Metal-free C-H arylation of imidazoheterocycles with aryl hydrazines

Article abstract of DOI:10.1039/c8ra01474d

A simple and efficient metal-free arylation of imidazo[1,2-a]pyridines at the C-3 position with arylhydrazine has been achieved at room temperature under ambient air conditions. Various 2,3-disubstituted imidazopyridines and imidazothiazoles were synthesized with high yields. The present methodology demonstrates the usefulness of commercially available aryl hydrazine as an arylating agent.

Full text of DOI:10.1039/c8ra01474d

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Metal-free C–H arylation of imidazoheterocycles
with aryl hydrazines†
Cite this: RSC Adv., 2018, 8, 12360
a
a
Sourav Jana,
Sadhanendu Samanta,
Avik K. Bagdi,b Valerii Z. Shirinianc
a
*
and Alakananda Hajra
Received 16th February 2018
Accepted 19th March 2018
A simple and efficient metal-free arylation of imidazo[1,2-a]pyridines at the C-3 position with arylhydrazine
has been achieved at room temperature under ambient air conditions. Various 2,3-disubstituted
imidazopyridines and imidazothiazoles were synthesized with high yields. The present methodology
demonstrates the usefulness of commercially available aryl hydrazine as an arylating agent.
DOI: 10.1039/c8ra01474d
rsc.li/rsc-advances
reactions using aryl halide/tosylate/mesylate as the aryl source.9
Despite these advances in the functionalization of this moiety,
Introduction
to the best of our knowledge, there is no metal-free protocol for
the arylation of imidazo[1,2-a]pyridines. This prompted us to
develop a transition-metal-free method for the arylation of
imidazo[1,2-a]pyridines. Herein, we report a direct C–H aryla-
tion of imidazo[1,2-a]pyridines using easily accessible arylhy-
drazine hydrochloride in the presence of 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) at room temperature under ambient air
(Scheme 1).
The development of efficient methodologies for the arylation of
biological active heterocycles has been of great importance over
the years.1 Traditionally, arylation is achieved via transition-
metal-catalyzed cross-coupling reactions.2 In the last decade,
transition-metal-catalyzed direct C–H arylation has emerged as
an alternative to the conventional cross-coupling reaction.3
However, use of a metal catalyst, ligand, and additives limits the
application of these methodologies. As such, it is desirable to
develop transition-metal-free methods for the arylation of
bioactive heterocycles.4 Arylhydrazine has recently been used as
an arylating agent due to its ready availability.5 Few methodol-
ogies have been developed using arylhydrazine for the arylation
of various heterocycles.5b,d,f,i,j
Imidazo[1,2-a]pyridine has attracted much interest due to its
wide range of applications in pharmaceuticals and material
science.6 The pharmacological activity of this moiety is depen-
dent on its substituents. Several bioactive compounds such as
g-secretase modulators (GSMs) (1), liver X receptor (LXR)
agonists (2), positive allosteric modulators (PAMs) of metabo-
tropic glutamate 2 receptor (3), GABAAa2/a3 agonists (4), anti-
leishmanial agents (5 and 6), and kinase inhibitors (7) contain
the arylimidazo[1,2-a]pyridine moiety as the core structure
(Fig. 1).7 As a consequence, a number of methodologies have
been developed for the synthesis and functionalization of this
moiety.8 Conventionally, arylation of imidazo[1,2-a]pyridine is
carried out by transition-metal-catalyzed cross-coupling
Results and discussion
We commenced our study by taking 2-phenylimidazo[1,2-a]
pyridine (1a) and phenyl hydrazine hydrochloride (2a) as the
model substrates for the arylation of imidazopyridines. Initially
we carried out the reaction using Et3N (4 equiv.) as a base in
MeCN. Gratifyingly, the expected 2,3-diphenyl imidazo[1,2-a]
aDepartment of Chemistry, Visva-Bharati (A Central University) Santiniketan, 731235,
West Bengal, India. E-mail: alakananda.hajra@visva-bharati.ac.in; http://www.
visvabharati.ac.in/AlakanandaHajra.html
bDepartment of Chemistry, TDB College, Raniganj, Burdwan 713347, India
cZelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prosp., 119991, Moscow,
Russian Federation
† Electronic supplementary information (ESI) available. CCDC 1589816. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra01474d
Fig. 1 Arylimidazo[1,2-a]pyridine containing bioactive molecules.
12360 | RSC Adv., 2018, 8, 12360–12367
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1, entry 20). When the reaction was carried in an oxygen
atmosphere, no further improvement in yield was observed
(Table 1, entry 21); however, in an inert atmosphere, only
a trace amount of the product was obtained (Table 1, entry 22).
Thus, the optimum yield was obtained by carrying out the
reaction using 4 equiv. of DBU in MeCN in ambient air (Table
1, entry 4).
Scheme 1 Arylation of imidazopyridines.
Aer establishing the optimized reaction conditions, we
investigated the substrate scope of this arylation reaction. For
this purpose, the effect of the substituent present at the 2-
position on the imidazo[1,2-a]pyridine moiety was rst tested
(Scheme 2). Imidazo[1,2-a]pyridines bearing a phenyl ring
with electron-donating as well as electron-withdrawing func-
tionality afforded the desired products with excellent yields
(3aa–3ia). The commercially available drug, zolimidine, was
also arylated under the present reaction conditions with 87%
yield (3ja). 2-Naphthyl imidazo[1,2-a]pyridine and 2-thio-
phenyl imidazo[1,2-a]pyridine also yielded the corresponding
products (3ka and 3la). Imidazo[1,2-a]pyridine containing an
aliphatic substituent at the 2-position effectively reacted with
phenyl hydrazine to generate the desired product (3ma).
Moreover, unsubstituted imidazo[1,2-a]pyridine afforded the
regioselectively 3-arylated product with good yield (3na).
pyridine was obtained in 56% yield within 4 h (Table 1, entry
1). On screening with other organic bases such as Et2NH,
iPr2NH, DBU and 1,4-diazabicyclo[2.2.2]octane (DABCO), it
was found that DBU was the optimal base, affording the
desired product in 83% yield (Table 1, entries 2–5). Inorganic
bases (K2CO3, Cs2CO3, K3PO4 and KOtBu) were also tested, but
none were as effective (Table 1, entries 6–9). Other solvents
including dimethyl sulfoxide (DMSO), dimethyl formamide
(DMF), dimethyl acetamide (DMA), MeNO2, dichloroethane
(DCE), H2O, MeOH and EtOH were not as effective as MeCN
(Table 1, entries 10–17). Increment of base loading did not
improve the yield, whereas decrement of base loading dimin-
ished the yield signicantly (Table 1, entries 18 and 19). The
reaction did not occur in the absence of base, which suggests
a signicant role for the base in this arylation reaction (Table
Table 1 Optimization of the reaction conditionsa
Entry
Base (equiv.)
Time
Solvent
Yieldb
1
2
3
4
5
6
7
8
Et3N (4)
Et2NH (4)
iPr2NH (4)
DBU (4)
DABCO (4)
K2CO3 (4)
Cs2CO3 (4)
K3PO4 (4)
KOtBu (4)
DBU (4)
DBU (4)
DBU (4)
DBU (4)
DBU (4)
DBU (4)
DBU (4)
DBU (4)
DBU (5)
DBU (3)
—
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
56%
45%
35%
83%
48%
45%
48%
39%
51%
60%
40%
30%
Trace
22%
NR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
DMA
MeNO2
DCE
H2O
MeOH
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
54%
41%
83%
55%
NRc
DBU (4)
DBU (4)
82%d
Tracee
a
Scheme 2 Scope of substrates: variation of C-2 substituents on the
imidazo[1,2-a]pyridine. Reaction conditions: 0.2 mmol of 1, 1.3 equiv.
of 2a and 4 equiv. of DBU in 3 mL MeCN at rt (27 ꢀC) for 4 h. aReaction
completed in 12 h. bReaction completed in 9 h.
Reaction conditions: 0.2 mmol of 1a, 1.3 equiv. of 2a and base in 3 mL
solvent at rt. b Isolated yield. c NR ¼ no reaction. d O2 atmosphere. e Ar
atmosphere.
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However, 3-phenylimidazo[1,2-a]pyridine did not react under on a gram scale. 6-Bromo-2,3-diphenylimidazo[1,2-a]pyridine
the present reaction conditions. It should also be mentioned reacted efficiently with phenyl hydrazine to afford the product 3ra
that 2,3-diphenylimidazo[1,2-a]pyridine (3aa) and 2-(4- without signicant decrement of the yield (77%).
methoxyphenyl)-3-phenylimidazo[1,2-a]pyridine (3ca) are
known as potent antileishmanial agents.7d
To assess the general applicability of the protocol, different
arylhydrazine hydrochlorides were also reacted with 2-phenyl-
Next, the effect of the substituent on the pyridine ring of the imidazo[1,2-a]pyridine, as shown in Scheme 4. Different aryl-
imidazo[1,2-a]pyridine moiety was tested (Scheme 3). Imidazo[1,2- hydrazines bearing substituents such as –Me, –Cl, –Br afforded
a]pyridines bearing different substituents such as –Me, –Cl, –Br the corresponding arylated products (3ab–3ae) with good to
and –CN on the pyridine rings successfully afforded the corre- excellent yields. However, arylhydrazines with strong electron-
sponding arylated products with high to excellent yields (3oa–3ta). withdrawing groups such as –NO2 and –CN were unable to
The structure of 8-methyl-2,3-diphenylimidazo[1,2-a]pyridine (3oa) produce the desired products under the present reaction
was conrmed by single crystal X-ray crystallography analysis.10 conditions.
Applicability of the present methodology was also demonstrated
Next, the applicability of this arylation method was extended
to other imidazoheterocycles such as imidazo[1,2-a]thiazole
and benzo[d]imidazo[2,1-b]thiazole (Scheme 5). Gratifyingly,
this methodology successfully afforded the corresponding ary-
lated products (4a and 4b) without any difficulties.
The synthesized product was further functionalized employ-
ing Sonogashira and Suzuki coupling reactions (Scheme 6).8c
6-Bromo-2,3-diphenylimidazo[1,2-a]pyridine (3ra) was reacted
with ethynylbenzene (Scheme 6, eqn A) to afford 2,3-diphenyl-6-
(phenylethynyl)imidazo[1,2-a]pyridine (5) in excellent yield
(95%). 2,3,6-Triphenylimidazo[1,2-a]pyridine (6) was synthesized
in good yield (75%) via a Suzuki reaction between 6-bromo-2,3-
Scheme
5 Substrate scope of imidazo[2,1-b]thiazole: reaction
conditions: 0.2 mmol of imidazo[1,2-a]thiazole, 1.3 equiv. of 2 and 4
equiv. of DBU in 3.0 mL MeCN at rt (27 ꢀC) for 4 h.
Scheme 3 Scope of substrates: variation of substituents on imidazo
[1,2-a]pyridine at pyridine rings: reaction conditions: 0.2 mmol of 1, 1.3
equiv. of 2a and 4 equiv. of DBU in 3.0 mL MeCN at rt (27 ꢀC) for 4 h.
a
Reaction at 5.0 mmol scale.
Scheme 6 Synthetic application: reaction conditions (A): 0.2 mmol of
3ra and 0.2 mmol of phenyl acetylene with 10 mol% PdCl2(PPh3)2 and
10 mol% Cu I dissolved in 2 mL Et3N/DMF (1 : 1) under Ar atmosphere at
Scheme 4 Scope of substrates: variation of substituents on arylhy- 50 ꢀC for 24 h. Reaction conditions (B): 0.2 mmol of 3ra and 1 equiv. of
drazine: reaction conditions: 0.2 mmol of 1a, 1.3 equiv. of 2 and 4 phenyl boronic acid with 2 mol% Pd(PPh3)4 and 2.1 equiv. of K2CO3 in
equiv. of DBU in 3.0 mL MeCN at rt (27 ꢀC) for 4 h.
2 mL DMF/H2O (2 : 1) under Ar atmosphere at 100 ꢀC for 4 h.
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diphenylimidazo[1,2-a]pyridine (3ra) and phenyl boronic acid
(Scheme 6, eqn B).
Conclusions
A number of control experiments were performed to inves-
tigate the reaction pathway. The reactions were carried out in
the presence of radical scavengers such as 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and benzo-1,4-quinone
(BQ). The formation of a trace amount only of the products
indicates that the reaction probably proceeds through a radical
pathway (Scheme 7, eqn (A)). Furthermore, the formation of
a trace amount of the product in an argon atmosphere suggests
that aerial oxygen plays a vital role in this reaction (Scheme 7,
eqn (B)).
On the basis of the control experiments and literature
reports,5b,f,i the probable mechanism of the reaction is outlined
in Scheme 8. Initially the phenyl radical is formed from the
phenyl hydrazine in the presence of base under aerobic condi-
tions. The generated phenyl radical reacts with the imidazo[1,2-
a]pyridine moiety to afford the radical intermediate A. Inter-
mediate A is oxidized into the intermediate B under aerobic
conditions. Finally, the product is obtained from the interme-
diate B via elimination of a proton.
In summary, we have developed a metal-free convenient
methodology for the arylation of imidazo[1,2-a]pyridines
employing arylhydrazine as an arylating agent at room
temperature. The present methodology offers a practical route
for the synthesis of various 2,3-disubstituted imidazo[1,2-a]
pyridines with a wide range of functional groups. Imidazo[2,1-b]
thiazole and benzo[d]imidazo[2,1-b]thiazole were also arylated
under the present reaction conditions in good yields. We believe
our present protocol for arylation will nd useful applications
in organic synthesis, the pharmaceutical industry, and material
science.
Experimental section
General information
Reagents were purchased from commercial sources and used
1
without further purication. H and 13C{1H} nuclear magnetic
resonance (NMR) spectra were determined on a 400 MHz
1
spectrometer. H NMR spectra were determined on a 400 MHz
spectrometer as solutions in CDCl3. Chemical shis are
expressed in parts per million (d) and the signals are reported
as s (singlet), d (doublet), t (triplet), m (multiplet), dd (double
doublet), and coupling constants (J) are given in Hz. 13C{1H}
NMR spectra were recorded at 100 MHz in CDCl3 solution.
Chemical shis as internal standard are referenced to CDCl3 (d
1
¼ 7.26 for H and d ¼ 77.16 for 13C{1H} NMR) as the internal
standard. Thin layer chromatography (TLC) was performed on
a silica gel-coated glass slide. Commercially available solvents
were freshly distilled before the reaction. All reactions involving
moisture-sensitive reactants were executed using oven-dried
glassware. X-ray single crystal data were collected using MoKa
˚
(l ¼ 0.71073 A) radiation with Charged Coupled Device (CCD)
area. All the imidazoheterocycles were prepared by our reported
methods.8e,f
Scheme 7 Control experiments.
General experimental procedure for the arylation of imidazo
[1,2-a]pyridines (3)
A mixture of imidazo[1,2-a]pyridine (1, 0.20 mmol, 1 equiv.) and
arylhydrazine hydrochloride (2, 0.26 mmol, 1.3 equiv.) was
dissolved in 3 mL MeCN at room temperature (rt) in a reaction
tube. Then, 4 equiv. of DBU (120 mL) was added to the reaction
mixture and stirred in air for 4 h unless otherwise mentioned.
Aer completion of the reaction, the reaction mixture was
extracted with ethyl acetate and washed with water. The organic
phase was dried over anhydrous Na2SO4. The crude residue was
obtained aer evaporating the solvent under reduced pressure
and was nally puried by column chromatography on silica gel
(60–120 mesh) using petroleum ether and ethylacetate as an
eluent to afford the pure product.
2,3-Diphenylimidazo[1,2-a]pyridine (3aa):.7d,8e White solid
(45 mg, 83%), mp: 149–150 ꢀC (lit. 149–150 ꢀC); 1H NMR (CDCl3,
400 MHz): d 7.96 (d, J ¼ 6.8 Hz, 1H), 7.70–7.65 (m, 3H), 7.55–7.44
(m, 5H), 7.28–7.19 (m, 4H), 6.76–6.72 (m, 1H); 13C{1H} NMR
Scheme 8 Plausible reaction pathway.
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(CDCl3, 100 MHz): d 144.9, 142.5, 134.2, 130.8, 130.0, 129.7, 100 MHz): d 148.5, 145.0, 140.0, 136.2, 133.7, 131.1, 130.7, 130.0,
129.0, 128.4, 128.2, 127.6, 124.8, 123.4, 121.2, 117.6, 112.4. 129.7, 129.3, 129.0, 125.6, 123.7, 122.8, 122.2, 117.8, 112.9; anal.
3-Phenyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3ba). White solid calcd for C19H13N3O2: C, 72.37; H, 4.16; N, 13.33; found C, 72.51;
(51 mg, 89%), mp: 97–99 ꢀC; 1H NMR (CDCl3, 400 MHz): d 7.95 H, 4.07; N, 13.24%.
(d, J ¼ 6.8 Hz, 1H), 7.68 (d, J ¼ 9.2 Hz, 1H), 7.56–7.44 (m, 7H),
2-(3-Phenylimidazo[1,2-a]pyridin-2-yl)phenol (3ia). White
1
ꢀ
7.21–7.17 (m, 1H), 7.09 (d, J ¼ 8.0 Hz, 2H), 6.72 (t, J ¼ 6.8 Hz, solid (50 mg, 88%), mp: 84–86 C; H NMR (CDCl3, 400 MHz):
1H), 2.32 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): d 144.8, 142.5, d 13.04 (brs, 1H), 7.84 (d, J ¼ 6.8 Hz, 1H), 7.65–7.55 (m, 4H),
137.4, 131.3, 130.8, 130.1, 129.6, 129.1, 128.9, 128.1, 124.7, 7.50–7.48 (m, 2H), 7.28–7.24 (m, 1H), 7.16–7.12 (m, 2H), 7.03 (d,
123.3, 120.8, 117.5, 112.3, 21.3; anal. calcd for C20H16N2: C, J ¼ 8.4 Hz, 1H), 6.81–6.77 (m, 1H), 6.58–6.54 (m, 1H); 13C{1H}
84.48; H, 5.67; N, 9.85; found C, 84.31; H, 5.78; N, 9.91%.
NMR (CDCl3, 100 MHz): d 157.9, 142.5, 140.9, 131.3, 130.0,
2-(4-Methoxyphenyl)-3-phenylimidazo[1,2-a]pyridine
129.8, 129.7, 129.6, 129.4, 127.2, 125.4, 123.2, 118.5, 117.7,
(3ca):.7d White solid (52 mg, 86%), mp: 134–135 ꢀC (lit. Mp 135– 116.9, 116.7, 113.0; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
ꢀ
136 C); H NMR (CDCl3, 400 MHz): d 7.94 (d, J ¼ 7.2 Hz, 1H),
7.67 (d, J ¼ 8.8 Hz, 1H), 7.61–7.57 (m, 2H), 7.55–7.44 (m, 5H),
C
19H15N2O: 287.1179; found: 287.1179.
2-(4-(Methylsulfonyl)phenyl)-3-phenylimidazo[1,2-a]pyri-
7.21–7.17 (m, 1H), 6.83–6.81 (m, 2H), 6.72 (t, J ¼ 6.8 Hz, 1H), dine (3ja). Yellow liquid (61 mg, 87%); 1H NMR (CDCl3, 400
3.79 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): d 159.3, 144.8, MHz): d 7.94 (d, J ¼ 6.8 Hz, 1H), 7.87–7.81 (m, 4H), 7.70 (d, J ¼
130.9, 130.1, 129.6, 129.4, 129.2, 128.9, 126.7, 124.7, 123.3, 9.2 Hz, 1H), 7.59–7.54 (m, 3H), 7.45–7.43 (m, 2H), 7.244–7.241
120.4, 117.4, 113.8, 112.3, 55.3.
(m, 1H), 6.80–6.77 (m, 1H), 3.04 (s, 3H); 13C{1H} NMR (CDCl3,
2-(4-Fluorophenyl)-3-phenylimidazo[1,2-a]pyridine (3da):.7d 100 MHz): d 145.1, 140.0, 138.9, 130.7, 130.0, 129.6, 128.6, 128.0,
White solid (53 mg, 92%), mp: 104 ꢀC; 1H NMR (CDCl3, 400 127.5, 127.3, 126.7, 125.6, 123.6, 117.9, 113.0, 44.6; HRMS (ESI-
MHz): d 7.95 (d, J ¼ 6.8 Hz, 1H), 7.67–7.61 (m, 3H), 7.55–7.42 (m, TOF) m/z: [M + H]+ calcd for C20H17N2O2S: 349.1005; found:
5H), 7.22–7.18 (m, 1H), 6.99–6.93 (m, 2H), 6.74 (t, J ¼ 7.6 Hz, 349.0998.
1H); 13C{1H} NMR (CDCl3, 100 MHz): d 162.5 (d, JC–F ¼ 245 Hz),
2-(Naphthalen-2-yl)-3-phenylimidazo[1,2-a]pyridine (3ka).
144.9, 141.7, 130.8, 130.4 (d, JC–F ¼ 3 Hz), 129.8 (d, JC–F ¼ 9 Hz), White solid (60 mg, 94%), mp: 117–118 ꢀC; 1H NMR (CDCl3, 400
129.7, 129.1, 124.9, 123.4, 120.9, 117.6, 115.7, 115.3 (d, JC–F ¼ 22 MHz): d 8.25 (s, 1H), 8.00 (d, J ¼ 7.2 Hz, 1H), 7.78–7.67 (m, 5H),
Hz), 112.5.
2-(4-Chlorophenyl)-3-phenylimidazo[1,2-a]pyridine
7.54–7.48 (m, 5H), 7.44–7.40 (m, 2H), 7.25–7.21 (m, 1H), 6.77–
(3ea). 6.74 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): d 145.1, 142.4,
Yellow semi solid (55 mg, 91%); 1H NMR (CDCl3, 400 MHz): 133.6, 132.9, 131.7, 130.9, 130.0, 129.7, 129.1, 128.5, 127.8,
d 7.97 (d, J ¼ 7.2 Hz, 1H), 7.69 (d, J ¼ 9.2 Hz, 1H), 7.62–7.60 (m, 127.6, 127.3, 126.1, 126.09, 126.06, 124.9, 123.4, 121.6, 117.6,
2H), 7.56–7.52 (m, 3H), 7.47–7.45 (m, 2H), 7.28–7.21 (m, 3H), 112.5; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H17N2:
6.79–6.75 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz): d 145.0, 321.1386; found: 321.1386.
141.4, 133.4, 132.8, 130.8, 129.8, 129.7, 129.4, 129.2, 128.6,
125.0, 123.4, 121.3, 117.7, 112.5; anal. calcd for C19H13ClN2: C, White solid (44 mg, 79%), mp: 65–67 C; H NMR (CDCl3, 400
3-Phenyl-2-(thiophen-2-yl)imidazo[1,2-a]pyridine
(3la).
1
ꢀ
74.88; H, 4.30; N, 9.19; found C, 75.09; H, 4.40; N, 9.01%.
MHz): d 7.83 (d, J ¼ 6.8 Hz, 1H), 7.65 (d, J ¼ 9.2 Hz, 1H), 7.59–
2-(3-Bromophenyl)-3-phenylimidazo[1,2-a]pyridine
(3fa). 7.50 (m, 5H), 7.22–7.16 (m, 2H), 7.09 (dd, J ¼ 3.6 Hz, 0.8 Hz, 1H),
Yellow solid (58 mg, 83%), mp: 122–123 ꢀC; 1H NMR (CDCl3, 400 6.93–6.91 (m, 1H), 6.71 (t, J ¼ 6.8 Hz, 1H); 13C{1H} NMR (CDCl3,
MHz): d 7.95–7.91 (m, 2H), 7.67 (d, J ¼ 9.2 Hz, 1H), 7.57–7.43 (m, 100 MHz): d 144.7, 137.7, 137.6, 131.1, 129.7, 129.5, 129.1, 127.5,
6H), 7.36 (d, J ¼ 8.8 Hz, 1H), 7.24–7.20 (m, 1H), 7.10 (t, J ¼ 125.3, 125.0, 124.6, 123.3, 120.0, 117.3, 112.5; anal. calcd for
8.0 Hz, 1H), 6.75 (t, J ¼ 6.8 Hz, 1H); 13C{1H} NMR (CDCl3, 100
C17H12N2S: C, 73.89; H, 4.38; N, 10.14; found C, 74.13; H,
MHz): d 144.9, 140.9, 136.4, 131.0, 130.8, 130.5, 129.8, 129.4, 4.31; N, 10.02%.
129.3, 129.2, 126.5, 125.1, 123.5, 122.6, 121.7, 117.7, 112.6; anal.
2-Isobutyl-3-phenylimidazo[1,2-a]pyridine (3ma). Yellow
1
calcd for C19H13BrN2: C, 65.35; H, 3.75; N, 8.02; found C, 65.52; liquid (36 mg, 72%); H NMR (CDCl3, 400 MHz): d 8.00 (d, J ¼
H, 3.83; N, 8.09%.
7.2 Hz, 1H), 7.58 (d, J ¼ 8.8 Hz, 1H), 7.54–7.51 (m, 2H), 7.45–7.41
(m, 3H), 7.16–7.12 (m, 1H), 6.71–6.68 (m, 1H), 2.64 (d, J ¼
3-Phenyl-2-(4-(triuoromethyl)phenyl)imidazo[1,2-a]pyri-
1
dine (3ga). White solid (58 mg, 85%), mp: 67–68 C; H NMR 7.2 Hz, 2H), 2.25–2.14 (m, 1H), 0.89 (d, J ¼ 6.8 Hz, 6H); 13C{1H}
(CDCl3, 400 MHz): d 7.94 (d, J ¼ 6.8 Hz, 1H), 7.77 (d, J ¼ 8.0 Hz, NMR (CDCl3, 100 MHz): d 144.6, 130.1, 129.7, 129.3, 128.9,
2H), 7.69 (d, J ¼ 9.2 Hz, 1H), 7.58–7.51 (m, 5H), 7.45–7.43 (m, 128.3, 126.8, 124.1, 123.2, 117.2, 111.8, 36.9, 29.1, 22.7; anal.
2H), 7.25–7.21 (m, 1H), 6.78–6.74 (m, 1H); 13C{1H} NMR (CDCl3, calcd for C17H18N2: C, 81.56; H, 7.25; N, 11.19; found C, 81.21;
100 MHz): d 145.0, 140.9, 137.9, 130.8, 130.0, 129.9, 129.4, 129.0 H, 7.41; N, 11.38%.
ꢀ
(q, JC–F ¼ 37 Hz), 128.2, 127.1 (q, JC–F ¼ 270 Hz), 126.2, 125.3 (q,
3-Phenylimidazo[1,2-a]pyridine (3na).9d Colorless liquid
JC–F ¼ 6 Hz), 123.5, 122.1, 117.8, 112.7; HRMS (ESI-TOF) m/z: [M (27 mg, 70%); 1H NMR (CDCl3, 400 MHz): d 8.33 (d, J ¼ 6.8 Hz,
+ H]+ calcd for C20H14F3N2: 339.1104; found: 339.1107.
1H), 7.69 (s, 1H), 7.67 (d, J ¼ 8.8 Hz, 1H), 7.57–7.49 (m, 4H),
2-(3-Nitrophenyl)-3-phenylimidazo[1,2-a]pyridine
(3ha). 7.43–7.38 (m, 1H), 7.21–7.16 (m, 1H), 6.81–6.78 (m, 1H); 13C{1H}
Brown solid (49 mg, 78%), mp: 147–148 ꢀC; 1H NMR (CDCl3, 400 NMR (CDCl3, 100 MHz): d 146.2, 132.6, 129.4, 129.3, 128.3,
MHz): d 8.32 (t, J ¼ 2.0 Hz, 1H), 7.88–7.86 (m, 1H), 7.78–7.73 (m, 128.1, 125.8, 124.3, 123.4, 118.3, 112.6.
2H), 7.49 (d, J ¼ 9.2 Hz, 1H), 7.39–7.33 (m, 3H), 7.26–7.20 (m,
8-Methyl-2,3-diphenylimidazo[1,2-a]pyridine (3oa).8d White
3H), 7.07–7.03 (m, 1H), 6.60–6.56 (m, 1H); 13C{1H} NMR (CDCl3, solid (52 mg, 91%), mp: 104–106 ꢀC; 1H NMR (CDCl3, 400 MHz):
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d 7.82 (d, J ¼ 6.8 Hz, 1H), 7.67–7.64 (m, 2H), 7.51–7.41 (m, 5H), NMR (CDCl3, 100 MHz): d 145.1, 142.9, 135.0, 133.9, 132.1, 130.0,
7.28–7.19 (m, 3H), 6.98–6.96 (m, 1H), 6.63 (t, J ¼ 6.8 Hz, 1H), 129.4, 128.5, 128.3, 127.8, 125.1, 123.2, 117.7, 117.1, 112.7.
2.69 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): d 145.4, 142.1,
134.6, 130.8, 130.3, 129.5, 128.8, 128.4, 128.3, 127.6, 127.4, (3ad). Yellow liquid (55 mg, 81%); H NMR (CDCl3, 400 MHz):
123.5, 121.6, 121.3, 112.4, 17.3.
3-(2,4-Dichlorophenyl)-2-phenylimidazo[1,2-a]pyridine
1
d 7.72 (d, J ¼ 8.8 Hz, 1H), 7.67 (d, J ¼ 2.0 Hz, 1H), 7.61–7.59 (m,
7-Methyl-2,3-diphenylimidazo[1,2-a]pyridine (3pa).8e White 3H), 7.37 (dd, J ¼ 8.0 Hz, 2.0 Hz, 1H), 7.32–7.26 (m, 5H), 6.79 (t, J
solid (46 mg, 81%), mp: 131–133 ꢀC; 1H NMR (CDCl3, 400 MHz): ¼ 6.8 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): d 145.3, 143.7,
d 7.84 (d, J ¼ 6.8 Hz, 1H), 7.66–7.63 (m, 2H), 7.53–7.42 (m, 6H), 136.9, 136.5, 134.8, 133.8, 130.5, 129.0, 128.6, 128.4, 127.9,
7.29–7.22 (m, 3H), 6.56 (dd, J ¼ 7.2 Hz, 1.6 Hz, 1H), 2.41 (s, 3H); 127.8, 125.2, 123.8, 117.7, 114.7, 112.6; anal. calcd for
13C{1H} NMR (CDCl3, 100 MHz): d 145.3, 142.0, 135.9, 134.3,
C19H12Cl2N2: C, 67.27; H, 3.57; N, 8.26; found C, 67.54; H,
130.8, 130.1, 129.6, 128.8, 128.3, 128.1, 127.4, 122.6, 120.6, 3.58; N, 8.09%.
115.9, 115.1, 21.4. 3-(2-Bromophenyl)-2-phenylimidazo[1,2-a]pyridine
(3ae).
6-Chloro-2,3-diphenylimidazo[1,2-a]pyridine (3qa). Yellow Semi solid (59 mg, 85%); 1H NMR (CDCl3, 400 MHz): d 7.84 (d, J
solid (53 mg, 87%), mp: 142–144 ꢀC; 1H NMR (CDCl3, 400 MHz): ¼ 7.2 Hz, 1H), 7.72 (d, J ¼ 8.8 Hz, 1H), 7.64–7.58 (m, 3H), 7.46–
d 7.968–7.961 (m, 1H), 7.65–7.61 (m, 3H), 7.58–7.51 (m, 3H), 7.36 (m, 3H), 7.30–7.22 (m, 4H), 6.79–6.76 (m, 1H); 13C{1H} NMR
7.45–7.43 (m, 2H), 7.30–7.25 (m, 3H), 7.16 (dd, J ¼ 9.6 Hz, (CDCl3, 100 MHz): d 145.0, 143.0, 134.2, 134.1, 133.7, 131.4,
2.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz): d 143.5, 143.2, 131.2, 128.56, 128.51, 128.0, 127.7, 126.5, 125.0, 124.0, 120.2,
133.8, 130.7, 129.8, 129.4, 129.3, 128.4, 128.1, 127.9, 126.1, 117.6, 112.3; anal. calcd for C19H13BrN2: C, 65.35; H, 3.75; N,
121.2, 120.7, 118.0, 115.6; anal. calcd for C19H13ClN2: C, 74.88; 8.02; found C, 65.11; H, 3.83; N, 8.14%.
H, 4.30; N, 9.19; found C, 75.06; H, 4.36; N, 9.26%.
General experimental procedure for the arylation of imidazo
6-Bromo-2,3-diphenylimidazo[1,2-a]pyridine (3ra). White [2,1-b]thiazole (4a and 4b). A mixture of imidazo[2,1-b]thiazole
solid (57 mg, 82%), mp: 201–202 ꢀC; 1H NMR (CDCl3, 400 MHz): (0.20 mmol, 1 equiv.) and arylhydrazine hydrochloride (2,
d 8.06 (s, 1H), 7.65–7.63 (m, 2H), 7.59–7.52 (m, 4H), 7.46–7.44 0.26 mmol, 1.3 equiv.) was dissolved in 3 mL MeCN at room
(m, 2H), 7.29–7.25 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz): temperature in a reaction tube. Then 4 equiv. of DBU (120 mL)
d 143.3, 142.0, 133.8, 130.7, 129.9, 129.4, 129.3, 128.4, 128.3, was added to the reaction mixture and stirred in air for 4 h. Aer
128.1, 127.9, 123.4, 121.6, 118.3, 107.2; anal. calcd for completion of the reaction, the reaction mixture was extracted
C
19H13BrN2: C, 65.35; H, 3.75; N, 8.02; found C, 65.18; H, with ethyl acetate and washed with water (3 times). The organic
3.67; N, 8.11%.
phase was evaporated, and crude product was puried by
2,3-Diphenylimidazo[1,2-a]pyridine-6-carbonitrile
(3sa). column chromatography on silica gel (60–120 mesh) using
White solid (50 mg, 84%), mp: 151–153 ꢀC; 1H NMR (CDCl3, 400 petroleum ether and ethylacetate as an eluent to afford the pure
MHz): d 8.34 (s, 1H), 7.74 (d, J ¼ 10.0 Hz, 1H), 7.68–7.65 (m, 2H), product.
7.62–7.56 (m, 3H), 7.45–7.43 (m, 2H), 7.32–7.28 (m, 4H); 13C{1H}
5,6-Diphenylimidazo[2,1-b]thiazole (4a). Yellow liquid
NMR (CDCl3, 100 MHz): d 144.7, 143.9, 133.0, 130.7, 130.1, (44 mg, 80%); 1H NMR (CDCl3, 400 MHz): d 7.62–7.59 (m, 2H),
130.0, 129.7, 128.6, 128.5, 128.3, 128.2, 124.4, 122.2, 118.5, 7.46–7.43 (m, 4H), 7.42–7.40 (m, 1H), 7.37 (d, J ¼ 4.4 Hz, 1H),
116.9, 98.6; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H14N3: 7.29–7.27 (m, 2H), 7.24–7.20 (m, 1H), 6.81 (d, J ¼ 4.8 Hz, 1H);
296.1182; found: 296.1166.
13C{1H} NMR (CDCl3, 100 MHz): d 149.1, 134.6, 130.6, 129.38,
8-Bromo-2,3-diphenylimidazo[1,2-a]pyridine (3ta). White 129.35, 128.49, 128.43, 127.7, 127.2, 117.6, 112.5; anal. calcd for
solid (48 mg, 69%), mp: 164–167 ꢀC; 1H NMR (CDCl3, 400 MHz):
17H12N2S: C, 73.89; H, 4.38; N, 10.14; found C, 73.98; H,
C
d 7.93 (dd, J ¼ 6.8 Hz, 0.8 Hz, 1H), 7.70–7.67 (m, 2H), 7.55–7.42 4.31; N, 10.13%.
(m, 7H), 7.30–7.26 (m, 2H), 6.62 (t, J ¼ 7.2 Hz, 1H); 13C{1H} NMR
6-Methoxy-2-phenyl-3-(o-tolyl)benzo[d]imidazo[2,1-b]thia-
(CDCl3, 100 MHz): d 152.7, 146.9, 134.0, 133.8, 130.8, 129.7, zole (4b). Semi solid (61 mg, 82%); 1H NMR (CDCl3, 400 MHz):
129.3, 128.53, 128.50, 128.4, 127.8, 127.1, 122.8, 113.0, 112.3; d 7.56–7.54 (m, 2H), 7.52–7.48 (m, 1H), 7.43 (dd, J ¼ 7.6 Hz,
anal. calcd for C19H13BrN2: C, 65.35; H, 3.75; N, 8.02; found C, 1.6 Hz, 2H), 7.36 (t, J ¼ 8.0 Hz, 1H), 7.25–7.16 (m, 4H), 6.68 (dd, J
65.49; H, 3.68; N, 7.94%.
¼ 8.8 Hz, 2.4 Hz, 1H), 6.47 (d, J ¼ 9.2 Hz, 1H), 3.80 (s, 3H), 2.12
2-Phenyl-3-(o-tolyl)imidazo[1,2-a]pyridine (3ab).7e White (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): d 156.9, 146.5, 142.5,
1
ꢀ
ꢀ
solid (51 mg, 89%), mp: 124–126 C (lit. 124–126 C); H NMR 139.4, 134.6, 131.9, 130.8, 130.1, 130.0, 128.4, 127.3, 127.2,
(CDCl3, 400 MHz): d 7.71–7.65 (m, 3H), 7.56 (d, J ¼ 6.8 Hz, 1H), 127.0, 126.9, 126.1, 123.2, 113.3, 113.1, 108.8, 55.9, 19.9; HRMS
7.45–7.43 (m, 2H), 7.36–7.34 (m, 2H), 7.26–7.18 (m, 4H), 6.74– (ESI-TOF) m/z: [M + H]+ calcd for C23H19N2OS: 371.1213; found:
6.70 (m, 1H), 2.01 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): 371.1203.
d 144.9, 139.3, 132.4, 131.9, 131.1, 129.8, 129.3, 129.0, 128.5,
Experimental procedure for the synthesis of 2,3-diphenyl-6-
127.5, 127.3, 127.1, 124.6, 123.5, 120.1, 117.5, 112.3, 19.5.
(phenylethynyl)imidazo[1,2-a]pyridine (5).
A
mixture of
3-(4-Chlorophenyl)-2-phenylimidazo[1,2-a]pyridine (3ac).9f 6-bromo-2,3-diphenylimidazo[1,2-a]pyridine (3ra, 0.2 mmol, 70
1
ꢀ
ꢀ
White solid (52 mg, 86%), mp: 171–173 C (lit. 173–175 C); H mg), phenylacetylene (0.2 mmol, 22 mL), bis(triphenylphosphine)
NMR (CDCl3, 400 MHz): d 7.94 (d, J ¼ 7.2 Hz, 1H), 7.68 (d, J ¼ palladium(II) dichloride (10 mol%, 14 mg) and copper iodide
9.2 Hz, 1H), 7.64–7.62 (m, 2H), 7.50 (d, J ¼ 8.4 Hz, 2H), 7.39 (d, J ¼ (10 mol%, 3.8 mg) was taken in a reaction vessel in 2 mL of a solu-
8.8 Hz, 2H), 7.32–7.20 (m, 4H), 6.76 (t, J ¼ 6.8 Hz, 1H); 13C{1H} tion of DMF/Et3N (1/1, v/v) under argon and it was stirred at 50 ꢀC
temperature for 24 h. Aer cooling, the reaction mixture was
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extracted with ethyl acetate. The organic layer was evaporated, and
crude product was puried by column chromatography on silica gel
(60–120 mesh) using petroleum ether and ethylacetate as an eluent
to afford the pure product. Pure product was obtained as a white
A. B. Charette, Acc. Chem. Res., 2013, 46, 412; (e)
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2009, 42, 1074.
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F. Bellina, Adv. Synth. Catal., 2015, 357, 3777; (b)
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9219.
1
ꢀ
solid (70 mg, 95%), mp: 189–191 C; H NMR (CDCl3, 400 MHz):
d 8.13 (m, 1H), 7.68–7.63 (m, 3H), 7.57–7.44 (m, 7H), 7.36–7.24 (m,
7H); 13C{1H} NMR (CDCl3, 100 MHz): d 143.7, 143.3, 133.9, 131.6,
130.9, 129.8, 129.4, 129.3, 128.7, 128.5, 128.4, 128.1, 127.8, 127.7,
126.2, 122.6, 121.4, 117.3, 109.2, 90.6, 85.8; anal. calcd for C27H18N2:
C, 87.54; H, 4.90; N, 7.56; found C, 87.84; H, 4.72; N, 7.44%.
Experimental procedure for the synthesis of 2,3,6-tripheny-
limidazo[1,2-a]pyridine (6). A mixture of 6-bromo-2,3-dipheny-
limidazo[1,2-a]pyridine (3ra, 0.2 mmol, 70 mg), phenyl boronic
acid (0.2 mmol, 24 mg), tetrakis(triphenylphosphine) palla-
dium(0) (2 mol%, 4.6 mg) and potassium carbonate (2.1 equiv.
58 mg) was taken in a reaction vessel in 2 mL of a solution of
DMF/H2O (2/1, v/v) under argon and it was stirred at 100 ꢀC
temperature for 4 h. Aer completion of the reaction, the
reaction mixture was cooled to room temperature, quenched
with water, and extracted with dichloromethane. The organic
layer was evaporated, and crude product was puried by column
chromatography on silica gel (60–120 mesh) using petroleum
ether and ethylacetate as an eluent to afford the pure product.
Pure product was obtained as a white solid (52 mg, 75%), mp:
165–167 ꢀC; 1H NMR (CDCl3, 400 MHz): d 8.11 (s, 1H), 7.75 (d, J
¼ 9.6 Hz, 1H), 7.69–7.67 (m, 2H), 7.56–7.46 (m, 8H), 7.44–7.41
(m, 2H), 7.38–7.34 (m, 1H), 7.31–7.25 (m, 3H); 13C{1H} NMR
(CDCl3, 100 MHz): d 144.2, 143.1, 137.7, 134.2, 130.8, 129.9,
129.7, 129.18, 129.12, 128.4, 128.2, 127.9, 127.6, 127.09, 127.00,
125.6, 121.6, 120.6, 117.5; anal. calcd for C25H18N2: C, 86.68; H,
5.24; N, 8.09; found C, 86.90; H, 5.13; N, 7.97%.
¨
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Conflicts of interest
´
M. K. Cyranski and D. T. Gryko, J. Org. Chem., 2012, 77, 5552.
There are no conicts to declare.
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Acknowledgements
A. H. and V. Z. S. acknowledge the nancial support from DST,
New Delhi (Indo-Russian joint project # INT/RUS/RFBR/P-295)
and Russian Foundation for Basic Research, Russia (Ref. # 17-
53-45127).
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