMR (δ, ppm in CDCl3, 100 MHz):
184.70, 147.34, 145.40, 138.78, 132.70, 132.29, 128.96,
128.80, 128.65, 123.53, 118.20, 110.05. HRMS-ESI: Calcd.
for C14H10BrN2O (M + H)+: 300.9971, Found: 300.9955.
2.2.2e (6-Chloroimidazo[1,2-a]pyr◦idin-3-yl)phenylmetha
1
none 4m:10c White solid; M.p.: 138 C. H NMR (δ, ppm
in DMSO-d6, 400 MHz): 7.59 (t, J = 7.4 Hz, 2H); 7.69 (t,
J = 7.4 Hz, 1H); 7.78 (dd, J1 = 9.2 Hz, J2 = 2.0 Hz,
1H); 7.88 (d, J = 7.2 Hz, 2H); 7.94 (d, J = 9.6 Hz, 1H);
8.31 (s, 1H); 9.68 (d, J = 1.6 Hz, 1H). 13C NMR (δ, ppm
in DMSO-d6, 100 MHz): 183.78, 146.75, 145.38, 138.26,
132.36, 130.49, 128.78, 128.72, 126.01, 123.16, 122.3+2,
118.26. HRMS-ESI: Calcd. for C14H10ClN2O (M + H) :
257.0476, Found: 257.0454.
2.2.2f (6-Fluoroimidazo[1,2-a]pyridin-3-yl)phenylmetha
none 4n:10c Light yellow solid; M.p.: 131–132 ◦C. 1H NMR
(δ, ppm in DMSO-d6, 400 MHz): 7.58 (t, J = 7.6 Hz, 2H);
7.68 (t, J = 7.4 Hz, 1H); 7.80 (td, J1 = 8.6 Hz, J2 = 2.4 Hz,
1H); 7.87 (d, J = 8.4 Hz, 2H); 7.97 (dd, J1 = 9.6 Hz,
J2 = 5.2 Hz, 1H); 8.30 (s, 1H); 9.62 (dd, J1 = 5.0 Hz, J2 =
2.6 Hz, 1H). 13C NMR (δ, ppm in CDCl3, 100 MHz): 184.72;
2.2.3d Ethyl6-bromo-8-(2-ethoxy-2-oxoethoxy)H-imidaz
o[1,2-a]pyridine-3-carboxylate 5d: White solid, M.p.: 92–
94 ◦C. 1H NMR (δ, ppm in CDCl3, 400 MHz): 1.31 (t,
J = 7.0 Hz, 3H, CH3), 1.43 (t, J = 7.0 Hz, 3H, CH3),
4.30 (q, J = 7.2 Hz, 2H, CH2), 4.43 (q, J = 7.2 Hz,
2H, CH2), 4.97 (s, 2H, CH2), 6.81 (s, 1H, ArH), 8.21 (s,
1H, ArH), 9.17 (s, 1H, ArH). 13C NMR (δ, ppm in CDCl3,
400 MHz): 167.60, 160.29, 146.66, 140.95, 140.27, 121.59,
117.03, 111.40, 108.55, 66.42, 61.80, 60.80, 14.36, 14.11.
HRMS-ESI: Calcd. for C14H16BrN2O5(M+H)+: 371.0237,
Found: 371.0231.
2.2.3e 6-Bromo-8-(cyanomethoxy)H-imidazo[1,2-a]pyrid
ine-3-carbonitrile 5e: Light brown solid, M.p.: 207–208 ◦C.
1H NMR (δ, ppm in DMSO-d6, 400 MHz): 5.50 (s, 2H, CH2),
7.46 (s, 1H, ArH), 8.43 (s, 1H, ArH), 8.66 (s, 1H, ArH).
13C NMR (δ, ppm in DMSO-d6, 100 MHz): 145.70, 142.83,
154.80 (d, JC−F = 239.7 Hz); 145.14; 143.56 (d, JC−F
=
1.7 Hz); 138.38; 132.62; 128.80 (d, JC−F = 2.9 Hz); 121.94
(d, JC−F = 24.9 Hz); 117.48 (d, JC−F = 9.7 Hz); 116.601;
116.172. HRMS-ESI: Calcd. for C14H10FN2O (M + H)+:
241.0772, Found: 241.0767.
2.2c Typical procedure for preparation of 5a–5f (5a as
an example): A solution of 0.11 g 2-amino-3-hydroxypyri-
dine (1e, 1 mmol) and 0.24 g DMF-DMA (2 mmol) in

55 Page 4 of 8
J. Chem. Sci. (2018) 130:55
O
N
Br
3a
N
O
+ DMF-DMA
DMF, 65 o
C
N
2a
N
N
solvent/base/temperature
N
1a
NH2
O
4a
O
Scheme 1. Synthesis of ethyl imidazo[1,2-a]pyridine-3-carboxylate 4a.
139.63, 121.70, 116.11, 112.31, 111.16, 108.89,+99.79, 55.29. 2H); 8.28 (s, 1H); 8.44 (d, J = 9.6 Hz, 1H). 13C NMR (δ,
HRMS-ESI: Calcd. for C10H6BrN4O (M + H) : 276.9719, ppm in CDCl3, 100 MHz): 182.53, 149.32, 140.31, 140.19,
Found: 276.9715.
137.69, 133.36, 129.43, 128.79, 126.95, 126.85, 123.59.
2.2.3f 2-(3-Benzoyl-6-bromoH-imidazo[1,2-a]pyridin-8-y HRMS-ESI: Calcd. for C13H9ClN3O (M + H)+: 258.0429,
loxy)-1-phenylethanone 5f: Light yellow solid, M.p.: 212– Found: 258.0420.
215 ◦C. 1H NMR (δ, ppm in DMSO-d6, 400 MHz): 6.01 (s,
2H, CH2), 7.51 (s, 1H, ArH), 7.61 (t, J = 7.6 Hz, 4H, ArH),
7.71 (m, 2H, ArH), 7.90 (d, J = 7.2 Hz, 2H, ArH), 8.06 (d,
3. Results and Discussion
J = 7.2 Hz, 2H, ArH), 8.21 (s, 1H, ArH), 9.42(s, 1H, ArH).
13C NMR (δ, ppm in DMSO-d6, 100 MHz): 193.50, 184.50,
3.1 Optimization of the reaction conditions of 4a
147.52, 144.25, 141.47, 138.81, 134.55, 134.40, 132.86,
129.26, 129.19, 128.43, 124.25, 121.17, 112.64, 109.8+3,
Initially, we found that treatment of 2-aminopyridine
71.84. HRMS-ESI: Calcd. for C22H16BrN2O3(M + H) :
◦
1a with DMF-DMA in DMF at 65 C resulted in
435.0339, Found: 435.0332.
the formation of (E)-N, N-dimethy-Nꢀ-(pyridin-2-yl)-
formamidine 2a clearly by TLC in consistence with
2.2d Typical procedure for preparation of 3-substitu-
ted imidazo[1,2-b]pyridazines 8a–8c(8a as an exam-
literature report.17
Then, we turned our attention to the optimization
of reaction conditions of the second step, namely
the cyclization process between the intermediate 2a
and ethyl bromoacetate 3a, to establish an efficient
two-step one-pot procedure for the synthesis of ethyl
imidazo[1,2-a]pyridine-3-carboxylate 4a (Scheme 1).
As shown in Table 1, different bases and solvents were
investigated at varied temperatures. The reaction was
found to proceed smoothly in the presence of 1.5 equiva-
lent of NaHCO3 in DMF at 85 ◦C, delivering the product
4a in 83% yield (Table 1, entry 1). Decrease or increase
in temperature had no positive effect on the reaction
efficiency (Table 1, entry 2–3). Switching to other sol-
vents such as EtOH and dioxane, led to inferior results
(Table 1, entries 4–5). Other inorganic and organic bases
were also found to promote this transformation albeit
in relatively low yields (Table 1, entry 6–12). Taken
together, we found that the optimal protocol for the sec-
ond step of preparing 4a was to conduct the reaction in
DMF at 85 ◦C with 1.5 equivalent of NaHCO3 as a base.
The complete synthesis of 4a was adopted as a two-step
one-pot procedure.
ple): A solution of 0.130 g 6-chloropyridazin-3-amine (6,
1 mmol) and 0.24 g DMF-DMA (2 mmol) in 2 mL DMF was
stirred at 65 ◦C for 3 h. Then, 0.126 g NaHCO3(1.5 mmol),
0.033 g KI (0.2 mmol) and 0.217 g ethyl bromoacetate (3a,
1.3 mmol) were added sequentially. The mixture was stirred at
85◦C. AfterthereactionwascompletedasmonitoredbyTLC,
it was diluted with 20 mL water and extracted with CHCl3
(3 × 20 mL). The combined organic extract was washed with
water, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by silica gel
column chromatography (chloroform/hexane, 3:1) to afford
pure product 8a.
2.2.4a Ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carbox-
ylate 8a: Light brown solid; M.p: 92–93 ◦C. 1H NMR (δ, ppm
in CDCl3, 400 MHz): 1.45 (t, J = 7.2 Hz, 3H, CH3); 4.48 (q,
J = 7.0 Hz, 2H, CH2); 7.28 (d, J = 9.2 Hz, 1H, ArH); 8.03
(d, J = 9.6 Hz, 1H, ArH); 8.39 (s, 1H, ArH). 13C NMR (δ,
ppm in CDCl3, 100 MHz): 158.20, 148.38, 140.93, 140.67,
127.40, 121.51, 120.48+, 61.08, 14.33. HRMS-ESI: Calcd. for
C9H9ClN3O2(M + H) : 226.0378, Found: 226.0377.
2.2.4b 6-Chloroimidazo[1,2-b]pyridazi◦ne-3-carbonitrile
1
8b:11 Light yellow solid; M.p.: 143–144 C. H NMR (δ,
ppm in CDCl3, 400 MHz): 7.34 (d, J = 9.6 Hz, 1H); 8.07
(d, J = 9.6 Hz, 1H); 8.26 (s, 1H). 13C NMR (δ, ppm in
CDCl3, 100 MHz): 159.83, 149.39, 141.72, 139.61, 127.74,
123.00, 109.12. HRMS-ESI: Calcd. for C7H4ClN4(M+H)+:
179.0119, Found: 179.0113.
3.2 Synthesis of 3-substituted
imidazo[1,2-a]pyridines 4a–4n
2.2.4c (6-Chloroimidazo[1,2-b]pyridazin-3-yl)(phenyl)me
◦
1
thanone 8c:10a Light yellow solid; M.p.: 257–258 C. H
With the above optimized two-step one-pot procedure,
the reactions of 2-aminopyridine 1a and DMF-DMA
NMR (δ, ppm in DMSO-d6, 400 MHz): 7.59 (t, J = 7.4 Hz,
2H); 7.69 (t, J = 9.6 Hz, 2H); 7.99 (d, J = 7.2 Hz, with
several
active
electrophiles
RCH2Br

J. Chem. Sci. (2018) 130:55
Page 5 of 8 55
Table 1. Optimization of the reaction conditions for the second-step condensation of 4aa.
Entry
Base
Solvent
Time (h)b
Temperature (oC)c
Yield (%)d
1
2
3
4
5
6
7
8
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
EtOH
Dioxane
DMF
EtOH
Dioxane
DMF
1
1.5
1
3
1.5
2
3
2
1
1
85
75
95
reflux
85
85
reflux
85
85
85
85
83
81
79
63
65
70
51
56
65
47
39
46
9
10
11
12
NaOH
C5H5N
Et3N
DMF
DMF
DMF
7
5
85
aReac◦tion conditions: 2-Aminopyridine 1a (1.0 mmol) and DMF-DMA (2.0 equiv) were mixed and stirred in DMF (2 mL)
at 65 C for 2 h. Then, ethyl bromoacetate 3a (1.3 equiv) and base (1.5 equiv) were added and the stirring continued for
additional 1–7 h. bReaction time for the second step. cReaction temperature for the second step. dIsolated yield based on 1a.
X
X
R
Br
N
3a-e
+
DMF-DMA
DMF, 65 oC
N
DMF, NaHCO3, 85 o
C
N
2a-d
N
N
N
1a-d
NH2
X
4a-n
R
Scheme 2. Synthesis of 3-substituted imidazo[1,2-a]pyridines 4a–4n.
(R
=
CN, CO2Et, COPh, 4’-MeO-PhCO and ranging from 74% to 89% (Tables 2, entry 1 and
4’-F-PhCO) 3a–3e were carried out successfully to give 5–8). On the other hand, the reactions of 1b–1d
corresponding 3-substituted imidazo[1,2-a]pyridines (containing Br, Cl and F, respectively) and DMF-DMA
4a, 4e–4h in good yields (Scheme 2, Table 2, entry with3arequiredlongerreactiontimeandtheyieldswere
1, 5–8). 2-Amino-5-halopyridines 1b–1d and DMF- slightly lower compared with 1a (Tables 2, entry 1–4).
DMA with ethyl bromoacetate 3a also participated As for the reactions of 1b–1d and DMF-DMA with less
well in this conversion (Scheme 2, Table 2, entry reactive electrophiles 3b and 3c, 20 mol% KI was neces-
2–4). However, further expansion of the two-step one- sary for better yields (Tables 2, entry 9–14), most likely
pot process to the reaction of 2-amino-5-halopyridines through more reactive iodide species.
1b–1d and DMF-DMA with bromoacetonitrile 3b or
2-bromoacetophenone 3c under the same reaction con-
ditions gave the desired bicyclic products in very low
yields (< 20%), along with some unknown by-products.
3.3 Synthesis of 3-substituted
imidazo[1,2-a]pyridines 5a–5f
Fortunately, the addition of 20 mol% KI into the second-
step reaction mixture significantly improved the yields
because bromide group in 3b–3c could be substituted
with iodide to generate more reactive iodoacetonitrile
and 2-iodoacetophenone. With KI as an additive in the
second step, we successfully conducted the reactions
of 1b–1d and DMF-DMA with bromoacetonitrile 3b or
2-bromoacetophenone 3c to afford the corresponding 3-
substituted imidazo[1,2-a]pyridines 4i–4n in moderate
to good yields (Scheme 2, Table 2, entries 9–14).
The results presented in Table 2 demonstrated that
electron-withdrawing groups in the pyridine ring
reduced the reactivity to form the products. 2-Aminopy
ridine 1a afforded the desired products in high yields
During the course of expanding the substrate scope of
the two-step one-pot reaction, we found that the reac-
tion of 2-amino-3-hydroxypyridine 1e and DMF-DMA
with ethyl bromoacetate 3a under the optimal reac-
tion conditions (without KI) gave rise to the formation
of an unexpected product 5a in which the hydroxyl
group underwent a substitution reaction with the active
electrophile along with the imidazole ring formation.
However, intermediate 2e was detected as the major
product by TLC analysis. Notably, the substitution
reaction still occurred inevitably without NaHCO3 or
adding the solution of 0.8 equivalent of 3a–3c in DMF
dropwise in the second step of the reaction. Finally,
when 2.5 equivalent of 3a–3c and 2.5 equivalent of

55 Page 6 of 8
J. Chem. Sci. (2018) 130:55
Table 2. Substitution of compounds 1-4 according to Scheme 2a.
Entry
1
X
3
Time(h)b
Product
Yield (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1a
1a
1b
1c
1d
1b
1c
1d
H
Br
Cl
F
H
H
3a (R = CO2Et)
3a (R = CO2Et)
3a (R = CO2Et)
3a (R = CO2Et)
3b (R = CN)
1
3
3
4
1
1
1
1
3
3
4
1.5
1.5
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
83
80
76
73
78
89
74
87
75
71
59
87
78
68
3c (R = COPh)
3d (R = 4ꢀ-MeO-PhCO)
3e (R = 4ꢀ-F-PhCO)
3b (R = CN)
H
H
9d
1d
11d
12d
13d
14d
Br
Cl
F
Br
Cl
F
3b (R = CN)
3b (R = CN)
3c (R = COPh)
3c (R = COPh)
3c (R = COPh)
aReaction conditions: 2-Aminopyridine or its derivatives 1a–1f (1.0 mmol) and DMF-DMA (2.0 equiv) were mixed and stirred
◦
in DMF (2 mL) at 65 C for 2–3 h. Then, active electrophiles 3a–3e (1.3 equiv) and NaHCO3 (1.5 equiv) were added and
the stirring continued at 85 ◦C for additional 1–4 h. bReaction time for the second step. cIsolated yield based on 1a–1f. dThe
second step of the reaction was run with 0.2 equivalent of KI.
OCH2R
X
OH
N
N
X
OH
R
Br
3a-c
DMF, NaHCO3, 85 o
N
DMF-DMA
+
DMF, 65 oC
X
N
N
C
N
1e-f
NH2
R
5a-f
2e-f
Scheme 3. Synthesis of 3-substituted imidazo[1,2-a]pyridines 5a–5f.
Table 3. Substitution of compounds 1, 2 and 5 according to Scheme 3a.
Entry
1
X
3
Time (h)b
Product
Yield (%)c
1
2
3
4
5
6
1e
1e
1e
1f
1f
1f
H
H
H
Br
Br
Br
3a (R = CO2Et)
3b (R = CN)
1
1
1
1
3
3
5a
5b
5c
5d
5e
5f
84
74
75
72
64
67
3c (R = COPh)
3a (R = CO2Et)
3b (R = CN)
3c (R = COPh)
aReaction conditions: 2-Amino-3-hydroxypyridine 1e–1f (1.0 mmol) and DMF-DMA (2.0 equiv) were mixed and stirred in
DMF (2 mL) at 65 ◦C for 1 h. Then, active electrophiles 3b–3c (2.5 equiv), NaHCO3 (3 equiv) were added and the stirring
continued at 85 ◦C for additional 1–3 h. bReaction time for the second step. cIsolated yield based on 1e–1f.
NaHCO3 were used in the second step of the reaction, 3-substituted fused imidazo-heterocyclic compounds.
various 3-substituted imidazo[1,2-a]pyridines 5a–5f Intermediate (E)-Nꢀ-(6-chloropyridazin-3-yl)-N, N-
were obtained in good yields (Scheme 3, dimethyformamidine 7 that formed in near quantita-
Table 3).
tive yield, as detected by TLC,17 subsequently reacted
with 3a–3c in situ and afforded the desired 3-substituted
imidazo[1,2-b]pyridazines 8a–8c in moderate yields
with NaHCO3 as a base and KI (20 mol%) as an additive
3.4 Synthesis of 3-substituted
imidazo[1,2-b]pyridazines 8a–8c
◦
at 85 C (Scheme 4, Table 4). This reaction repre-
For further investigation, 6-chloropyridazin-3-amine sents a novel approach for the synthesis of 3-substituted
6 was also tested to synthesize the corresponding imidazo[1,2-b]pyridazines.

J. Chem. Sci. (2018) 130:55
Page 7 of 8 55
Cl
Cl
N
Br
R
3a-c
+
NH2
N
DMF-DMA
N
N
DMF, 65 o
C
Cl
N
DMF, NaHCO3, KI, 85 oC
N
7
N
N
N
6
8a-8c
R
Scheme 4. Synthesis of 3-substituted imidazo[1,2-b]pyridazines 8a–8c.
Table 4. Synthesis of 3-substituted imidazo[1,2-b]pyridazines 8a–8ca.
Entry
3
Time (h)b
Product
Yield (%)c
1
2
3
3a (R = CO2Et)
3b (R = CN)
3
4
3
8a
8b
8c
73
60
57
3c (R = COPh)
aReaction conditions: 6-Chloropyridazin-3-amine 6 (1.0 mmol) and DMF-DMA (2.0 equiv) were mixed and stirred in DMF
(2 mL) at 65 ◦C for 3 h. Then, active electrophiles 3a–3c (1.3 equiv), NaHCO3 (1.5 equiv) and KI (0.2 equiv) were added and
the stirring continued at 85 ◦C for additional 3–4 h. bReaction time for the second step. cIsolated yield based on 6.
4. Conclusions
384; (b) Ulloora S, Shabaraya R, Aamir S and Adhikari
A V 2013 New imidazo[1,2-a]pyridines carrying active
pharmacophores: Synthesis and anticonvulsant studies
Bioorg. Med. Chem. Lett. 23 1502
In summary, we have developed a convenient and
straight-forward two-step one-pot method for the prepa-
ration of a wide variety of 3-substituted imidazo
[1,2-a]pyridines and 3-substituted imidazo[1,2-b]pyrid
azines from readily available starting materials. The
second step of the reaction is based on the conden-
sation of intermediate (E)-N,N-dimethy-Nꢀ-(pyridin-2
-yl)-formamidineanditsderivativesor(E)-Nꢀ-(6-chloro
pyridazin-3-yl)-N, N-dimethyformamidine with active
electrophiles RCH2Br (R = CN, CO2Et, COPh, 4’-
MeO-PhCO and 4’-F-PhCO) in the presence of
NaHCO3.
2. (a) Ramachandran S, Panda M, Mukherjee K, Choud-
hury N R, Tantry S J, Kedari C K, Ramachandran V,
Sharma S, Ramya V K, Guptha S and Sambandamurthy
V K 2013 Synthesis and structure activity relationship
of imidazo[1,2-a]pyridine-8-carboxamides as a novel
antimycobacterial lead series Bioorg. Med. Chem. Lett.
23 4996; (b) Shukla N M, Salunke D B, Yoo E, Mutz
C A, Balakrishna R and David S A 2012 Antibacte-
rial activities of Groebke-Blackburn-Bienaymé-derived
imidazo[1,2-a]pyridin-3-amines Bioorg. Med. Chem.
Lett. 20 5850
3. (a) Elkakmaoui A, Gueiffier A, Miiavet J C, Blache Y
and Chapat J P 1994 Synthesis and antiviral activity of 3-
substituted imidazo[1,2-a]pyridine Bioorg. Med. Chem.
Lett. 4 1937; (b) Lhassani M, Chavignon O, Chezal J
M, Teuladeb J C, Chapat J P, Snoeckc R, Andrei G,
Balzarini J, De Clercq E and Gueiffier A 1999 Syn-
thesis and antiviral activity of imidazo[1,2-a]pyridines
Eur. J. Med. Chem. 34 271; (c) Enguehard-Gueiffier
C, Musiu S, Henry N, Véron J-B, Mavel S, Neyts
J, Leyssen P, Paeshuyse J and Gueiffier A 2013 3-
Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines
and analogues, novel Flaviviridae inhibitors Eur. J. Med.
Chem. 64 448; (d) Manvar P, Shaikh F, Kakadiya R,
Mehariya K, Khunt R, Pandey B and Shah A 2016
Synthesis of novel imidazo[1,2-a]pyridine-4-hydroxy-
2H-coumarins by Groebke–Blackburn–Bienaymé mul-
ticomponent reaction as potential NS5B inhibitors Tetra-
hedron 72 1293
Supplementary Information (SI)
Copies of the original spectra (1H NMR, 13C NMR, mass,
etc.) of all the molecules reported in the experimental section
are included in Supplementary Information. Supplementary
Information is available at www.ias.ac.in/chemsci.
Acknowledgements
We gratefully acknowledge the financial support by the
research project (ZR2014BM014) from Shandong Provincial
Natural Science Foundation and Shandong Youbang Bio-
chemical Technology Co., LTD.
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