Rhodium catalyzed direct C3-ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with ethyl diazoacetate

Article abstract of DOI:10.1016/j.tet.2020.130998

An efficient and environment-friendly C3-ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with ethyl diazoacetate in the presence of a Rh(II) catalyst was developed. Such strategy not only enables the synthesis of zolpidem, but also provides a way to

Full text of DOI:10.1016/j.tet.2020.130998

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Rhodium catalyzed direct C3-ethoxycarbonylmethylation of imidazo[1,2-a]pyridines
with ethyl diazoacetate
Qiuyao Huang, Hui Dong, Bingbing Li, Wenhao Hu, Yuanxiang Wang
PII:
S0040-4020(20)30094-6
https://doi.org/10.1016/j.tet.2020.130998
TET 130998
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 November 2019
Revised Date: 11 January 2020
Accepted Date: 31 January 2020
Please cite this article as: Huang Q, Dong H, Li B, Hu W, Wang Y, Rhodium catalyzed direct C3-
ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with ethyl diazoacetate, Tetrahedron (2020), doi:
https://doi.org/10.1016/j.tet.2020.130998.
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Rhodium catalyzed direct C3-ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with ethyl
diazoacetate
Qiuyao Huang†, Hui Dong†, Bingbing Li, Wenhao Hu, Yuanxiang Wang*
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006

1
Tetrahedron
journal homepage: www.elsevier.com
Rhodium catalyzed direct C3-ethoxycarbonylmethylation of imidazo[1,2-a]pyridines
with ethyl diazoacetate
Qiuyao Huang†, Hui Dong†, Bingbing Li, Wenhao Hu, Yuanxiang Wang
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient and environment-friendly C3-ethoxycarbonylmethylation of imidazo[1,2-
a]pyridines with ethyl diazoacetate in the presence of a Rh(II) catalyst was developed. Such
strategy not only enables the synthesis of zolpidem, but also provides a way to generate
synthetic intermediates to afford cellular active anticancer agents.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Rhodium
Ethoxycarbonylmethylation
Imidazo[1,2-a]pyridine
Ethyl diazoacetate
1. Introduction
Imidazo[1,2-a]pyridines represent privileged scaffolds in
azaheterocycle chemistry and medicinal chemistry [1], and
have been found to be the core structure of many natural
products and marketed drugs [2], including alpidem,
necopidem, saripidem, zolpidem (Ambien®), olprinone, DS-
1, minodronic acid, divalpon, and zolimidine. As
imidazo[1,2-a]pyridines exhibit privileged drug-like
properties and favorable pharmacokinetics profiles, more
and more efforts have been made to develop new drug
candidates based on imidazo[1,2-a]pyridine scaffold. Veken
group discovered a novel class of urokinase plasminogen
activator (uPA) inhibitors with C3-aminated imidazo[1,2-
a]pyridine scaffold for cancer therapy [3]. Maekawa lab
reported C3-methylated imidazo[1,2-a]pyridine derivatives
as melanin-concentrating hormone receptor 1 (MCHR1)
antagonist used as antiobesity agents [4]. Trigewell and
coworkers developed a series of efficacious insulin-like
growth factor-1 receptor (IGF-1R) kinase inhibitors derived
from C2-heteroarylimidazo[1,2-a]pyridine scaffold with
improved cellular anticancer activities and favorable pk
properties [5]. Heckmann et al identified a first- in-class
autotaxin inhibitor based on the 2,3,6 trisubstituted
imidazo[1,2-a]pyridine, which is currently being evaluated
in an exploratory phase 2a study for the treatment of
Figure 1. Therapeutic agents derived from imidazo[1,2-
a]pyridine.
idiopathic pulmonary fibrosis [6]. Merk group designed and
developed a high-affinity farnesoid X receptor (FXR)
modulator comprising imidazo[1,2-a]pyridine core scaffold
for nonalcoholic steatohepatitis (NASH) treatment, which
showed extraordinary selectivity for FXR and favorable
metabolic stability compared to steroidal FXR agonists [7].
Taken together, imidazo[1,2- a]pyridine scaffold represents
a promising area for identification of lead structures towards
drug discovery.
Corresponding author.
E-mail: wangyx95@mail.sysu.edu.cn
†These authors contributed equally to this work

2
Tetrahedron
Recently, through the high-throughput computational
Rh(OAc)2. Various solvents were tested (Table 1, entry 1-7),
and chloroform (Table 1, entry 2) showed the best activity
screening and structure-based drug design, we identified a
new series of cellular active signal transducer and activator
of transcription 3 (STAT3) inhibitors with the core structure
of C3-ethoxycarbonylmethylated imidazo[1,2-a]pyridine,
which is an ester analogue of zolpidem and alpidem (Fig. 1).
Previously, such a structural motif can be prepared through
C3-alkylation of imidazo[1,2-a]pyridine with xanthates
under the mechanism of xanthate-based radical addition
reaction [8]. However, high temperature and several
equivalents of oxidants were utilized in the process.
Therefore, a more effective and environment-friendly
approach to achieve C3-ethoxycarbonylmethylimidazo[1,2-
a]pyridine is still needed.
N
N2
R1
N
R2
Rh2(oct)4 (10 mol%)
CHCl3, rt, 4h, -N2
N
R1
R2
+
N
H
CO2Et
Me
CO2Et
2a
3
1
Me
N
N
N
N
N
N
Me
CO2Et
CO2Et
CO2Et
3d, 87%
3b, 95%
Br
3c, 72%
Br
N
N
N
N
N
N
Br
CO2Et
CO2Et
CO2Et
3g, 82 %
3e, 94%
3f, 74 %
Inspired by the nucleophilicity of C-3 position of
imidazo[1,2-a]pyridines [9] and electrophilicity of the
carbene intermediates generating from the Rh(II) catalyst
and diazo compounds [10], we envisioned that direct C3-
ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with
ethyl diazoacetate might be achieved in the presence of a Rh
(II) catalyst. Therefore, in continuation of our e orts on the
development of expeditious methods for the synthesis of
imidazo[1,2-a]pyridine analogues to generate promising lead
compounds for drug discovery [11], we started a campaign
to develop an expeditious approach to access C3-
ethoxycarbonylmethylated imidazo[1,2-a]pyridines. Most
notably, Lee et al. reported a Rh (II)-catalyzed regioselective
C3-alkylation of 2-arylimidazo[1,2-a]pyridine with aryl α-
diazoesters this year [12]. Herein, we report an efficient and
environment-friendly C3-ethoxycarbonylmethylation of
imidazo[1,2-a]pyridines with ethyl diazoacetate in the
presence of Rh (II) catalyst.
OMe
MeO
N
N
N
N
N
N
MeO
CO2Et
CO2Et
CO2Et
3i, 75%
3j,
87%
3h, 90%
N
N
N
N
N
OMe
N
MeO2C
F
CO2Et
CO2Et
CO2Et
3k, 55%
3l, 73%
3m, 86%
N
N
N
N
CN
Me
F
N
N
CO2Et
CO2Et
CO2Et
3n, 67%
3o, 77%
3p, 76%
N
N
N
NO2
OCF3
N
N
N
CO2Et
CO2Et
CO2Et
3s, 72%
3r, 77%
3q, 92%
Table 1
Optimization of reaction conditionsa
Cl
N
N
MeO
MeO
N
N
N
N
F
CF3
CO2Et
CO2Et
CO2Et
3v, 72%
3t, 75%
3u
, 83%
Entry
1
Catalyst
Solvent
CH2Cl2
CHCl3
DCE
Yield [%]b
MeO
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
71
79
67
50
40
64
39
89
35
28
15
27
55
N
N
MeO
N
N
N
Cl
CN
NO2
2
N
Me
CO2Et
CO2Et
3
CO2Et
3w, 87%
3x, 75%
3y, 69%
4
THF
Scheme 1. Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a
(1.5 equiv), Rh2(oct)4 (10 mol%), CHCl3 (4 mL), Isolated yields.
5
Toluene
CH3CN
1,4-dioxane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
6
7
c
and afforded title C3-ethoxycarbonylmethylated 2-phenyl-
imidazo[1,2-a]pyridine 3a in 79% yield. Encouraged by this
result, further evaluation of a range of Rh(II) catalysts was
performed (entries 8−14 in Table 1). Interestingly, the nature
of the catalyst had a profound impact on the reaction and
Rh2(oct)4 proved to be the most e ective (Table 1, entry 8).
The desired compound 3a was gratifyingly afforded in 89%
yield using Rh2(oct)4 and chloroform.
8
Rh2(oct)4
9
Rh2(TFA)4
10
11
12
13
[Rh(COD)Cl]2
[Rh(COD)OH]2
[Rh(C2H4)Cl]2
Rh2(esp)2
aReaction conditions: 1a (0.2 mmol, 1.0 equiv) was reacted with
2a (1.5 equiv) and catalyst (10 mol %) in solvent under a N2
atmosphere.
With optimal reaction conditions in hand, we next turned
our attention to the scope of 2-aryl-imidazo[1,2-a]pyridines
that can participate in this coupling reaction (Scheme 1).
Initially, we fixed the phenyl function at the C-2 position of
imidazo[1,2-a]pyridine and then examined the e ciency of
the reaction with various substituents on the pyridine
sca old. As shown in Scheme 1, the C3-
ethoxycarbonylmethylation
a]pyridines tolerated a large number of substrates, furnishing
the corresponding title compounds (3b 3j) in good to
bIsolated yields.
cRh2(oct)4: [Rh(C7H15CO2)2]2.
2. Results and discussion
Guided by the theory mentioned above, our investigation
commenced with a survey of appropriate solvent using 2-
phenylimidazo[1,2-a]pyridine (1a) and ethyl 2-diazoacetate
of
2-phenyl-imidazo[1,2-
(
2a) as the model substrates under the influence of 10 mol%
–

3
Rh2(oct)4
(10 mol%)
excellent yields. Incorporation of a methyl group at the C-8,
C-7, and C-6 positions of imidazo[1,2-a]pyridine a orded
3b, 3c, 3d in yields of 95%, 72%, and 87%, respectively.
Similarly, introduction of an electron-withdrawing group
(Br) or electron-donating group (MeO) at any of the C-8/C-
7/C6 position of the imidazo[1,2-a]pyridine also provided
N
N2
N
(a)
+
N
CDCl3, rt,
4h, -N2
N
H
CO2Et
H
CO2Et
(D)H
1a
2a
3a 100% H
89% yield
N
Rh2(oct)4
(10 mol%)
N2
the corresponding products in good to excellent yields (3e
–
N
(b)
N
H
+
3g and 3h 3j). Particularly noteworthy is that C-8 and C-6
-
N
D2O (2 equiv)
CHCl3, rt,
4h, -N2
H
CO2Et
CO2Et
(D)H
substituted imidazo[1,2-a]pyridines seemed to be more
reactive than C-7 substituted ones. It should also be noted
that C-6 methoxycarbonylated imidazo[1,2-a]pyridine gave
slightly lower yield, a ording the corresponding 3k in 55%
yield. Interestingly, the presence of both methyl and fluoro
1a
2a
3a 63% H 37% D
89% yield
Scheme 3. Deuterium-labelling experiments.
(
3l) was still suitable for this reaction.
To
investigate
the
mechanism
reaction, we
of
the
ethoxycarbonylmethylation
conducted
Afterwards, with the pyridine sca old of imidazo[1,2-
deuterium-labelling experiments (Scheme 3). Firstly, the
reaction solvent was changed to CDCl3 from CHCl3 and
gave a product without deuterium, which rules out the
possibility that the hydrogen atom came from the solvent
(Scheme 3a). Then D2O was added to the reaction solution,
and resulted in the formation of the title compound with
37% deuterium incorporation, indicating that the hydrogen
atom could be derived partly from water present in the
solvent (Scheme 3b).
a]pyridine unsubstituted, a series of functional groups at the
para position of the C-2 phenyl ring were explored (3 –3 ).
m
r
It was found that all substituents either with electron-
donating (OMe and methyl) or electron-withdrawing
properties (F, OCF3, NO2, and CN) were tolerated under
this reaction with yields between 67 and 92%. Furthermore,
steric-hindrance (3s) can also be tolerated in this reaction.
As evident from the yield of products 3a–3s, it can be
concluded that electronic e ects associated with electron-
donating/withdrawing substituents on the C-2 phenyl ring
and the pyridine sca old of the imidazo[1,2-a]pyridine do
not significantly a ect the reactivity. To confirm this
conclusion, we incorporated diverse substituents to C-2
phenyl ring and the pyridine sca old of the imidazo[1,2-
a]pyridine and examined the reaction efficiency. As shown
in scheme 3, both substituted imidazo[1,2-a]pyridine at C-2
phenyl ring and the pyridine sca old underwent reactions
smoothly and provided the products 3t-3y with yields
between 69 and 87%.
Scheme 4. A possible mechanism.
Based on our above experimental results and previous
reports,13
a
possible mechanism for the C3-
ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with
ethyl diazoacetate is proposed in Scheme 4. Initially, a
carbene complex
rhodium (II) catalyst, followed by electrophilic attack at the
C3-carbon of the imidazo[1,2-a]pyridine 1a resulting in the
A is formed from 2a in the presence of
Scheme 2. Reaction conditions: 1z (0.2 mmol, 1.0 equiv),
(1.5 equiv), Rh2(oct)4 (10 mol%), CHCl3 (4 mL), Isolated yields.
2
formation of rhodium-bound zwitterionic intermediate
Deprotonation of intermediate furnished intermediate
B.
C,
Furthermore, the optimized reaction conditions were
successfully extended to diazo compounds to expand the
scope of the methodology. Under the same reaction
conditions, Zolpidem (4a) was prepared from imidazo[1,2-
a]pyridine (1z) and 2-diazo-N,N-dimethylacetamide in 85%
yield (Scheme 2). Its ethyl analogue 4b was also obtained in
75% yield. Methyl 2-diazoacetate and phenyl 2-diazoacetate
were also well tolerated under the optimized reaction
conditions and gave the title compounds, 4c and 4d, in 82%
and 78% yield, respectively.
B
which underwent proton transform to afford compound 3a
.
3. Conclusion
In summary, we have developed a highly effective and
environment-friendly strategy for the regioselective C3-
ethoxycarbonylmethylation of imidazo[1,2-a]pyridines with
ethyl diazoacetate in the presence of a Rh(II) catalyst. Such
method not only enables the synthesis of zolpidem, but also
provides a way to generate synthetic intermediates to
achieve cellular active STAT3 inhibitors. Further e orts on
the structure-activity study of STAT3 inhibitors derived
from this scaffold will be reported in due course.

4
Tetrahedron
4. Experimental section
1H), 4.21 (q, 2H), 4.01 (s, 2H), 2.42 (s, 3H), 1.27 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 145.4, 144.1, 135.5,
134.1, 128.5 (d, J = 4.2 Hz), 127.7, 122.9, 115.8, 115.0, 112.3,
61.5, 30.7, 21.2, 14.1; MS(EI) m/z 295.14 (M+); HRMS calcd for
C18H18N2O2 (M+) 295.1441, found:295.1433.
4.1 General experimental details
1H NMR spectral data were recorded on Varian Mercury 400
NMR spectrometer and 13C NMR data were recorded on Varian
Mercury 100 NMR spectrometer. Chemical shifts were quoted in
parts per million (ppm) referenced to the residual undeuterated
solvent peak or 0.0 ppm for tetramethylsilane, and the signals are
described as br (broad singlet), d (doublet), dd (doublet of
doublet), m (multiple), q (quarter), s (singlet), and t (triplet).
Coupling constants (J values) are given in Hz. Low-resolution
mass spectra (MS) and high-resolution mass spectra (HRMS)
were recorded at an ionizing voltage of 70 eV on a
Finnigan/MAT95 spectrometer. Column chromatography was
carried out on silica gel (200–300 mesh). Analytical TLC was
performed silica gel plates and visualized under ultraviolet light
(254 nm).
Ethyl
2-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3d). Yellow solid (87%); 1H NMR (400 MHz, CDCl3) δ 8.02 (d,
J = 6.7 Hz, 1H), 7.84 (d, J = 7.1 Hz, 2H), 7.47 (dd, J = 14.2, 6.5
Hz, 3H), 7.38 (t, J = 6.8 Hz, 1H), 6.72 (d, J = 6.1 Hz, 1H), 4.24
(q, 2H), 4.02 (s, 2H), 2.43 (s, 3H), 1.29 (t, 3H); 13C NMR (100
MHz, CDCl3) δ 169.48 (s), 145.48 (s), 144.26 (s), 135.49 (s),
134.17 (s), 128.56 (d, J = 10.8 Hz), 127.76 (s), 122.95 (s), 116.00
(s), 115.01 (s), 112.38 (s), 68.23 (s), 61.53 (s), 61.00 (s), 30.82
(s), 21.26 (s), 14.14 (s); MS(EI) m/z 295.14 (M+); HRMS calcd
for C18H18N2O2 (M+) 295.1441, found:295.1444.
Ethyl
2-(8-bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
1
(3e). Yellow solid (94%); H NMR (400 MHz, CDCl3) δ 8.12 (d,
J = 5.6 Hz, 1H), 7.84 (d, J = 6.9 Hz, 2H), 7.48 (dd, J = 14.2, 6.4
Hz, 3H), 7.40 (d, J = 6.1 Hz, 1H), 6.75 (d, J = 6.7 Hz, 1H), 4.24 –
4.22 (q, 2H), 4.03 (s, 2H), 1.27 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.1, 165.0, 145.4, 142.9, 133.6 (d, J = 3.1
Hz), 129.8, 128.9, 128.6, 128.1, 126.9, 123.1, 114.8, 112.3, 111.7,
61.7, 61.3, 31.0, 14.1(d, J = 6.3 Hz); MS(EI) m/z 359.03 (M+);
HRMS calcd for C17H15BrN2O2 (M+) 359.0390, found:359.0395.
4.2 General procedure for the preparation of compounds 3 and
zolpidem
A dried flask was charged with imidazo[1,2-a]pyridine (0.2
mmol, 1.0 equiv.), Ph2(oct)4 (0.02 mmol, 10 mol%), and CHCl3
(4 mL). Diazoester 2 (0.3 mmol, 1.5 equiv.) was added into the
mixture dropwise under a nitrogen atmosphere. The reaction
mixture was stirred at room temperature for 4h and then
concentrated in vacuum. The crud product was purified by
chromatography (EtOAc:Hexane=1:2) to yield corresponding
imidazo[1,2-a]pyridine.
Ethyl
2-(7-bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3f). Yellow solid (74%); 1H NMR (400 MHz, CDCl3) δ 8.01 (d,
J = 7.3 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 7.3 Hz, 2H), 7.47 (t, J
= 7.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 6.96 (dd, J = 7.2, 1.6 Hz,
1H), 4.22 (q, J = 7.1 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 145.1, 133.5, 128.6 (d,
J = 12.2 Hz), 128.2, 124.1, 119.8, 118.3, 116.2, 113.3, 61.8, 30.7,
14.1; MS(EI) m/z 359.03 (M+); HRMS calcd for C17H15BrN2O2
(M+) 359.0390, found:359.0389.
5. Spectrum
Ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a).
1
Yellow solid (89%); H NMR (400 MHz, CDCl3) δ 8.14 (d, J =
Ethyl
2-(6-bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3g). Yellow solid (82%); 1H NMR (400 MHz, CDCl3) δ 8.32 (d,
J = 1.0 Hz, 1H), 7.85 – 7.81 (m, 2H), 7.59 (d, J = 9.5 Hz, 1H),
7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.31 (dd, J = 9.5,
1.8 Hz, 1H), 4.28 (q, 2H), 4.05 (s, 2H), 1.33 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 169.0, 165.2, 145.4, 143.4, 133.5,
129.8, 128.6 (d, J = 8.9 Hz), 128.1, 127.9, 124.0, 118.2, 113.5,
107.1, 61.8, 61.2, 30.7, 14.0(d, J = 17.6 Hz); MS(EI) m/z 359.03
(M+); HRMS calcd for C17H15BrN2O2 (M+) 359.0390,
found:359.0384.
6.9 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 9.1 Hz, 1H),
7.49 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.24 (t, 1H),
6.88 (td, J = 6.8, 0.9 Hz, 1H), 4.26 – 4.22 (q, 2H), 4.06 (s, 2H),
1
1.29 (t, 3H); D NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.8 Hz,
1H), 7.86 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.49 (t, J
= 7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.23 (t, 1H), 6.86 (t, J =
6.8 Hz, 1H), 4.24 (q, 2H), 4.05 (s, 1H), 4.03 (s, 1H), 1.28 (t, J =
1
7.1 Hz, 3H); H NMR（CDCl3）(400 MHz, CDCl3) δ 8.13 (d, J
= 6.9 Hz, 1H), 7.85 (dd, J = 5.1, 3.3 Hz, 2H), 7.67 (d, J = 9.1 Hz,
1H), 7.48 (dd, J = 10.4, 4.7 Hz, 2H), 7.41 – 7.37 (m, 1H), 7.25 –
7.20 (m, 1H), 6.86 (td, J = 6.8, 1.0 Hz, 1H), 4.23 (q, 2H), 4.05 (s,
0.66H), 4.03(s,0.60H)1.28 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.4, 145.0, 144.6, 134.0, 128.6 (d, J = 4.4 Hz),
127.9, 124.5, 123.7, 117.6, 113.0, 112.3, 77.3, 77.1, 76.8, 61.6,
30.8, 14.1; MS(EI) m/z 281.12 (M+); HRMS calcd for
C17H16N2O2 (M+) 281.1285, found:281.1280.
Ethyl 2-(8-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3h). Yellow solid (90%); 1H NMR (400 MHz, CDCl3) δ 7.87 (d,
J = 7.2 Hz, 2H), 7.73 (d, J = 6.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H),
7.35 (t, J = 7.4 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 7.6
Hz, 1H), 4.21 (q, 2H), 4.01 (d, J = 3.7 Hz, 5H), 1.26 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 149.1, 143.7,
139.4, 134.0, 128.7, 128.4, 127.7, 116.5, 114.0, 112.3, 100.7,
61.5, 55.8, 31.0, 14.1; MS(EI) m/z 311.13 (M+); HRMS calcd for
C18H18N2O3 (M+) 311.1390, found:311.1396.
Ethyl
2-(8-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3b). Yellow solid (95%); 1H NMR (400 MHz, CDCl3) δ 7.99 (d,
J = 6.8 Hz, 1H), 7.88 – 7.84 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H),
7.40 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.78 (t, J = 6.8
Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.03 (s, 2H), 2.69 (s, 3H), 1.29
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 145.4,
144.1, 134.3, 128.8, 128.5, 127.7, 127.5, 123.3, 121.5, 113.3,
112.3, 61.5, 30.9, 17.1, 14.1; MS(EI) m/z 295.14 (M+); HRMS
calcd for C18H18N2O2 (M+) 295.1441, found:295.1434.
Ethyl 2-(7-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3i). Yellow solid (75%); H NMR (400 MHz, CDCl3) δ 7.99 –
1
7.93 (m, 1H), 7.81 (d, J = 7.2 Hz, 2H), 7.46 (dd, J = 10.3, 4.9 Hz,
2H), 7.37 (d, J = 7.2 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 6.58 (dd,
J = 7.4, 2.4 Hz, 1H), 4.21 (q, J = 7.1, 3.2 Hz, 2H), 3.98 (s, 2H),
3.86 (s, 3H), 1.27 (t, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4,
157.8, 146.3, 143.6, 134.1, 128.5, 128.2, 127.6, 124.2, 111.7,
107.1, 94.5, 61.4, 55.4, 30.6, 14.0; MS(EI) m/z 311.13 (M+);
HRMS calcd for C18H18N2O3 (M+) 311.1390, found:311.1397.
Ethyl
2-(7-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3c). Yellow solid (72%); 1H NMR (400 MHz, CDCl3) δ 8.01 (d,
J = 7.0 Hz, 1H), 7.84 – 7.80 (m, 2H), 7.47 (t, J = 7.7 Hz, 2H),
7.42 (s, 1H), 7.37 (t, J = 7.4 Hz, 1H), 6.70 (dd, J = 7.0, 1.5 Hz,

5
Ethyl 2-(6-methoxy-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3j). Yellow solid (87%); H NMR (400 MHz, CDCl3) δ 7.84 (d,
61.8, 30.8, 14.1; MS(EI) m/z 306.12 (M+); HRMS calcd for
C18H15N3O2(M+) 306.1237, found:306.1235.
1
J = 7.2 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.47 (t, J
= 7.2 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.03 (d, J = 9.6 Hz, 1H),
4.23 (q, J = 6.9 Hz, 2H), 4.01 (s, 2H), 3.86 (s, 3H), 1.28 (t, J =
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 149.4, 144.5,
142.0, 134.0, 128.5 (d, J = 18.0 Hz), 127.7, 119.6, 117.6, 113.8,
105.7, 61.6, 56.2, 31.1, 14.2; MS(EI) m/z 311.13 (M+); HRMS
calcd for C18H18N2O3 (M+) 311.1390, found:311.1388.
Ethyl 2-(2-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-3-
yl)acetate (3q). Yellow solid (92%); 1H NMR (400 MHz, CDCl3)
δ 8.16 (d, J = 6.7 Hz, 1H), 7.89 (d, J = 7.4 Hz, 2H), 7.68 (d, J =
9.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H),
6.90 (t, J = 6.6 Hz, 1H), 4.24 (q, J = 6.7 Hz, 2H), 4.03 (s, 2H),
1.29 (t, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.2,
149.0, 145.0, 143.2, 132.8, 129.9, 124.8, 123.7, 121.1, 117.6,
113.1, 112.6, 61.7, 30.8, 14.1.MS(EI) m/z 365.10 (M+); HRMS
calcd for C18H15F3N2O3 (M+) 365.1108, found:365.1110.
Methyl 3-(2-ethoxy-2-oxoethyl)-2-phenylimidazo[1,2-a]pyridine-
1
6-carboxylate (3k). Yellow solid (55%); H NMR (400 MHz,
CDCl3) δ 8.95 (s, 1H), 7.86 – 7.83 (m, 2H), 7.80 (dd, J = 9.4, 1.6
Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.43 (t,
J = 7.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.12 (s, 2H), 3.99 (s,
3H), 1.31 (t, 3H); 13C NMR (100 MHz, CDCl3) δ 169.0, 165.4,
146.2, 145.5, 133.3, 128.6 (d, J = 17.9 Hz), 128.3, 128.1, 124.2,
116.8, 116.3, 114.1, 61.8, 52.4, 30.6, 14.1; MS(EI) m/z 339.13
(M+); HRMS calcd for C19H18N2O4 (M+) 339.1339,
found:339.1330.
Ethyl 2-(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)acetate (3r).
Yellow solid (77%); H NMR (400 MHz, CDCl3) δ 8.33 (dd, J =
1
8.8, 1.7 Hz, 2H), 8.20 (d, J = 6.9 Hz, 1H), 8.10 – 8.04 (m, 2H),
7.70 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 8.5, 7.5 Hz, 1H), 6.95 (t, J
= 6.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.07 (s, 2H), 1.31 (t, 3H);
13C NMR (100 MHz, CDCl3) δ 168.8, 147.2, 145.3, 142.1, 140.6,
129.0, 125.4, 123.9 (d, J = 6.3 Hz), 117.9, 114.4, 113.1, 62.0,
30.9, 14.1; MS(EI) m/z 326.11 (M+); HRMS calcd for
C17H15N3O4 (M+) 326..1135, found:326.1135.
Ethyl
2-(6-fluoro-7-methyl-2-phenylimidazo[1,2-a]pyridin-3-
1
yl)acetate (3l). Yellow solid (73%); H NMR (400 MHz, CDCl3)
δ 8.04 (d, J = 4.8 Hz, 1H), 7.82 – 7.79 (m, 2H), 7.48 (t, J = 10.5,
4.8 Hz, 3H), 7.40 – 7.36 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.99
(s, 2H), 2.39 (s, 3H), 1.30 (t, 3H); 13C NMR (100 MHz, CDCl3) δ
169.2, 154.1, 152.2, 145.2, 142.9, 133.8, 128.5 (d, J = 17.5 Hz),
127.9, 127.3, 127.1, 117.0 (d, J = 5.4 Hz), 113.5, 110.1, 109.7,
61.7, 30.9, 15.2 (d, J = 3.1 Hz), 14.1; MS(EI) m/z 313.13 (M+);
HRMS calcd for C18H17FN2O2 (M+) 313.1340, found:313.1336.
Ethyl 2-(2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)acetate
(3s). Yellow solid (72%); H NMR (400 MHz, CDCl3) δ 8.21 (s,
1
1H), 8.01 (d, J = 6.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.84 –
7.79 (m, 2H), 7.73 (d, J = 6.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H),
7.37 (t, J = 9.0, 5.3 Hz, 2H), 7.09 (t, 1H), 6.71 (t, J = 6.7 Hz, 1H),
4.12 (q, 2H), 3.94 (s, 2H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 169.3, 145.0, 144.3, 133.4, 132.9, 131.4,
128.3 (d, J = 7.1 Hz), 127.6(d, J = 10.3 Hz), 126.5, 126.2 (d, J =
5.9 Hz), 124.7, 123.8, 117.4, 113.3, 112.4, 61.6, 30.8, 14.2;
MS(EI) m/z 331.14 (M+); HRMS calcd for C21H18N2O2 (M+)
331.1441, found:331.1449.
Ethyl 2-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)acetate
(3m). Yellow solid (86%); 1H NMR (400 MHz, CDCl3) δ 8.11 (d,
J = 6.9 Hz, 1H), 7.80 – 7.77 (m, 2H), 7.66 (d, J = 9.0 Hz, 1H),
7.23 – 7.18 (m, 1H), 7.03 – 6.99 (m, 2H), 6.85 (td, J = 6.8, 0.9
Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 4.02 (s, 2H), 3.86 (s, 3H), 1.27
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 159.5,
144.9, 144.5, 129.8, 126.6, 124.3, 123.6, 117.4, 114.1, 112.2 (d, J
= 12.5 Hz), 61.5, 55.3, 30.8, 14.1; MS(EI) m/z 311.13 (M+);
HRMS calcd for C18H18N2O3 (M+) 311.1390, found:311.1387.
Ethyl 2-(2-(4-fluorophenyl)-7-methoxyimidazo[1,2-a]pyridin-3-
yl)acetate (3t). Yellow solid (75%); 1H NMR (400 MHz, CDCl3)
δ 7.97 (d, J = 7.2 Hz, 1H), 7.80 (s, 2H), 7.15 (t, J = 8.0 Hz, 2H),
6.91 (s, 1H), 6.63 – 6.57 (m, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.95
(s, 2H), 3.87 (s, 3H), 1.28 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 169.4, 163.5, 161.5, 158.0, 146.4, 143.1, 130.3 (d,
J = 3.2 Hz), 130.0 (d, J = 8.1 Hz), 124.2, 115.6, 115.4, 111.5,
107.4, 94.6, 61.6, 55.5, 30.7, 14.1.MS(EI) m/z 329.12 (M+);
HRMS calcd for C18H17FN2O3 (M+) 329.1269, found:329.1272.
Ethyl
2-(2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)acetate
1
(3n). Yellow solid (67%); H NMR (400 MHz, CDCl3) δ 8.15 –
8.13 (m, 1H), 7.85 – 7.81 (m, 2H), 7.68 (d, J = 9.0 Hz, 1H), 7.27
– 7.23 (m, 1H), 7.17 (t, J = 8.3 Hz, 2H), 6.89 (t, J = 6.8 Hz, 1H),
4.23 (q, J = 7.1, 0.8 Hz, 2H), 4.01 (s, 2H), 1.28 (t, J = 0.9 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 169.3, 163.7, 161.7, 145.0,
143.6, 130.3(d, J = 8.1 Hz), 130.0, 124.8, 123.7, 117.5, 115.6,
115.5, 112.8, 112.5, 61.7, 30.8, 14.1; MS(EI) m/z 299.11 (M+);
HRMS calcd for C17H15FN2O2 (M+) 299.1190, found:299.1183.
Ethyl2-(7-methoxy-2-(4-(trifluoromethyl)phenyl)imidazo[1,2-
1
a]pyridin-3-yl)acetate (3u). Yellow solid (83%); H NMR (400
MHz, CDCl3) δ 8.04 (d, J = 7.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 2H),
7.69 (d, J = 8.1 Hz, 2H), 7.08 (s, 1H), 6.65 (dd, J = 7.5, 2.4 Hz,
1H), 4.23 (q, 2H), 3.99 (s, 2H), 3.86 (s, 3H), 1.29 (t, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.3, 146.6, 142.0, 137.5, 128.4,
125.7, 125.4 (d, J = 3.7 Hz), 124.3, 112.6, 107.9, 94.6, 61.7, 55.5,
30.6, 14.0; MS(EI) m/z 379.12 (M+); HRMS calcd for
C19H17F3N2O3 (M+) 379.1264, found:379.1272.
Ethyl
2-(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate
(3o).
1
Yellow solid (77%); H NMR (400 MHz, CDCl3) δ 8.12 (d, J =
6.6 Hz, 1H), 7.73 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 9.0 Hz, 1H),
7.29 (d, J = 7.4 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 6.86 (t, J = 6.6
Hz, 1H), 4.22 (q, 2H), 4.03 (s, 2H), 2.41 (s, 3H), 1.27 (t, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4, 144.8, 144.4,
137.7, 130.9, 129.3, 128.5, 124.5, 123.7, 117.4, 112.7, 112.4,
61.6, 30.8, 21.3, 14.1; MS(EI) m/z 295.14 (M+); HRMS calcd for
C18H18N2O2 (M+) 295.1441, found:295.1447.
Ethyl
2-(7-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)acetate
(3v). Yellow solid (72%); 1H NMR (400 MHz, CDCl3) δ 8.05 (d,
J = 7.3 Hz, 1H), 7.80 (d, J = 7.4 Hz, 2H), 7.64 (d, J = 2.0 Hz,
1H), 7.47 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 6.82 (dd, J
= 7.3, 2.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.00 (s, 2H), 1.26 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.1, 145.4,
144.8, 133.5, 131.1, 128.6, 128.2, 124.1, 116.4, 114.0, 113.3,
61.8, 30.7, 14.1; MS(EI) m/z 315.08 (M+); HRMS calcd for
C17H15ClN2O2 (M+) 315.0895, found:315.0890.
Ethyl
2-(2-(4-cyanophenyl)imidazo[1,2-a]pyridin-3-yl)acetate
1
(3p). Yellow solid (76%); H NMR (400 MHz, CDCl3) δ 8.19 –
8.14 (m, 1H), 8.02 (dt, J = 33.3, 16.7 Hz, 3H), 7.78 (d, 1H), 7.69
(t, J = 8.8 Hz, 1H), 7.31 – 7.27 (m, 1H), 6.98 – 6.87 (m, 1H),
4.25 (q, 2H), 4.04 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 145.3, 142.5, 138.6, 132.4 (d, J =
19.4 Hz), 129.0, 126.4, 125.7, 125.3 (d, J = 24.1 Hz), 125.2 –
125.1, 123.8, 118.8, 117.9, 114.1, 113.0 (d, J = 9.8 Hz), 111.4,
Ethyl 2-(2-(4-cyanophenyl)-7-methoxyimidazo[1,2-a]pyridin-3-
1
yl)acetate (3w). Yellow solid (87%); H NMR (400 MHz, CDCl3)
δ 7.99 (dd, J = 11.7, 7.9 Hz, 3H), 7.75 (d, J = 8.3 Hz, 2H), 6.92
(d, J = 2.4 Hz, 1H), 6.64 (dd, J = 7.5, 2.4 Hz, 1H), 4.24 (q, 2H),

6
Tetrahedron
3.98 (s, 2H), 3.89 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR
There are no conflicts to declare.
(100 MHz, CDCl3) δ 168.0, 157.4, 145.7, 140.8, 137.7, 131.3,
127.6, 123.3, 118.0, 112.0, 110.0, 107.1, 93.7, 60.8, 54.6, 29.8,
13.1; MS(EI) m/z 336.13 (M+); HRMS calcd for C19H17N3O3 (M+)
336.1343, found: 336.1345.
Acknowledgments
This work was supported by grants from National Natural
Science Foundation of China (Grant 21977128) and Guangdong
Natural Science Fund (Grant 2018A030313300). Start-up
funding from Sun Yat-Sen University and Guangdong Innovative
and Entrepreneurial Research Team Program (Grant
2016ZT06Y337) are also highly appreciated. We thank Professor
Yu Qian and Huang Qiu for helpful discussions on reaction
mechanism.
Ethyl 2-(7-methoxy-2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-
yl)acetate (3x). Yellow solid (75%); 1H NMR (400 MHz, CDCl3)
δ 8.33 (d, J = 8.6 Hz, 2H), 8.04 (dd, J = 11.7, 8.1 Hz, 3H), 6.94
(d, J = 2.1 Hz, 1H), 6.65 (dd, J = 7.5, 2.3 Hz, 1H), 4.25 (q, J =
7.1 Hz, 2H), 4.01 (s, 2H), 3.90 (s, 3H), 1.30 (t, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.9, 158.4, 146.9 (d, J = 17.0 Hz), 141.5,
140.8, 128.6, 124.3, 123.8, 113.4, 108.2, 94.6, 61.9, 55.6, 30.8,
14.1; MS(EI) m/z 356.12 (M+); HRMS calcd for C18H17N3O5 (M+)
356.1221, found: 356.1220.
References and notes
1. (a) R. Goel, V. Luxami and K. Paul, Org. Biomol. Chem., 2015,
13, 3525-3555; (b) A. Deep, R. K. Bhatia, R. Kaur, S. Kumar, U.
K. Jain, H. Singh, S. Batra, D. Kaushik and P. K. Deb, Curr. Top.
Med. Chem., 2017, 17, 238-250.
2. (a) P. G. George, G. Rossey, M. Sevrin, S. Arbilla, H. Depoortere
and A. E. L. E. R. S. Wick, Monogr, Ser., 1993, 8, 49; (b) H.
Depoortere and P. George, US 5064836, 1991; (c) D. J. Sanger,
Behav. Pharmacol., 1995, 6, 116; (d) B. Du, A. Shan, Y. Zhang,
X. Zhong, D. Chen and K. Cai, Am. J. Med. Sci., 2014, 347, 178;
(e) K. A. Wa ord, M. B. van Niel, Q. P. Ma, E. Horridge, M. B.
Herd, D. R. Peden, D. Belelli and J. J. Lambert,
Ethyl
2-(2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridin-3-
yl)acetate (3y). Yellow solid (69%); 1H NMR (400 MHz, CDCl3)
δ 7.90 (s, 1H), 7.82 – 7.75 (m, 2H), 7.60 – 7.55 (m, 1H), 7.47 –
7.39 (m, 2H), 7.09 (dd, J = 8.4, 4.5 Hz, 1H), 4.22 (q, 2H), 3.98 (s,
2H), 2.38 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.3, 144.1, 143.0, 133.8, 132.5, 129.7, 128.7, 128.0,
122.4, 121.3, 116.8, 112.7, 61.9, 30.8, 18.4, 14.1; MS(EI) m/z
328.10 (M+); HRMS calcd for C18H17ClN2O2 (M+) 329.1051,
found: 329.1053.
Neuropharmacology, 2009, 56, 182; (f) Y. Uemura, S. Tanaka, S.
Ida and T. Yuzuriha, J. Pharm. Pharmacol., 1993, 45, 1077; (g) L.
A. Sorbera, J. Castaner and P. A. Leeson, Drugs Fut., 2002, 27,
935; (h) R. Pellón, A. Ruíz, E. Lamas and C. Rodríguez, Behav.
Pharmacol., 2007, 18, 81; (i) D. Belohlavek and P. Malfertheiner,
Scand. J. Gastroenterol Suppl., 1979, 54, 44.
N, N-dimethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-
yl)acetamide (zolpidem). Yellow solid (85%); H NMR (400
1
MHz, CDCl3) δ 7.99 (s, 1H), 7.53 (t, J = 7.6 Hz, 3H), 7.26 (d, J =
8.0 Hz, 2H), 7.04 (d, J = 9.1 Hz, 1H), 4.08 (s, 2H), 2.94 (s, 3H),
2.88 (s, 3H), 2.40 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz,
DMSO) δ 168.5, 143.3, 143.0, 136.9, 132.5, 129.5, 128.0, 127.4,
122.8, 121.0, 116.3, 115.6, 37.4, 35.7, 29.3, 21.2, 18.2; MS(EI)
m/z 308.17(M+); HRMS calcd for C19H21N3O (M+) 308.1737,
found: 308.1745.
3. R. Gladysz, Y. Adriaenssens, H. De Winter, J. Joossens, A. M.
Lambeir, K. Augustyns and P. Van der Veken, J. Med. Chem.,
2015, 58, 9238-9257.
4. H. Lgawa, M. Takahashi, K. Kakegawa, A. Kina, M. Lkoma, J.
Aida, T. Yasuma, Y. Kawata, S. Ashina, S. Yamamoto, M.
Kundu, U. Khamrai, H. Hirabayashi, M. Nakayama, Y. Nagisa, S.
Kasai and T. Maekawa, J. Med. Chem., 2016, 59, 1116-1139.
5. S. L. Degorce, S. Boyd, J. O. Curwen, R. Ducray, C. T. Halsall, C.
D. Jones, F. Lach, E. M. Lenz, M. Pass, S. Pass and C. Trigwell, J.
Med. Chem., 2016, 59, 4859-4866.
6. N. Desroy, C. Housseman, X. Bock, A. Joncour, N. Binevenu,
L,Cherel, V. Labeguere, E. Rondet, C. Peixoto, J. M, Grassot, O.
Picolet, D. Annoot, N. Triballeau, A. Monjardet, E. Wakselman.
V. Roncoroni, S. Le Tallec, R. Blangue, C. Cotteraux, N.
Vandervoort, T. Christophe, P. Mollat, M. Lamers, M. Auberval,
B. Hrvacic, J. Ralic, L. Oste, E. Van der Aar, R. Brys and B.
Heckmann, J. Med. Chem., 2017,60, 3580-3590.
N,N-diethyl-2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-
yl)acetamide (4b). White solid(75%);1H NMR (500 MHz, CDCl3) δ
7.94 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 9.1 Hz, 1H), 7.20
(d, J = 7.8 Hz, 2H), 6.98 (dd, J = 9.1, 1.3 Hz, 1H), 4.00 (d, J = 2.8
Hz, 2H), 3.31 (q, J = 7.1 Hz, 2H), 3.15 (q, J = 7.1 Hz, 2H), 2.34 (s,
3H), 2.27 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1 Hz,
3H);13C NMR (100 MHz, CDCl3) δ 167.4, 143.7, 143.0, 137.6, 131.2,
129.3, 128.3, 127.9, 122.3, 122.0, 116.0, 114.3, 42.3, 40.6, 30.2, 21.2,
18.4, 14.0, 13.0; MS(EI) m/z 334.21(M+); HRMS calcd for
C23H27NO (M+) 334.2134, found: 334.2145.
7. D. Flesch, S. Y. Cheung, J. Schmidt, M. Gabler, P. Heitel, J.
Kramer, A. Kaiser, M. Hartmann, M. Lindner, K. Luddens-
Damgen, J. Heering, C. Lamers, H. Luddens, M. Wurglics, E.
Proschak, M. Schubert-Zsilavecz and D. Merk, J. Med. Chem.,
2017, 60, 7199-7205.
Methyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate
(4c). White solid (82%); 1H NMR (500 MHz, CDCl3) δ 7.76 (s, 1H),
7.65 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 7.9 Hz,
2H), 6.96 (dd, J = 9.2, 1.5 Hz, 1H), 3.93 (s, 2H), 3.68 (s, 3H), 2.32 (s,
3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 144.3,
143.9, 137.4, 131.3, 129.3, 128.2, 127.5, 121.9, 121.2, 116.6, 112.1,
52.4, 30.4, 21.2, 18.3; MS(EI) m/z 293.15(M+); HRMS calcd for
C20H20O2 (M+) 293.1520, found: 293.1525.
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Phenyl 2-(6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)acetate
(4d). White solid(78%); 1H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H),
7.81 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 9.2 Hz, 1H), 7.41 – 7.36 (m,
2H), 7.33 (d, J = 7.9 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.12 – 7.08
(m, 3H), 4.26 (s, 2H), 2.43 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.1, 157.9, 150.5, 144.6, 144.1, 137.8, 131.1, 129.6 –
129.3, 128.4 127.9, 126.2, 122.3, 121.3,118.9, 116.7, 115.9, 111.8,
30.8, 21.3, 18.4; MS(EI) m/z 355.16(M+); HRMS calcd for
C25H22O2 (M+) 355.1623, found: 355.1642.
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Declaration of competing interest
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Supplementary Material
Supplementary data to this article can be found online at
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1. An efficient and environment-friendly C3-ethoxycarbonylmethylation of
imidazo[1,2-a]pyridines was developed.
2. The drug, zolpidem, was prepared in high yield using this methodology.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: