An efficient access to 2,3-diarylimidazo[1,2-a]pyridines via silver(I)-catalyzed C-H bond functionalization

Article abstract of DOI:10.1007/s00706-017-1950-8

Abstract: An efficient and economic Ag-catalyzed method for the direct cross-coupling of unactivated imidazo[1,2-a]pyridines with arylboronic acids has been developed. This approach leads to the formation of corresponding 2,3-diarylimidazo[1,2-a]pyridine derivatives as biological and pharmaceutical materials of interest in good yields under mild reaction conditions. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-1950-8

Monatsh Chem
DOI 10.1007/s00706-017-1950-8
ORIGINAL PAPER
An efficient access to 2,3-diarylimidazo[1,2-a]pyridines
via silver(I)-catalyzed C-H bond functionalization
Mehdi Khoshneviszadeh1 Mehdi Soheilizad2 Maryam Fardpour2 Mohammad Mahdavi3
•
•
•
Received: 18 October 2016 / Accepted: 5 March 2017
Ó Springer-Verlag Wien 2017
Abstract An efficient and economic Ag-catalyzed method
for the direct cross-coupling of unactivated imidazo[1,2-
a]pyridines with arylboronic acids has been developed.
This approach leads to the formation of corresponding 2,3-
diarylimidazo[1,2-a]pyridine derivatives as biological and
pharmaceutical materials of interest in good yields under
mild reaction conditions.
Introduction
During the recent decades, the transition-metal-catalyzed
C-H bond activation reactions of heterocycles with aryl
groups for the formation of heteroaromatic molecules have
gained considerable importance among synthetic chemists
[1–9]. Although different transition metals have been
employed in these reactions, trying to find novel methods
using inexpensive and highly efficient transition-metal
catalysts is still attractive.
Graphical abstract
Imidazo[1,2-a]pyridines are one of the interesting bio-
logically
active
nitrogen-containing
heterocyclic
compounds with a wide range of biological activities such
as antiviral [10], antibacterial [11], antifungal [12, 13],
antiprotozoal [14], antiherpes [15], and anti-apoptotic
properties [16]. Imidazo[1,2-a]pyridine unit is an essential
scaffold in a number of sedative and anxiolytic commercial
drugs such as saripidem, necopidem, and alpidem (Fig. 1).
Regarding the remarkable biological activities of imi-
dazo[1,2-a]pyridines, a number of synthetic routes for the
construction of this valuable scaffold have been reported
using a transition-metal-catalyzed cross-coupling reactions
in the literature. For instance, in 2000, Enguehard et al.
reported a Suzuki-type cross-coupling reaction on 2-sub-
stituted 3-iodoimidazo[1,2-a]pyridines to afford 2,3-
diarylimidazo[1,2-a]pyridines [17]. In 2012, Cao et al.
reported a copper-catalyzed direct C-3 arylation of 2-sub-
stituted imidazo[1,2-a]pyridines with aryl iodides,
bromides, and triflates [18]. In 2013, Liu et al. reported a
Rh-catalyzed C-H arylation of imidazo[1,2-a]pyridines
with aryl halides or triflates [19]. In 2014, Zhao et al.
reported a palladium-catalyzed cross-coupling of imi-
dazo[1,2-a]pyridines with arylboronic acids [20]. In the
same year, Wang et al. reported a palladium-catalyzed
cross-coupling reaction of imidazo[1,2-a]pyridines with
Keywords C–H activation reaction Á Direct arylation Á
2,3-Diarylimidazo[1,2-a]pyridines Á
Imidazo[1,2-a]pyridine
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-1950-8) contains supplementary
material, which is available to authorized users.
& Mohammad Mahdavi
Mahdavi_chem@yahoo.com
1
Medicinal and Natural Products Chemistry Research Center,
Shiraz University of Medical Sciences, Shiraz, Iran
2
School of Chemistry, College of Science, University of
Tehran, PO Box 14155-6455, Tehran, Iran
3
Tehran University of Medical Science, Endocrinology and
Metabolism Research Center, Endocrinology and Metabolism
Clinical Sciences Institute, Tehran, Iran
123

M. Khoshneviszadeh et al.
Fig. 1 Examples of
commercially available
imidazo[1,2-a]pyridine-based
drugs
Scheme 1
arenes [21]. Also recently, a number of metal-catalyzed C–
H activation arylation reactions on 2-substituted imi-
The effects of different silver catalysts, oxidants, addi-
tives, and solvents were screened. We started our
investigations by screening the formation of the desired
coupling product in the presence of 10 mol% AgNO3 as
the catalyst, 1 equiv. of K2S2O8 as the oxidant, and 1
equiv. of TFA as an additive in 6 cm3 of CH2Cl2:H2O
with the ratio 1:1 at rt which led to 54% product yield
(entry 1). Among the other examined silver(I) catalysts,
AgNO3 gave the highest yield in combination with
K2S2O8 as the oxidant. Using other silver(I) catalysts
such as Ag2CO3 and Ag2O decreased the reaction yield
as well as other oxidants such as Na2S2O8 and H2O2
(entries 2–5). We next examined the amounts of catalyst
and oxidant with different ratios (entries 6–15). Finally,
we studied the effect of the solvent on the reaction
progress. The use of other solvents like CH3CN:H2O and
acetone:H2O dramatically suppressed the yield and were
totally ineffective (entry 16, 17). It was clearly con-
cluded that the best results were obtained with 20 mol%
AgNO3 and 3 equiv. of K2S2O8, TFA as an additive in
CH2Cl2:H2O with the ratio 1:1 (entry 11).
dazo[1,2-a]pyridines
to
afford
2,3-disubstituted
imidazo[1,2-a]pyridines are reported in the literature
[22–28].
As can be concluded from the previous reports starting
from imidazo[1,2-a]pyridines, some drawbacks such as
using expensive transition-metal catalysts and being lim-
ited to use the halogen/triflate-bearing starting materials
suppress the ease of making new compounds by directly
starting from C–H target bonds. Therefore, introducing
efficient, facile, and economical methods to achieve the
direct C–H functionalization of target compounds to pro-
duce the corresponding cross-coupling products is of great
importance. Hence, we herein described the first example
of direct cross-coupling of imidazo[1,2-a]pyridines with
arylboronic acids at C-3 position in the presence of AgNO3
as an absolutely inexpensive catalyst under mild reaction
conditions.
Results and discussion
With the optimized reaction conditions available for the
Ag-catalyzed synthesis of 2,3-diarylimidazo[1,2-a]pyridi-
nes, we investigated the substrates scope. Different
2-arylimidazo[1,2-a]pyridines with various aryl boronic
acids were examined, and the results are summarized in
Table 2. As shown in Table 2, different electron-donating
and electron-withdrawing substituents on the aryl ring of
arylboronic acids were tolerated and the resulting corre-
sponding products 3a–3h were obtained in good yields.
On the basis of the previous reports, a plausible mech-
anism for the formation of 2,3-diarylimidazo[1,2-
a]pyridines 3 is given in Scheme 2. It has been reported
In continuation of our researches on preparation of
N-containing heterocyclic compounds [29–32], herein, we
report an efficient and economic approach for synthesis of
2,3-diarylimidazo[1,2-a]pyridines 3a–3h via direct Ag-
catalyzed cross-coupling reaction of unactivated
2-arylimidazo[1,2-a]pyridines 1 with arylboronic acids 2
(Scheme 1).
To achieve the optimized reaction conditions, 2-
phenylimidazo[1,2-a]pyridine (1a) and phenylboronic
acid (2a) were chosen as the model substrates (Table 1).
123

An efficient access to 2,3-diarylimidazo[1,2-a]pyridines via silver(I)-catalyzed C-H bond…
Table 1 Effect of different reaction conditions on synthesis of 2,3-diphenylimidazo[1,2-a]pyridine
Entry
Catalyst
Oxidant
Additive
Solvent
Yield/%a
1
AgNO3
Ag2CO3
Ag2O
K2S2O8
K2S2O8
K2S2O8
Na2S2O8
H2O2
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH2Cl2/H2O
CH3CN/H2O
Acetone/H2O
54
2
48
3
43
4
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
50
5
10
6b
7c
8d
9e
10f
11g
12h
13i
14j
15k
16
17
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
64
58
40
34
53
71
50
35
48
61
Trace
Trace
Reaction conditions: 2-phenylimidazo[1,2-a]pyridine (1a, 1 mmol), phenylboronic acid (2a, 1.5 mmol), catalyst (10 mol%), oxidant (1 eq.),
TFA (1 eq), solvent (1:1), rt, 12 h
a
Isolated yields
b
Catalyst (10 mol%), oxidant (2 eq.)
c
Catalyst (10 mol%), oxidant (3 eq.)
d
Catalyst (10 mol%), oxidant (4 eq.)
e
Catalyst (20 mol%), oxidant (1 eq.)
f
Catalyst (20 mol%), oxidant (2 eq.)
g
Catalyst (20 mol%), oxidant (3 eq.)
h
Catalyst (20 mol%), oxidant (4 eq.)
i
Catalyst (30 mol%), oxidant (1 eq.)
j
Catalyst (30 mol%), oxidant (2 eq.)
k
Catalyst (30 mol%), oxidant (3 eq.)
[33–35] that persulfate anion in the presence of Ag(I) dis-
proportionates into sulfate radical anion, sulfate dianion,
and Ag(II) ion. Next, arylboronic acid, through the reduc-
tion of Ag(II) into Ag(I), provides an aryl radical. This aryl
radical could react with the protonated imidazopyridine
A to give radical cation B. Then, a hydrogen atom can be
removed from radical cation B by sulfate radical anion to
produce protonated imidazopyridine C. Finally, the desired
product 3 can be afforded after a basic workup (Scheme 2).
In conclusion, we have developed a novel, facile, and
economic Ag-catalyzed direct cross-coupling reaction of
unactivated imidazo[1,2-a]pyridines with arylboronic acids
for the first time. The present method represents an
efficient way to produce the corresponding imidazo[1,2-
a]pyridine derivatives in good yields under mild reaction
conditions.
Experimental
All chemicals were purchased from Merck and Fluka
companies. All yields refer to isolated products. 1H and 13
C
NMR spectra were recorded on a Bruker (Rheinstetten,
Germany) NMR spectrometer (at 500 and 400 MHz) using
tetramethylsilane (TMS) as internal standard. Melting
points were determined in a capillary tube. The progress of
123

M. Khoshneviszadeh et al.
Table 2 The substrate scope of 2,3-diarylimidazo[1,2-a]pyridine derivatives (Scheme 1)
Entry
Prod
Ar0
Ar
M.p./°C
Lit. m.p./°C
Yield/%a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
Ph
Ph
150–152
134–136
144–145
143–145
181–183
163–165
102–105
138–139
149–150 [22]
136–137 [22]
146–147 [28]
141–142 [22]
181–182 [22]
163–164 [28]
101–102 [22]
138–139 [28]
71
73
75
70
72
76
79
77
Ph
4-Me-Ph
4-F-Ph
4-NO2-Ph
4-Pyridyl
3-Me-Ph
Ph
Ph
Ph
Ph
Ph
3g
3h
4-MeO-Ph
4-Cl-Ph
Ph
Reaction conditions: all reactions were performed with 1 (1 mmol), 2 (1.5 mmol), AgNO3 (20 mol%), oxidant (3 eq.), TFA (1 eq.), 6 cm3
CH2Cl2:H2O (1:1), rt, 12 h
a
Isolated yields
Scheme 2
the reaction was followed with TLC using silica gel SILG/
UV 254 and 365 plates. All products are known com-
chromatography using hexane:ethyl acetate (1:4) to obtain
desired products.
1
pounds and their structures were deduced by H and 13C
Acknowledgements This research was supported by the Iran
National Science Foundation (INSF).
NMR spectroscopies.
Typical procedure for the preparation
of compounds 3a–3h
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To a solution of imidazo[1,2-a] pyridine (1 mmol, 1equiv)
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dichloromethane and washed with 5% sodium bicarbonate.
The aqueous layer was extracted with dichloromethane
(3 9 4 cm3), dried over sodium sulfate, and evaporated in
vacuum. Purification was performed by column
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