Synthesis of imidazo[1, 2-a]pyridines via the silver acetate-catalyzed Groebke-Blackburn-Bienayme reaction with ethylene glycol as a biodegradable and sustainable solvent

Article abstract of DOI:10.1002/jhet.3746

An efficient, silver-based catalytic system has been designed for the synthesis of biologically important 3-aminoimidazo-fused heterocycles via the Groebke-Blackburn-Bienayme reaction, in which AgOAc was used as a catalyst and ethylene glycol as a solvent

Full text of DOI:10.1002/jhet.3746

Received: 28 January 2019
DOI: 10.1002/jhet.3746
Revised: 30 August 2019
Accepted: 30 August 2019
A R T I C L E
Synthesis of imidazo[1, 2-a]pyridines via the silver acetate-
catalyzed Groebke-Blackburn-Bienayme reaction with
ethylene glycol as a biodegradable and sustainable solvent
1
1,2
2
3
Mustafa Hussain
| Jianhui Liu
| Lu Fu | Mehdi Hasan
1
State key laboratory of fine chemical,
Dalian University of Technology, Dalian,
People's Republic of China
Abstract
An efficient, silver-based catalytic system has been designed for the synthesis
of biologically important 3-aminoimidazo-fused heterocycles via the Groebke-
Blackburn-Bienayme reaction, in which AgOAc was used as a catalyst and eth-
ylene glycol as a solvent from isocyanides, various aryl aldehydes and an
2
School of Petroleum and Chemical
Engineering, Dalian University of
Technology, Panjin Campus, Panjin,
Liaoning Province, People's Republic of
China
2-amino heterocycle were also used. Good to excellent yields, high atomic
3
Department of Chemistry, University of
economy and environmentally friendly conditions are the potential features of
this one-pot process.
Baltistan, Skardu, Pakistan
Correspondence
Jianhui Liu, School of Petroleum and
Chemical Engineering, Dalian University
of Technology, Panjin Campus, Panjin,
Liaoning Province 124221, People's
Republic of China.
Email: liujh@dlut.edu.cn
Funding information
National Key Research and Development
Program of China, Grant/Award Number:
2016YFA0602900; National Natural
Science Foundation of China
1
| INTRODUCTION
as an important moiety in many commercially available
drugs, such as zolpidem (insomnia treatment drug),
Over the past two decades, significant advances have
been achieved using the multicomponent reaction (MCR)
for the synthesis of pharmaceuticals and natural
alpidem (anxiolytic drug), olprinone (acute heart failure
treatment), zolimidine (an anti-peptic ulcer drug), and
the optically active drug GSK812397 (anti-HIV
[
13–17]
[1–3]
infection)
(Figure 1). In addition, some of the
products.
The catalytic Groebke-Blackburn-Bienayme
imidazo [1, 2-a] pyridines show fluorescence under the
ultraviolet light, which interfered with the enzymatic
assay; therefore, this moiety could also be used in fluores-
reaction (GBBR) is a synthetically useful MCR to estab-
lish the 3-aminoimidazo-fused heterocyclic scaffold by a
one-pot formation of the C N and C C bonds with good
[
18–20]
cent dyes.
Due to the wide medicinal utility of such
[4–7]
atomic economy.
This reaction has been widely used
a bicyclic structure, different methods of synthesis based
on isocyanides, aldehydes, and 2-aminoazides have been
developed in the presence of various catalysts such as
ionic liquids ([bmim]Br), ZnCl , ZrCl , RuCl , KF, BiCl ,
for the synthesis of bioactive compounds with a broad
spectrum of pharmacological and biological applications,
such as antiviral, antibacterial, fungicidal, and anti-
2
4
3
3
[8–12]
inflammatory properties.
Because of these proper-
LaCl Á7H O, Yb (OTf) , Sc (OTf) , Yb (OTf) /Ag CO ,
3
2
3
3
3
2
3
[
21–35]
ties, the imidazo[1,2-a]pyridine (IPY) scaffold was used
CuI, NH Cl, AcOH, InCl , and AgOTf.
Besides
4
3
J Heterocyclic Chem. 2020;1–10.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
HUSSAIN ET AL.
FIGURE 1 Selected biologically and medicinally active molecules of imidazo[1, 2-a]pyridines
GBBR, IPYs were also synthesized by different other
methods in the absence of isonitrile. For examples,
unique features due to green reaction conditions, non-
toxic, economical catalyst, reduced pollution, and opera-
tional simplicity. In continuation of our research
Pd (OAc) -catalyzed three-component reaction of
2
2
1
-aminopyridine,
-bromo-4-nitrobenzene under microwave irradiation.
2-bromo-1-phenylethanone,
and
program on the development of MCRs with a greener
[
36]
[45]
method,
herein, we develop the green synthesis of
Zeng et al reported the efficient method for construction
of IPY skeleton by intermolecular oxidative diamination
of alkynes via copper (II) and iron (III) cocatalyzed C N
3-aminoimidazo-fused heterocycles via the GBBR by
using 2-amino substituted heterocycles, aldehydes, and
isocyanides with AgOAc catalyst having coordination
capability with unsaturated bonds and activate
[37]
bond formation.
Chen et al reported a metal-free effi-
[
46–48]
cient synthesis of IPYs by a cyclization reaction of
isocyanide ( NC).
Furthermore, EG was used as
[38]
2
-aminopyridines and alkynoates.
CuBr catalyzed aer-
the promoter, with a high boiling point, low viscosity,
high specific energy, and easily miscible with many other
obic oxidative coupling of 2-aminopyridines with
cinnamaldehydes, which help in the formation of
[
49–53]
organic solvents.
3
-formyl-2-phenyl-imidazo[1,2-a]-pyridines was reported
[39]
by Jaideep group in 2015.
These IPY scaffolds were
2
| RESULTS AND DISCUSSION
synthesized by the reaction of 2-aminopyridines with β-
keto esters by CBr mediated oxidative C N bond forma-
4
[40]
Initially, we performed this reaction starting from
-aminopyridine, benzaldehyde, and cyclohexyl
tion.
α,
Molecular iodine used as an excellent catalyst for
β-diamination of cyclohexanones with
2
isocyanide with different solvents at different tempera-
tures in the presence of silver catalysts (Table 1). We ini-
tially screened two different silver catalysts, AgOAc and
Ag CO , in three different solvents, including toluene,
2
-aminopyrimidines by aerobic oxidative were also
[41]
reported.
However, many of these methods still suffer from sev-
eral drawbacks and limitations such as low yields, long
reaction time, and tiresome work-up procedures as well
as the use of expensive and toxic metal catalysts. To over-
come these limitations, different methods have been
developed with environmental friendly solvents, espe-
2
3
DMSO, and EG (Table 1, entries 1-12).
We found that the yield of target 4 was obviously
improved when a silver salt was used as a catalyst but
compared with Ag CO catalyst AgOAc was superior
2
3,
[
42]
(
1
Table 1, entries 1, 2, 3 vs entries 4, 5, 7, 8, 9, 10, and
1, respectively). Then, we observed that the
cially in a deep eutectic solvent
and water without any
[43]
catalysts
nanoparticles as a catalyst.
or with fluconazole functionalized magnetic
[44]
reaction showed strong solvent dependence, that is, tolu-
ene and DMSO gave lower yields than EG (Table 1,
entries 1-2 vs entry 3 and entries 4-5 vs entry 7, 8,
9, and 10).
The catalyst-free reaction in EG gave the desired prod-
uct with a yield of 58%, which confirmed the power of
the EG to promote this conversion (Table 1, entry 6).
Next, we perceived that the reaction conditions also
They also have some disad-
vantages as difficulties in handling, the solubility of
organic materials and lack of sustainability. Although
various methods have been developed for the synthesis of
this imidazopyridine scaffold, there has been no report
date for the synthesis of these types of compounds by
using silver acetate as the catalyst in ethylene glycol
(EG) used as a promoter solvent. This new protocol has

HUSSAIN ET AL.
3
a
TABLE 1 Optimization of reaction condition
ꢀ
b
Entry
Catalyst
Solvent
Temp ( C)
Yield %
50
c
1
2
3
4
5
6
7
8
9
Ag
Ag
Ag
2
2
2
CO
CO
CO
3
3
3
DMSO
90
90
90
90
90
90
60
90
90
90
90
120
c
c
Toluene
55
Ethylene glycol
DMSO
70
c
AgOAc
AgOAc
—
65
c
Toluene
65
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
58
c
d
e
c
c
c
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
75
78
88
f
10
11
12
90
90
92
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (1 mmol), and solvent (3.5 mL).
b
c
Isolated yield.
Catalyst (30 mol%).
d
Catalyst (10 mol%).
Catalyst (20 mol%).
e
f
EG (1.5 mL).
depend on the amount of catalyst. The incremental addi-
tion of catalyst from 10% to 30% in EG drove the yield to
for the synthesis of imidazo [1,2-a] pyridines in our
screened condition by using various aldehydes, amines,
and isocyanates as shown in Table 2. Initially, we treated
2-aminopyridine with various aromatic aldehyde such as
benzaldehyde, 4-nitrobenzaldehyde, 2-, 3-, 4-fluoro benz-
aldehyde, and 2-hydroxy benzaldehyde in combination
with cyclohexyl isocyanide (Table 2, 4a-4g). All the prod-
ucts were obtained in good to excellent yield which
depended on the electronic environment of amines and
aldehydes. An aromatic aldehyde with electron with-
drawing group or without any inductive group such as
NO2, F, and Cl gave excellent yield in short reaction
time compared to electron-donating group such as OH as
shown (Table 2, 92%-85%).
To study the vastness of this reaction, we used
2-aminothiazole and 2-aminopyrimidine with different
aromatic aldehydes as shown in Table 2 (4h-4s). Good
results were obtained with yields of 75% to 90%. To
further expand the scope of the reaction, we used ter-
tiary butyl isocyanide with different aromatic aldehydes
and amines as shown in Table 2 (4t-4w). It is
9
0% (Table 1, entries 6-11). Moreover, the study of the
temperature effect on yield of product exhibited that our
product yield increased from moderate to high with
ꢀ
ꢀ
increasing temperature from 60 C to 90 C (Table 1,
entries 7-11). Interestingly, if we kept raising the temper-
ꢀ
ature started from 90 C, it had slightly effect on the yield
and rate of the reaction (Table 1, entry 12). The best
result with a yield of 90% was obtained at an optimum
ꢀ
temperature of 90 C, with AgOAc (30 mol%) as the cata-
lyst and EG (1.5 mL) as the solvent. (Table 1, entry 10).
However, when we increased the amount of EG solvent
(
1.5-3.5 mL) with AgOAc (30 mol%) as the catalyst, at an
ꢀ
optimum temperature of 90 C, we get the same amount
of yield 90% with out any difference. However, when we
decreased the amount of catalyst AgOAc from 30 to
1
0 mol%, the yield of desire product were decreased
(Table 1, entry 11 vs entries 8, 9, and 10).
According to the above results, we then investigated
the various substrates to study the scope and limitation

4
HUSSAIN ET AL.
a,b
TABLE 2 One-pot synthesis of imidazo [1, 2-a] pyridines 4
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), and catalyst (20 mol%)..
b
Isolated yields.
c
ꢀ
Reactions performed at 90 C in EG (1.5 mL) solvent.
d
The reaction time was 2 h.

HUSSAIN ET AL.
5
FIGURE 2 ORTEP plot of single
crystals of compounds 4d and 4e [Color
figure can be viewed at
wileyonlinelibrary.com]
SCHEME 1 Possible reaction mechanism of AgOAc-catalyzed Groebke-Blackburn-Bienayme reaction (GBBR)
important to mention here that all aryl aldehydes
with ortho-substituents gave a lower yield of products
due to steric hindrance compared to those with meta-
or para-substituents (4c, 4f, 4g, 4j, 4m, 4n, 4v,
and 4p).
The possible reaction mechanism is proposed as
shown in Scheme 1. Initially, the silver catalyst activated
the benzaldehyde through the coordination of the car-
bonyl oxygen, which then condensed with the amine car-
bon to give imine intermediate III. Next, Ag(I) activates
the isocyanide and promotes it to attack imine carbon
and formed intermediate V, which was activated by
amphoteric EG. In addition, EG also helped transfer a
proton to form intermediate VI. Cyclization and proton
transfer with the aid of EG furnished the final product
VIII by eliminating EG.
The structure of the imidazo[1,2-a]pyridines (4) was
unambiguously supported by the ORTEP plot structure
[54,55]
analysis for 4d and 4e, as shown in Figure 2.
The
ORTEP analysis showed that these products are mono-
clinic, with the P21/n space group at the 50% probability
level for a thermal ellipsoid.

6
HUSSAIN ET AL.
ꢀ
1
3
3
| EXPERIMENTAL SECTION
.1 | General information
to 218 C. H NMR (400 MHz, CDCl
4
3
): δ 8.35 to 8.30 (m,
H, ArH), 8.09 (d, J = 8.0 Hz, 1H, ArH), 7.58 (d,
J = 8.0 Hz, 1H, ArH), 7.24 to 7.21 (m, 1H, ArH), 6.88 to
.84 (m, 1H, ArH), 3.12 (d, J = 4.0 Hz, 1H), 3.00 (d,
J = 4.0 Hz, 1H), 1.87 to 1.84 (m, 2H), 1.75 to 1.73 (m,
2H), 1.63 to 1.61 (m, 1H), 1.28 to 1.17 (m, 6H). C NMR
100 MHz, CDCl ) δ: 146.51, 142.12, 141.16, 134.39,
6
Chemicals and solvents were purchased from commercial
suppliers and used as received. H NMR (400 and
1
13
13
5
00 MHz) and C NMR (125 and 100 MHz) spectra were
(
3
recorded with a Bruker Avance II 500 and 400 NMR
spectrometer at 295 K in CDCl . Chemical shifts are
reported in parts per million (ppm), and the residual sol-
vent peak was used as an internal reference: H (chloro-
form δ 7.26) and C (chloroform δ 77.0). Multiplicity
was indicated as follows: s (singlet), d (doublet), t (trip-
let), q (quartet), m (multiplet), dd (doublet of doublets),
brs (broad singlet). High-resolution mass spectra (HRMS)
were recorded with a quadrupole analyzer using an ESI
source (Agilent technologies G6224A). TLC was per-
formed on commercially prepared 100 to 400 mesh silica
gel GF254 plates and visualization was affected at 254 nm.
1
5
27.27, 126.55, 124.93, 123.86, 122.70, 117.85, 112.29,
7.11, 34.30, 25.61, 24.83. HRMS (ESI): m/z calcd for
3
+
1
C H N O [M + H] : 337.3950; found: 337.1668.
19
20 4 2
13
N-Cyclohexyl-2-(2-fluorophenyl)imidazo[1,2-a]
pyridine-3-amine (4c): Yield: 78%; yellow solid; mp
ꢀ ꢀ
70 C to 172 C. H NMR (500 MHz, CDCl ): δ 8.15 (d,
3
J = 5.0 Hz, 1H, ArH), 7.94 to 7.90 (m, 1H, ArH), 7.57 (d,
J = 10.0 Hz, 1H, ArH), 7.36 to 7.31 (m, 1H, ArH), 7.29 to
.21 (m, 1H, ArH), 7.18 to 7.13 (m, 1H, ArH), 6.80 (t,
1
1
7
J = 10.0 Hz, 1H, ArH), 3.45 (brs, 1H), 2.68 (brs, 1H), 1.73
to 1.71 (m, 2H), 1.60 (brs, 2H), 1.49 (brs, 1H), 1.29 to 1.21
1
3
(
m, 6H). C NMR (125 MHz, CDCl ) δ: 159.52 (d,
3
J = 243.750 Hz), 142.04, 131.73 (d, J = 2.5 Hz), 131.59 (d,
J = 5.0 Hz), 129.18 (d, J = 8.0 Hz), 126.97, 124.69 (d,
J = 3.75 Hz), 123.83, 122.97, 122.51 (d, J = 13.75 Hz),
3
.2 | General procedure for the synthesis
of N-cyclohexyl-2-phenylimidazo[1,2-a]
pyridine-3-amine (4a-4s)
1
2
3
15.63 (d, J = 21.25 Hz), 111.57, 56.68, 41.99, 34.04, 25.66,
+
A mixture of benzaldehyde (1.5 mmol, 0.15 mL), 2-amino
heterocycle (1 mmol, 0.10 mL), and cyclohexyl isocyanide
4.83. HRMS (ESI): m/z calcd for C H N F [M + H] :
19
20 3
10.3884; found: 310.1720.
N-Cyclohexyl-2-(3-fluorophenyl)imidazo[1,2-a]
pyridine-3-amine (4d): Yield: 85%; yellow crystals; mp
(1.0 mmol, 0.10 mL) in EG (3 mL) in a round-bottom
ꢀ
flask was stirred at reflux for 1 to 2 hours at 90 C, and
the reaction was monitored by TLC (ethyl acetate/n-hex-
ane, 4:6) (as shown in Table 1). After completion of the
reaction, the reaction mixture was allowed to cool to
room temperature, and the precipitates were filtered. The
obtained crude products were purified by recrystalliza-
tion with ethanol to give products 4 in high yield. Com-
pounds 4c, 4d, 4g, 4j, 4k, 4m, 4o, 4p, 4r, 4t, 4u, 4v, and
ꢀ
ꢀ
1
2
8
08 C to 209 C. H NMR (500 MHz, CDCl ): δ 8.11 to
3
.09 (m, 1H, ArH), 7.86 to 7.83 (m, 2H, ArH), 7.57 to 7.54
(
m, 1H, ArH), 7.45 to 7.39 (m, 1H, ArH), 7.18 to 7.14 (m,
1
1
1
H, ArH), 7.05 to 7.00 (m, 1H, ArH), 6.81 (t, J = 10.0 Hz,
H, ArH), 3.08 to 3.07 (brs, 1H), 3.00 to 2.99 (brs, 1H)
.91 to 1.83 (m, 2H), 1.73 to 1.71 (brs, 2H), 1.61 to 1.60
13
(
brs, 1H) 1.22 to 1.17 (m, 6H). C NMR (100 MHz,
4
w were purified by column chromatography using an
CDCl ) δ: 163.1 (d, J = 242.45 Hz), 141.61, 136.78 (d,
3
ethyl acetate/n-hexane, 4:6 solvent system. Out of 23 com-
pounds 8 (4a, 4b, 4e, 4f, 4h, 4n, 4t, and 4w) are known
and 15 (4c, 4d, 4g, 4i-4s, 4u, and 4v) are unknown.
J = 8.75 Hz), 135.46, 129.93 (d, J = 7.5 Hz), 125.20,
1
24.22, 122.72, 122.54 (d, J = 3.75 Hz), 117.53, 114.04 (d,
J = 20.0 Hz), 113.87 (d, J = 22.5 Hz), 111.78, 56.96, 34.21,
5.69, 24.84. HRMS (ESI): m/z calcd for C H N F
N-Cyclohexyl-2-phenylimidazo[1,2-a]pyridine-
2
ꢀ
19 20 3
3
1
1
-amine (4a): Yield: 88%; greenish solid; mp 178 C to
80 C. H NMR (400 MHz, CDCl ): δ 8.12 (d, J = 8.0 Hz,
H, ArH), 8.06 to 8.04 (m, 2H, ArH), 7.58 to 7.55 (m, 1H,
+
ꢀ
1
[
M + H] : 310.3884; found: 310.1717.
N-Cyclohexyl-2-(4-fluorophenyl)imidazo[1,2-a]
pyridine-3-amine (4e): Yield: 89%; light yellow crystals;
3
ArH), 7.49 to 7.45 (m, 2H, ArH), 7.35 to 7.32 (m, 1H,
ArH), 7.16 to 7.12 (m, 1H, ArH), 6.81 to 6.78 (m, 1H,
ArH), 3.01 to 2.95 (m, 1H,NH), 1.84 to 1.81 (m, 2H), 1.71
to 1.69 (m, 2H), 1.59 to 1.57 (m, 1H), 1.24 to 1.12 (m, 6H).
ꢀ
ꢀ
1
mp 177 C to 180 C. H NMR (500 MHz, CDCl ): δ 8.13
3
(
(
d, J = 5.0 Hz, 1H, ArH), 8.04 to 8.01 (m, 2H, ArH), 7.59
d, J = 10.0 Hz, 1H, ArH), 7.21 to 7.19 (m, 1H, ArH), 7.16
13
to 7.12 (m, 2H, ArH), 2.95 to 2.91 (m, 1H), 1.81 to 1.78
C NMR (100 MHz, CDCl ) δ: 141.60, 136.50, 134.40,
3
(
(
m, 2H), 1.70 to 1.68 (brs, 3H), 1.58 (brs, 1H) 1.29 to 1.27
1
1
28.56, 127.34, 127.14, 125.02, 124.00, 122.76, 117.31,
11.64, 56.95, 34.17, 25.72, 24.82. HRMS (ESI): m/z calcd
13
m, 6H). C NMR (125 MHz, CDCl ) δ: 162.31 (d,
3
+
J = 245.0 Hz), 141.20, 135.25, 129.90, 128.88 (d,
J = 7.5 Hz), 124.73, 124.61, 122.83, 116.97, 115.49 (d,
J = 21.25 Hz), 112.09, 56.84, 34.18, 25.69, 24.80. HRMS
for C H N [M + H] : 292.3980; found: 292.1812.
19
21 3
N-Cyclohexyl-2-(4-nitrophenyl)imidazo[1,2-a]pyr-
ꢀ
idine-3-amine (4b): Yield: 92%; yellow solid; mp 215 C

HUSSAIN ET AL.
7
+
ꢀ
ꢀ
1
(
ESI): m/z calcd for C H N F [M + H] : 310.3884;
156 C to 160 C. H NMR (500 MHz, CDCl ): δ 8.52 (s,
19
20
3
3
found: 310.1718.
1H, ArH), 8.45 (d, J = 5.0 Hz, 1H, ArH), 8.06 to 8.03 (m,
2H, ArH), 7.39 to 7.28 (m, 2H, ArH), 7.19 to 7.15 (t,
J = 10.0 Hz, 1H, ArH), 6.87 (dd, J = 10.0 Hz, 5.0 Hz, 1H,
ArH), 2.68 (brs, 1H), 1.72 to 1.70 (m, 2H), 1.61 (s, 2H),
N-Cyclohexyl-2-(2-hydroxyphenyl)imidazo[1,2-a]
pyridine-3-amine (4f): Yield: 75%; greenish solid; mp
ꢀ ꢀ
55 C to 158 C. H NMR (500 MHz, CDCl ): δ 8.21 (d,
3
1
1
1
3
J = 5.0 Hz, 1H, ArH), 8.00 (d, J = 10.0 Hz, 1H, ArH), 7.51
1.51 (brs, 1H), 1.26 (s, 1H), 1.10 to 1.08 (m, 6H). C
(
(
1
1
d, J = 8.0 Hz, 1H, ArH), 7.26 to 7.19 (m, 2H, ArH), 7.02
d, J = 10.0 Hz, 1H, ArH), 6.88 (m, 2H, ArH), 3.02 (brs,
NMR (125 MHz, CDCl ) δ: 159.48 (d, J = 243.75 Hz),
3
1
49.27, 144.97, 133.40 (d, J = 2.5 Hz), 132.06 (d,
J = 3.75 Hz), 130.55, 129.73 (d, J = 8.75 Hz), 125.40,
24.84 (d, J = 2.5 Hz), 121.57 (d, J = 21.25 Hz), 115.58
H), 1.84 to 1.81 (m, 2H), 1.72 to 1.70 (m, 2H), 1.61 to
13
.59 (m, 2H) 1.20 to 1.12 (m, 6H). C NMR (125 MHz,
1
CDCl ) δ: 157.51, 148.99, 139.39, 135.74, 129.16, 126.38,
3
(d, J = 22.50 Hz) 108.10, 57.01, 33.98, 25.57, 24.74.
1
5
24.84, 123.49, 122.55, 118.70, 117.71, 116.45, 112.38,
+
HRMS (ESI): m/z calcd for C H N F [M + H] :
1
8
19
4
6.97, 34.06, 25.71, 24.85. HRMS (ESI): m/z calcd for
3
11.374; found: 311.1672.
N-Cyclohexyl-2-(3-fluorophenyl) imidazo[1,2-a]
pyrimidin-3-amine (4k): Yield: 82%; yellow solid; mp
+
C H N O [M + H] : 308.3970; found: 308.1760.
19
21 3
N-Cyclohexyl-2-(2,6-dichlorophenyl)imid-
azo[1,2-a]pyridine-3-amine (4g): Yield: 72%; yellow
ꢀ
ꢀ
1
1
8
7
6
1
1
74 C to 178 C. H NMR (500 MHz, CDCl ): δ 8.43 to
3
ꢀ
ꢀ
1
crystal; mp 144 C to 148 C. H NMR (500 MHz, CDCl ):
3
.42 (m, 1H, ArH), 8.34 (d, J = 5.0 Hz, 1H, ArH), 7.84 to
.80 (m, 2H, ArH), 7.36 to 7.32 (m, 1H, ArH), 6.98 to
.95 (m, 1H, ArH), 6.79 to 6.77 (m, 1H, ArH), 3.13 (brs,
H), 3.05 (s, 1H), 2.92 (brs, 1H), 1.76 to 1.74 (m, 2H),
.65 to 1.63 (m, 2H), 1.54 (brs, 1H), 1.23 to 1.10 (m, 6H).
δ 8.19 (d, J = 5.0 Hz, 1H, ArH), 7.65 (d, J = 10.0 Hz, 1H,
ArH), 7.44 to 7.42 (m, 2H, ArH), 7.32 to 7.28 (m, 1H,
ArH), 7.21 (t, J = 10.0 Hz, 1H, ArH), 2.93 (d, J = 10.0 Hz,
1
1
H), 2.76 to 2.73 (m, 1H), 1.77 to 1.74 (m, 2H), 1.61 to
.59 (m, 2H), 1.51 to 149 (m, 1H), 1.11 to 1.05 (m, 6H).
13
C
NMR (125 MHz, CDCl3) δ: 163.08 (d,
1
3
C NMR (125 MHz, CDCl ) δ: 141.43, 136.38, 132.53,
3
J = 243.75 Hz), 149.60, 144.58, 137.01, 136.04 (d,
J = 9.0 Hz), 130.39, 130.02 (d, J = 8.0 Hz), 123.57, 122.85
1
5
30.10, 128.12, 126.86, 124.11, 122.98, 117.71, 111.91,
6.58, 33.83, 25.66, 24.60. HRMS (ESI): m/z calcd for
(
d, J = 3.0 Hz), 114. 64 (d, J = 21.0 Hz), 114.22 (d,
+
C H Cl N [M + H] : 360.3970; found: 360.1035.
19
19
2 3
J = 23.0 Hz), 108.20, 57.15, 34.20, 25.61, 24.76. HRMS
N-Cyclohexyl-2-(phenyl)imidazo[1,2-a]pyrimidin-
+
(
ESI): m/z calcd for C H N F [M + H] : 311.3764;
18 19 4
ꢀ
3
-amine (4h): Yield: 85%; yellowish powder; mp 175 C
found: 311.1671.
ꢀ
1
to 176 C. H NMR (500 MHz, CDCl ): δ 8.49 (d,
3
N-Cyclohexyl-2-(4-fluorophenyl) imidazo[1,2-a]
pyrimidin-3-amine (4l): Yield: 86%; yellow crystals;
J = 5.0 Hz, 1H, ArH), 8.43 (dd, J = 10.0 Hz, 4.0 Hz, 1H,
ArH), 8.11 (d, J = 5.0 Hz, 2H, ArH), 7.48 to 7.45 (m, 2H,
ArH), 7.36 to 7.33 (m, 1H, ArH) 6.85 to 6.82 (m,1H,
ArH), 3.16 (brs, 1H), 2.99 (brs, 1H), 1.82 to 1.80 (m, 2H),
ꢀ
ꢀ
1
mp 169 C to 170 C. H NMR (500 MHz, CDCl ): δ 8.41
3
(
brs, 1H, ArH), 8.33 (d, J = 10.0 Hz), 8.05 to 8.03 (m,
13
1H, ArH), 7.09 to 7.06 (m, 1H, ArH), 6.78 to 6.76 (m,
1
.71 to 1.69 (m, 3H), 1.29 to 1.16 (m, 6H). C NMR
1
2
6
H, ArH), 3.02 (brs, 1H,), 2.89 (s, 1H), 1.74 to 1.72 (m,
H), 1.64 to 1.62 (m, 2H), 1.53 (brs, 1H), 1.19 to 1.09 (m,
(
125 MHz, CDCl ) δ: 149.20, 144.47, 137.80, 133.69,
3
1
3
30.40, 128.49, 127.75, 127.33, 123.37, 108.03, 57.02,
1
3
H).
C NMR (125 MHz, CDCl ) δ: 162.52 (d,
3
4.08, 25.60, 24.71. HRMS (ESI): m/z calcd for C H N
20 4
18
+
J = 246.25 Hz), 149.40, 144.52, 137.38, 130.35, 129.81 (d,
J = 2.5 Hz), 129.16 (d, J = 8.75 Hz), 122.85, 115. 52 (d,
J = 21.25 Hz), 108.17, 57.03, 34.18, 25.62, 24.73. HRMS
[
M + H] : 293.3860; found: 293.1767.
N-Cyclohexyl-2-(4-nitrophenyl)imidazo[1,2-a]
pyrimidin-3-amine (4i): Yield: 90%; light yellowish
+
ꢀ
ꢀ
1
(ESI): m/z calcd for C H N F [M + H] : 311.3764;
1
8
19
4
solid; mp 275 C to 278 C. H NMR (500 MHz, CDCl ): δ
3
found: 311.1667.
8
8
6
.49 to 8.48 (m, 1H, ArH), 8.34 to 8.32 (2H, ArH), 8.28 to
.25 (m, 2H, ArH), 8.01 (d, J = 10.0 Hz 1H, ArH), 6.85 to
.82 (m, 1H, ArH), 3.12 (d, J = 5.0 Hz, 1H), 3.09 (d,
N-Cyclohexyl-2-(2,6-dichlorophenyl)imid-
azo[1,2-a]pyrimidin-3-amine (4m): Yield: 78%; yellow
ꢀ
ꢀ
1
crystals; mp 148 C to 150 C. H NMR (500 MHz, CDCl ):
J = 5.0 Hz, 1H), 2.91 (d, J = 4.0 Hz, 1H) 1.78 to 1.75 (m,
3
δ 8.48 to 8.47 (m, 1H, ArH), 8.40 to 8.38 (m, 1H, ArH),
2
6
1
1
H), 1.67 to 1.65 (m, 2H), 1.56 (brs, 1H), 1.20 to 1.11 (m,
13
7.38 to 7.36 (m, 2H, ArH), 7.26 to 7.23 (m, 1H, ArH), 6.83
H). C NMR (125 MHz, CDCl ) δ: 158.84, 150.42,
3
(
(
dd, J = 10.0 Hz, 5.0 Hz, 1H, ArH), 2.66 (brs, 1H), 2.56
46.92, 146.42, 140.39, 130.74, 130.45, 127.72, 123.92,
brs, 1H), 1.67 to 1.65 (m, 2H), 1.54 to 1.52 (m, 2H), 1.45
08.60, 57.33, 34.32, 25.54, 24.76. HRMS (ESI): m/z calcd
13
+
to 141 (m, 1H), 1.07 to 0.96 (m, 6H). C NMR (125 MHz,
CDCl ) δ: 149.32, 144.46, 136.27, 134.62, 132.21, 130.58,
130.28, 128.13, 125.35, 108.20, 56.84, 33.78, 25.57, 24.54.
for C H N O [M + H] : 337.3950; found: 337.1668.
18
19 5 2
N-Cyclohexyl-2-(2-fluorophenyl)imidazo [1,2-a]
pyrimidin-3-amine (4j): Yield: 75%; green solid; mp
3

8
HUSSAIN ET AL.
+
HRMS (ESI): m/z calcd for C H N Cl [M + H] :
3
7.96 (m, 1H, ArH), 7.36 to 7.35 (m, 1H, ArH), 7.26 to 7.24
(m,1H, ArH) 7.21 to 7.17 (m,1H, ArH), 7.01 to 6.99
(m,1H, ArH), 6.92 to 6.88 (m, 2H, ArH), 6.80 (d,
J = 8.0 Hz 1H), 3.48 to 3.41 (m, 1H), 2.99 to 2.94(m, 1H),
1.87 to 185 (m, 2H), 1.74 to 1.72 (m, 2H), 1.62 to 1.60 (m,
18
18
4
2
61.2700; found: 361.0985.
N-Cyclohexyl-6-(4-nitrophenyl)imidazo[2,1-b]
thiazol-5-amine (4n): Yield: 90%; yellow crystals; mp
64 C to 168 C. H NMR (400 MHz, CDCl ): δ 8.26 to
.19 (m, 4H, ArH), 7.35 (d, J = 4.0 Hz 1H, ArH), 6.84
ꢀ
ꢀ
1
1
8
3
13
1H), 1.29 to 1.15 (m, 6H). C NMR (100 MHz, CDCl ) δ:
3
(
d, J = 4.0 Hz, 1H, ArH), 2.98 (brs, 2H), 1.88 (s, 2H),
155.57, 143.68, 136.90, 130.68, 128.43, 126.32, 125.21,
119.07, 117.59, 117.07, 112.42, 57.60, 33.73, 25.60, 24.75.
1
.74 (s, 2H), 1.63 to 1.61 (m, 1H), 1.26 to 1.24 (m, 6H).
1
3
+
C NMR (100 MHz, CDCl ) δ: 146.07, 145.87, 141.36,
HRMS (ESI): m/z calcd for C H N SO [M + H] :
3
17 19 3
1
3
35.29, 129.05, 126.12, 123.93, 116.88, 113.10, 57.57,
314.3990; found: 314.0600.
4.27, 25.61, 24.79. HRMS (ESI): m/z calcd for
N-Cyclohexyl-6-(2,6-dichlorophenyl)imidazo[2,1-b]
thiazol-5-amine(4s): Yield: 82%; yellow crystals; mp
+
C H N O S [M + H] : 343.4170; found: 343.1231.
N-Cyclohexyl-6-(2-fluorophenyl)imidazo[2,1-b]
thiazol-5-amine (4o): Yield: 78%; yellow crystals; mp
1
7
18
4
2
ꢀ
ꢀ
1
143 C to 145 C. H NMR (500 MHz, CDCl ): δ 7.34 to 7.31
3
(m, 3H, ArH), 7.19 (s, 1H, ArH), 6.72 (d, J = 5.0 Hz), 2.79
(brs, 1H), 2.68 to 2.64 (m, 1H), 1.70 to 1.67 (m, 2H,), 1.54
to 1.52 (m, 2H), 1.45 to 1.43 (m, 1H), 1.10 to 0.90 (m, 6H).
ꢀ
ꢀ
1
1
7
7
55 C to 160 C. H NMR (400 MHz, CDCl ): δ 7.77 to
3
.73 (m, 1H, ArH), 7.30 (d, J = 8.0 Hz 1H, ArH), 7.22 to
.16 (m, 1H, ArH), 7.08 to 7.03 (m, 1H, ArH), 6.70 (d,
13
C NMR (100 MHz, CDCl ) δ: 144.49, 136.56, 132.67 (d,
3
J = 4.0 Hz,1H, ArH), 2.66 (brs, 1H), 1.70 to 1.67 (m, 3H),
J = 8.0 Hz), 129.79, 129.08, 128.05, 117.00, 111.87, 57.07,
33.73, 25.64, 24.59. HRMS (ESI): m/z calcd for
1
.51 to 1.55 (m, 2H), 1.46 (brs, 1H), 1.09 to 0.97 (m, 6H).
1
3
+
C NMR (125 MHz, CDCl ) δ: 157.99 (d, J = 242.50 Hz),
C H N Cl S [M + H] : 366.4170; found: 366.0600.
3
17 17
3
2
1
1
44.04, 130.64 (d, J = 2.5 Hz), 130.04 (d, J = 3.75 Hz),
27.54 (d, J = 8.75 Hz), 123.56 (d, J = 2.5 Hz), 121.56 (d,
N-(tert-Butyl)-2-phenylimidazo[1,2-a]pyridine-
ꢀ
3-amine (4t): Yield: 92%; Greenish crystal; mp 160 C to
ꢀ
1
J = 15.0 Hz), 116.19, 114.60 (d, J = 22.5 Hz), 110.79,
6.48, 32.91, 24.64, 23.79. HRMS (ESI): m/z calcd for
165 C. H NMR (400 MHz, CDCl ): δ 8.18 (d,
3
5
J = 8.0 Hz, 1H, ArH), 8.06 to 8.04 (m, 1H, ArH), 7.84
to 7.82 (m, 2H, ArH), 7.60 to 7.57 (m, 1H, ArH), 7.38 to
7.34 (m, 3H, ArH), 7.27 to 7.23 (m, 1H, NH), 7.12 to
+
C H N FS [M + H] : 316.4170, found: 316.1273.
N-Cyclohexyl-6-(3-fluorophenyl)imidazo[2,1-b]
thiazol-5-amine (4p): Yield: 85%; yellow crystals; mp
17
18 3
7.08 (m, 1H, ArH), 6.75 to 6.71 (m, 1H, ArH), 1.03 (s,
ꢀ
ꢀ
1
13
1
32 C to 138 C. H NMR (400 MHz, CDCl ): δ 7.75 to
9H). C NMR (100 MHz, CDCl ) δ: 141.83, 139.03,
3
3
7
.73 (m, 2H, ArH), 7.34 to 7.32 (m, 2H, ArH), 6.96 to 6.91
134.74, 124.50, 123.51, 117.09, 111.61, 56.44, 30.26.
+
(m,1H, ArH), 6.77 to 6.76 (m, 1H), 2.97 (brs, 2H), 1.87 (s,
HRMS (ESI): m/z calcd for C H N [M + H] :
17
19 3
2
H), 1.73 to 1.72 (m,2H), 1.62 to 1.59 (m, 1H), 1.26 to 1.21
266.3600; found: 266.1661.
13
(m, 6H). C NMR (100 MHz, CDCl ) δ: 163.11 (d,
N-(tert-Butyl)-2-(4-nitrophenyl)imidazo[1,2-a]pyri-
3
ꢀ
J = 243.0 Hz), 145.15, 137.09, 137.00, 129.84 (d,
J = 8.0 Hz), 127.51, 121.52(d, J = 3.0 Hz), 117.01, 113.27
dine-3-amine (4u): Yield: 85%; yellow solid; mp 155 C to
ꢀ
1
160 C. H NMR (400 MHz, CDCl ): δ 8.23 to 8.18, (m, 4H,
3
(d, J = 22.0 Hz), 112. 88 (d, J = 23.0 Hz), 112.11, 57.47,
ArH), 8.12 (d, J = 8.0 Hz, 1H, ArH), 7.49 to 7.48 (m, 1H,
3
4.18, 25.69, 24.79. HRMS (ESI): m/z calcd for
ArH), 7.14 to 7.13 (m, 1H, ArH), 6.77 to 6.75 (m, 1H,
ArH), 2.95 (brs, 1H, NH), 1.03 (s, 9H). C NMR
+
13
C H N FS [M + H] : 316.4104; found: 316.1277.
17
18 3
N-Cyclohexyl-6-(4-fluorophenyl)imidazo[2,1-b]
thiazol-5-amine (4q): Yield: 88%; yellow crystals; mp
(100 MHz, CDCl ) δ: 149.01, 146.71, 142.58, 142.00, 137.21,
3
128.43, 124.96, 123.60, 123.38, 117.80, 112.01, 56.84, 30.51.
ꢀ
ꢀ
1
+
1
22 C to 128 C. H NMR (400 MHz, CDCl ): δ 7.95 to
HRMS (ESI): m/z calcd for C H N O [M + H] :
3
17 18 4 2
7
.92 (m, 2H, ArH), 7.33 to 7.32 (m, 1H, ArH), 7.11 to 7.09
311.3570; found: 311.1508.
(m,2H, ArH), 6.76 to 6.75 (m,1H, ArH), 2.94 (brs, 1H),
N-(tert-Butyl)-2-(3-fluorophenyl)imidazo[1,2-a]
1
1
.86 (brs, 2H), 1.71 (brs,2H), 1.61 to 1.59 (m, 1H), 1.24 to
pyridine-3-amine (4v): Yield: 80%; yellow crystal; mp
13
ꢀ ꢀ
210 C to 215 C. H NMR (500 MHz, CDCl ): δ 8.14, (d,
3
1
.17 (m, 6H). C NMR (100 MHz, CDCl ) δ: 161.71 (d,
3
J = 244.0 Hz), 145.03, 136.82, 130.95 (d, J = 3.0 Hz),
27.81 (d, J = 8.0 Hz), 126.71, 117.05, 115.30 (d,
J = 21.0 Hz), 111.80 (d, J = 23.0 Hz), 57.44, 34.16, 25.71,
J = 10.0 Hz, 1H, ArH), 7.67 to 7.63 (m, 2H, ArH), 7.48 to
7.46 (m, 1H, ArH), 7.33 to 7.29 (m, 1H, ArH), 7.09 to 7.06
(m, 1H, ArH), 6.95 to 6.92 (m, 1H, ArH), 6.73 to 6.70 (m,
1
+
13
2
4.77. HRMS (ESI): m/z calcd for C H N FS [M + H] :
1H, ArH), 2.94 (brs, 1H, NH), 1.00 (s, 9H). C NMR
17
18 3
3
16.4104; found: 316.1284.
N-Cyclohexyl-6-(2-hydroxyphenyl)imidazo[2,1-b]
thiazol-5-amine (4r): Yield: 87%; yellow crystals; mp
(125 MHz, CDCl ) δ: 162.88 (d, J = 243.75 Hz), 142.11,
3
138.38, 137.55, (d, J = 8.75 Hz), 149.01, 129.69 (d,
J = 8.75 Hz), 128.43, 124.31, 123.72 (d, J = 3.75 Hz),
123.44, 117.49, 114.96 (d, J = 22.00 Hz), 114.16 (d,
ꢀ ꢀ
51 C to 153 C. H NMR (400 MHz, CDCl ): δ 7.98 to
3
1
1

HUSSAIN ET AL.
9
J = 21.05 Hz), 111.52, 56.53, 30.36. HRMS (ESI): m/z
H. C. Hoppe, T. Khan, L. A. Nkabinde, Bioorg. Med. Chem.
2011, 19, 4227.
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hedron Lett. 2015, 56, 1038.
[13] A. K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun.
+
calcd for C H N F [M + H] : 284.3504; found:
17
18 3
[
[
2
84.1563.
N-(tert-Butyl)-2-phenylimidazo[1,2-a] pyrimidin-
ꢀ
3
2
-amine (4w): Yield: 88%; green solid; mp 220 C to
ꢀ
35 C. H NMR (400 MHz, CDCl ): δ 7.91 to 7.90 (m, 2H,
3
1
ArH), 7.39 to 7.34 (m, 2H, ArH), 7.29 to 7.27 (m, 1H,
ArH), 6.78 to 6.76 (m, 2H, ArH), 3.11 (brs, 1H, NH), 0.98
13
2015, 51, 155.
(
s, 9H). C NMR (100 MHz, CDCl ) δ: 158.27, 149.51,
3
[
[
[
[
14] K. Mizushige, T. Ueda, K. Yukiiri, H. Suzuki, Olprinone: Car-
1
1
44.96, 140.84, 134.30, 131.15, 128.37, 127.93, 121.97,
diovas. Drug Rev. 2002, 20, 163.
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18 4
16
+
[
M + H] : 267.3480; found: 266.1600.
4
| CONCLUSION
30229.
In conclusion, we have shown that imidazo[1, 2-a]pyri-
dines can be accessed in a one-pot three-component
manner starting from isocyanates and different aromatic
aldehydes and amines via an AgOAc-catalyzed GBBR
with EG as the solvent. The relatively cheap silver cata-
lyst, environmentally friendly conditions, simple work-up
procedures, and generation of no side products consti-
tuted the unique features for the new protocol.
[18] O. N. Burchak, L. Mugherli, M. Ostuni, J. J. Lacap,
M. Y. Balakirev, J. Am. Chem. Soc. 2011, 133, 10058.
[
[
[
[
[
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2
ACKNOWLEDGMENTS
[24] S. K. Guchhait, V. Chaudhary, C. Madaan, Org. Biomol. Chem.
012, 10, 9271.
2
This work was supported by the National Key Research
and Development Program of China (2016YFA0602900)
and the National Natural Science Foundation of China.
[
[
25] S. Rostamnia, A. Hassankhani, RSC Adv. 2013, 3, 18626.
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ORCID
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2
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Mustafa Hussain https://orcid.org/0000-0002-1881-
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