Molecular iodine enabled generation of iminyl radicals from oximes: A facile route to imidazo[1,2-a]pyridines and its regioselective C-3 sulfenylated products from simple pyridines

Article abstract of DOI:10.1016/j.tet.2021.132125

An iodine promoted simple and environment friendly protocol has been developed to access imidazo[1,2-a]pyridines from unfunctionalized pyridines and oxime esters. This straightforward method efficiently converts the substrates into corresponding products affording moderate to good yields with large functional group tolerance. Additionally extensive investigation revealed that regioselective domino C-3 methyl sulfenylated imidazo[1,2-a]pyridines were also accessible first time from pyridines and oxime esters in DMSO solvent. The reaction operates through metal-free generation of iminyl radicals from easily accessible oxime esters, to build up the second heterocyclic ring on pyridines.

Full text of DOI:10.1016/j.tet.2021.132125

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Molecular iodine enabled generation of iminyl radicals from oximes: A
facile route to imidazo[1,2-a]pyridines and its regioselective C-3
sulfenylated products from simple pyridines
*
Deepak Singh, Soumyadeep Roy Chowdhury, Shyamal Pramanik, Soumitra Maity
Department of Chemistry, Indian Institute of Technology (ISM), Dhanbad, JH, 826004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 January 2021
Received in revised form
An iodine promoted simple and environment friendly protocol has been developed to access imidazo
[
1,2-a]pyridines from unfunctionalized pyridines and oxime esters. This straightforward method effi-
ciently converts the substrates into corresponding products affording moderate to good yields with large
functional group tolerance. Additionally extensive investigation revealed that regioselective domino C-3
methyl sulfenylated imidazo[1,2-a]pyridines were also accessible first time from pyridines and oxime
esters in DMSO solvent. The reaction operates through metal-free generation of iminyl radicals from
easily accessible oxime esters, to build up the second heterocyclic ring on pyridines.
25 March 2021
Accepted 27 March 2021
Available online xxx
Keywords:
Iodine
©
2021 Elsevier Ltd. All rights reserved.
Imidazopyridine
Regioselective
Sulfenylation
Metal free
1. Introduction
[7b] described a Cu-catalyzed formal aza-[3 þ 2] cycloaddition
reaction of pyridine derivatives with highly functionalized -diazo
a
Imidazo-pyridine is an important class of nitrogen-bridgehead
heterocycles frequently found in many biologically active com-
pounds [1]. Among them, imidazo[1,2-a]pyridines (IPs) display
very interesting biological activities such as antifungal, anti-
inflammatory, antitumor, antiviral, antiprotozoal, antibacterial,
and antipyretic [2].Importantly, IPs constitutethe key structure of
many marketed drugs, like Zolpidem, Zolimidine, Alpidem, Sar-
ipidem, Necopidem and Olprinone [3]. Furthermore, their unique
photo-physical properties make them useful in material and allied
sciences [4].Accordingly, various efficient strategies to imidazo[1,2-
a]pyridines have been developed [5]. Conventional synthesis of IPs
mainly rely on reaction of functionalized pyridine derivatives,
usually 2-amino pyridines [6] with variety of coupling partners
oxime ethers. Recently Adimurthy [7c] and Huang [7d] indepen-
dently utilized vinyl azides and enamides as the nitrogen source to
construct imidazo[1,2-a]pyridine frameworks on pyridine ring by
copper catalysis. Moreover, Litvinov et al. reported [7i] a base
induced cyclization protocol to IPs from p-bromophenacyl bromide
and pyridines under heating conditions. However, all of these
methods are suffer with the limited accessibility of the highly
functionalized coupling partners: 1,2-diaza-1,3-dienes,
a-diazo
oxime ethers, vinyl azides and enamides which restrict the syn-
thetic versatility of IPs. In addition, the success of these methods
are majorly depending on the effective use of copper catalysts with
additives and/or solvent. Consequently, a simple and easily avail-
able versatile coupling partner which overcomes the above limi-
tations certainly advances the synthesis of IPs from pyridines.
Owing to cheap and readily accessible with versatility, oximes
are widely used in chemical industry and academia as starting
materials [8]. Recently, the development of transition metal catal-
ysis has further expanded the scope of this substrate in organic
synthesis [9]. Particularly, reductive cleavage of NeO bond of
ketoximes provides a unique structural skeleton ‘NeCeC’ which
could be fused with diverse partners to construct azaheterocycles
[10]. In fact, this strategy had been established in the synthesis of
including ketones [6a-e], isonitriles [6f-g],a-halocarbonyls [6h-j] or
olefins [6k-n] under condensation and/or oxidative conditions. A
straight forward route to access IPs from unfunctionalized pyri-
dines are quite rare and only a few reports are there in literature
(
Scheme 1a) [7]. Fabio et al. [7a] reported a novel thermal synthesis
of IPs derivatives from pyridines and 1,2-diaza-1,3-dienes. Lee et al.
*
Corresponding author.
E-mail address: smaity@iitism.ac.in (S. Maity).
https://doi.org/10.1016/j.tet.2021.132125
040-4020/© 2021 Elsevier Ltd. All rights reserved.
0
Please cite this article as: D. Singh, S.R. Chowdhury, S. Pramanik et al., Molecular iodine enabled generation of iminyl radicals from oximes: A
facile route to imidazo[1,2-a]pyridines and its regioselective C-3 sulfenylated products from simple pyridines, Tetrahedron, https://doi.org/
10.1016/j.tet.2021.132125

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
Table 1
Screening of protecting groups. .
a
Entry
R
Yielda (%)
Entry
R
Yield (%)
1
2
3
.
.
.
H
Ac
Boc
22
26
24
4.
5.
6.
Bz
Ts
Ms
38
N.R
N.R
a
Unless otherwise noted, all reactions were carried out with: 1 (0.5 mmol), 2a
(
0.2 mmol), catalyst (20 mol %), solvent (acetonitrile) (2 mL) at heating (110 OC) in a
reaction tube for 6 h in air.
After defining benzoyl as the optimal protecting group, we set
out to find the optimized reaction condition (Table 2). Accepting the
initial result from Table 1, we went ahead to fix other reaction pa-
rameters for improving yield. Varying the solvent from polar
aprotic DMF to other common solvents like nitromethane, NMP,
HFIP, and MeOH (entries 1e6) hardly provided the desired imidazo
[
1,2-a]pyridine. Moreover, acetonitrile was appeared to be
the best one compared to other productive solvents, chloro-
Scheme 1. IPs synthesis from unfunctionalized pyridines.
benzene, and toluene (entries 7e8). Next increasing the equiva-
lency of iodine from 20 mol% to 50 mol%, boosted up the reaction
yield up to 48% (entry 9) and became consistent with further raising
the equivalency of iodine. It is noticeable that a maximum yield of
62% (entry 10) was obtained when the temperature was raised to
various fused nitrogen heterocycles including imidazo[1,2-a]pyri-
dines[7f-h] and others [11]. However, in this reaction the reactive
iminyl radical was generated from ketoxime by exposure of metal
catalyst with additives that introduce toxic waste to the environ-
ment. So a metal-free method could render a modified better
technique to access these targeted heterocycles under environment
benign conditions [12].
In recent years, molecular iodine has emerged as a flexible and
environmentally benign reagent for various organic trans-
formations [13]. Furthermore, the discovery of complementary
redox-reactivity of iodine in transition metal-catalyzed coupling
reactions has opened a new opportunity to test radical reactions
ꢀ
140 C and beyond the optimal temperature, the yield decreased
gradually. At this point excess loading of iodine didn’t help to
improve the yield of 3a (entry 11). Furthermore, the reaction got
ꢀ
completely inhibited below the minimum temperature of 100
C
Table 2
a
Optimization of the reaction conditions. .
[
14]. Within this context, seminal iodine-catalyzed redox reaction
of oxime esters were explored by Deng [15a-b] and Gao [15c].
Inspired by these works [15] we hypothesized that iminyl radical
generated from oxime esters by iodine might couple with pyridine
generating IPs under metal-free conditions (Scheme 1b). As a part
of our ongoing research on sustainable methods development [16],
herein we report for the first time a simple molecular iodine-
catalyzed synthesis of imidazo[1,2-a]pyridines by the intermolec-
ular oxidative coupling of ketoxime and pyridines under metal and
additive-free conditions. Additionally, regioselective C-3 methyl-
sulphenated IPs were also synthesized by applying the same pro-
tocol using DMSO as methylthiolated source through a domino
process.
o
Yield (%)b
Entry
Catalyst (mol%)
Solvent
Temp ( C)
1
2
3
4
5
6
7
8
9
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
I
2
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(20)
(50)
MeCN
DMF
110
110
110
110
110
110
110
110
110
140
140
100
140
140
140
140
140
140
38
Trace
n.r.
n.r
n.r.
n.r.
23
20
48
62
15
MeNO
NMP
HFIP
2
MeOH
PhCl
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
. Results and discussion
10
I2 (50)
1
1
1
1
1
1
2
3
4
5
I
I
2
(100)
(50)
2
n.r.
n.r
To investigate the finest starting material, we started with ace-
TBAI(50)
KI(50)
PhI(OAc)
e
tophenone oxime with unfunctionalized pyridine (2a) in presence
n.r.
trace
n.r.
n.r.
36
O
of 20 mol% molecular iodine under 110 C of temperature for 6 h.
2
(100)
c
Initially, acetonitrile was selected as a solvent and in this case, a
promising 22% yield of the desired product was observed (Table 1,
entry 1). Protecting the free oxime-hydroxyl group certainly
improved the yield of 3a and the best yield was achieved with the
benzoyl derivative (entries 2e4). The use of sulfonyl groups such as
mesyl or tosyl derivatives of oxime converts the starting material to
amide through Beckmann Rearrangement [17] and no IP product
was formed (entries 5e6).
16
d
e
1
1
7
8
I
I
2
(50)
(50)
2
a
Reaction conditions: 1a (0.5 mmol), 2a (0.2 mmol), I
2
(x mmol), solvent (2 mL)
for 6 h in air.
b
Isolated yields after column chromatography; n.r. ¼ no reaction.
c
d
e
2
In the absence of I .
Degassed condition under argon.
With oxygen balloon.
2

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
(
entry 12). Other iodine sources (KI, TBAI, and PIDA) were also
final products 3n-3o respectively, in marginal yields. Unfortunately,
oxime esters derived from alkyl ketones such as cyclohexanone and
acetone were not amenable to this condition (3q-3r).
studied, but didn’t found any better result (entries 13e15). When
the reaction was carried out in the absence of iodine the reaction
scope completely withheld (entry 16). This suggests that molecular
iodine is one of the essential element for the reaction. Controlled
experiment revealed that replacing aerobic reaction atmosphere
with argon completely prohibited the reaction scope (entry 17). On
the other hand, using a fully oxygenated reaction atmosphere dis-
played significantly lower yield (entry 18) probably due to the
damage of substrates through aerial oxidation at elevated tem-
perature. Considering Oxime ester as a limiting substrate, further
increment of the concentration of pyridine did not help to get
better yields (for details see SI).
Now, with the optimized reaction condition in hand we moved
to investigate the substrate scope and generality of the aforemen-
tioned process. A large variety of oxime esters derived from aryl
methyl ketones smoothly participated in the reaction with good to
moderate yields (Table 3). This iodine catalyzed reaction permits a
broad spectrum of functional group tolerance and making it quite a
general process. Aryl methyl ketoxime esters bearing highly
electron-donating 4-methoxy (3b) and prominent electron-
withdrawing groups like 4-Fluoro (3e) or 3-nitro (3i) on the aryl
rings, comfortably participated with good yields making the reac-
tion quite insensitive towards the electronic effects. Whereas other
aryl methyl ketoxime benzoate incorporated with bromine, hy-
droxyl groups (3f-3h) substituted in aryl rings, all reacted smoothly
to produce corresponding IPs. Oxime esters containing -ortho or
Next, we tried to explore the scope of substituted pyridines
(Table 4). Generally, it was found that the substituted pyridine
derivatives displayed lower yields compared to pyridine. Interest-
ingly pyridines substituted with electron rich methyl (4a, 4b, and
4f) and electron deficient fluoro, cyano groups (4c, 4d) reacted
similarly affording corresponding IPs in moderate yields [18a].
Moreover, C-2 substituted pyridine (4e) which was sterically less
reactive, also found no problem to participate in this process albeit
with a lower yield. Lastly, pyridines, fused with aromatic rings such
as quinoline (4g) and isoquinoline (4h) underwent fair involvement
in this method affording moderate yields [18b].
Inducting sulfenyl substructures into aromatic or hetero-
aromatic rings is considered to be a fundamental and formidable
area of research interest for synthetic chemists in recent years. This
process gives a clear-cut route to synthesize thioethers which
sometimes exhibit useful physicochemical properties amenable for
biological and material applications [19]. Some of the very impor-
tant pharmaceutical entities come from the aforementioned thio-
ethers family [20]. Although significant attempts had been made
for the C-3 sulfenylation of imidazo[1, 2-a]pyridines [21], but their
regioselective C-3 methylsulfenylation is quite less [22]. Moreover,
the majority of these methods are primarily focussing on C-3
functionalization of IPs in a stepwise process. On the other hand,
direct access of the C-3 functionalized IPs from unfunctionalized
pyridines through a single step domino process is completely un-
explored. During our course of solvent optimization studies in IPs
synthesis, C-3 methylsulfenated IP (5a) was isolated in moderate
yields when DMSO was used as solvent unaffecting other reaction
parameters. In this context, we are reporting an iodine-mediated
environment-friendly direct method to access regioselective C-3
methylsulfenylated imidazo[1,2-a]pyridine where DMSO is
employed as methyl thiolating agent as well as solvent.
-
meta substituted aryl ring, possess significantly lower yields with
respect to -para substituted aryl counterparts (3c, 3d vs 3b).
Moreover, sterically bulky oxime esters derived from 1-naphthyl
methyl ketone (3j) and 1-tetralone (3p) can also be well accom-
modated into the protocol albeit with lower yields. This indicates
steric hindrance plays a negative impact on the transition state of
the reaction. Oxime esters derived from pyridine-2-yl, thiophen-2-
yl and furan-2-yl ketones were also productive, leading to the
products (3k-3m) in lower yield respectively. Pleasingly aryl
ketoxime benzoates prepared from 2-substituted acetophenone
derivatives such as valerophenone and deoxybenzoin afforded the
Furthermore, to check the substrate scope a showcase of
structurally diverse methylsulphanylated IPs were prepared from
corresponding oxime esters and pyridines (Table 5). To our delight
Table 3
Scope of Oxime esters:a,b
.
a
ꢀ
Reaction Conditions, unless otherwise noted: 1 (0.5 mmol), 2a (0.2 mmol), I2 (0.1 mmol), acetonitrile (2 mL), heated under 140 C for 6 hrs in air.
isolated yields.
b
3

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
Table 4
Scope of pyridine derivatives.[a,b].
a
ꢀ
Reaction Conditions:1b (0.5 mmol), 2 (0.2 mmol), I2 (0.1 mmol), acetonitrile (2 mL), heated under 140 C for 6 hrs in air.
Isolated yields after column chromatography.
b
Table 5
Substrate scope of 3-sulfenylimidazopyridines synthesis.[a,b].
a
ꢀ
Reaction Conditions: 1 (0.5 mmol), 2 (0.2 mmol), I2 (0.1 mmol), DMSO (2 mL), heated under 140 C for 6 hrs in air.
Isolated yields after column chromatography
b
aryl methyl oxime esters bearing electron rich, and electron defi-
(Scheme 2a). Furthermore, it was observed that benzoyl protecting
group of oxime ester was ended up with benzoic acid, as evident
from the H NMR spectra of bicarbonate unwashed reaction
mixture of 2a and 1e (Scheme 2b) [23]. To further understand the
thiolation reaction mechanism, the reaction of 2-phenylimidazo
[1,2-a]pyridine (3a) was performed with iodine in DMSO, which
gave
cient aryl rings (5b-f, j), all participated in the reaction but with
lower yields. Furthermore, substituted pyridines were also
accommodated into the target methylsulfanylated products (5g-i).
To gain a better inside into the mechanism we have done a series
of controlled experiments. Previously it was evident that without
aerial oxygen or iodine the reaction got completely inhibited
1
(
Table 1, entries 16e17). After that when TEMPO was introduced to
expected 3-methylthioimidazo[1,2-a]pyridine (5a) in 23% yield
(Scheme 5c) [22b-c]. This result provides information that thio-
lation might be taken place after formation of parent imidazo[1,2-a]
pyridine ring.
the reaction mixture under optimum reaction conditions, it failed
to provide the desired product. This observation indicated that a
radical process might be involved in the present transformation
4

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
further extension of this strategy to obtain regioselective C-3
methylthiolated imidazopyridines in DMSO solvent through a sin-
gle step domino process makes this process attractive for diversi-
fied synthesis. Overall this effort provided a rare and extended case
study to explore the role of iodine in the oxidative coupling reaction
to provide Imidazo[1,2-a]pyridine and it’s regioselective C-3
methylthiolated functionalization.
4. Experimental section
4.1. General information
All commercially available chemicals and reagents were used
without any further purification unless otherwise stated. All re-
actions were carried out in oven-dried glassware under argon or
nitrogen atmosphere with freshly distilled anhydrous solvents [24].
The progress of the reaction was monitored by thin layer chroma-
tography (TLC) using silica gel Aluminium Sheet (Merck, TLC Silica
gel 60 F254). All compounds were purified through column chro-
matography using silica gel (230e400 mesh). Nuclear magnetic
resonance spectra were recorded on Bruker Avance III HD 400 in-
Scheme 2. Mechanistic studies.
Although the mechanism involved here is not clear at present, a
plausible route for the progress of the reaction was depicted based
on the above mechanistic studies and previous reports (Scheme 3)
strument. Chemical shifts (
solvent signals, CDCl referenced at
7.16 ppm for 13C. TMS are used as internal standard and Coupling
d
) are quoted in ppm relative to residual
[
13a,15]. First, oxime ester 1a undergoes reductive cleavage to
3
d
7.26 ppm for 1H and
iminyl radical B, where molecular iodine promotes the NeO bond
reduction of oxime[13a], [15b-c] through intermediate A. In this
7
þ
constants (J) are quoted in hertz (Hz). Multiplicity is reported with
the following abbreviations: s ¼ sin-glet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, dt ¼ doublet of triplets, td ¼ triplet of doublets,
tt ¼ triplet of triplets. HRMS were recorded using (ESI) mass
process, hypervalent iodine species (I ) IOBz liberated as the initial
by-product. After isomerization, B readily transforms to a-carbon
radical C which later undergoes coupling with Iodine radical to
produce D as intermediate. Next, pyridine present in the reaction
mixture offers a nucleophilic substitution to generate iminium in-
termediate E, which readily participates in electrocyclisation to
afford F. In this case liberated hydrogen iodide oxidizes the
hypervalent iodine species to benzoic acid. Finally, the intermediate
F aromatizes through aerial oxidation to imidazopyridine 3a. The
later investigation suggested that the action of iodine and DMSO
under elevated temperature converted 3a into its C-3 methyl-
sulfenylated imidazo[1,2-a]pyridine 5a [22b-c].
ꢀ
spectrometer. Melting points ( C) are uncorrected.
4.2. General procedure for molecular iodine promoted synthesis of
imidazo[1, 2-a]pyridine
To an oven-dried pressure tube equipped with a magnetic stir
bar was charged with molecular iodine (0.1 mmol), corresponding
oxime ester (0.5 mmol), pyridine (0.2 mmol) derivatives and 2 mL
of dry acetonitrile. After mixing the reaction components by
shaking, the tube was sealed with an airtight screw cap. After that,
3
. Conclusion
ꢀ
the reaction mixture was stirred at 140 C temperature in oil bath
for 6 h. The completion of the reaction was confirmed by TLC. Then
the crude reaction mixture was washed with saturated sodium
thiosulphate solution (5 mL) and saturated sodium bicarbonate
solution (5 mL). The resulting mixture was extracted with ethyl
acetate (3 ꢁ 6 mL). The combined organic layer was washed with
In conclusion, we have disclosed a simple and metal-free
approach to deliver pharmaceutically active Imidazo[1,2-a]pyri-
dine from cheap and easily accessible starting material like oxime
ester with pyridine. Moreover, molecular iodine is employed here
as an environmentally friendly catalyst. In this case, iodine triggers
cleavage of NeO bond of oxime esters to generate reactive iminyl
radicals which regioselectively coupled with pyridines ended up
the Imidazo[1,2-a]pyridines as a value-added product. Importantly,
2 4
brine and dried over anhydrous Na SO . Then the mixture was
concentrated in a rotary evaporator and the residue was purified by
silica gel column chromatography with a plug of neutral alumina to
the top of the column to afford the desired imidazo[1,2-a]pyridine
as a key product.
4.3. General procedure for molecular iodine promoted synthesis of
C-3 methylsulfenylated imidazo[1,2-a]pyridine
To an oven-dried pressure tube equipped with a magnetic stir
bar was charged with molecular iodine (0.1 mmol), corresponding
oxime ester (0.5 mmol), pyridine (0.2 mmol) derivatives and 2 mL
of dry DMSO. After mixing the reaction components by shaking, the
tube was sealed with an airtight screw cap. After that, the reaction
ꢀ
mixture was stirred at 140 C temperature in a preheated oil bath
for 6 h. The completion of the reaction was confirmed by TLC. After
that, the crude reaction mixture was washed with both saturated
sodium thiosulphate solution (5 mL) and saturated sodium bicar-
bonate solution (5 mL). The resulting mixture was extracted with
ethyl acetate (3 ꢁ 6 mL). The combined organic layer was washed
Scheme 3. Plausible reaction mechanism.
2 4
with brine and dried over anhydrous Na SO . Then the mixture was
5

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
concentrated in a rotary evaporator and the residue was purified by
silica gel column chromatography with a plug of neutral alumina to
the top of the column to afford the desired 3-methylthiolated
imidazo[1,2-a]pyridine product.
124.5, 116.3, 115.5, 111.9, 107.5.
2-(3-bromophenyl)imidazo[1,2-a]pyridine (Tables 3 and 3h).
[7f] Light yellow Solid; mp 129e131 C; 61% yield (33 mg); R
ꢀ
f
1
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
(
400 MHz, CDCl (ppm) 8.12e8.09 (m, 2H), 7.87e7.84 (m, 2H),
3
) d
4
.4. Characterization data of products
7.63e7.61 (m, 1H), 7.44 (ddd, J ¼ 8.3, 1.8, 1.0 Hz, 1H), 7.29 (t,
J ¼ 7.9 Hz, 1H), 7.18 (ddd, J ¼ 9.1, 6.8, 1.3 Hz, 1H), 6.78 (td, J ¼ 6.8,
13
1
2
-phenylimidazo[1,2-a]pyridine (Tables 3 and 3a) [7f]. Light
3
1.0 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 145.8, 144.3,
ꢀ
yellow Solid; mp 135e137 C; 62% yield (24 mg); R
f
value ¼ 0.3
135.9, 130.9,130.4,129.1,125.8,125.2,124.6,123.1,117.7, 112.8,108.6.
1
[
d
EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR (400 MHz, CDCl
3
)
2-(3-nitrophenyl)imidazo[1,2-a]pyridine (Tables 3 and 3i).
ꢀ
(ppm) 8.10 (d, J ¼ 6.8 Hz, 1H), 7.96 (d, J ¼ 7.4 Hz, 2H), 7.85 (s, 1H),
.63 (d, J ¼ 9.1 Hz, 1H), 7.44 (t, J ¼ 7.6 Hz, 2H), 7.33 (t, J ¼ 7.4 Hz, 1H),
[7h] Yellow Solid; mp 201e202 C; 74% yield (35 mg); R
f
value ¼ 0.3
1
7
7
[EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR (400 MHz, CDCl
(ppm) 8.78 (s, 1H), 8.35 (d, J ¼ 7.7 Hz, 1H), 8.19 (d, J ¼ 7.0 Hz, 2H),
8.01 (s, 1H), 7.68 (d, J ¼ 9.1 Hz, 1H), 7.63 (t, J ¼ 8.0 Hz, 1H), 7.27 (dd,
3
)
13
1
.18e7.13 (m, 1H), 6.76 (t, J ¼ 6.6 Hz, 1H); C{ H} NMR (101 MHz,
d
3
CDCl ) d (ppm) 145.9, 145.8, 133.8, 128.9, 128.1, 126.2, 125.7, 124.8,
13
1
117.6, 112.6, 108.2.
J ¼ 15.4, 7.7 Hz, 1H), 6.87 (t, J ¼ 6.7 Hz, 1H); C{ H} NMR (101 MHz,
2
-(4-methoxyphenyl)imidazo[1,2-a]pyridine (Tables 3 and
CDCl (ppm) 147.8, 145.0, 142.5, 134.8, 130.9, 128.8, 125.0, 124.6,
3
) d
ꢀ
3
b) [7f]. Yellowish solid; mp 133e135 C; 77% yield (34 mg); R
f
121.6, 119.9, 116.9, 112.2, 108.2.
1
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
2-(naphthalen-1-yl)imidazo[1,2-a]pyridine (Tables 3 and 3j).
ꢀ
(
400 MHz, CDCl
3
)
d
(ppm) 8.06 (dt, J ¼ 6.8,1.2 Hz,1H), 7.90e7.86 (m,
[7f] Light yellow Solid; mp 158e160 C; 47% yield (23 mg); R
f
1
2
1
H), 7.75 (s, 1H), 7.60 (d, J ¼ 9.6 Hz,1H), 7.13 (ddd, J ¼ 9.2, 6.8, 1.2 Hz,
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
13
H), 6.98e6.94 (m, 2H), 6.73 (td, J ¼ 6.8, 1.1 Hz, 1H), 3.84 (s, 3H);
C
(400 MHz, CDCl
3
)
d
(ppm) 8.63e8.61 (m, 1H), 8.14 (dt, J ¼ 6.8,1.1 Hz,
1
{
H} NMR (101 MHz, CDCl
3
)
d
(ppm) 159.7, 145.8, 145.7, 127.4, 126.6,
1H), 7.92e7.87 (m, 2H), 7.83 (dd, J ¼ 6.7, 1.4 Hz, 2H), 7.71 (d,
J ¼ 9.5 Hz, 1H), 7.57e7.55 (m, 1H), 7.53e7.50 (m, 2H), 7.20 (ddd,
125.6, 124.6, 117.4, 114.2, 112.3, 107.3, 55.4.
13
1
2
-(2-methoxyphenyl)imidazo[1,2-a]pyridine (Table 3 and 3c)
J ¼ 9.1, 6.7, 1.2 Hz, 1H), 6.79 (td, J ¼ 6.8, 0.9 Hz, 1H); C{ H} NMR
ꢀ
[
7f]. Light yellow Solid; mp 94e96 C; 41% yield (18 mg); R
f
3
(101 MHz, CDCl ) d (ppm) 145.5, 145.3, 134.0, 131.9, 131.6, 128.5,
1
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 2:3 (v/v)]; H NMR
400 MHz, CDCl
(ppm) 8.41 (dd, J ¼ 7.7, 1.8 Hz, 1H), 8.18 (s, 1H),
.10 (d, J ¼ 6.8 Hz, 1H), 7.61 (dd, J ¼ 9.2, 0.7 Hz, 1H), 7.31 (ddd,
J ¼ 8.2, 7.4, 1.9 Hz, 1H), 7.15e7.09 (m, 2H), 7.00 (dd, J ¼ 8.3, 0.6 Hz,
128.4,127.8,126.5,126.0,125.9,125.6,125.5,124.7,117.8,112.5,111.3.
(
8
3
)
d
2-(pyridin-2-yl)imidazo[1,2-a]pyridine (Tables 3 and 3k). [25]
ꢀ
Brown yellow Solid; mp 135e137 C; 33% yield (13 mg); R
f
1
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
13
1
1
(
1
H), 6.72 (td, J ¼ 6.8, 0.9 Hz, 1H), 3.98 (s, 3H); C{ H} NMR
101 MHz, CDCl (ppm): 156.8, 144.5, 141.2, 128.9, 128.7, 125.7,
24.6, 122.4, 121.1, 117.3, 112.6, 112.1, 110.9, 55.5.
(400 MHz, CDCl (ppm) 8.62e8.60 (m, 1H), 8.24 (s, 1H), 8.18 (d,
3
) d
3
)
d
J ¼ 8.0 Hz, 1H), 8.13 (d, J ¼ 6.8 Hz, 1H), 7.77 (td, J ¼ 7.8, 1.8 Hz, 1H),
7.65e7.62 (m, 1H), 7.23e7.15 (m, 2H), 6.78 (td, J ¼ 6.8, 0.8 Hz, 1H);
13
1
2
-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridine (Tables
3
3
C{ H} NMR (101 MHz, CDCl ) d (ppm) 152.7, 149.4, 137.2, 130.0,
ꢀ
and 3d). [7g] Yellow Solid; mp 104e106 C; 47% yield (24 mg); R
f
128.4, 126.2, 125.4, 122.9, 120.8, 117.8, 113.0, 111.1.
1
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 1:1 (v/v)]; H NMR
2-(thiophen-2-yl)imidazo[1,2-a]pyridine Tables 3 and 3l). [7f]
ꢀ
(
400 MHz, CDCl
3
)
d
(ppm) 8.09 (d, J ¼ 6.7 Hz, 1H), 7.79 (s, 1H), 7.61
Yellowish Solid; mp 136e138 C; 39% yield (16 mg); R
f
value ¼ 0.3
1
(
d, J ¼ 9.1 Hz, 1H), 7.57 (d, J ¼ 1.7 Hz, 1H), 7.44 (dd, J ¼ 8.3, 1.8 Hz,
[EtOAc: Petroleum ether ¼ 2:8 (v/v)]; H NMR (400 MHz, CDCl
(ppm) 8.05 (dd, J ¼ 6.8, 0.8 Hz, 1H), 7.74 (s, 1H), 7.59 (d, J ¼ 9.2 Hz,
1H), 7.46 (d, J ¼ 3.5 Hz, 1H), 7.29 (d, J ¼ 5.0 Hz, 1H), 7.17e7.12 (m,
3
)
1
1
d
H), 7.15 (t, J ¼ 8.2 Hz, 1H), 6.92 (d, J ¼ 8.3 Hz, 1H), 6.75 (t, J ¼ 6.7 Hz,
d
13
1
H), 3.99 (s, 3H), 3.92 (s, 3H); C{ H} NMR (101 MHz, CDCl
(ppm) 149.3, 149.1, 145.8, 145.6, 126.9, 125.6, 124.7, 118.6, 117.4,
12.5, 111.4, 109.3, 107.6, 56.1, 56.0.
3
)
1
3
1
1H), 7.08 (dd, J ¼ 5.0, 3.7 Hz, 1H), 6.75 (t, J ¼ 6.7 Hz, 1H); C{ H}
1
NMR (101 MHz, CDCl (ppm) 145.5, 140.8, 137.5, 127.9, 125.5,
3
) d
2
-(4-fluorophenyl)imidazo[1,2-a]pyridine (Tables 3 and 3e).
125.1, 125.0, 123.8, 117.3, 112.7, 107.5.
ꢀ
[
7f] Brown yellow Solid; mp 156e158 C; 60% yield (25 mg); R
f
2-(furan-2-yl)imidazo[1,2-a]pyridine (Tables 3 and 3m). [7f]
1
ꢀ
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
400 MHz, CDCl
(ppm) 8.10 (d, J ¼ 6.7 Hz,1H), 7.93e7.90 (m, 2H),
.79 (s, 1H), 7.62 (d, J ¼ 9.1 Hz, 1H), 7.19e7.15 (m, 1H), 7.12 (t,
Brown black Solid; mp 88e90 C; 36% yield (13 mg); R
f
value ¼ 0.3
1
(
7
3
)
d
[EtOAc: Petroleum ether ¼ 2:8 (v/v)]; H NMR (400 MHz, CDCl
3
)
d
(ppm) 8.11 (d, J ¼ 6.8 Hz, 1H), 7.80 (s, 1H), 7.61e7.59 (m, 1H),
13
1
J ¼ 8.7 Hz, 2H), 6.77 (t, J ¼ 6.7 Hz, 1H); C{ H} NMR (101 MHz,
CDCl
(ppm) 162.9 (d, J ¼ 247.4 Hz), 145.8, 145.0, 130.0, 127.9 (d,
J ¼ 8.5 Hz), 125.7, 125.0, 117.6, 115.8 (d, J ¼ 22.0 Hz), 112.7, 107.9;
NMR (376 MHz, CDCl
7.48e7.47 (m, 1H), 7.18 (ddd, J ¼ 9.1, 6.8, 1.3 Hz, 1H), 6.89 (d,
J ¼ 3.4 Hz, 1H), 6.79 (td, J ¼ 6.8, 1.0 Hz, 1H), 6.51 (dd, J ¼ 3.3, 1.8 Hz,
3
) d
19
13
1
F
3
1H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 149.6, 145.7, 142.2,
3
)
d
(ppm): ꢂ114.1 (s, 1F).
137.9, 125.8, 125.2, 117.4, 112.7, 111.7, 108.0, 106.9.
2
-(4-bromophenyl)imidazo[1,2-a]pyridine (Tables 3 and 3f).
2-phenyl-3-propylimidazo[1,2-a]pyridine (Tables 3 and 3n).
ꢀ
[
[
d
7f] Yellow Solid; mp 210e212 C; 65% yield (35 mg); R
f
value ¼ 0.3
[26] Pale yellow oil; 23% yield (11 mg); R
f
value ¼ 0.3 [EtOAc: Pe-
1
1
EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR (400 MHz, CDCl
(ppm) 8.10 (dt, J ¼ 6.8, 1.1 Hz, 1H), 7.83e7.82 (m, 2H), 7.80 (d,
J ¼ 1.9 Hz, 1H), 7.62e7.60 (m, 1H), 7.56e7.53 (m, 2H), 7.18 (ddd,
3
)
troleum ether ¼ 3:7 (v/v)]; H NMR (400 MHz, CDCl
3
) d
(ppm) 7.95
(d, J ¼ 6.9 Hz, 1H), 7.78 (dd, J ¼ 8.3, 1.0 Hz, 2H), 7.64 (d, J ¼ 8.9 Hz,
1H), 7.46 (t, J ¼ 7.6 Hz, 2H), 7.37e7.33 (m, 1H), 7.16 (ddd, J ¼ 9.1, 6.8,
1.3 Hz, 1H), 6.81 (td, J ¼ 6.8, 1.2 Hz, 1H), 3.06e3.02 (m, 2H), 1.76 (dd,
13
1
J ¼ 8.9, 6.8, 1.2 Hz, 1H), 6.78 (td, J ¼ 6.8, 0.9 Hz, 1H); C{ H} NMR
101 MHz, CDCl (ppm) 145.8, 144.7, 132.8, 131.9, 127.6, 125.7,
25.1, 122.0, 117.6, 112.8, 108.4.
13
1
(
1
3
)
d
J ¼ 15.6, 7.6 Hz, 2H), 1.05 (t, J ¼ 7.4 Hz, 3H); C{ H} NMR (101 MHz,
3
CDCl ) d (ppm) 144.5, 142.4, 135.0, 128.6, 128.3, 127.5, 123.6, 123.1,
4
-(imidazo[1,2-a]pyridin-2-yl)phenol (Tables 3 and 3g). [22b]
120.8, 117.7, 112.1, 25.9, 21.2, 14.3.
2,3-diphenylimidazo[1,2-a]pyridine (Tables 3 and 3o). [7f]
Light yellow solid; mp 149e151 C; 22% yield (12 mg); R
ꢀ
Brown Solid; mp 142e144 C; 41% yield (17 mg); R
f
value ¼ 0.3
1
ꢀ
[
d
EtOAc: Petroleum ether ¼ 1:1 (v/v)]; H NMR (400 MHz, DMSO‑d
6
)
f
1
(ppm): 9.54 (s,1H), 8.48 (dt, J ¼ 6.8,1.1 Hz,1H), 8.21 (s,1H), 7.77 (d,
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
(400 MHz, CDCl
(ppm) 7.97 (d, J ¼ 6.9 Hz,1H), 7.71e7.65 (m, 3H),
7.55e7.45 (m, 5H), 7.31e7.27 (m, 3H), 7.25e7.19 (m, 1H), 6.75 (td,
J ¼ 8.6 Hz, 2H), 7.53e7.51 (m, 1H), 7.20 (ddd, J ¼ 9.2, 6.7, 1.2 Hz, 1H),
3
) d
13
1
6
(
.86 (dd, J ¼ 6.8, 1.0 Hz, 1H), 6.82 (d, J ¼ 8.7 Hz, 2H); C{ H} NMR
13
1
101 MHz, DMSO‑d (ppm): 157.3, 144.9, 144.6, 126.1, 126.6, 124.9,
6
)
d
J ¼ 6.8, 0.9 Hz, 1H); C{ H} NMR (101 MHz, CDCl
3
) d (ppm) 144.1,
6

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
ꢀ
[7f] Brown yellow Solid; mp 175e177 C; 38% yield (21 mg); R
f
1
1
42.6, 134.3, 130.9, 130.1, 129.7, 129.0, 128.4, 128.2, 127.6, 124.8,
23.4, 121.2, 117.7, 112.4.
,6-dihydronaphtho[1′,2’:4,5]imidazo[1,2-a]pyridine
1
value ¼ 0.5 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
5
(400 MHz, CDCl
3
)
d
(ppm) 8.72 (d, J ¼ 7.9 Hz, 1H), 7.93 (d, J ¼ 8.8 Hz,
ꢀ
(
Tables 3 and 3p). [27] Brown yellow Solid; mp 147e149 C; 35%
yield (15 mg); R
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H NMR (400 MHz, CDCl
(ppm) 7.98 (dd, J ¼ 7.7, 0.7 Hz, 1H), 7.86
dt, J ¼ 6.8, 1.2 Hz, 1H), 7.63 (dt, J ¼ 9.3, 0.9 Hz, 1H), 7.31 (td, J ¼ 7.3,
.4 Hz,1H), 7.24e7.17 (m, 2H), 7.13 (ddd, J ¼ 8.9, 6.8, 1.2 Hz, 1H), 6.80
2H), 7.86 (d, J ¼ 7.1 Hz, 1H), 7.71 (s, 1H), 7.68 (d, J ¼ 7.9 Hz, 1H),
f
7.65e7.61 (m, 1H), 7.57e7.53 (m, 1H), 7.01e6.98 (m, 3H), 3.86 (s,
1
13
1
3
)
d
3
3H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 159.3, 143.9, 143.2,
(
1
129.5, 128.7, 128.5, 128.0, 127.2, 127.0, 123.8, 123.5, 123.0, 114.2,
112.9, 109.0, 55.4.
13
(
{
td, J ¼ 6.8, 1.0 Hz, 1H), 3.21 (t, J ¼ 7.8 Hz, 2H), 7.10e7.06 (m, 2H);
C
2-(4-methoxyphenyl)imidazo[1,2-a]quinoline (Tables 4 and
1
H} NMR (101 MHz, CDCl
3
)
d
(ppm) 145.9, 140.7, 135.0, 131.4, 128.2,
4h). [28] Brownish gummy; 34% yield (19 mg); R
f
value ¼ 0.5
1
127.4, 127.3, 123.6, 122.9, 122.6, 119.8, 117.6, 112.3, 28.8, 19.1.
[EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR (400 MHz, CDCl
3
)
2
-(4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridine
d
(ppm) 8.22 (s, 1H), 7.95e7.91 (m, 3H), 7.79 (dd, J ¼ 7.9, 1.2 Hz, 1H),
ꢀ
(
Tables 4 and 4a). [6l] Brown yellow Solid; mp 130e132 C; 45%
7.63 (ddd, J ¼ 8.5, 7.4, 1.4 Hz, 1H), 7.58 (d, J ¼ 9.5 Hz, 1H), 7.50 (d,
J ¼ 9.4 Hz, 1H), 7.45 (dd, J ¼ 10.9, 3.9 Hz, 1H), 6.99 (d, J ¼ 8.9 Hz, 2H),
yield (21 mg); R
f
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H NMR (400 MHz, CDCl
(ppm) 7.96 (d, J ¼ 6.6 Hz, 1H), 7.89 (d,
J ¼ 8.8 Hz, 2H), 7.74 (s, 1H), 6.97 (d, J ¼ 8.8 Hz, 2H), 6.93 (d,
1
13
1
3
)
d
3
3.86 (s, 3H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 159.6, 144.1,
144.2,132.6,129.3,128.9,127.2,126.7, 126.2,124.7, 123.5,117.1,115.2,
114.3, 105.9, 55.5.
13
J ¼ 6.9 Hz, 1H), 6.66 (t, J ¼ 6.8 Hz, 1H), 3.85 (s, 3H), 2.65 (s, 3H);
C
1
{
H} NMR (101 MHz, CDCl
3
)
d
(ppm) 159.5, 146.2, 145.2, 127.5, 127.4,
3-(methylthio)-2-phenylimidazo[1,2-a]pyridine (Tables 5 and
ꢀ
126.9, 123.4, 123.3, 114.2, 112.3, 107.9, 55.4, 17.3.
5a). [22b] Brown yellow Solid; mp 65e67 C; 40% yield (19 mg); R
f
1
2
-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine
value ¼ 0.5 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
ꢀ
(
Tables 4 and 4b). [6a] Pale yellow Solid; mp 140e141 C; 50% yield
(400 MHz, CDCl
3
)
d
(ppm) 8.49e8.46 (m, 1H), 8.28 (dd, J ¼ 8.2,
1
(
24 mg); R
f
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H
1.0 Hz, 2H), 7.68 (dt, J ¼ 9.3,1.0 Hz,1H), 7.50e7.46 (m, 2H), 7.41e7.36
(m, 1H), 7.31e7.26 (m, 1H), 6.93 (td, J ¼ 6.8, 1.2 Hz, 1H), 2.25 (s, 3H);
3
NMR (400 MHz, CDCl ) d
(ppm) 7.96 (d, J ¼ 6.9 Hz, 1H), 7.86 (d,
13
1
J ¼ 8.8 Hz, 2H), 7.68 (s, 1H), 7.36 (s, 1H), 6.96 (d, J ¼ 8.9 Hz, 2H), 6.58
3
C{ H} NMR (101 MHz, CDCl ) d (ppm) 148.9, 146.4, 133.9, 128.5,
13
1
(
(
1
dd, J ¼ 6.9, 1.5 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 3H); C{ H} NMR
101 MHz, CDCl (ppm) 159.6, 146.2, 145.5, 135.5, 127.4, 126.8,
24.8, 115.8, 115.0, 114.2, 106.7, 55.4, 21.5.
128.4, 128.3, 126.1, 124.4, 117.7, 112.9, 111.5 18.3.
3
)
d
2-(4-methoxyphenyl)-3-(methylthio)imidazo[1,2-a]pyr-
idine(Tables 5 and 5b). [22b] Brown yellow oil; 43% yield (23 mg);
1
8
-fluoro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine
R
f
value ¼ 0.4 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
ꢀ
(
Tables 4 and 4c). Brown yellow Solid; mp 143e145 C; 46% yield
(400 MHz, CDCl
3
)
d
(ppm) 8.46 (d, J ¼ 6.8 Hz, 1H), 8.25 (d, J ¼ 8.9 Hz,
1
(
22 mg); R
f
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
(ppm) 7.93e7.90 (m, 3H), 7.83 (d,
J ¼ 3.1 Hz,1H), 6.97 (d, J ¼ 8.9 Hz, 2H), 6.88e6.84 (m,1H), 6.70e6.66
H
2H), 7.64 (d, J ¼ 8.9 Hz, 1H), 7.27 (ddd, J ¼ 8.3, 5.3, 1.2 Hz, 1H), 7.02
(d, J ¼ 8.8 Hz, 2H), 6.91 (td, J ¼ 6.8, 0.7 Hz, 1H), 3.87 (s, 3H), 2.25 (s,
3
NMR (400 MHz, CDCl ) d
1
3
1
3
3H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 159.9, 148.9, 146.5,
m, 1H), 3.85 (s, 3H); 13C{ H} NMR (101 MHz, CDCl
1
d
(ppm) 159.9,
129.7, 126.6, 125.9, 124.3, 117.6, 113.1, 112.7, 110.6, 55.4, 18.3.
(
3
)
1
51.6 (d, J ¼ 253.0 Hz), 146.3, 127.7, 126.0, 121.9, 114.3, 111.4 (d,
2-(4-fluorophenyl)-3-(methylthio)imidazo[1,2-a]pyridine
(Tables 5 and 5c) [22b] Brown yellow Solid; mp 88e90 C; 29% yield
19
ꢀ
J ¼ 7.1 Hz), 108.7, 107.1 (d, J ¼ 17.1 Hz), 55.5; F NMR (376 MHz,
1
CDCl
3
)
d
þ
(ppm): ꢂ129.8 (s,1F). HRMS (ESI) m/z calcd for C14
H12FN
2
O
(15 mg); R
NMR (400 MHz, CDCl
2H), 7.65 (dd, J ¼ 8.9, 0.9 Hz, 1H), 7.29 (ddd, J ¼ 9.0, 6.8, 1.3 Hz, 1H),
f
value ¼ 0.7 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H
[MþH] : 243.0934; found: 243.0928.
3
) d (ppm) 8.47e8.45 (m, 1H), 8.30e8.26 (m,
2
-(4-methoxyphenyl)imidazo[1,2-a]pyridine-7-carbonitrile
ꢀ
13
(
Tables 4 and 4d). Brown Solid; mp 157e159 C; 46% yield (23 mg);
7.16 (t, J ¼ 8.8 Hz, 2H), 6.93 (td, J ¼ 6.8, 0.9 Hz, 1H), 2.24 (s, 3H);
C
1
1
R
(
f
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]; H NMR
400 MHz, CDCl (ppm) 8.19e8.17 (m, 1H), 7.98 (s, 1H), 7.90 (d,
J ¼ 4.7 Hz, 2H), 7.87 (s, 1H), 6.99 (d, J ¼ 8.8 Hz, 2H), 6.92 (dd, J ¼ 6.9,
{ H} NMR (101 MHz, CDCl
3
)
d
(ppm) 163.0 (d, J ¼ 247.9 Hz), 148.1,
3
)
d
146.5, 130.2 (d, J ¼ 7.5 Hz), 126.2, 124.4, 117.7, 115.5 (d, J ¼ 21.9 Hz),
19
112.9, 111.2, 18.2; F NMR (376 MHz, CDCl
1F).
3
)
d
(ppm): ꢂ113.48 (s,
13
1
1.5 Hz, 1H), 3.86 (s, 3H); C{ H} NMR (101 MHz, CDCl
3
) d (ppm)
1
60.5,149.2,143.6,127.8,126.1,125.3,123.3,117.9,114.5,112.8,109.6,
2-(3-bromophenyl)-3-(methylthio)imidazo[1,2-a]pyridine
(Tables 5 and 5d). Brown yellow Solid; mp 88e90 C; 38% yield
þ
ꢀ
106.9, 55.5; HRMS (ESI) m/z calcd for
C
15
H
12
N
3
O
[MþH] :
1
2
50.0980; found: 250.0975.
(24 mg); R
NMR (400 MHz, CDCl
J ¼ 7.8 Hz, 1H), 7.65 (d, J ¼ 9.0 Hz, 1H), 7.50 (d, J ¼ 7.9 Hz, 1H),
f
value ¼ 0.6 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H
2
-(4-methoxyphenyl)-5-phenylimidazo[1,2-a]pyridine
3
)
d
(ppm) 8.47 (d, J ¼ 6.8 Hz, 2H), 8.25 (d,
(
Tables 4 and 4e). Brownish gummy; 31% yield (19 mg); R
f
1
13
1
value ¼ 0.5 [EtOAc: Petroleum ether ¼ 3:7 (v/v)]. H NMR (400 MHz,
7.35e7.28 (m, 2H), 6.95 (t, J ¼ 6.8 Hz, 1H), 2.25 (s, 3H); C{ H} NMR
(101 MHz, CDCl (ppm) 147.3, 146.5, 136.0, 131.3, 131.2, 130.0,
CDCl
3
)
d
(ppm) 7.86 (s, 1H), 7.84 (d, J ¼ 2.6 Hz, 2H), 7.68e7.63 (m,
3
) d
3H), 7.60e7.54 (m, 3H), 7.26 (t, J ¼ 8.0 Hz, 1H), 6.94 (d, J ¼ 8.9 Hz,
2
d
126.8, 126.4, 124.4, 122.7, 117.8, 113.1, 112.1, 18.3; HRMS (ESI) m/z
13
1
þ
H), 6.74e6.72 (m, 1H), 3.84 (s, 3H); C{ H} NMR (101 MHz, CDCl
3
)
calcd for C14
H12BrN
2
S [MþH] : 318.9905; found: 318.9909.
(ppm) 159.7, 146.5, 145.6, 138.2, 134.7, 129.9, 129.4, 128.4, 127.5,
3-(methylthio)-2-(3-nitrophenyl)imidazo[1,2-a]pyridine
(Tables 5 and 5e). Brown yellow Solid; mp 126e128 C; 35% yield
ꢀ
126.6, 125.1, 116.1, 114.2, 112.8, 105.9, 55.4; HRMS (ESI) m/z calcd for
þ
1
C
20
H
2
17
N
2
O [MþH] : 301.1341; found: 301.1338.
(20 mg); R
NMR (400 MHz, CDCl
f
value ¼ 0.6 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
H
-(4-methoxyphenyl)-6,8-dimethylimidazo[1,2-a]pyridine
3
)
d
(ppm) 9.22 (t, J ¼ 1.9 Hz, 1H), 8.65 (d,
ꢀ
(
Tables 4 and 4f). Brown yellow Solid; mp 147e149 C; 40% yield
J ¼ 7.8 Hz, 1H), 8.49 (d, J ¼ 6.9 Hz, 1H), 8.21 (ddd, J ¼ 7.8, 2.1, 0.8 Hz,
1H), 7.68e7.61 (m, 2H), 7.37e7.31 (m, 1H), 6.99 (td, J ¼ 6.8, 0.9 Hz,
1
(
20 mg); R
f
value ¼ 0.4 [EtOAc: Petroleum ether ¼ 3:7 (v/v)];
(ppm) 7.87 (d, J ¼ 8.8 Hz, 2H), 7.73 (s, 1H),
.64 (s, 1H), 6.95 (d, J ¼ 8.8 Hz, 2H), 6.79 (s, 1H), 3.84 (s, 3H), 2.61 (s,
H
1
3
1
NMR (400 MHz, CDCl
7
3
3
)
d
3
1H), 2.30 (s, 3H); C{ H} NMR (101 MHz, CDCl ) d (ppm) 148.6,
146.6, 146.3, 135.8, 134.0, 129.4, 126.8, 124.5, 123.1, 122.9, 118.0,
H), 2.25 (s, 3H); 13C{ H} NMR (101 MHz, CDCl
1
)
d
(ppm) 159.4,
113.4, 112.6, 18.3; HRMS (ESI) m/z calcd for C14
286.0650; found: 286.0652.
H
12
N
3
O
S [MþH] :
þ
3
2
145.2, 144.9, 127.4, 127.1, 126.6, 126.5, 121.7, 121.2, 114.1, 107.6, 55.4,
þ
18.2, 17.1; HRMS (ESI) m/z calcd for C16
17
H N
2
O [MþH] : 253.1341;
2-(2-methoxyphenyl)-3-(methylthio)imidazo[1,2-a]pyridine
(Tables 5 and 5f). Brown yellow oil; 26% yield (14 mg); R
value ¼ 0.3
[EtOAc: Petroleum ether ¼ 2:3 (v/v)]; H NMR (400 MHz, CDCl
found: 253.1335.
f
1
2
-(4-methoxyphenyl)imidazo[2,1-a]isoquinoline (Table 4 4g).
3
)
7

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
d
(ppm)): 8.42 (d, J ¼ 6.8 Hz, 1H), 7.72 (d, J ¼ 9.1 Hz, 1H), 7.50 (dd,
References
J ¼ 7.5, 1.7 Hz, 1H), 7.43e7.39 (m, 1H), 7.30e7.26 (m, 1H), 7.08e7.02
13
[1] (a) H. Tomoda, T. Hirano, S. Saito, T. Mutai, K. Araki, Bull. Chem. Soc. Jpn. 72
(
{
m, 2H), 6.94 (td, J ¼ 6.8, 1.0 Hz, 1H), 3.83 (s, 3H), 2.20 (s, 3H);
C
(
(
1999) 1327;
1
3
H} NMR (101 MHz, CDCl ) d (ppm) 157.6, 148.3, 146.5, 132.3, 130.0,
b) Y. Katsura, S. Nishino, Y. Inoue, M. Tomoi, H. Takasugi, Chem. Pharm. Bull.
1
28.3, 125.5, 124.3, 123.3, 120.5, 118.0, 112.8, 111.2, 55.7, 17.9; HRMS
40 (1992) 371;
þ
(c) B. Dubinsky, D.A. Shriver, P.J. Sanfilippo, J.B. Pres, A.J. Tobia,
M.E. Rosenthale, Drug Dev. Res. 21 (1990) 277;
(
ESI) m/z calcd for C15
H
15
N
2
OS [MþH] : 271.0905; found: 271.0910.
8
-methyl-3-(methylthio)-2-phenylimidazo[1,2-a]pyridine
(
d) J.E. Starrett, T.A. Montzka, A.R. Crosswell, R.L. Cavanagh, J. Med. Chem. 32
(1989) 2204;
e) A.J. Guildford, M.A. Tometzki, R.W. Turner, Synthesis (1983) 987;
ꢀ
(
Tables 5 and 5g). [22b] Brown yellow Solid; mp 103e105 C; 32%
(
yield (16 mg); R
f
value ¼ 0.5 [EtOAc: Petroleum ether ¼ 1:9 (v/v)];
1
(f) E.S. Hand, W.W. Paudler, J. Org. Chem. 45 (1980) 3738.
2] (a) H.L. Koo, H.L. DuPont, Curr. Opin. Gastroenterol. 26 (2010) 17;
(b) M. Hranjec, M. Kralj, I. Piantanida, M. Sedi, L. Suman, K. Pavel,
G. Karminski-Zamola, J. Med. Chem. 50 (2007) 5696;
H NMR (400 MHz, CDCl
3
) d
(ppm) 8.35 (d, J ¼ 6.7 Hz, 1H), 8.27 (dd,
[
J ¼ 8.3, 1.3 Hz, 2H), 7.48 (dd, J ¼ 8.1, 7.0 Hz, 2H), 7.38 (dd, J ¼ 11.7,
4
2
1
.4 Hz, 1H), 7.09e7.07 (m, 1H), 6.85 (t, J ¼ 6.8 Hz, 1H), 2.67 (s, 3H),
.25 (s, 3H); 1 C{ H} NMR (101 MHz, CDCl
3
) d
3 1
(c) C. Enguehard-Gueiffier, A. Gueiffier, Mini Rev. Med. Chem. 7 (2007) 888;
(ppm) 148.7, 146.8,
34.3, 128.6, 128.5, 128.2, 127.8, 124.8, 122.2, 112.8, 111.8, 18.4, 16.9.
-(methylthio)-2-phenylimidazo[1,2-a]pyridine-7-
(d) S.K. Kotovskaya, Z.M. Baskakova, V.N. Charushin, O.N. Chupakhin,
E.F. Belanov, N.I. Bormotov, S.M. Balakhnin, O.A. Serova, Pharm. Chem. J. 39
(2005) 574;
3
(
1
(
e) K. Mizushige, T. Ueda, K. Yukiiri, H. Suzuki, Cardivasc. Drug Rev. 20 (2002)
63;
f) J.J. Kaminsky, A.M. Doweyko, J. Med. Chem. 40 (1999) 427.
carbonitrile (Tables
5
and 5h). Brown yellow Solid; mp
value ¼ 0.6 [EtOAc: Petroleum
(ppm) 8.56e8.54 (m,
H), 8.28 (dd, J ¼ 8.4, 1.2 Hz, 2H), 8.03 (d, J ¼ 1.1 Hz, 1H), 7.52e7.48
m, 2H), 7.45e7.41 (m, 1H), 7.07 (dd, J ¼ 7.0, 1.5 Hz, 1H), 2.28 (s, 3H);
ꢀ
1
28e130 C; 38% yield (20 mg); R
f
1
ether ¼ 1:9 (v/v)]; H NMR (400 MHz, CDCl
3
)
d
[3] (a) M. Hranjec, M. Kralj, I. Piantanida, M. Sedic, L. Suman, K. Pavelic,
G.K. Zamola, J. Med. Chem. 50 (2007) 5696;
1
(b) S.K. Kotouskaya, Z.M. Baskakova, V.N. Charushin, O.N. Chupakhin,
(
E.F. Belanov, N.I. Bormotov, S.M. Balakhnin, O.A. Serova, Pharm. Chem. J. 39
(2005) 12;
1
3
1
3
C{ H} NMR (101 MHz, CDCl ) d (ppm) 151.5, 144.2, 132.9, 129.2,
(c) J.J. Kaminski, A.M. Doweyko, J. Med. Chem. 40 (1997) 427;
128.7, 128.4, 125.2, 123.5, 117.6, 114.9, 113.1, 108.5, 18.1; HRMS (ESI)
þ
(d) C. Hamdouchi, J.d. Blas, M.d. Prado, J. Gruber, B.A. Heinz, L. Vance, J. Med.
Chem. 42 (1999) 50;
(e) E. Badawey, T. Kappe, Eur. J. Med. Chem. 30 (1995) 327;
(f) M. Lhassani, O. Chavignon, J.M. Chezal, J.C. Teulade, J.P. Chapat, R. Snoeck,
G. Andrei, J. Balzarini, E.D. clercq, A. Gueiffier, Eur. J. Med. Chem. 34 (1999)
m/z calcd for C15
H
12
N
3
S [MþH] : 266.0752; found: 266.0755.
3
-(methylthio)-2-phenylimidazo[2,1-a]isoquinoline (Tables 5
ꢀ
and 5i). Brown yellow Solid; mp 83e85 C; 37% yield (21 mg); R
f
1
value ¼ 0.7 [EtOAc: Petroleum ether ¼ 1:9 (v/v)]; H NMR
271.
(
(
1
400 MHz, CDCl
m, 2H), 8.27 (d, J ¼ 7.3 Hz, 1H), 7.73e7.71 (m, 1H), 7.67e7.63 (m,
H), 7.61e7.57 (m, 1H), 7.54e7.50 (m, 2H), 7.42e7.38 (m, 1H), 7.14
3
)
d
(ppm) 8.76 (dd, J ¼ 7.8, 1.1 Hz, 1H), 8.38e8.36
[4] (a) A.J. Stasyuk, M. Banasiewicz, M.K. Cyranski, D.T. Gryko, J. Org. Chem. 77
(2012) 5552;
(b) R. Salim, E.E. Chihbi, H. Oudda, F.E. Hajjaji, M. Taleb, S. Jodeh, J. Bio-Tribo
Corros. 5 (2019) 14.
13
1
(
d
d, J ¼ 7.3 Hz, 1H), 2.28 (s, 3H); C{ H} NMR (101 MHz, CDCl
3
)
[
5] (For some excellent reviews, see:). (a) A.K. Bagdi, A. Hajra, Chem. Rec. 16
(2016) 1868;
(ppm) 152.7, 147.3, 144.2, 134.2, 130.2, 128.7, 128.5, 128.2, 128.1,
(
(
(
b) C. Ravi, S. Adimurthy, Chem. Rec. 17 (2017) 1019;
c) A.K. Bagdi, S. Santra, K. Monir, A. Hajra, Chem. Commun. 51 (2015) 1555;
d) K. Pericherla, P. Kaswan, K. Pandey, A. Kumar, Synthesis 47 (2015) 887;
127.0, 123.8, 123.6, 121.2, 113.6, 113.3, 18.1; HRMS (ESI) m/z calcd for
þ
C
18
H
2
15
N
2
S [MþH] : 291.0956; found: 291.0959.
-(3,4-dimethoxyphenyl)-3-(methylthio)imidazo[1,2-a]pyri-
(e) G.K. Reen, A. Kumar, P. Sharma, Beilstein J. Org. Chem. 15 (2019) 1612.
6] Few selected examples of IPs synthesis from 2-aminopyridine with other
coupling partners: with ketone, see:. (a) A.K. Bagdi, M. Rahman, S. Santra,
A. Majee, A. Hajra, Adv. Synth. Catal. 355 (2013) 1741;
[
dine (Tables 5 and 5j). Yellow low melting Solid; 35% yield (21 mg);
1
R
(
(
f
value ¼ 0.3 [EtOAc: Petroleum ether ¼ 2:3 (v/v)]; H NMR
400 MHz, CDCl
(ppm) 8.47 (dd, J ¼ 6.8, 0.9 Hz, 1H), 7.94e7.92
m, 2H), 7.65 (dd, J ¼ 10.0, 0.9 Hz, 1H), 7.30e7.27 (m, 1H), 6.98 (d,
3
)
d
(b) D.C. Mohan, R.R. Donthiri, S.N. Rao, S. Adimurthy, Adv. Synth. Catal. 355
(
(
(
2013) 2217;
c) C. Huo, J. Tang, H. Xie, Y. Wang, J. Dong, Org. Lett. 18 (2016) 1016;
d) K. Pericherla, Pinku, P. Khedar, B. Khungar, K. Parang, A. Kumar, RSC Adv. 3
J ¼ 8.1 Hz, 1H), 6.92 (td, J ¼ 6.8, 0.9 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H),
.25 (s, 3H); 13C{ H} NMR (101 MHz, CDCl
1
)
d
(ppm) 149.4, 148.1,
2
3
(2013) 18923;
e) Z.-J. Cai, S.-Y. Wang, S.-J. Ji, Adv. Synth. Catal. 355 (2013) 2686 (With iso-
nitrile and aldehydes, see);
f) W. An, W. Wang, T. Yu, Y. Zhang, Z. Miao, T. Meng, J. Shen, Eur. J. Med.
Chem. 112 (2016) 367;
g) M.K.W. Mackwitz, A. Hamacher, J.D. Osko, J. Held, A. Sch o€ ler,
D.W. Christianson, M.U. Kassack, F.K. Hansen, Org. Lett. 20 (2018) 3255 (With
-halocarbonyls, see);
(
148.7, 146.4, 126.8, 126.0, 124.3, 121.0, 117.5, 112.8, 111.5, 111.1, 110.7,
þ
5
3
6.1, 56.0, 18.2; HRMS (ESI) m/z calcd for C16
01.1011; found: 301.1010.
H
17
N
2
O
2
S [MþH] :
(
(
a
Declaration of competing interest
(
(
h) M.-A. Hiebel, Y. Fall, M.-C. Scherrmann, S.B. Raboin, Eur. J. Org Chem.
2014) 4643;
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.
(i) S. Takizawa, J. Nishida, T. Tsuzuki, S. Tokito, Y. Yamashita, Inorg. Chem. 46
(
(
2007) 4308;
j) J.F. Campos, M.-C. Scherrmann, S. Berteina-Raboina, Green Chem. 21 (2019)
1531 (With olefins, see);
(
(
k) S. Santra, A.K. Bagdi, A. Majee, A. Hajra, Adv. Synth. Catal. 355 (2013) 1065;
l) S.K. Rasheed, D.N. Rao, P. Das, Asian J. Org. Chem. 5 (2016) 1213;
Acknowledgments
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1073;
n) E.P.A. Talbot, M. Richardson, J.M. McKenna, F.D. Toste, Adv. Synth. Catal.
56 (2014) 687.
1
(
3
We are grateful to DST-INSPIRE (IFA 13-CH-90), SERB (ECR/2016/
0
00270) and IIT(ISM)-TEQIP-III for financial support. DS & SRC
[7] (a) O.A. Attanasi, L. Bianchi, L.A. Campisi, L.D. Crescentini, G. Favi, F. Mantellini,
Org. Lett. 15 (2013) 3646;
thank IIT(ISM) Dhanbad for their research fellowships. SP thanks
CSIR for his doctoral fellowship. The authors sincerely acknowledge
the NMR facility created under the DST-FIST program (SR/FST/CSI-
(b) S. Park, H. Kim, J.Y. Son, K. Um, S. Lee, Y. Baek, B. Seo, P.H. Lee, J. Org. Chem.
82 (2017) 10209;
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Chem. 79 (2014) 11277;
2
56/2013) in the Department of Chemistry at IIT(ISM) Dhanbad.
(
(
(
(
(
(
(
d) X. Zhou, H. Yan, C. Ma, Y. He, Y. Li, J. Cao, R. Yan, G. Huang, J. Org. Chem. 81
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132125.
8

D. Singh, S.R. Chowdhury, S. Pramanik et al.
Tetrahedron xxx (xxxx) xxx
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2
(
(
7
(
1
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9