Dual role of p-tosylchloride: Copper-catalyzed sulfenylation and metal free methylthiolation of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c5ob02475g

Copper-catalyzed regioselective C-3 sulfenylation of imidazo[1,2-a]pyridines using p-tosylchloride as a benign source of sulfenylating agents has been developed. On the other hand, p-tosylchloride mediated thiomethylation of imidazo[1,2-a]pyridines with dimethylsulfoxide as a source of thiomethylation under metal-free conditions was also described.

Full text of DOI:10.1039/c5ob02475g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Subbarayappa,
C. Darapanenei and C. Ravi, Org. Biomol. Chem., 2016, DOI: 10.1039/C5OB02475G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 8
View Article Online
DOI: 10.1039/C5OB02475G
Journal Name
ARTICLE
Dual Role of p–Tosylchloride: Copper–Catalyzed Sulfenylation and
Metal free Methylthiolation of Imidazo [1, 2–a] pyridines
Chitrakar Ravi, Darapaneni Chandra Mohan and Subbarayappa Adimurthy*
Received 00th January 20xx,
Accepted 00th January 20xx
Copper–catalyzed regioselective C–3 sulfernylation of imidazo[1, 2–a]pyridines using p-tosylchloride as benign source of
sulfernylating agent has been developed. On the other hand, p-tosylchloride mediated thiomethylation of imidazo[1, 2–
a]pyridines with dimethylsulfoxide as a source of thiomethylation under metal–free conditions was also described.
DOI: 10.1039/x0xx00000x
www.rsc.org/
also unstable to air and moisture.22 Some of the sulfenylating
reagents such as sulfenylhydrazides are not commercially
available and also expensive.23 Our intention was to develop a
method for the selective C–3 sulfenylation of imidazo[1,2-
a]pyridines using cheap and easily available starting materials
and reagents and can be performed under mild reaction
conditions. Here, we disclose copper-catalysed selective
sulfenylation of imidazo[1,2–a]pyridines with tosyl chlorides as
benign source of sulfenylating agent and we also demonstrated
that transition metal-free methylthiolation of imidazo[1,2–
Introduction
Selectively substituted imidazo[1,2–a]pyridines represent key
structural motifs in medicinal chemistry due to their
pharmaceutical activities.1-6 Particularly C–3 substituted
imidazo[1,2–a]pyridine derivatives necopidem, saripidem, and
zolpidem are clinically used as neuroactive drugs including
other candidates such as alpidem, (as an anxiolytic agent),
olprinone (the treatment of acute heart failure), minodronic
acid7 zolimidine (peptic ulcer),8,9 optically active GSK812397
a]pyridines using dimethyl sulfoxide as
a source of
(HIV infection)10 (figure S1). Indeed, remarkable progress has
been achieved by various groups
thiomethylating agent under mild reaction conditions.
11-13
on the synthesis of IP
derivatives including our own group.14-16 Due to the presence of
multiple C–H bonds in imidazo[1,2–a]pyridine moiety, it is very
challenging for the selective C–3 functionalization. Therefore,
there is a continued interest to develop selective C–H (C3)
functionalization of these imidazo[1,2–a]pyridine scaffolds.
Results and discussion
We initially started our investigation by employing
commercially available of 2-phenylimidazo[1,2–a]pyridine 1a
with 4-methylbenzene-1-sulfonyl chloride (p-TsCl) 2a as the
model substrates (Table 1). The reaction of 1a with 2a in NMP
as a solvent at 65°C using CuI as a catalyst in a closed tube,
traces of desired product 2-phenyl-3-(p-tolylthio)imidazo[1,2–
a]pyridine 3a was observed (Table 1, entry 1). Increase of the
reaction temperature to 100 °C, the yield of 3a was increased to
35% (Table 1, entry 2). Under these conditions, CuI replaced by
CuBr, no product was observed (Table 1, entry 3). With t-BuOK
(20 mol %) and 1, 10-phenanthroline were employed as an
additive and ligand, no product formation and 30% of 3a
Scheme 1. Sulfenylation of Imidazo [1, 2–a] pyridines
In particularly the insertion of sulfenyl groups on the aza-
aromatic rings can impart marked biological activities.17,18
Compared to C-3 arylation/alkylation of imidazo[1,2–
a]pyridines,19 the corresponding sulfenylation is rarely
reported.20,21 However, the reported synthetic approaches have
was observed respectively (Table 1, entries 4 and 5). Conducting
the reaction under oxygen atmosphere (balloon), and in open
air trace amount of product formation was observed (Table 1,
entries 6 and 7). Increasing the temperature (120 °C) and
some drawbacks such as use of thiols as sulfenyl agent is catalyst loading (20 mol%) the yield of 3a was increased to 62%
hazardous (possess unpleasant odors) very difficult to handle,
(Table 1, entries 8–10). Further increase of temperature (140 °C)
no improvement in yield was observed (Table 1, entry 11).24
Also checked with CuCl, CuBr and without Catalyst but no
product formation was observed(Table 1, entries 12–14). Then
we screened different catalysts such as I2, NCS, NBS, NIS, Cu(0),
Cu(OAc)2 iron salts like FeCI2, FeCl3, Fe(OTf)2 and Pd(OAc)2 in
Academy of Scientific & Innovative Research, CSIR–Central Salt & Marine
Chemicals Research Institute, G. B. Marg, Bhavnagar–364 002. Gujarat (INDIA).
*E-mail: adimurthy@csmcri.org
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 8
ARTICLE
Journal Name
these cases either no reaction of low yields were observed
(Table 1, entries 15–24). When PPh3 was used as reducing
agent25 as well as a ligand at 130°C, 65% yield of 3a was
observed (Table 1, entry 25). Using 3 equivalent of 2a (w.r.t. 1a),
surprisingly an excellent yield of 3a was 95% obtained (Table 1,
entry 26). To check the efficiency of the reaction under these
conditions, but without catalyst (CuI) no reaction was observed
(Table 1, entry 27).
View Article Online
DOI: 10.1039/C5OB02475G
Scheme 2. Selectivity experiments
Under these optimized conditions (Table 1, entry 26), the
2,4,6-trimethylbenzenesulfonyl chloride and naphthalene-1-
sulfonyl chloride react smoothly and afford the corresponding
sulfenylated imidazo[1,2–a]pyridines 3aa–3ag with yields
ranging from 40% to 90%. Under the optimized conditions, the
scope for sulfenylation of substituted imidazo[1,2–a]pyridines
and related substrates with 4-methylbenzenesulfonyl chloride
was examined (Table 3). The reaction of 4-methylbenzene-1-
sulfonyl chloride 2a with methyl and halogen (Br and Cl)
reaction of unsubstituted imidazo[1, 2–a]pyridine
5 was
subjected with standard conditions (entry 26), the selective C-3
sulfenylated product 5a was isolated in 24% yield (Scheme 2,
eq. 1). When C-3 substituted substrate 3-methylimidazo[1,2-
a]pyridine 8 was subjected to the same reaction conditions, the
formation desired product 8a was not observed (Scheme 2, eq.
2).
Table 1. Optimization of Reaction Conditions for 3aa
Table 2. Scope of different sulfonyl chlorides on sulfenylation of 1a
aReaction conditions: 1 (0.25 mmol), 2 (0.75 mmol), CuI(10mol%), PPh3(0.75
mmol), toluene (2 mL), 130°C, closed tube, isolated yields.
substituted phenylimidazo[1, 2–a]pyridines under the optimized
conditions gave selectively C-3 sulfenylated products 3b-3e in
excellent yields (81-98%). Bromo and methyl disubstituted
phenylimidazo[1, 2–a]pyridine also afford the corresponding C–3
sulfenylated product 3f in good yield. Then we focused on
sulfenylation of phenyl ring substituted imidazo[1, 2–a]pyridines.
The presence of electron-donating groups (Me, Et, OMe and SMe) at
para and ortho position of phenyl ring could react smoothly with 2a
and afford the selective C–3 sulfenylated products 3g–3k up to 92%
yields. Surprisingly, ortho-dimethoxyphenyl derivative gave
quantitative yield of desired sulfenylated product 3l despite its steric
hindrance. Further, the presence of electron withdrawing groups
(such as CN) at either ortho/para-position of the phenyl ring 2-
phenylimidazo[1,2–a]pyridines provided desired products 3m–3p in
good to excellent yields (60-92%).
The present system is also applicable to heterocyclic and alkenyl
substituted derivatives 2-(thiophen-2-yl)imidazo[1,2– a]pyridine 3q
and (E)-2-styrylimidazo[1,2–a]pyridine 3r, and obtained in 65% and
85% yields respectively. Interestingly, other heterocyclic compounds
like 2-phenylbenzo[d]imidazo[2,1–b]thiazole also reactive with 2a
under the present conditions and yield the desired product 3s in 52%
yield.
aReaction conditions: 1a (0.25 mmol), 2a (0.75 mmol),CuI(10mol%),
PPh3(0.75mmol), toluene (2mL), 130°C, Closed tube, 24 h, isolated yields. b t-
BuOK(20 mol%), c 1,10-phenanthroline (20 mol%), dO2-balloon, e open air. f
PPh3(3eq), nr: No reaction.
With an optimized catalytic system in hand (Table 1, entry 26),
next we investigated the influence of different sulfonyl
chlorides 2 on the sulfenylation of imidazo[1,2–a]pyridine 1
(Table 2). The benzenesulfonyl chlorides having different
substituent groups at para positions of arene ring including
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Intermediate A in
View Article Online
p-tolylhypochlorothioite intermediate A 18
presence of CuI undergo oxidative additDioOnI: t1o0.1f0o3r9m/Ct5hOeB0h2i4g7h5lGy
electrophilic Cu(III) complex . Nucleophilic addition of 1a to the
complex generates carbocation intermediate C. Subsequent
.
Table 3. Scope for sulfenylation of imidazo[1,2–a]pyridines with 2a
B
B
oxidation of
C
yield the desired product sulfenylimidazo[1,2–
a]pyridine 3a
.
During the course of solvent optimization studies for
sulfenylation of imidazopyridines (Table S1, entries 11 and 12),
the formation of methylthiolated imidazo[1,2–a]pyridine 4a
was isolated in 30 and 39% yields respectively when DMSO was
used as solvent under the conditions studied. In these studies,
DMSO was act as thiomethanol source. When we checked the
literature reports for methylthiolation of heterocyclic
compounds, very few reports existed with transition metal
catalysts29-30 and in presence of strong acidic conditions.31
aReaction conditions: 1 (0.25 mmol), 2a (0.75 mmol), CuI(10 mol%),
PPh3(0.75 mmol), toluene (2.0 mL), 130°C, Closed tube, isolated yields.
The present method not only demonstrates the high degree of
functional group tolerance with broad substrate scope, but also
overcomes the electronic and steric factors associated with
substituent groups.
Scheme 5. Selectivity experiments
Table 4. Screening of different sulfonylchloridesa
Scheme 3. Control experiments
aReaction conditions: 2-phenylimidazo[1,2-a]pyridine (0.25 mmol),
tosylchloride (0.375 mmol),DMSO (0.2mL), DCE (0.5mL), 100°C, air, isolated
yields.
Scheme 4. Plausible mechanism
As we observed 39% of methylthiolation product 4a under
metal-free conditions, we further screened the effect of
solvents, temperature and other conditions to obtain the
optimum yield of desired product 4a (see Table S2, entry 10 in
the supporting information).
To ascertain the reaction mechanism, some control
experiments were performed (Scheme 3). Reactions with
diphenyl disulfide and sodiumsulfinate as sulfenylating agents
in place of 2a under the optimised conditions, only 13% and
traces amount of desired product 3a was isolated respectively
(Scheme 3). These reactions suggest that, 2a is a better
sulfenylating agent for the present transformation.
Based on the literature reports18 and our observations, a
probable reaction mechanism has been proposed (Scheme 4).26-
28
Initially, when 4-methylbenzene-1-sulfonyl chloride was
heated in presence of PPh3 at the high temperature it generates
Fig.1. OTREP diagram of the compound 4d.
J. Name., 2013, 00, 1-3 | 3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 8
ARTICLE
Journal Name
The best result was obtained using DMSO/DCE (0.2/0.5 mL) as However, either strong electron donating or withdrawing
View Article Online
solvent combination, 1.5 equivalents of 2a (w.r.t. 1a) as groups failed to give the desired products 4g and
DOI: 10.1039/C54OhB0. 2W47i5tGh
promoter,32 in an open air, at 100 °C, 8 h reaction time. Under methyl and halogen (Br and Cl) substituents on either sides of
these optimized conditions (Table S2, entry 10), the reaction of phenyl ring gave moderate to good yields (40-63%) of
unsubstituted imidazo[1, 2–a]pyridine
DMSO , the selective C-3 sulfenylated product
in 63% yield (Scheme 5, eq. 1). When C-3 substituted substrate
3-methylimidazo[1,2-a]pyridine was subjected to the same
reaction conditions, the formation desired product was not
5 was subjected with corresponding methylthiolated products 4i–4o including 52%
6
7
was isolated yield of (E)-2-styrylimidazo[1,2–a]pyridine 4p
.
8
9
observed (Scheme 5, eq. 2). These experiments (Scheme 5)
indicate that, the regioselective sulfenylation of imidazo[1,2–
a]pyridines occurs exclusively at C–3 position only, no reaction
take place if the C–3 position is substituted by any other groups.
Under the optimised conditions, different sulfonyl chlorides as
promoter were studied for methylthiolation of 1a (table 4).
Among these, p-TsCl 2a proved to be the best source to get the
Scheme 7. Plausible Mechanism
maximum yield of the desired product 4a
.
Table 5. Substrate scope of thiomethylationa
Further, to ascertain the reaction mechanism of
methylthiolations with DMSO, we performed some control
experiments (Scheme 6). To understand the role of the halide,
we have checked the reaction of 1a with different hydro halides
like HCl and HBr, in place of 2a under the conditions studied,
however no reaction was observed with HCl and 23% yield of 4a
was isolated with HBr (Scheme 6, eq. 1). The reaction of 1a with
PTSA and (COCl)2 instead of 2a under the optimization
conditions, 35% and 77% of product 4a was isolated (Scheme
6, eqs. 2 and 3). Based on the literature reports and control
experiments
proposed (Scheme 7). Initially the reaction of 2a with DMSO
may generate Swern like intermediate . Which may convert
into intermediate , and its subsequent reaction with 1a leads
the formation of imidazolium ion intermediate . Finally, its
a plausible reaction mechanism has been
A
B
C
aReaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), DMSO 6 (0.2 mL),
oxidation will give the desired product 4a with subsequent
demethylation.33
DCE(0.5 mL), air, 8.0 h, isolated yields.
After optimization of the conditions for the model reaction, the
scope and limitation of this method for the methylthiolated
Conclusions
imidazo[1, 2–a]pyridines
4 was studied (Table 5). The tandem
In conclusion we revealed a novel and an efficient method for
sulfenylation of imidazo[1, 2–a]pyridines using commercially
available and environment-friendly sources of sulfenylating
agents p-tosylchloride and DMSO. The method is pertinent to a
wide range of imidazo[1,2–a]pyridines with good functional
group tolerance and deliver good to excellent yields of
sulfenylated products. The present strategy features an easy
operational procedure under mild reaction conditions.
methylthiolation of imidazo[1,2–a]pyridines with electron-
donating (Me and SMe) and as well as partially withdrawing
groups (Br, Cl and F) on the phenyl ring of phenylimidazo[1, 2–
a]pyridines gave low to good yields (23–67%) of corresponding
methylthiolated products 4b–4f. One the structure of 4d was
further confirmed by single crystal XRD analysis (Figure 1).
Experimental
All commercially available chemicals and reagents were used without
1
any further purification unless otherwise indicated. H and 13C NMR
spectra were recorded at 500, and 125 MHz, respectively. The
spectra were recorded in CDCl3 as solvent. Multiplicity was indicated
as follows: s (singlet); d (doublet); t (triplet); m (multiplet); dd
(doublet of doublets), etc. and coupling constants (J) were given in
Hz. Chemical shifts are reported in ppm relative to TMS as an internal
1
standard. The peaks around delta values of H NMR (7.2), and 13C
Scheme 6. Control experiments
NMR (77.0) are correspond to deuterated solvent chloroform
respectively. Mass spectra were obtained using electron impact (EI)
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
ionization method. Progress of the reactions was monitored by thin 1339, 828, 698, 486. HRMS calcd for C25H19N2S: 379.1269, found:
View Article Online
layer chromatography (TLC). All products were purified through 379.1288.
DOI: 10.1039/C5OB02475G
column chromatography using silica gel 100-200 mesh size using 3-(Mesitylthio)-2-phenylimidazo[1,2-a]pyridine (3af)
hexane/ethyl acetate as eluent unless otherwise indicated.
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 159 °C; 78%
1
General procedure for thioarylation of imidazo[1,2–a]pyridines yield(67.0 mg); H NMR (500 MHz, CDCl3) δ 8.16(d, J = 7.5 Hz, 2H),
(3a)23
7.89(d, J = 7.0 Hz, 1H), 7.63(d, J = 9.0 Hz, 1H), 7.46(t, J = 7.5 Hz, 2H),
A clean washed boiling tube equipped with a magnetic stir bar was 7.37(t, J = 7.5 Hz, 1H), 7.17(t, J = 8.5 Hz, 1H), 6.78(s, 2H), 6.72(t, J =
charged with 2-phenylimidazo[1,2–a]pyridine 1a (0.0485 g, 0.25 7.0 Hz, 1H), 2.19(s, 6H), 2.17(s, 3H). 13C NMR (125 MHz, CDCl3) δ
mmol), 4-methylbenzene-1-sulfonyl chloride 2a (0.0953 g, 0.75 149.0, 145.8, 140.2, 137.6, 132.9, 129.7, 128.7, 128.4, 128.0, 127.4,
mmol), CuI (0.00475 g, 0.025 mmol), Triphenyl phosphene (0.0965 g, 126.8, 125.2, 124.2, 117.4, 112.5.109.1, 21.5, 20.7. IR (KBr) 3037,
0.75 mmol) and toluene(2mL). The above mixture was stirred for 24h 2947, 1648, 1460, 1437, 1345, 1228, 1156, 1024, 846, 736, 580.
at 130°C in closedtube, and then the mixture was poured into 10 mL HRMS calcd for C22H21N2S: 345.1425, found: 345.1428.
of saturated sodium bicarbonate solution. The product was 3-(Naphthalen-1-ylthio)-2-phenylimidazo[1,2-a]pyridine (3ag)34
extracted with Ethyl acetate (10 mL × 3) and dried with anhydrous (Eluent: 20% EtOAc/hexane); White solid; 82% yield(72.5 mg); 1H
Na2SO4. Removal of the solvent under reduced pressure, the left out NMR (500 MHz, CDCl3) δ 8.24(t, J = 7.0 Hz, 3H), 7.75(d, J = 9.0 Hz,
residue was purified through column chromatography using silica gel 2H), 7.70(t, J = 6.5 Hz, 1H), 7.68(d, J = 8.5 Hz, 1H), 7.55(t, J = 6.5 Hz,
(15% EtOAc/hexane) to get 3a in 95 % yield (0.0753g).
1H), 7.43-7.39(m, 2H), 7.38-7.34(m, 4H), 7.30(t, J = 7.5 Hz, 1H), 7.15-
2-Phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (3aa)34
7.13(m, 1H). 6.79(t, J = 6.5 Hz, 1H), 13C NMR (125 MHz, CDCl3) δ 151.4,
(Eluent: 20% EtOAc/hexane); White solid; 81% yield (60.9 mg); 1H 147.1, 133.2, 132.4, 131.7, 129.1, 128.7, 125.3, 128.38, 123.30,
NMR (500 MHz, CDCl3) δ 8.24-8.20(m, 3H), 7.72(d, J = 9.0 Hz, 1H), 127.6, 126.9, 126.7, 126.6, 125.6, 124.4, 123.7, 123.3, 117.5, 113.0,
7.42(t, J = 7.5 Hz, 2H), 7.35(t, J = 7.5 Hz, 1H), 7.29(t, J = 7.5 Hz, 1H), 106.0.
7.18(t, J = 7.5 Hz, 2H), 7.10(t, J = 7.5 Hz, 1H), 6.99(d, J = 7.5 Hz, 2H), 2-Phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3a)23
6.81(t, J = 6.5 Hz, 1H), 13C NMR (125 MHz, CDCl3) δ .159.3, 147.0, (Eluent: 20% EtOAc/hexane); White solid; 95% yield(75.3 mg); 1H
135.0, 133.2, 129.43, 128.4, 128.3, 128.2, 126.5, 125.9, 125.4, 124.3, NMR (500 MHz, CDCl3) δ 8.16(d, J = 7.0 Hz, 1H), 8.13(d, J = 7.0 Hz, 2H)
117.5, 112.9, 106.1.
7.63(d, J = 8.5 Hz, 2H), 7.33(t, J = 7.5 Hz, 2H), 7.26 (d, J = 8.0 Hz, 1H),
7.20 (t, J = 8.0 Hz, 1H), 6.91(d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H),
(4-Chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine (3ab)34
(Eluent: 20% EtOAc/hexane); White solid; 90% yield(75.7 mg); 1H 6.73 (t, J = 6.5 Hz, 1H) 2.14(s, 3H). 13C NMR (125 MHz, CDCl3) δ 151.1,
NMR (500 MHz, CDCl3) δ 8.24(d, J = 6.5 Hz, 1H), 8.19(d, J = 7.5 Hz, 146.9, 135.9, 133.3, 131.4, 130.1, 128.4, 128.3, 126.4, 125.7, 124.4,
2H), 7.74 (d, J = 9.0 Hz, 1H), 7.44(t, J = 7.5 Hz, 2H), 7.39-7.33(m, 2H), 117.5, 112.9, 106.7, 20.7.
7.18 (d, J = 8.5 Hz, 2H), 6.93-6.87(m, 3H), 13C NMR (125 MHz, CDCl3) 8-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3b)23
δ 151.6, 147.1, 133.7, 133.1, 132.0, 129.5, 128.7, 128.4, 128.2, 126.7, (Eluent: 20% EtOAc/hexane); White solid; 95% yield (78.6 mg); 1H
124.2, 117.7, 113.2, 105.6.
2-Phenyl-3-((4-(trifluoromethyl)phenyl)thio)imidazo[1,2-
a]pyridine (3ac)
NMR (500 MHz, CDCl3) δ 8.19(d, J = 7.5 Hz, 2H), 8.14(d, J = 7.0 Hz,
1H), 7.47(s, 1H), 7.42(t, J = 7.5 Hz, 2H), 7.35(d, J = 7.5 Hz, 1H), 7.02(d,
J = 8.0 Hz, 2H), 6.90(d, J = 7.0 Hz, 2H), 6.68(d, J = 6.5 Hz, 1H), 2.42(s,
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 162°C; 83% yield 3H), 2.25(s,3H). 13C NMR (125 MHz, CDCl3) δ 151.0, 147.4, 137.7,
(76.7 mg); 1H NMR (500 MHz, CDCl3) δ 8.20(d, J = 6.5 Hz, 1H),8.16(d, 135.8, 133.5, 131.8, 130.1, 128.3, 128.2, 125.6, 123.6, 116., 115.5,
J = 7.5 Hz, 1H), 7.75(d, J = 9.0 Hz, 1H), 7.42(t, J =8.5 Hz, 4H), 7.38- 105.9, 101.6, 21.3, 20.8.
7.32(m, 2H), 7.05(d, J = 8.5 Hz, 2H), 6.87(t, J = 6.5 Hz, 1H), 13C NMR 6-Methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3c)22
(125 MHz, CDCl3) δ 151.9, 147.3, 140.4, 132.9, 129.7, 128.3, 127.0, (Eluent: 20% EtOAc/hexane); White solid; 81% yield (67.0 mg); 1H
126.9, 126.2, 125.1, 124.9, 124.1, 117.7, 113.3, 104.4 . IR (KBr) 2940, NMR (500 MHz, CDCl3) δ 8.19(d, J = 7.5Hz, 2H), 8.07(s, 1H), 7.53(d, J
1630, 1601, 1496, 1269, 1229, 1165, 1082, 1011, 829, 693, 587. = 7.0 Hz, 2H), 7.41(t, J =8.0 Hz, 2H), 7.18(d, J = 9.0 Hz, 1H), 7.03(d, J
HRMS calcd for C20H14N2F3S: 371.0830, found: 371.0840.
3-((4-(Tert-butyl)phenyl)thio)-2-phenylimidazo[1,2-a]pyridine
(3ad)
= 8.0 Hz, 2H), 6.91(d, J = 8.5 Hz, 2H), 2.31(s, 3H), 2.26(s.3H). 13C NMR
(125 MHz, CDCl3) δ 151.0, 146.6, 135.8, 133.5, 131.8, 130.1, 129.6,
128.3, 128.2, 125.7, 125.5, 122.28, 122.2, 116.9, 106.1, 103.7, 20.8,
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 139°C; 40% yield 18.3.
(36.8 mg); 1H NMR (500 MHz, CDCl3) δ 8.29(d, J = 6.5 Hz, 1H), 8.23(d, 6-Chloro-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3d)
J = 7.5 Hz, 2H), 7.72(d, J = 9.0 Hz, 1H), 7.43(t, J = 7.5 Hz, 2H), 7.37- (Eluent: 20% EtOAc/hexane); White solid; m.p.: 166 °C; 98%
7.29(m, 2H), 7.22(d, J = 8.5 Hz, 2H),6.94(d, J = 8.5 Hz, 2H), 6.85(t, J = yield(86.2 mg); 1H NMR (500 MHz, CDCl3) δ 8.30 (s, H), 8.20 (d, J = 7.0
6.5 Hz, 1H),1.23(s, 9H). 13C NMR (125 MHz, CDCl3) δ 150.1, 149.2, Hz, 2H), 7.65 (d, J = 9.5 Hz, 1H), 7.43 (t, J = 7.0 Hz, 2H), 7.37 (t, J =
146.9, 33.3, 131.5, 128.4, 128.3, 126.5, 126.4, 125.4, 124.5, 117.5, 8.0 Hz, 1H), 7.27-7,25(m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.90(d, J = 8.5
112.9, 106.7, 34.3, 31.1. IR (KBr) 3023, 2960, 1629, 1490, 1348, 1268, Hz, 2H), 2.26 (s, 3H), 13C NMR (125 MHz, CDCl3) δ 151.8, 145.2,
1232, 1113, 1008, 828, 746, 696, 547. HRMS calcd for C23H23N2S: 146,3, 132.9, 130.8, 130.2, 128.7, 128.4, 1282. 127.9, 125.9, 122.4,
359.1582, found: 359.1592.
3-([1,1'-Biphenyl]-4-ylthio)-2-phenylimidazo[1,2-a]pyridine (3ae)
121.4, 117.9, 107.7, 20.8. IR (KBr) 3427, 2921, 2373, 1439, 1327,
1077, 796, 692, 485. HRMS calcd for C21H18N2ClS: 365.0879, found:
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 136 °C; 70% 365.0846.
1
yield(65.8 mg); H NMR (500 MHz, CDCl3) δ 8.28(d, J = 7.0 Hz, 1H), 6-Bromo-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3e)22
8.23(d, J = 7.5 Hz, 2H), 7.74(d, J = 9.0 Hz, 1H), 7.74-7.40(m, 6H), 7.42- (Eluent: 20% EtOAc/hexane); White solid; 95% yield(93.5 mg); 1H
7.36(m, 3H), 7.32-7.03(m, 2H), 7.05(d, J = 7.5 Hz, 2H), 6,84(t, J = 6.5 NMR (500 MHz, CDCl3) δ 8.41(s, 1H), 8.20 (d, J = 7.5 Hz, 2H), 7.60 (d,
Hz, 1H), 13C NMR (125 MHz, CDCl3) δ 151.3, 147.0, 139.9, 139.0, J = 9.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 2H), 7.39-7.35 (m, 2H), 7.04 (d, J =
134.1, 133.2, 128.7, 128.5, 128.38, 128.31, 128.0, 127.3, 126.7, 7.5 Hz, 2H), 6.91 (d, J = 8.0Hz, 2H), 2.26 (s, 3H), 13C NMR (125 MHz,
125.8, 124.4, 117.5, 113.0, 106.0. IR (KBr) 3028, 2254, 1629, 1473, CDCl3) δ 151.6, 145.3, 136.3, 132.8, 130.8, 130.2, 130.0, 128.7, 128.4,
128.2, 125.8, 124.6, 118.8, 107.9, 107.6, 20.8.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 8
ARTICLE
Journal Name
6-Bromo-8-methyl-2-phenyl-3-(p-tolylthio)imidazo[1,2-a]pyridine
(3f)
2955, 2831, 1630, 1490, 1223, 1040, 807, 744, 425. HRMS calcd for
View Article Online
C22H21N2O2S: 377.1324, found: 377.1328.
DOI: 10.1039/C5OB02475G
(Eluent: 20% EtOAc/hexane); liquid; 64% yield(65.4 mg); 1H NMR 4-(3-(p-Tolylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile (3m)23
(500 MHz, CDCl3) δ 8.29(s, 1H), 8.19 (d, J = 7.5 Hz, 2H), 7.43-7.36(m, (Eluent: 20% EtOAc/hexane); White solid; 79% yield(67.1 mg); 1H
3H), 7.19(s, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 2.69(, NMR (500 MHz, CDCl3) δ 8.39(d, J = 8.5 Hz, 2H),8.29(d, J = 7.0 Hz, 1H),
3H), 2.26(s, 3H). 13C NMR (125 MHz, CDCl3) δ 145.8, 136.1, 131.2, 7.72-7.68(m, 3H), 7.35(t, J = 8.5 Hz, 1H),7.03(d, J = 8.0 Hz, 2H),6.91-
130.4, 130.2, 129.0, 128.8, 128.7, 128.5, 128.4, 125.8, 122.4, 107.79, 6.87(m, 3H), 2.24(s, 3H). 13C NMR (125 MHz, CDCl3) δ 148.4, 146.9,
107.75, 20.8, 16.6. IR (Nujol) 3429, 2916, 1600, 1485, 1437, 1338, 137.8, 136.4, 132.0, 130.5, 130.2, 128.5, 127.0, 125.8, 124.4, 118.8,
1079, 805, 693, 486. HRMS calcd for C21H18N2SBr: 409.0374, found: 117.7, 113.4, 111.5, 108.3, 20.7.
409.0379.
4-(8-Methyl-3-(p-tolylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile
2-(4-(Methylthio)phenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3g) (3n)
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 126 °C; 72% (Eluent: 20% EtOAc/hexane); White solid; m.p.: 162 °C; 72% yield
1
1
yield(65.0 mg); H NMR (500 MHz, CDCl3) δ 8.25(d, J = 7.5 Hz, 1H), (82.0 mg); H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 2H), 8.06
8.18(d, J = 8.5 Hz, 2H), 7.70(d, J = 6.0 Hz, 1H), 7.30(d, J = 6.5 Hz, 3H), (d, J = 7.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.04(d, J = 7.0 Hz, 1H), 6.92
7.00(d, J = 8.0 Hz, 2H), 6.90(d, J = 8.5 Hz, 2H), 6.82(t, J = 6.5 Hz, 1H), (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 2H), 6.70 (t, J = 7.0 Hz, 1H) 2.59
2.48(s,3H0, 2.23(s, 3H). 13C NMR (125 MHz, CDCl3) δ 10.5, 146.9, (s, 3H), 2.15(s, 3H). 13C NMR (125 MHz, CDCl3) δ 147.8, 1477.2, 138.0,
139.1, 135.9, 131.3, 130.1, 130.0, 128.5, 126.5, 126.0, 125.7, 124.3, 136.1, 131.8, 130.7, 130.1, 128.5, 127.7, 125.6, 122.1, 118.9, 113.3,
117.3, 112.8, 106.4, 20.7, 15.4. IR (KBr) 2917, 1597, 1459, 1339, 1094, 111.2, 108.4, 20.6, 16.5. IR (KBr) 2921, 2218, 1603, 1488, 1348, 1248,
801, 728, 483. HRMS calcd for C21H19N2S2: 363.0990, found: 845, 813, 747, 550, 505. HRMS calcd for C22H18N3S: 356.1221, found:
363.0983.
356.1209.
2-(2-Fluorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3h)
4-(7-Methyl-3-(p-tolylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile
(Eluent: 20% EtOAc/hexane); liquid; 89% yield(74.2 mg); 1H NMR (3o)
(500 MHz, CDCl3) δ 8.18(d, J = 6.5 Hz, 1H), 7.74-7.61(m, 2H), 7.42- (Eluent: 20% EtOAc/hexane); White solid; m.p.: 201 °C; 60%
7.28(m, 2H), 7.23-7.14(m, 2H), 6.99(d, J = 8.0 Hz, 2H), 6.86-6.82(m, yield(53.1 mg); 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 2H),
3H), 2.22(s, 3H) 13C NMR (125 MHz, CDCl3) δ 147.6 (d, J = 72.5 Hz), 7.98(s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.52(d, J = 9.0 Hz, 1H), 7.11(d, J =
135.8,131.9, 131., 130.3(d, J = 7.6 Hz), 129.9, 126.3, 125,9, 124.5, 9.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H),6.79 (d, J = 8.0 Hz, 2H), 2.22 (s,
123.8, 121.6 (d, J = 14.0 Hz), 117.7, 116.0(d, J = 22.5 Hz), 113.0, 109.4, 3H), 2.15(s, 3H). 13C NMR (125 MHz, CDCl3) δ 148.2, 146.0, 137.9,
20.7. IR (Nujol) 3401, 2923, 1892, 1631, 1489, 1342, 1222, 1099, 803, 136.2, 131.9, 130.8, 130.2, 128.4, 125.5, 123.4, 122.0, 118.8, 117.0,
757, 483. HRMS calcd for C20H16N2FS: 335.1018, found: 335.1013.
111.4, 107.7, 20.7, 18.2. IR (KBr) 2920, 2219, 1605, 1492, 1464, 1334,
856, 801, 555, 477. HRMS calcd for C22H18N3S: 356.1221, found:
2-(4-Chlorophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3i)22
(Eluent: 20% EtOAc/hexane); White solid; 92% yield(81.2 mg); 1H 356.1209.
NMR (500 MHz, CDCl3) δ 8.26(d, J = 7.0 Hz, 1H), 8.19(d, J = 8.5 Hz, 2-(8-Methyl-3-(p-tolylthio)imidazo[1,2-a]pyridin-2-yl)benzonitrile
2H), 7.70(d, J = 9.0 Hz, 1H), 7.39 (d, J = 9.0 Hz, 2H), 7.30(t, J = 7.5 Hz, (3p)
1H), 7.01(d, J = 8.0 Hz, 2H),6.88-6.66(m, 3H), 2.23(s, 3H), 13C NMR (Eluent: 20% EtOAc/hexane); White solid; m.p.: 162 °C; 74%
1
(125 MHz, CDCl3) δ 149.8, 146.9, 136.1, 134.4, 131.8, 131.0, 130.1, yield(66.0 mg); H NMR (500 MHz, CDCl3) δ 8.58(s, 1H), 8.50 (d, J =
129.9, 128.5, 126.7, 125.7, 124.4, 117.5, 113.0, 107.0, 20.8.
2-(4-Bromophenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3j)
8.0 Hz, 1H), 8.17 (d, J = 6.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.51(t, J
= 8.0 Hz, 1H), 7.15 (d, J = 6.5 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.88 (d,
Eluent: 20% EtOAc/hexane); White solid; m.p.: 131 °C; 79% yield J = 8.0 Hz, 2H), 6.81(t, J = 7.0 Hz, 1H), 2.70(s, 3H), 2.26 (s, 3H). 13C
(80.1 mg); 1H NMR (500 MHz, CDCl3) δ 8.16(d, J = 6.5 Hz, 1H), 8.01(d, NMR (125 MHz, CDCl3) δ 147.8. 147.3, 136.2, 135.0, 132.4, 131.8,
J = 8.0 Hz, 2H), 7.61(d, J = 9.0 Hz, 1H), 7.44(d, J = 8.5 Hz, 2H), 7.21(t, J 131.4, 130.2, 127.8, 125.8, 122.2, 118.8, 113.4, 112.4, 108.0, 20.7,
= 8.0 Hz, 1H), 6.91(d, J = 8.0 Hz, 2H), 6.78-6.73(m, 3H), 2.13(s, 3H).13C 16.6. IR (KBr) 2920, 2218, 1608, 1488, 1348, 1248, 845, 812, 747, 550,
NMR (125 MHz, CDCl3) δ 149.7, 146.9, 136.1, 132.2, 131.4, 131.0, 505. HRMS calcd for C22H18N3S: 356.1221, found: 356.1209.
130.1, 129.7, 126.7, 125.7, 124.4, 123.1, 122.8, 122.2, 17.5, 113.1, 2-(Thiophen-2-yl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3q)
107.0, 20.8. IR (KBr) 3029, 2859, 1629, 1480, 1382, 1230, 1081, 800, (Eluent: 20% EtOAc/hexane); White solid; m.p.: 210 °C; 65%
1
669, 479. HRMS calcd for C20H16N2SBr: 343.1269, found: 343.1254.
yield(52.4 mg); H NMR (500 MHz, CDCl3) δ 8.25(d, J = 7.0 Hz, 1H),
8.00(d, J = 3.5 Hz, 1H), 7.68(d, J = 9.0 Hz, 1H),7.36(d, J = 5.0 Hz, 1H),
2-(4-Methoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3k)23
(Eluent: 20% EtOAc/hexane); White solid; 54% yield(47.1 mg); 1H 7.28(t, J = 9.0 Hz, 1H), 7.09(t, J = 4.0 Hz, 1H),7.00(d, J = 8.5 Hz, 2H),
NMR (500 MHz, CDCl3) δ 8.09(d, J = 6.5 Hz, 1H), 7.67(d, J = 6.5 Hz, 6.96(d, J = 8.0 Hz, 2H), 6.81(t, J = 6.0 Hz, 1H), 2.23(s, 3H). 13C NMR
1H), 7.23(t, J = 8.0 Hz, 1H), 7.09(t, J = 7.5 Hz, 2H), 7.01(t, J = 8.0 Hz, (125 MHz, CDCl3) δ 146.8, 146.4, 136.2, 136.1, 130.8, 13.00, 127.6,
2H), 6.88 (d, J = 8.5 Hz, 2H), 6.82(s, 2H), 6.79-6.75(m, 2H), 3.62(s, 126.6, 126.4, 126.1, 124.2, 117.2, 112.9, 106.0, 20.7. IR (KBr) 3043,
3H), 3.51(s, 3H). 13C NMR (125 MHz, CDCl3) δ 153.1, 151.6, 150.1, 2918, 1630, 1488, 1339, 748, 687, 483. HRMS calcd for C18H15N2S2:
149.9, 146.9, 135.6, 129.0, 126.0, 125.0, 124.3, 123.2, 117.7, 116.6, 323.0677, found: 323.0696.
115.6, 112.9, 112.2, 108.8, 55.7, 55.6.
(E)-2-Styryl-3-(p-tolylthio)imidazo[1,2-a]pyridine (3r)
2-(2,6-Dimethoxyphenyl)-3-(p-tolylthio)imidazo[1,2-a]pyridine (3l) Eluent: 20% EtOAc/hexane); White solid; m.p.: 170 °C; 85%
1
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 141 °C; 99% yield(73.0 mg); H NMR (500 MHz, CDCl3) δ 8.18(d, J = 7.0 Hz, 1H),
1
yield(93.0 mg); H NMR (500 MHz, CDCl3) δ 8.16(d, J = 7.0 Hz, 1H), 7.83(d, J = 16.0 Hz, 1H), 7.66-7.60(m, 3H), 7.50(d, J = 16.0 Hz, 1H),
7.74(d, J = 9.0 Hz, 1H), 7.28(t, J = 8.0 Hz, 1H), 7.11(s, 1H), 6.99(d, J = 7.35(t, J = 7.5 Hz, 2H), 7.29-7.24(m, 2H), 7.01(d, J = 8.0 Hz, 2H), 6.95(d,
8.5 Hz, 2H), 6.90(s, 2H), 6.87(d, J = 8.0 Hz, 2H), 6,82(t, J = 6.5 Hz, 1H), J = 8.5 Hz, 2H), 6.78 (t, J = 6.5 Hz, 1H), 2.24(s, 3H). 13C NMR (125 MHz,
3.709(s, 3H), 3.62(s, 3H), 223(s,3H). 13C NMR (125 MHz, CDCl3) δ CDCl3) δ 149.9, 147.4, 136.9, 136.2, 132.6, 131.2, 130.0, 128.5, 127.9,
153.1, 151.5, 149.8, 146.7, 135.4, 131.7, 129.7, 125.7, 124.3, 123.2, 126.8, 126.5, 124.2, 118.2, 117.7, 112.5, 109.6, 20.7. IR (KBr) 3032,
117.6, 116.7, 115.5, 112.8, 112.1, 109.3, 55.7, 55.5, 20.7. IR (KBr) 2921, 1631, 1443, 1339, 1231, 921, 731, 680, 482. HRMS calcd for
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
C22H19N2S: 343.1269, found: 343.1254.
Eluent: 20% EtOAc/hexane); White solid; m.p.: 109V°ieCw; A4rt1ic%le Oynielinlde
2-Phenyl-3-(p-tolylthio)benzo[d]imidazo[2,1-b]thiazole (3s)23
(32.7 mg); 1H NMR (500 MHz, CDCl ) δ 8.48(d, J = 6.5 Hz, 1H), 8.19(d,
DOI: 10.1039/C5OB02475G
3
Eluent: 20% EtOAc/hexane); White solid; 52% yield(48.6 mg); 1H J = 8.6 Hz, 2H), 7.68(d, J = 8.5 Hz, 1H), 7.61(d, J = 8.5 Hz, 2H), 7.31(t, J
NMR (500 MHz, CDCl3) δ 8.26-8.21((m, 1H),7.92-7.89(m, 2H), 7.57(t, = 8.0 Hz, 1H), 6.96(t, J = 6.5 Hz, 1H), 2.25(s, 3H). 13C NMR (125 MHz,
J = 5.0 Hz, 1H), 7.50(d, J = 16.0 Hz, 1H), 6.98-6.94(m, 2H), 2.28(s,3H). CDCl3) δ 148.9, 147.7, 132.9, 131.2, 127.7, 125.6, 119.0, 114.4, 19.5.
13C NMR (125 MHz, CDCl3) δ138.1,138.0, 136.5, 135.9, 133.4, 132.9, IR (KBr) 3370, 2922, 2372, 1650, 1493, 1227, 827, 728, 699, 508.
131.6,130.0,129.5,129.3,129.0,128.1,128.0,127.9,127.7,126.2,126.0 HRMS calcd for C14H12N2SBr: 318.9905, found: 318.9911.
,125.4,124.3,123.8,114.2,21.2.
8-Methyl-3-(methylthio)-2-phenylimidazo[1,2-a]pyridine (4i)
General procedure for thiomethylation of imidazo[1,2-a]pyridines (Eluent: 20% EtOAc/hexane); White solid; m.p.: 102 °C; 51%
1
(4a)31
yield(32.6 mg); H NMR (500 MHz, CDCl3) δ 8.28(d, J = 6.5 Hz, 1H),
A clean washed boilingtube equipped with a magnetic stir bar was 8.18(d, J = 7.0 Hz, 2H), 7.40(t, J = 7.5 Hz, 2H), 7.30(t, J = 7.5 Hz, 1H),
charged with 2-phenylimidazo[1,2-a]pyridine 1a (0.0485 g, 0.25 7.01(d, J = 7.0 Hz, 1H), 6.78(t, J = 7.0 Hz, 1H), 2.59 (s, 3H), 2.17(s, 3H).
mmol), 4-methylbenzene-1-sulfonyl chloride 2a (0.0733 g, 0.375 13C NMR (125 MHz, CDCl3) δ 148.5, 146.6, 134.0, 128.4, 128.3, 128.0,
mmol) , Dimethyl sulphoxide(0.2 mL) and Dichloroethane (0.5 mL). 127.6, 124.7, 122.0, 116.1, 112.7, 111.6, 29.6, 18.2. IR (KBr) 2922,
The above mixture was stirred for 8h to open air at 100°C, and then 1732, 1468, 1255, 1071, 743, 699. HRMS calcd. for C15H15N2S:
the mixture was poured into 10 mL of saturated sodium bicarbonate 255.0956, found: 255.0956.
solution. The product was extracted with Ethyl acetate (10 mL × 3) 2-(4-Chlorophenyl)-6-methyl-3-(methylthio)imidazo[1,2-a]pyridine
and dried with anhydrous Na2SO4. Removal of the solvent under (4j)
reduced pressure, the left out residue was purified through column (Eluent: 20% EtOAc/hexane); liquid; m.p.: 152 °C 63% yield(45.1 mg);
chromatography using silica gel (15% EtOAc/hexane) to get 4a in 91 1H NMR (500 MHz, CDCl3) δ 8.17(d, J = 8.5 Hz, 3H), 7.47(d, J = 9.0 Hz,
% yield (0.054g), white solid. 1H NMR (500 MHz, CDCl3) δ 8.46 (d, J = 1H), 7.35(d, J = 8.0 Hz, 2H), 7.07(d, J = 8.5 Hz, 1H), 2.32(s, 3H), 2.16(s,
8.0 Hz, 1H), 8.29 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 9.0 Hz, 1H), 7.48 (t, J 3H). 13C NMR (125 MHz, CDCl3) δ 1487.3, 145.3, 1333.9, 132.4, 129.2,
= 7.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.91 (t, J 129.1, 128.4, 122.6, 121.9, 116.8, 110.9, 18.3, 18.1. IR (Nujol) 2919,
= 6.5 Hz, 1H), 2.24 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 148.7, 146.2, 1647, 1490, 1404, 1330, 1085, 1008, 841, 726. HRMS calcd for
133.7, 128.2, 128.1, 125.8, 124.1, 117.5, 112.6, 18.0. HRMS calcd for C15H14N2SCl: 289.0566, found: 289.0576.
C14H13N2S: 241.0788, found: 241.0788.
3-(Methylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (4b)
2-(2-Chlorophenyl)-8-methyl-3-(methylthio)imidazo[1,2-a]pyridine
(4k)
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 102 °C; 42% yield (Eluent: 20% EtOAc/hexane); liquid; 60% yield (43.5 mg); 1H NMR
(26.8 mg); 1H NMR (500 MHz, CDCl3) δ 8.49(d, J = 6.5 Hz, 1H), 8.18(d, (500 MHz, CDCl3) δ 8.32(d, J = 6.5 Hz, 1H), 7.67(t, J = 7.5 Hz, 1H),
J = 7.5 Hz, 2H), 7.67(d, J = 9.0 Hz, 1H), 7.30-7.26(m, 4H), 6.93(t, J = 7.41-7.37(m, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.18(t, J = 8.5 Hz, 1H), 7.11(d,
6.5 Hz, 1H), 2.41(s, 3H), 2.26(s, 3H). 13C NMR (125 MHz, CDCl3) δ J = 7.0 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 2.66(s, 3H), 2.22(s, 3H). 13C
148.9, 146.2, 138.1, 130.8, 129.1, 128.1, 125.8, 124.1, 117.4, 116.2, NMR (125 MHz, CDCl3) δ 161.2, 159.2, 146.9, 145.1, 132.3, 130.06,
112.6, 111.0, 29.6, 21.3. HRMS calcd for C15H15N2S: 255.0946, found: 130.00, 127.8, 124.6, 123.9, 123.3, 120.0, 115.8, 115.7, 114.0, 112.8,
255.0956.
17.8, 16.8. IR (Nujol) 2923, 1625, 1483, 1354, 1221, 1096, 764, 546.
HRMS calcd for C15H14N2SCl: 289.0566, found: 289.0569.
6-Methyl-3-(methylthio)-2-phenylimidazo[1,2-a]pyridine (4l)
3-(Methylthio)-2-(4-(methylthio)phenyl)imidazo[1,2-a]pyridine
(4c)
(Eluent: 20% EtOAc/hexane); liquid; 23% yield (16.1 mg); 1H NMR (Eluent: 20% EtOAc/hexane); White solid; m.p.: 121 °C; 40%
1
(500 MHz, CDCl3) δ 8.48(d, J = 6.5 Hz, 1H), 8.25(d, J = 8.0 Hz, 2H), yield(25.3 mg); H NMR (500 MHz, CDCl3) δ 8.28(d, J = 7.0 Hz, 1H),
7.36(d, J = 7.5 Hz, 2H), 7.29(t, J = 7.0 Hz, 1H), 6.94(t, J = 7.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.35 (s, 1H), 7.30(t, J
2.54(s, 3H), 2.26(s, 3H). 13C NMR (125 MHz, CDCl3) δ 148.2, 146.2, = 7.0 Hz, 1H), 6.70 (d, J = 7.0 Hz, 1H), 2.36(s, 3H), 2.17(s, 3H). 13C NMR
138.7, 128.4, 126.1, 125.9, 124.1, 117.4, 112.7, 18.1, 15.5. IR (Nujol) (125 MHz, CDCl3) δ 148.6, 146.7, 142.3, 137.7, 133.8, 128.3, 128.19,
3400, 2922, 2316, 1649, 1458, 1344, 1094, 824, 757, 690. HRMS 128.12, 123.4, 116.2, 116.0, 115.3, 110.6, 29.6, 21.3. IR (KBr) 2920,
calcd for C15H15N2S2: 287.0677, found: 287.0679.
2-(4-Chlorophenyl)-3-(methylthio)imidazo[1,2-a]pyridine (4d)
2369, 1638, 1489, 1352, 1263, 776, 672. HRMS calcd for
C15H15N2S:255.0956, found: 255.0938.
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 95 °C; 51% yield (34.8 6-Bromo-8-methyl-3-(methylthio)-2-phenylimidazo[1,2-a]pyridine
mg); 1H NMR (500 MHz, CDCl3) δ 8.46(d, J = 8.5 Hz, 3H), 7.66(d, J = (4m)
7.5 Hz, 1H), 7.43(s, 2H), 7.29(t, J = 7.5 Hz, 1H), 6.94(d, J = 6.0 Hz, 1H), (Eluent: 20% EtOAc/hexane); yellow solid; m.p.: 132 °C; 43% yield
2.25(s, 3H). 13C NMR (125 MHz, CDCl3) δ 147.5, 146.3, 134.1, 132., (35.3 mg); 1H NMR (500 MHz, CDCl3) δ 8.47 (s, 1H), 8.26(d, J = 7.0 Hz,
129.4, 128.5, 126.1, 124.2, 117.6, 112.8, 111.4, 18.0. IR (KBr) 2918, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.38(t, J = 7.5 Hz, 1H), 7.17(s, 1H), 2.65(s,
2370, 1698, 1462, 1340, 1089, 842, 732, 551. HRMS calcd for 3H), 2.25(s, 3H). 13C NMR (125 MHz, CDCl3) δ 148.8, 145.0, 133.6,
C14H12N2SCl: 275.0410, found: 275.0415.
2-(2-Fluorophenyl)-3-(methylthio)imidazo[1,2-a]pyridine (4e)
128.7, 128.3, 128.0, 122.2, 112.2, 107.5, 18.2, 16.6. IR (KBr) 2919,
2372, 1648, 1474, 1398, 968, 776, 694, 691. HRMS calcd for
Eluent: 20% EtOAc/hexane); White solid; m.p.: 110 °C; 67% yield C15H14N2SBr: 343.1269, found: 343.1254.
(42.6 mg); 1H NMR (500 MHz, CDCl3) δ 8.37(d, J = 6.5 Hz, 1H), 7.622 - 6-Chloro-2-(2-fluorophenyl)-3-(methylthio)imidazo[1,2-a]pyridine
> 7.62 (m, 2H), 7.35-7.30(m, 1H), 7.23(t, J = 7.0 Hz, 1H), 7.18(t, J = 7.0 (4n)
Hz, 1H), 7.12(t, J = 9.0 Hz, 1H), 6.88(t, J = 7.0 Hz, 1H), 2.16(s, 3H). 13
C
(Eluent: 20% EtOAc/hexane); White solid; m.p.: 115 °C; 45% yield
NMR (125 MHz, CDCl3) δ 161.1(d, J = 248 Hz), 146.5, 145.5, 132.0, (33.0 mg); 1H NMR (500 MHz, CDCl3) δ 8.48(s, 1H), 7.58(t, J = 7.0 Hz,
130.1(d, J = 8.0 Hz), 125.7, 124.1, 123.9, 122.0(d, J = 14.0 Hz), 117.8, 1H), 7.64(d, J = 9.5 Hz, 1H),7.43-7.39(m, 1H), 7.29-7.18(m, 3H),
115.9 (d, J = 22.0 Hz), 113.7, 112.8, 17.7. IR (KBr) 2925, 1719, 1630, 2.25(s, 3H) 13C NMR (125 MHz, CDCl3) δ 161.1(d, J = 248 Hz), 146.5,
1478, 1344, 1222, 1099, 968, 799, 759. HRMS calcd for C14H12N2SF: 144.8, 131.9, 130.4(d, J = 7.0 Hz), 127.2, 124.0, 122.2, 121.6(d, J =
259.0705, found: 259.0715.
17.5 Hz), 118.3, 116.0 (d, J = 22.0 Hz), 114.6, 17.8. IR (KBr) 2925, 1474,
2-(4-Bromophenyl)-3-(methylthio)imidazo[1,2-a]pyridine (4f)
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 8
ARTICLE
Journal Name
13. X. Xiao, Y. Xie, S. Bai, Y. Deng, H. Jiang, W. Zeng, Org.
1325, 1218, 1073, 806, 755, 668, 456. HRMS calcd for C14H11N2FSCl:
293.0316, found: 293.0310.
View Article Online
Lett. 2015, 17, 3998.
DOI: 10.1039/C5OB02475G
14. D. C. Mohan, S. N. Rao, S. Adimurthy, J. Org. Chem.
2013, 78, 1266.
15. D. R. Reddy, P. Venkatanarayana, N.N.K.Reddy, D.
Bairagi, S. Adimurthy, J. Org.Chem. 2014, 79, 11277.
16. D. C. Mohan, S. N. Rao, C. Ravi. S. Adimurthy, Asian J.
Org. Chem. 2014, 3, 609.
17. G. J. Mukund, M. Shelke, Cameron, T. S. Kumar, A. J.
Org. Chem. 2015, 80, 5272.
18. Q. Wu, D. Zhao, X. Qin, J. Lan, J. You, Chem. Commun.,
2011, 47, 9188.
19. H. Cao, H. Zhan, Y. Lin, X. Lin, Z. Du, H. Jiang, Org. Lett.
2012, 14, 7.
3-(Methylthio)-2,6-diphenylimidazo[1,2-a]pyridine (4o)
Eluent: (50% EtOAc/hexane); White solid; m.p.: 186 °C; 61%
yield(48.2 mg); 1H NMR (500 MHz, CDCl3) δ 8.57(s, 1H), 8.24(d, J = 7.0
Hz, 2H), 7.65(d, J = 9.5 Hz, 1H), 7.56(d, J = 7.0 Hz, 2H), 7.7.50-7.39(m,
5H), 7.36-7.31(m, 2H), 2.20(s, 3H). 13C NMR (125 MHz, CDCl3) δ 149.3,
145.6, 137.3, 133.7, 129.1, 128.5, 128.3, 128.2, 1281, 127.7, 127.1,
126.9, 126.7, 126.5, 121.4, 117.4, 11.7, 18.2. IR (KBr) 3056, 2964,
1335, 1261, 1094, 1021, 804, 762, 693, 513. HRMS calcd for
C20H17N2S: 317.1112, found: 317.1111.
(E)-3-(Methylthio)-2-styrylimidazo[1,2-a]pyridine (4p)
Eluent: (30% EtOAc/hexane); liquid; 52% yield(34.6 mg); 1H NMR
(500 MHz, CDCl3) δ 8.31(d, J = 6.5 Hz, 1H),7.67(d, J = 16.0 Hz, 1H)
7.55(t, J = 8.0 Hz, 3H), 7.42(d, J = 16.5 Hz, 1H), 7.30(t, J = 7.5 Hz, 2H),
7.22-7.199m, 2H), 6.81(t, J = 6.5 Hz, 1H), 2.20(s, 3H), 13C NMR (125
MHz, CDCl3) δ 148.0. 146.9, 1371, 131.8, 128.6, 127.8, 126.8, 126.3,
124.0, 118.4, 117.2, 113.8, 112.4, 18.7. IR (Nujol) 3399, 2921, 1634,
1496, 1344, 1263, 1074, 969, 758, 451. HRMS calcd for C16H15N2S:
267.0956, found: 267.0969.
20. C. Ravi, D. C. Mohan, S. Adimurthy, Org. Lett. 2014, 16
,
2978.
21. Yan, S. Y. Liu, B. Liu, Y.Liu, B.F. Shi, Chem. Commun. 2015,
51, 4069.
22. M. Hiebel, S. B. Raboin, Green Chem. 2015, 17, 937.
23. A. K. Bagdi, S. Mitra, M. Ghosh, A. Hajra, Org. Biomol.
Chem. 2015, 13, 3314.
24. When we screened different solvents like polar and
nonpolar, reactions were not efficient and produced
traces amounts of product 3a (see Table S1, supporting
information).
25. C. Shen, P. Zhang, Q. Sun, S. Bai, T. S. A. Hor, X. Liu, Chem.
Soc. Rev. 2015, 44, 291.
3-(Methylthio)imidazo[1,2-a]pyridine (7)
Eluent: (30% EtOAc/hexane); liquid; 63% yield(24.8 mg); 1H NMR
(500 MHz, CDCl3) δ 8.40 (d, J = 7.0 Hz, 1H), 7.77(s, 1H), 7.65(d, J = 9.0
Hz, 1H), 7.26(t, J = 8.0 Hz, 1H), 6.93(t, J = 7.0 Hz, 1H), 2.27(s, 3H). 13
C
NMR (125 MHz, CDCl3) δ 1140.0, 125.2, 123.9, 118.0, 112.7, 29.6. IR
(Nujol) 2923, 2853, 1648, 1462, 1093, 805, 759. HRMS calcd for
C8H9N2S: 165.0486, found: 165.0487.
26. C. Zhang, N. Jiao, J. Am. Chem. Soc. 2010, 132, 28.
27. A. E. King, T. C. Brunold, S. S. Stahl, J. Am. Chem. Soc.
2009, 131, 5044.
Acknowledgements
28. O. Basl, C.-J. Li, Chem. Commun. 2009, 4124.
29. P. Sharma, S. Rohilla, N. Jain, J. Org. Chem. 2015, 80
,
CSIR-CSMCRI Communication No. 187/2015. C. R. and D. C. M
are thankful to AcSIR for their Ph.D. enrolment and the
“Analytical Discipline and Centralized Instrumental Facilities”
for providing instrumentation facilities. D.C.M. is also thankful
to UGC, New Delhi for his fellowship. We thank DST,
Government of India (SR/S1/OC-13/2011), for financial support.
We also thank CSIR-CSMCRI (OLP-0076) for partial assistance.
4116.
30. C. Dai, Z. Xu, F. Huang, Z. Yu, Y. Gao, J. Org. Chem. 2012,
77, 4414.
31. S. M. Patila, S. Kulkarni, M. Mascarenhas, R. Sharma, S.
M. Roopan, A. Roychowdhury, Tetrahedron, 2013, 69
8255.
,
32. After screening of different sulfonyl chlorides as
promoters, 4-methylbenzene-1-sulfonyl chloride 2a was
found to be the best for this transformation (see Table
S3, ESI).
33. W. Zhao, P. Xie, Z. Bian, A. Zhou, H. Ge, M. Zhang, Y.
Ding, L. Zheng, J. Org. Chem. 2015, 80, 9167−9175.
34. W. Ge, X. Zhu, Y. Wei, Eur. J. Org. Chem. 2013, 6015.
Notes and references
1. F. Couty, G. Evano, in: Comprehensive Heterocyclic
Chemistry III, (eds.: Katritzky A. R.; Ramsden, C. A.;
Scriven, E. F. V.; Taylor R. J. K.), Elsevier, Oxford, 2008,
11, 409.
2. J. Liu, Q. Chen, Huaxue Jinzhan, 2010, 22, 631.
3. C. A. E. Gueiffier Gueiffier Mini-Rev. Med. Chem. 2007,
7
, 888.
4. G. Bartholini, L.E.R.S. Monograph Series, 1993,
8
, 1.
5. E. Abignente, de. Actualites Chimie Therapeutique,
1991, 18, 193.
6. S. Z. Langer, S. Arbilla, J. Benavides, B. Scatton, Adv.
Biochem. Psychopharmacol, 1990, 46, 61.
7. K. Mizushige, T. Ueda, K. Yukiiri, H. Suzuki, Cardiovasc.
Drugs Rev. 2002, 20, 163.
8. L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P.
Rugarli, A. Biancotti, A. Gamba, W. J. Murmann, Med.
Chem. 1965,
9. Boerner, R. J. Moller, H. J. Psychopharmakother, 1997,
, 145.
8, 305.
4
10. K. Gudmundsson and S. D. Boggs. PCT Int. Appl.WO
2006026703, 2006.
11. 11. S. Liu, H. Xi, J. Zhang, X. Wu, Q. Gao, A. Wu, Org.
Biomol. Chem. 2015, 13, 8807- 8811.
12. V. B. Kurteva, L. A. Lubenov, D. V. Antonova, RSC Adv.
2014, 4, 175.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins