S-Aryl Arenesulfonothioate and Copper Acetate Mediated Arylthiolation of 2-Arylpyridines and Heteroarenes

Article abstract of DOI:10.1021/acs.joc.9b01954

Copper acetate mediated regioselective ortho-arylthiolation of 2-arylpyridines has been accomplished for the first time using S-aryl arenesulfonothioate as the arylthiolating agent. The reaction shows good functional group tolerance and gives thioarylated products in 67-89% yields. This reagent is a good alternative to unpleasant smelling arylthiols. Experimental evidence suggests an unprecedented insertion of an arylthio unit from both parts of the reagent (SPh and p-TolSO₂) in the presence of copper acetate. Indoles and imidazopyridines also undergo facile reaction at the C-3 position and furnish thioarylated derivatives in good yields.

Full text of DOI:10.1021/acs.joc.9b01954

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Article
S-Aryl Arenesulfonothioate and Copper Acetate Mediated
Arylthiolation of 2-Aryl Pyridines and Heteroarenes
Poonam Sharma, and Nidhi Jain
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01954 • Publication Date (Web): 06 Sep 2019
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The Journal of Organic Chemistry
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S-Aryl Arenesulfonothioate and Copper Acetate Mediated
Arylthiolation of 2-Aryl Pyridines and Heteroarenes
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Poonam Sharma and Nidhi Jain*
Department of Chemistry, Indian Institute of Technology, New Delhi-110016
N
N
Ar/
Ar/
HetAr
HetAr
ArSO2SAr
H
SAr
Cu(OAc)2, 120 oC, 6h
H
SAr
X
R1
R3
X
K2CO3
R1
R3
N
N
R2
R2
29 examples, 67-89% Yields
Ligand free! Solvent free!Oxidant free!
(
X = N or C)
ABSTRACT: Copper acetate mediated regioselective ortho-arylthiolation of 2-aryl pyridines has been accomplished for the first
time using S-aryl arenesulfonothioate as the arythiolating agent. Reaction shows good functional group tolerance and gives
thioarylated products in 67-89% yields. This reagent is a good alternative of the unpleasant smelling arylthiols. Experimental
evidences suggest an unprecedented insertion of arylthio unit from both the parts of the reagent (SPh and p-TolSO ) in the presence
2
of copper acetate. Indoles and imidazopyridines also undergo facile reaction at C-3 position, and furnish thioarylated derivates in
good yields.
3
INTRODUCTION
arenes has been developed. Since its inception, this area has
grown exponentially as it provides the target molecules in a
straightforward manner.
Aryl sulfides are ubiquitous structural motifs in numerous
biologically active natural products, pharmaceuticals,
materials etc. and have significant synthetic utility as building
blocks of organosulfur compounds. A few examples of
biologically active arylthiolated molecules are shown in figure
Functionalized pyridines find significant application in the
synthesis of drugs, pharmaceuticals, herbicides and
agrochemicals. In this regard, pyridine as a directing group
1
4
1.
has been explored extensively for a variety of C-H
functionalizations such as alkylation, alkenylation, cyanation,
5
Cl
NH2
CH2CH3
S
Cl
Cl
carbonylation, acylation, amidation, trifluoromethylation,
amination, azidation, nitration, halogenation, silylation and
borylation. Generally, these reactions require toxic heavy
metal salts or expensive transition metal catalysts such as Rh,
Ru, Pt and Pd. Literature searches on pyridine directed
arylthiolation on arene ring revealed only few reports where
the reactions were accomplished using Pd and Rh metal
N
S
Cl
S
O
H2N
N
N
Ar
S
H
O
O
O
(2)
(1)
Ar = 4-benzoyl-L-glutamate
N
H
dihydrofolate reductase
(DHFR) inhibitors or antifolate
EP3 receptor antagonist
Cl
Cl
NO2
S
O
S
NH2
N
6
A
B
C
catalysts (Scheme 1).
N
Scheme 1: Various reagents for arylthiolation of 2-phenyl
pyridines
O
(3)
(4)
Diaryl Sulfides (3) and (4) as LFA-1/ICAM-1 Antagonists
Figure 1. Selected examples of biologically active arylthiolated
molecules
C-S bond formation, thus, holds immense importance from
the perspective of organic synthesis. Traditional approach for
synthesizing highly functionalized aryl sulfide scaffolds
involves transition metal catalyzed cross-coupling of aryl
2
halides with aryl thiols as coupling partners. Though the
reaction provides access to variety of aryl sulfides bearing
various functional groups, need for pre-functionalizing arenes
in the form of aryl halides limits its use. To overcome this
challenge, chemistry involving C-H bond functionalization of
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Page 2 of 9
Previous work
A) Pd catalyst
(B) Rh catalyst (C) Cu catalyst
(
1a) (1.0 equiv) with S-phenyl benzenesulfonothioate (2a) (1.5
(
o
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
equiv) and water as solvent at 120 C. However, we could not
observe any traces of desired product and decided to modify
the reaction conditions. The same reaction was performed in
oxidant, Ligand
Ag cocatalyst
oxidant
solvent
oxidant
solvent
or
Lewis acid, solvent
O
ArSSAr or
O
S
or
N
Ph
N
Ar
N
2
presence of Cu(OAc) under solvent free conditions. As
H
ArSSAr
PhSH
desired, 2-(4-methyl-2-(phenylthio)phenyl)pyridine (3a) was
obtained in 73% yield. Pleased with the finding, we decided to
optimize the reaction further. Screening of solvents such as
dioxane, toluene and chlorobenzene decreased the yield to
52%, 47% and 64% respectively (Table 1, entries 2-4). In
polar solvents such as DMF, water and THF, either the
product did not form or formed in trace amounts. Hence, neat
conditions were used for further optimization. Replacing
Cu(OAc) with Pd(OAc) or other copper catalysts such as
2 2
Cu(OTf) CuO and CuI (entry 5 ) was detrimental for the
reaction. The reaction quenched under oxidative conditions in
presence of K S O and O (entry 6 ), while the yield
2 2 8 2
enhanced to 89% under inert atmosphere (entry 7). Decreasing
the amount of Cu(OAc) to 0.5 equiv and 0.75 equiv lowered
the yield to 30% and 65% respectively, while increasing it to
1
side products (entry 8 ). We noticed that decreasing the
amount of PhSO SPh to 1.0 equiv lowered the yield (entry 9).
The reaction was monitored at different time intervals of 2 h, 4
h, 6 h, and gave the products in 35%, 71% and 89% yields
respectively (entry 10 ). Further, lowering the temperature to
1
H
(40% yield)
SAr
R
N
SAr
R
O
Our work
N
N
Cu(OAc)2, ArSO2SAr
Ligand free! Oxidant free! Solvent free!
SAr
H
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
(72-89%)
In Pd catalyzed arylthiolation of 2-arylpyridines, reagents such
6a,6b
6c
as diaryldisulfides,
N-arylthiobenzamides
and N-
b-e
6d
(
Arylthio)i(a)mides have been employed while Rh catalyzed
2,
6
e
arylthioation has been achieved only with diaryldisulfides as
arylthiolating reagent. With an economical catalyst such as
copper acetate, there is only one report on phenylthiolation of
f-g
7
a
2
-phenyl pyridine by Yu and co-workers wherein through
one example they have demonstrated synthesis of 2-(2-
phenylthio)phenyl)pyridine (40% yield) using foul smelling
thiophenol as the thiolating reagent. With carbazole as
substrate, Cu(OAc) –promoted directed arylthiolation has
been reported using diaryldisulfides with prolonged heating
2
.5 equiv also gave reduced yield of 72% due to formation of
(
i-k
2
2
48 h) at 160 C. For methylthiolation, Qing and co-workers8
o
7b
(
m-o
disclosed CuF −K mediated reaction of 2-
a
2
2 2 8
S O
o
o
00 C or increasing it to140 C resulted in reduced product
phenylpyridinesusing DMSO as the methylthiolating reagent.
Though useful, the method employs harsh conditions, large
excess of CuF (4.0 equiv) and strong oxidant K S O (2.0
2 2 2 8
p-q
yields (entry 11 ).
Table 1. Optimization of the reaction conditions
a
equiv). Following this, in 2015, our group had demonstrated
methylthiolation with DMSO under milder conditions using
N
N
9
Cu(OAc)2 , PhSO SPh(2a)
SPh
copper acetate (1.0 equiv) and air. While these copper assisted
2
reactions proceeded smoothly with dimethyl sulfoxide
yielding methylthiolated products, the reactions failed to
furnish the corresponding phenylthiolated derivatives with
diphenyl sulfoxide. In view of the limited number of available
arylthiolating reagents, there is a pressing need for developing
efficient, cleaner and odourless arylthio transfer reagents. In a
recent report, Wang et al. reported CuI catalyzed azide–alkyne
(1a)
(3a)
S. No.
Solvent
Time (h)
% Yield 3a
1
2
3
4
5
6
7
8
9
-
12
12
12
12
12
12
12
12
12
-
73
52
47
Dioxane
cycloaddition
(CuAAC)
reaction
using
S-methyl
Toluene
benzenesulfonothioate as a methylthio group transfer reagent
1
0
during one pot synthesis of 5-methylthiotriazoles. The
reagent enabled efficient thiomethylation with sulfinate as a
leaving group. Following this, there was another report by
Adimurthy et al. wherein they used S-arylsulfonothioate to
achieve arylthiolation of activated C-H bond of heteroarenes
Chlorobenzene
64
(-)b-d, tracee
-
-
-
-
-
-
-
f
g
(-) , (-)
89h
11
with elimination of sulfinic acid as the leaving group.
30i
65j
72k
,
,
However, use of this reagent in context of directing group
assisted C-H bond arylthiolation does not exist. In view of the
above literature and continuing our search towards copper
assisted economic C-H functionalization pathways, we
embarked upon the present study. We report for the first time
the use of S-aryl arenesulfonothioate as an efficient and
ordourless reagent for carrying out arylthiolation of ortho C-H
bond of 2-aryl pyridines in the presence of copper acetate. The
methodology also allows facile access to arylthioated indole
and imidazopyridine derivatives.
72l
m
n
o
1
0
35 ,71 , 89
p
q
11
6
56
, 62
aReaction conditions: 2-ptolPy (1a) (0.1 mmol, 1 equiv), PhSO
2
SPh (2a)
o
(0.15 mmol, 1.5 equiv), Cu(OAc)
2
(0.1 mmol, 1equiv), 120 C, 12h.
b
Pd(OAc)2, Cu(OTf)2, CuO, eCuI, K S O , O2, N2, 0.5 equiv
c
d
f
g
h
i
2
2
8
j
k
l
2 2 2
Cu(OAc) , 0.75 equiv Cu(OAc) , 1.5 equiv Cu(OAc) , 1.0 equiv
PhSO SPh, 2 h, 4 h, 6 h, 100 C, 140 C.
2
m
n
o
p
o
q
o
A comparative analysis of 2a with other known thiolating
reagents such as PhSSPh, PhSH, PhSO Na, PhSO Cl, PhSOPh
and PhSO SNa was done as shown in table 2. It was found that
RESULTS AND DISCUSSION
2
2
We initiated the work by using reaction conditions of
Adimurthy’s report for arylthiolation on 2-(p-tolyl)pyridine
2
under the optimized reaction conditions; only PhSSPh and
2
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PhSH gave the phenylthiolated product 3a, albeit in lower
yields (52% and 30% respectively).
sulfonothioate reagent is not only the first report of its kind but
also provides a highly efficient and cost effective method by
1
2
3
4
5
6
7
8
9
employing Cu(OAc)
with other arylthiolating reagents.
Copper catalyzed arylthioation
imidazopyridines with aryl iodides using unsymmetrical
benzothiazolyl-containing disulfides, arene sulfinates,
diaryldisulfides and sulfur powder has been reported
previously. We decided to explore our condition for
arylthiolation of N-methyl indole (4a) (Scheme 3). It was
2
instead of Pd or Rh reported previously
Table 2. Optimisation with different arylthiolating
reagents
of
indoles12 and
1
3
N
Cu(OAc)2 (0.1 mmol), 120 o
C
N
S
6h, N2
SPh
(1a) (0.1 mmol)
(0.15 mmol)
(3a)
O
S
O
S
O
S
O
S
O
Na
S
Cl
S
S
S
O Na
O
S
O
S
SH
O
%
Yield of 3a
89
52
30
-
trace
-
trace
2 3
found that the reaction worked only in presence of K CO and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
desired phenylthiolated product (5a) was formed in 79% yield.
With 1,2-dimethyl-indole, 1,2-dimethyl-3-(phenylthio)-1H-
indole (5b) was obtained confirming the position of
phenylthioation at C-3. While electron donating methoxy
group at 5-position of indole gave 5-methoxy-1-methyl-3-
(phenylthio)-1H-indole (5c) in 84% yield; 5,6 difluoro
substitution resulted in lower yield (67%) of product 5d. 5-
chloro and 5-iodo-substituted indole derivatives gave
corresponding products 5e and 5f in moderate yields. Presence
of nitro substituent resulted in complete inhibition of the
reaction, and no product was formed. Changing N-methyl to
N-ethyl indole did not affect the reaction, and 5h was obtained
in 80% yield. Arylthiolating reagents substituted with electron
donating methoxy group (2b) and electron withdrawing chloro
group (2c) at 4-position furnished the corresponding
arylthiolated products 5i and 5j in 78% and 74% yields
respectively.
Convinced with the above findings, the scope of the
reactionwas explored next. Various 2-phenypyridines
substituted with electron donating as well as electron
withdrawing groups were examined (Scheme 2).
Scheme 2. Substrate scope with 2-arylpyridinesa
N
Cu(OAc)2 , ArSO2SAr (2)
Ar/
HetAr
N
Ar/
HetAr
120 oC, 6h
H
SAr
1
3
Ar = Ph, p-OMePh, p-ClPh
N
N
N
N
SPh
SPh
SPh
BnO
SPh
Et
3b (85%)
CF3
3a (89%)
3c (88%)
3d (75%)
Scheme 3. Arylthiolation of N-alkyl Indolesa
N
SPh
N
S
Ar
O2N
SPh
N
O
Cu(OAc)2,
ArSO2SAr (2)
K2CO3, 120 oC, 6h
N
R = Me, Et
SPh
X
N
X
R
X = H, 5-OMe, 5,6-diF, 5-Cl, 5-I, 5-NO2
Ar = Ph, 4-ClPh, 4-OMePh
3e (72%)
3f (84%)
3g (82%)
4
R
5
N
N
S
N
SPh
SPh
SPh
SPh
SPh
N
N
S
OMe
F
Cl
SPh
N
N
N
F
N
N
OMe
Cl
5a (79%)
5b (82%)
5c (84%)
5d (67%)
5e (73%)
3h (78%)
3i (74%)
3j (72%)
a
Reaction conditions: 2-ArPy (0.25 mmol), ArSO
2
SAr (0.375 mmol),
OMe
Cl
o
SPh
SPh
SPh
S
S
2 2
Cu(OAc) (0.25 mmol), 120 C, 6 h, N .
I
O2N
N
N
N
N
N
2
-phenylpyridine substituted with 4-methyl, 4-ethyl and 2-
benzyloxy substituents gave the phenylthiolated products 3a-
c in 89%, 85% and 88% yields respectively. With electron
Et
5h (80%)
5f (78%)
5g (0%)
5i (78%)
5j (74%)
aReaction conditions: N-alkyl Indole (0.25 mmol,1.0 equiv), ArSO
3
0.375 mmol, 1.5 equiv), Cu(OAc) (0.25 mmol, 1.0 equiv), K CO (0.25
SAr
2
3
(
2
2
o
withdrawing trifluoromethyl and nitro groups, the
corresponding products 3d and 3e were obtained in slightly
lower yields. The reaction was equally facile with 2-
naphthylpyridine. Coupling occurred at the less hindered
position to give the product 3f selectively. 2-benzofuranyl
pyridine (1g) and 2-benzimidazole pyridine (1h) yielded 3g
and 3h in 82% and 78% yields respectively. Substitution in
arylthiolating reagent at 4-position with electron donating
2
mmol, 1.0 equiv) 120 C, 6 h, N .
The reaction was further examined on 2-arylimidazopyridines
(Scheme 4). Arylthiolation took place at C-3 position and
arylthioated products 7a-7i formed in moderate to good yields.
Reaction of 2-phenylimidazo[1,2-a]pyridine (6a) afforded 2-
phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7a) in 87%
yield. Imidazopyridines substituted with 4-methyl, 2, 4
dimethyl, 4-methoxy and 4-ethoxy groups on 2-phenyl ring
gave the corresponding products 7b-7e in 82-89% yield.
methoxy
methoxybenzenesulfonothioate,
withdrawing chloro group
chlorobenzenesulfonothioate,
group
[S-(4-methoxyphenyl)
4-
electron
(2b)], and
[S-(4-chlorophenyl)
(2c)] furnished
4-
the
Notably,
the
yield
of
2-(2,4-dimethylphenyl)-3-
(phenylthio)imidazo[1,2-a]pyridine (7c) was not much
effected by the steric effect of methyl group at ortho position
in 2-(2,4-dimethylphenyl)imidazo[1,2-a]pyridine (6c). The
halo substituted derivatives showed an electronic dependence,
and gave the corresponding arylthioated products 7f, 7g and
corresponding arylthiolated products 3i and 3j in 74% and
2% yields respectively. The reaction was also carried out on
7
gram-scale starting from 1.0 g of 1a, and yielded 3a in 78%
yield (1.27 g). Notably, arylthiolation of 2-arylpyridines with
3
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7
h in 68%, 73% and 70% yields respectively due to electronic
mechanism has been proposed (see Figure S1 in the
Supporting information).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
withdrawing effect of halo groups. 4-chloro substitution in
arylthiolating reagent (2c) also yielded the product 7i in 77%
yield.
Scheme 4. Arylthiolation of 2-arylimidazopyridinesa
SAr
N
N
In summary, we report S-aryl arenesulfonothioate as an
efficient, clean and ordourless reagent to achieve
regioselective ortho-arylthiolation of 2-phenylpyridines in the
Cu(OAc)2, ArSO2SAr (2)
N
6
R1
K2CO3, 120 oC, 6h
R
N
7
R1
R
R = H, Me
R1 = 4-Me, 2,5-diMe, 4-OMe, 4-OEt, 4-F, 3-Br
2
presence of Cu(OAc) . This method shows high generality and
SPh
SPh
SPh
N
selectivity, and yields only monoarylthiolated products in
good yields. The conditions are quite versatile and allow
access to C-3 arylthiolated indoles and imidazopyridines as
well. Mechanistic investigations suggest involvement of both
the thiol parts of the reagent in arylthio transfer after
complexation with copper, though to different extents.
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
N
7a (87%)
7b (89%)
7c (85%)
SPh
SPh
SPh
N
N
N
OMe
OEt
F
N
N
N
7d (82%)
7e (88%)
7f (68%)
Experimental section
General Information
Cl
SPh
SPh
Br
S
N
N
N
All reagents and solvents were of pure analytical grade. Thin
layer chromatography (TLC) was performed on 60 F254 silica
gel, pre-coated on aluminum plates and revealed with either a
UV lamp (λ max= 254 nm) or iodine vapors. The products
were purified by column chromatography on silica gel
Cl
Ph
N
N
N
7g (73%)
7h (70%)
7i (77%)
aReaction conditions: 2-arylimidazopyridine (0.25 mmol, 1.0 equiv),
ArSO
K
2
SAr (0.375 mmol, 1.5 equiv), Cu(OAc)
3 2
CO (0.25 mmol, 1.0 equiv) 120 C, 6 h, N .
2
(0.25 mmol, 1.0 equiv),
o
2
1
19
13
230−400 mesh. H, F, and C{H} NMR spectra were
1
19
13
recorded on a 300 MHz ( H 300 MHz, F 282 MHz, C 75
MHz) and 400 and 500 MHz spectrometer ( H 400 MHz and
Scheme 5. Control experiments
1
Cu(OAc)2 , PhSO2SPh
(1)
1a
3a (87%)
500 resp) using CDCl as the solvent with tetramethylsilane
TEMPO (2 equiv)
20 oC, 6h
3
1
(TMS) as the internal standard at room temperature. Chemical
Cu(OAc)2 ,K2CO3, PhSO2SPh
TEMPO (2 equiv)
shifts are in δ (ppm) relative to TMS. The coupling constants
(J) are in Hz. High resolution mass spectra (HRMS) were
(2)
4a
5a (79%)
20 oC, 6h
1
recorded on
a
mass spectrometer using electrospray
Cu(OAc)2 , p-TolSO2SPh (2d)
(3)
N
120 oC, 6h
N
N
ionization-time-of- flight (ESI-TOF) reflectron experiments.
SPh
S(p-Tol)
3f'(17%)
1f
3f (68%)
All starting materials (1, 2, 4 and 6) are known compounds,
Cu(OAc)2
(4) p-TolSO2SPh
PhS-CuOAc
A)
p-TolSO2-CuOAc
and were synthesized using reported procedures. 2-aryl
(
(B)
14
15
pyridines (1a-1h) , S-aryl arenethiosulfonates (2a-2d), and
Mol. mass 232.1
by GCMS
Mol. mass 278.1
by GCMS
16
N-protected indoles (4a-4h) were synthesized following
Some mechanistic studies were carried out to understand the
reaction pathway. Reaction of 1a as well as 4a with 2a in
presence of 2.0 equivalents of TEMPO gave 3a and 5a in 87%
and 79% yields respectively [Scheme 5(1-2)], ruling out the
possibility of radical intermediates in the reaction. To check
which part of the reagent was involved in delivering
phenylthio group in the product, the reaction of 2-(naphthalen-
reported synthetic procedures. 2-arylimidazopyridines (6a,
1
7
18
6b, 6g) and (6c-6f, 6h) were prepared using by two
different methods reported previously.
General experimental procedure for arylthiolation of 2-
arylpyridines (3a-3j)
2
-arylpyridine (1a) (0.25 mmol, 1.0 equiv), S-phenyl
benzenethiosulfonate (0.375 mmol, 1.5 equiv) and Cu(OAc)
0.25 mmol, 1.0 equiv) were added in a 10 ml tube sealed with
2
2
-yl)pyridine (1f) was carried out with mixed reagent, S-
(
phenyl 4-methylbenzenesulfonothioate (2d). Interestingly, it
was found that a mixture of arylthiolated products (3f and 3f')
was obtained in the ratio 4:1, suggesting transfer of arylthio
a Teflon-lined cap and flushed with nitrogen. The contents
o
were heated for 6 h at 120 C in oil bath. The reaction was
monitored by TLC, after 6 h the reaction was completed. The
contents were extracted with ethyl acetate, dried over
anhydrous sodium sulfate, and concentrated at reduced
pressure. The product was purified through the column
chromatography on silica gel using hexane: EtOAc to give the
corresponding arylthiolated products.
2
unit from both SPh and p-TolSO motifs during the course of
reaction [Scheme 5(3)]. The differential reactivity of the two
can be explained in terms of the stability of their respective
copper intermediates A and B as shown in scheme 5 (4).
Apparently, intermediate A is more reactive and undergoes
faster kinetics owing to its lower stability than intermediate B,
as indicated by their ratio in the GC-MS of the reaction
mixture. Similar heterogeneity is reflected in the product
distribution of 1f with 3d. (see the Supporting information).
The transfer of both the thiol groups at the ortho-position
albeit in differential reactivity was the rationale behind
choosing symmetrical reagents to get one single compound in
high yield. On the basis of these observations, a plausible
General experimental procedure for arylthiolation of N-
alkyl indoles (5a-5j)
N-methylindole (4a) (0.25 mmol, 1.0 equiv), S-phenyl
benzenethiosulfonate (0.375 mmol, 1.5 equiv), K
2 3
CO (0.25
mmol, 1.0 equiv) and Cu(OAc) (0.25 mmol, 1.0 equiv) were
2
added in a 10 mL tube sealed with a Teflon-lined cap and
flushed with nitrogen. The contents were heated for 6 h at 120
4
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The Journal of Organic Chemistry
°C in oil bath. The reaction was monitored by TLC, after 6 h
7.81-7.76 (m, 1H), 7.64-7.60 (m, 2H), 7.52-7.49 (m, 1H),
7.39-7.35 (m, 3H), 7.34-7.33 (m, 2H), 7.32-7.27 (m, 2H);
C{ H} NMR (75 MHz, CDCl ): δ 157.0, 149.3, 143.4, ,
3
1
2
3
4
5
6
7
8
9
the reaction was completed. The contents were extracted with
ethyl acetate, dried over anhydrous sodium sulfate, and
concentrated at reduced pressure. The product was purified
through the column chromatography on silica gel using
hexane: EtOAc to give the corresponding arylthiolated
products.
1
3
1
138.0, 136.3, 133.6, 133.1, 131.0 (q, J = 32.5 Hz), 130.6,
129.6, 128.3, 126.8 q (J = 3.8 Hz), 124.1, 123.7 (q, J = 270
+
Hz), 122.8 q (J = 3.8 Hz), 122.8; MS (ESI) m/z 332 [M+H] ;
+
HRMS calcd. for C18
H
13
F
3
NS 332.0715; Found: 332.0717.
+
[M + H] .
General experimental procedure for arylthiolation of 2-
arylimidazopyridines (7a-7h)
2-(2-nitro-6-(phenylthio)phenyl)pyridine (3e):
2
-phenylimidazopyridine (6a) (0.25 mmol, 1.0 equiv), S-
phenyl benzenethiosulfonate (0.375 mmol, 1.5 equiv), K CO
0.25 mmol, 1.0 equiv) and Cu(OAc) (0.25 mmol, 1.0 equiv)
New, Isolated as colorless oil in Hexane/EtOAc (94/6), yield
1
72% (56 mg), R
MHz, CDCl
(d, J = 8Hz, 1H), 7.33-7.29 (m, 4H), 7.28-7.27 (m, 2H), 7.19-
f
= 0.58 (20% EtOAc/Hexane); H NMR (400
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
(
2
3
): δ 8.63-8.62 (m, 1H), 7.76-7.69 (m, 2H), 7.42
were added in a 10 mL tube sealed with a Teflon-lined cap and
flushed with nitrogen. The contents were heated for 6 h at 120
1
3
1
3
7.17 (m, 2H); C{ H} NMR (75 MHz, CDCl ): δ 154.11,
°
C in oil bath. The reaction was monitored by TLC, after 6 h
149.84, 141.15, 136.33, 134.0, 133.4, 133.88, 132.99, 132.55,
the reaction was completed. The contents were extracted with
ethyl acetate, dried over anhydrous sodium sulfate, and
concentrated at reduced pressure. The product was purified
through the column chromatography on silica gel using
hexane: EtOAc to give the corresponding arylthiolated
products.
129.77, 129.04, 128.83, 124.72, 123.13, 121.67. MS (ESI) m/z
+
+
13 2 2
309 [M+H] ; HRMS calcd. for C17H N O S 309.0692;
+
Found: 309.0696. [M + H] .
-(3-(phenylthio)naphthalen-2-yl)pyridine (3f):19
2
Isolated as colorless oil in Hexane/EtOAc (96/4), yield 84%
1
(
1
66 mg); H NMR (300 MHz, CDCl
H), 8.0 (s, 1H), 7.86-7.83 (m, 1H), 7.76-7.70 (m, 2H), 7.66-
7.64 (m, 2H), 7.48-7.44 (m, 2H), 7.33-7.32 (m, 1H), 7.30 (t, J
3
): δ 8.71 (d, J = 6.8 Hz,
Characterization data of synthesized compounds:
2
-(4-methyl-2-(phenylthio)phenyl)pyridine (3a):19
13
1
=
2.1 Hz, 1H), 7.29-7.27 (m, 1H), 7.25-7.20 (m, 3H); C{ H}
NMR (75 MHz, CDCl ): δ 158.3, 149.0, 139.2, 135.9, 135.6,
133.4, 133.2, 132.1, 132.0, 130.6, 130.0, 129.2, 128.0, 127.3,
27.0, 126.9, 126.4, 124.5, 122.2; MS (ESI) m/z 314 [M+H] ;
HRMS calcd.for C21
Isolated as colorless oil in Hexane/EtOAc (96/4), yield 89%
1
3
(
62 mg); H NMR (500 MHz, CDCl
3
): δ 8.67 (d, J = 5.0 Hz,
1
H), 7.69-7.67 (m, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.45 (d, J =
+
1
8.0 Hz, 1H), 7.28-7.26 (m, 2H), 7.25-7.23 (m, 2H), 7.21-7.18
+
H
16NS 314.0998; Found: 314.1000. [M +
(m, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 2.29 (s, 3H);
+
1
3
1
H] .
3
C{ H} NMR (75 MHz, CDCl ): δ 158.3, 149.0, 139.1, 139.0,
1
1
36.2, 135.8, 134.4, 132.6, 131.4, 130.4, 129.1, 128.0, 126.9,
(2-(3-(phenylthio)naphthalen-2-yl)pyridine
&
2-(3-(p-
+
24.3, 121.9, 21.1; MS (ESI) m/z 278 [M+H] ; HRMS calcd.
tolylthio)naphthalen-2-yl)pyridine) (3f & 3f'):
+
+
for C18H16NS 278.0998; Found: 278.1002 [M + H] .
Isolated as colorless oil in Hexane/EtOAc (96/4), (yield) 85%;
-(4-ethyl-2-(phenylthio)phenyl)pyridine (3b):20
1
2
3
H NMR (400 MHz, CDCl ): δ 8.73 (s, 1H), 8.705 (d, J = 4.0
Hz, 1H), 7.99 (s, 4H), 7.96 (s, 1H), 7.85-7.83 (m, 6H), 7.75-
7.74 (m, 4H), 7.73-7.71 (m, 6H), 7.68-7.64 (m, 1H), 7.56 (s,
Isolated as colorless oil in Hexane/EtOAc (96/4), Colorless
1
oil, yield 85% (62 mg); H NMR (300 MHz, CDCl
3
): δ 8.60-
1
5
3
H), 7.46-7.41 (m, 11H), 7.33-7.29 (m, 10H), 7.27-7.26 (m,
8
.58 (m, 1H), 7.63-7.58 (m, 1H), 7.50-7.46 (m, 1H), 7.40 (d, J
H), 7.24-7.23 (m, 10H), 7.11 (d, J = 8.0 Hz, 2H), 2.34 (s,
=
7.8 Hz, 1H), 7.21-7.18 (m, 3H), 7.17-7.16 (m, 1H), 7.15-
13
1
3
H); C{ H} NMR (125 MHz, CDCl ): δ 158.3, 158.2,
7
.14 (m, 1H), 7.14-7.12 (m, 1H), 7.11-7.10 (m, 1H), 7.08-7.06
1
3
1
149.0, 139.2, 138.6, 137.9, 136.0, 135.9, 135.6, 133.4, 133.2,
33.16, 132.1, 132.0, 130.6, 130.1, 129.9, 129.6, 129.4, 129.2,
(
m, 1H), (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H); C{ H}
NMR (100 MHz, CDCl ): δ 158.3, 149.0, 145.3, 139.3, 136.3,
35.8, 134.3, 131.6, 131.3, 130.5, 129.1, 126.9, 126.8, 124.3,
1
3
128.9, 128.0, 128.97, 127.3, 127.0, 126.9, 126.86, 126.7,
1
+
126.3, 126.0, 124.5, 122.2, 122.15, 21.2; MS (ESI) (3f) m/z
1
21.9; MS (ESI) m/z 292 [M+H] ; HRMS calcd. for
+
+
+
+
314 [M+H] ; HRMS calcd.for C21
H
16NS 314.0998; Found:
C
19
H18NS 292.1154; Found: 292.1141. [M + H] .
+
+
3
14.1000. [M + H] ; MS (ESI) (3f') m/z 328 [M+H] ; HRMS
calcd.for C22H18NS 328.1154; Found: 328.1145. [M + H] .
2
-(2-(benzyloxy)-6-(phenylthio)phenyl)pyridine (3c):
+
+
New, Isolated as colorless oil in Hexane/EtOAc (94/6), yield
2-(3-(phenylthio)dibenzo[b,d]furan-4-yl)pyridine (3g):
1
8
8% (81 mg), R
MHz, CDCl ): δ 8.73 (d, J = 4.5 Hz, 1H), 7.73-7.69 (m, 1H),
.39 (d, J = 8.0 Hz, 1H), 7.35-7.33 (m, 2H), 7.28-7.27 (m,
3H), 7.25-7.21 (m, 4H), 7.19-7.16 (m, 3H), 6.87 (d, J = 8.5
f
= 0.68 (20% EtOAc/Hexane) H NMR (500
New, Isolated as colorless oil in Hexane/EtOAc (94/6), yield
3
1
82% (72 mg), R
MHz, CDCl
7.71 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.4 Hz,
f
= 0.61 (20% EtOAc/Hexane); H NMR (400
7
3
): δ 8.74-8.73 (m, 1H), 7.83-7.81 (m, 1H), 7.75-
1
3
1
Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.03 (s, 2H); C{ H}
NMR(75 MHz, CDCl ): δ 156.5, 155.7, 149.2, 138.1, 137.0,
35.8, 135.0, 132.7, 131.1, 129.4, 129.1, 128.3, 127.5, 127.4,
26.6, 125.9, 123.1, 122.2, 111.2, 70.5; MS (ESI) m/z 370
M+H] ; HRMS calcd. for C24H20NOS 370.1260; Found:
70.1260. [M + H] .
-(2-(phenylthio)-4-(trifluoromethyl)phenyl)pyridine (3d):21
1
H), 7.35-7.31(m, 1H), 7.26-7.19 (m, 5H), 7.19-7.11 (m, 3H);
3
1
3
1
3
C{ H} NMR(75 MHz, CDCl ): δ 156.6, 154.4, 153.7, 149.4,
1
1
[
1
36.2, 135.8, 135.0, 131.9, 129.2, 127.4, 127.3, 126.6, 126.3,
+
+
126.0, 123.9, 123.5, 123.0, 122.8, 120.7, 120.6, 112.0; MS
+
+
+
23
(ESI) m/z 354 [M+H] ; HRMS calcd.for C H16NOS
3
3
+
54.0947; Found: 354.0941. [M + H] .
2
2
-(phenylthio)-1-(pyridin-2-yl)-1H-benzo[d]imidazole (3h):
Isolated as yellow solid in Hexane/EtOAc (95/5), yield 75%
1
(
3
62 mg); H NMR (300 MHz, CDCl ): δ 8.74-8.72 (m, 1H),
5
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The Journal of Organic Chemistry
Page 6 of 9
+
+
New, Isolated as brown liquid in Hexane/EtOAc (94/6), yield
270 [M+H] ; HRMS calcd.for C16
H
16NOS 270.0947; Found:
1
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
78% (59 mg), R
MHz, CDCl ): δ 8.66 (d, J = 4.5 Hz, 1H), 7.91 (t, J = 7.5 Hz,
1H), 7.72 (d, J =7.5 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.50-
= 0.63 (40% EtOAc/Hexane); H NMR (500
270.0941. [M + H] .
,6-difluoro-1-methyl-3-(phenylthio)-1H-indole (5d):
New, Isolated as yellow oil in Hexane/EtOAc (96/4), yield
f
3
5
7
1
.48 (m, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 6.5 Hz,
1
6
7% (46 mg), R
f
= 0.62 (10% EtOAc/Hexane); H NMR (400
H), 7.31-7.28 (m, 3H), 7.27-7.26 (m, 1H), 7.24-7.23 (m, 1H).
MHz, CDCl ): δ 7.34 (s, 1H), 7.31-7.29 (m, 1H), 7.19-7.12
m, 3H), 7.08-7.05 (m, 3H), 3.79 (s, 3H); C{ H} NMR(75
MHz, CDCl ) : δ 148.6 (dd, J = 241.1), 147.21 (dd, J = 238.6),
3
138.9 , 136.2 (d, J = 3.2 Hz), 132.6 (d, J = 10 Hz), 128.8,
25.8, 125.2 (J = 7.6 Hz), 125.0, 106.5 (J = 18.9 Hz), 101.2 ,
8.0 (d, J = 20.5), 33.5; MS (ESI) m/z 276 [M+H] ; HRMS
12 2
calcd.for C15H F NS 276.0653; Found: 276.0648. [M + H] .
-chloro-1-methyl-3-(phenylthio)-1H-indole (5e):24
3
1
3
1
C{ H} NMR (75 MHz, CDCl
3
): δ 149.5, 149.2, 143.5, 138.7,
13
1
(
1
1
C
35.7, 132.8, 130.8, 129.3, 128.5, 123.5, 123.2, 123.1, 120.2,
+
19.5, 110.5; MS (ESI) m/z 304 [M+H] ; HRMS calcd.for
+
+
18 14 3
H N S 304.0903; Found: 304.0916. [M+H] .
1
2
-(2-((4-methoxyphenyl)thio)-4-methylphenyl)pyridine (3i):
+
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
New, Isolated as colorless oil in Hexane/EtOAc (96/4), yield
1
7
4% (57 mg), R
MHz, CDCl ): δ 8.71-8.70 (m, 1H), 7.76-7.71 (m, 1H), 7.60-
.57 (m, 1H), 7.39-7.31 (m, 3H), 7.25-7.22 (m, 1H), 7.05-7.02
m, 1H), 6.88-6.84 (m, 3H), 3.81 (s, 3H), 2.24 (s, 3H);
f
= 0.61 (20% EtOAc/Hexane); H NMR (300
5
3
Isolated as white solid in Hexane/EtOAc (96/4), yield 73% (49
mg); H NMR (400 MHz, CDCl
s, 1H), 7.30-7.28 (m, 1H), 7.25-7.24 (m, 1H), 7.22-7.19 (m,
H), 7.16-7.15 (m, 2H), 7.08-7.04 (m, 2H), 3.84 (s, 3H);
C{ H} NMR (75 MHz, CDCl
28.8, 126.7, 125.8, 124.9, 123.0, 119.2, 110.9, 100.5, 33.4;
MS (ESI) m/z 274 [M+H] ; HRMS calcd.for C15H13ClNS
74.0452; Found: 274.0457. [M + H] .
7
1
3
): δ 7.58-7.57 (m, 1H), 7.35
(
(
13
1
C{ H} NMR(100 MHz, CDCl
3
): δ 159.7, 158.4, 149.0,
1
1
38.8, 137.2, 137.0, 136.0, 135.6, 130.0, 129.6, 126.6, 125.0,
1
3
1
3
): δ 139.2, 136.3, 136.0, 131.0,
+
124.2, 122.0, 114.9, 55.3, 21.3; MS (ESI) m/z 308 [M+H] ;
HRMS calcd.for C19
+ H] .
1
+
H
18NOS 308.1104; Found: 308.1117. [M
+
+
+
+
2
2-(2-((4-chlorophenyl) thio)-4-methylphenyl)pyridine (3j):
5
-iodo-1-methyl-3-(phenylthio)-1H-indole (5f):25
New, Isolated as colorless oil in Hexane/EtOAc (96/4), yield
Isolated as yellow oil in Hexane/EtOAc (96/4), yield 78% (71
mg); H NMR (300 MHz, CDCl
m, 1H), 7.25-7.24 (m, 1H), 7.19-7.12 (m, 3H), 7.08-7.05 (m,
H), 3.80 (s, 3H); C{ H} NMR (75 MHz, CDCl
36.7, 135.8, 132.3, 131.1, 128.8, 128.5, 125.7, 124.9, 111.8,
00.1, 84.5, 33.3; MS (ESI) m/z 365 [M+H] ;HRMS calcd.for
15
H13INS 365.9808; Found: 365.9801. [M+H] .
1
7
2% (56 mg), R
f
= 0.56 (10% EtOAc/Hexane); H NMR
1
3
): δ 7.94 (s, 1H), 7.54-7.51
(500 MHz, CDCl
3
): δ 8.66 (d, J = 5.0 Hz, 1H), 7.71-7.68 (m,
(
1H), 7.53 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.24-
1
3
1
3
1
1
C
3
): δ 139.2,
7
1
1
1
.21 (m, 2H), 7.19-7.17 (m, 3H), 7.167-7.15 (m, 1H), 7.10 (s,
H), 2.31 (s, 3H); C{ H} NMR(75 MHz, CDCl ): δ 158.2,
3
49.0, 139.2, 135.9, 134.9, 133.9, 132.9, 132.6, 132.5, 132.2,
1
3
1
+
+
30.4, 129.2, 128.3, 124.2, 122.0, 21.5; MS (ESI) m/z 312
+
+
1-ethyl-3-(phenylthio)-1H-indole (5h):
[M+H] ; HRMS calcd.for C18H15ClNS 312. 0608; Found:
+
3
12. 0620. [M + H] .
-methyl-3-(phenylthio)-1H-indole (5a):22
Isolated as colorless oil in Hexane/EtOAc (96/4), yield 80%
(51 mg); H NMR (400 MHz, CDCl ): δ 7.52 (d, J = 7.6 Hz,
H), 7.29-7.27 (m, 2H), 7.18-7.15 (m, 1H), 7.06-7.00 (m, 5H),
.94-6.92 (m, 1H), 4.06 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 6.8
Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ 139.6, 136.5,
3
133.2, 129.8, 128.5, 125.5, 124.4, 122.3, 120.3, 119.7, 109.7,
100.3, 41.1, 15.2; MS (ESI) m/z 254 [M+H] ; HRMS calcd.for
C H16NS 254.0998; Found: 254.0992. [M + H] .
16
1
1
3
1
6
Isolated as colorless oil in Hexane/EtOAc (96/4), yield 79%
1
(
1
47 mg); H NMR (400 MHz, CDCl
H), 7.38 (d, J = 8.1 Hz, 1H), 7.33-7.27 (m, 2H), 7.18-7.13
m, 3H), 7.10-7.08 (m, 2H), 7.05-7.02 (m, 1H), 3.84 (s, 3H).
3
), δ 7.61 (d, J = 7.7 Hz,
13
1
(
+
1
3
1
C{ H} NMR (75 MHz, CDCl
3
) δ 139.7, 137.6, 135.1, 129.9,
+
+
1
28.7, 125.7, 124.67, 122.6, 120.5, 119.8, 109.7, 100.6, 33.2.
3-((4-methoxyphenyl)thio)-1-methyl-1H-indole (5i):26
+
+
MS (ESI) m/z 262 [M+Na] ; HRMS calcd.for C15
262.0661; Found: 262.0655. [M +Na] .
H
13NNaS
+
Isolated as white solid in Hexane/EtOAc (95/5), White solid,
yield 78% (52 mg); H NMR (300 MHz, CDCl ): δ 7.54 (d, J
= 7.8 Hz, 1H), 7.23 (s, 1H), 7.20-7.17 (m, 2H), 7.15-7.08 (m,
1H), 7.06-7.01 (m, 2H), 6.65-6.61 (m, 2H), 3.67 (s, 3H), 3.60
s, 3H); C{ H} NMR (100 MHz, CDCl
34.6, 130.0, 129.8, 128.4, 122.5, 120.4, 119.7, 114.5, 109.7,
1
,2-dimethyl-3-(phenylthio)-1H-indole (5b):23
1
3
Isolated as colorless oil in Hexane/EtOAc (96/4), yield 82%
1
(
1
52 mg); H NMR (400 MHz, CDCl
H), 7.18 (d, J = 8.0 Hz, 1H), 7.12-7.09 (m, 1H), 7.03-6.99
m, 3H), 6.93-6.89 (m, 3H), 3.55 (m, 3H), 2.35 (s, 3H);
3
): δ 7.47 (d, J = 8.0 Hz,
1
3
1
(
3
): δ 157.8, 137.5,
1
1
C
(
+
02.3, 55.4, 33.1; MS (ESI) m/z 270 [M+H] ; HRMS calcd.for
1
3
1
3
C{ H} NMR(75 MHz, CDCl ): δ 143.0, 140.0, 137.2, 129.8,
+
+
16
H16NOS 270.0947; Found: 270.0949. [M + H] .
128.8, 125.5, 124.5, 121.8, 120.5, 119.0, 109.2, 98.0, 30.4,
3-((4-chlorophenyl)thio)-1-methyl-1H-indole (5j):26
+
+
1
2
1.0; MS (ESI) m/z 253 [M] ; HRMS calcd.for C16
H
15NS
+
53.0920; Found: 253.0916. [M] .
Isolated as white solid in Hexane/EtOAc (96/4), yield 74% (51
mg); H NMR (400 MHz, CDCl
.37 (d, J = 8.4 Hz, 1H), 7.31-7.23 (m, 2H), 7.16 (t, J = 7.6
Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 4.8 Hz, 2H),
.82 (s, 3H); C{ H} NMR (125 MHz, CDCl ): δ 138.3,
3
37.6, 135.1, 130.4, 129.6, 128.7, 127.0, 122.8, 120.7, 119.6,
09.9, 100.1, 33.2; MS (ESI) m/z 274 [M+H] ; HRMS
calcd.for C15H13ClNS 274.0452; Found: 274.0457. [M + H] .
1
5-methoxy-1-methyl-3-(phenylthio)-1H-indole (5c):
3
): δ 7.56 (d, J = 7.6 Hz, 1H),
7
New, Isolated as colorless oil in Hexane/EtOAc (95/5), yield
1
84% (56 mg), R
MHz, CDCl ) δ 7.29-7.27 (m, 2H), 7.17-7.14 (m, 2H), 7.10-
.08 (m, 2H), 7.06-7.04 (m, 2H), 6.95-6.93 (m, 1H), 3.82 (s,
f
= 0.42 (10% EtOAc/Hexane); H NMR (500
1
3
1
3
3
1
7
3
1
1
+
1
1
3
3
H), 3.79 (s, 3H). C{H} NMR (75 MHz, CDCl ) δ 155.06,
+
+
39.82, 135.49, 132.67, 130.67, 128.67, 125.55, 124.60,
13.14, 110.63, 100.90, 99.66, 55.87, 33.31. MS (ESI) m/z
2
-phenyl-3-(phenylthio)imidazo[1,2-a]pyridine (7a):27
6
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Isolated as yellow solid in Hexane/EtOAc (88/12), yield 87% New, Isolated as pale yellow liquid in Hexane/EtOAc (85/15),
1
1
1
2
3
4
5
6
7
8
9
(66 mg); H NMR (400 MHz, CDCl
7.63 (d, J = 8Hz, 1H), 7.35-7.28 (m, 2H), 7.25 (d, J = 7.6 Hz,
1H ), 7.22-7.18 (m, 1H), 7.15-7.07 (m, 2H), 7.03-7.00 (m,
): δ 8.16-8.11 (m, 3H),
yield 57% (86 mg), R
(500 MHz, CDCl ): δ 8.18-8.13 (m, 3H), 7.48 (s, 1H), 7.23-
7.20 (m, 2H), 7.15-7.09 (m, 3H), 6.99-6.97 (m, 2H), 6.72-6.71
f
= 0.59 (30% EtOAc/Hexane); H NMR
3
3
1
3
1
13
1
1
H), 6.90-6.88 (m, 2H), 6.73 (t, J = 6.8 Hz, 1H); C{ H}
NMR(100 MHz, CDCl ): δ 151.4, 147.1, 135.2, 133.2, 129.5,
28.7, 128.5, 126.8, 126.1, 125.6, 124.5, 117.6, 113.2, 106.7;
3
(m, 1H), 2.44 (s, 3H); C{ H} NMR(100 MHz, CDCl ): δ
3
163.03 (d, J = 246.5 Hz), 150.5, 147.5, 138.0, 135.4, 130.1 (d,
J = 8.1Hz), 129.7 (d, J = 3.32 Hz), 129.5, 126.1, 125.5, 123.7,
116.2, 115.7, 115.3 (d, J = 21.44 Hz), 105.2, 21.4; MS (ESI)
1
+
+
15 2
MS (ESI) m/z 303 [M+H] ; HRMS calcd.for C19H N S
+
+
+
3
03.0950; Found: 303.0942. [M + H] .
-(phenylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (7b):28
m/z 335 [M+H] ; HRMS calcd.for C20
H
16FN
2
S 335.1013;
+
Found: 335.1020 [M + H] .
3
2
(7g):
-(4-chlorophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
Isolated as yellow solid in Hexane/EtOAc (88/12), yield 89%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
9
1
(
70 mg); H NMR (300 MHz, CDCl
.12 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.29-7.26
m, 1H), 7.24-7.19 (m, 2H), 7.16-7.14 (m, 2H), 7.11-7.06 (m,
3
): δ 8.23-8.20 (m, 1H),
8
(
Isolated as white solid in Hexane/EtOAc (85/15), yield 73%
(61 mg); H NMR (500 MHz, CDCl ): δ 8.27 (d, J = 6.5 Hz,
3
1
1
3
1
1
C
H), 6.97 (d, J = 7.8 Hz, 2H), 6.78 (t, J = 6.6 Hz, 1H), 2.35 (s,
H); C{ H} NMR (75 MHz, CDCl ) δ 151.5, 147.1, 138.6,
3
1H), 8.17 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 9.0 Hz, 1H), 7.40
(d, J = 8.5 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0
Hz, 2H) 7.14 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 7.5 Hz, 2H),
6.88 (t, J = 7.0 Hz, 1H); C{ H} NMR (125 MHz, CDCl ): δ
3
150.2, 147.1, 134.9, 134.6, 131.9, 129.6, 129.5, 128.7, 127.0,
13
1
35.3, 130.5, 129.4, 129.2, 128.3, 126.6, 125.6, 124.5, 117.5,
+
13
1
13, 106.0, 21.4; MS (ESI) m/z 317 [M+H] ; HRMS calcd.for
+
+
20
H
17
N
2
S 317.1107; Found: 317.1103. [M + H] .
-(2,4-dimethylphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
7c):
New, Isolated as yellow semisolid in Hexane/EtOAc (88/12),
yield 85% (70 mg), R = 0.49 (30% EtOAc/Hexane), mp 87-89
C; H NMR (500 MHz, CDCl ): δ 8.19 (d, J = 6.5 Hz, 1H),
126.2, 125.6, 124.5, 117.7, 113.3, 106.5; MS (ESI) m/z 337
2
(
+
+
[M+H] ; HRMS calcd.for C19
3
H
14ClN
2
S 337.0561; Found:
+
37.0560s [M + H] .
2-(3-bromophenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
f
1
1
o
1
(7h):
3
7.72 (d, J = 9 Hz, 1H), 7.35-7.31 (m, 1H), 7.25 (s, 1H), 7.17 (t,
J = 8.0 Hz, 2H), 7.11-7.09 (m, 2H), 7.00 (d, J = 8.00 Hz, 1H),
Isolated as yellow semisolid in Hexane/EtOAc (85/15), yield
70% (67 mg); H NMR (500 MHz, CDCl ): δ 8.39 (s, 1H),
3
1
1
3
1
6
.90-6.86 (m, 3H), 2.34 (s, 3H), 2.33 (s, 3H); C{ H} NMR
8.29 (d, J = 7.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.74 (d, J =
9.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.38-7.35 (m, 1H), 7.30-
7.27 (m, 1H), 7.23-7.20 (m, 2H), 7.16-7.14 (m, 1H), 6.99 (d, J
(
75 MHz, CDCl ) δ 153.8, 146.9, 138.3, 137.3, 135.5, 131.2,
3
1
1
30.7, 130.1, 129.3, 126.2, 126.0, 125.9, 125.7, 124.6, 117.7,
+
13
1
12.9, 108.1, 21.3, 20.3; MS (ESI) m/z 331 [M+H] ; HRMS
= 7.5 Hz, 2H), 6.92-6.89 (m, 1H); C{ H} NMR (75 MHz,
CDCl ) δ 149.6, 147.1, 135.4, 134.8, 131.5, 131.3, 129.9,
29.5, 127.0, 126.8, 126.3, 125.8, 124.6, 122.6, 117.8, 113.3,
+
+
calcd.for C21
H
19
N
2
S 331.1263; Found: 331.1268. [M + H] .
3
1
2
-(4-methoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
+
2
8
107.1; MS (ESI) m/z 381 [M+H] ; HRMS calcd.for
C
(7d):
+
+
19
H
14BrN
2
S 381.0056; Found: 381.0050 [M + H] .
Isolated as brown semisolid in Hexane/EtOAc (85/15), yield
1
3-((4-chlorophenyl)thio)-2-phenylimidazo[1,2-a]pyridine
8
3
2% (68 mg); H NMR (400 MHz, CDCl ): δ 8.23-8.16 (m,
30
(7i):
3
H), 7.70 (d, J = 7.6 Hz, 1H), 7.31-7.29 (m, 1H), 7.18 (d, J =
5
3
.2 Hz, 2H), 7.11 (s, 1H), 7.11-6.95 (m, 4H), 6.82 (s, 1H),
Isolated as white solid in Hexane/EtOAc (88/12), yield 77%
(65 mg); H NMR (400 MHz, CDCl ): δ 8.24 (d, J = 6.8 Hz,
3
13
1
1
.82 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 160.0, 151.4,
1
1
47.1, 135.4, 129.7, 129.4, 126.6, 126.0, 125.5, 124.4, 117.4,
1H), 8.17 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.46-
7.42 (m, 2H), 7.40-7.32 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H),
6.92-6.86 (m, 3H); C{ H} NMR(100 MHz, CDCl ): δ 151.7,
3
+
13.9, 112.9, 105.5, 55.3; MS (ESI) m/z 333 [M+H] ; HRMS
+
+
13
1
calcd.for C20
H
17
N
2
OS 333.1056; Found: 333.1071. [M + H] .
147.3, 133.8, 133.2, 132.1, 129.6, 128.8, 128.5, 128.4, 128.3,
2
(
-(4-ethoxyphenyl)-3-(phenylthio)imidazo[1,2-a]pyridine
7e):
New, Isolated as yellow semisolid in Hexane/EtOAc (85/15),
yield 88% (76 mg), R = 0.44 (30% EtOAc/Hexane), mp 94-
6 C; H NMR (500 MHz, CDCl ): δ 8.23 (d, J = 6.5 Hz,
+
126.9, 124.4, 117.8, 113.3, 105.7; MS (ESI) m/z 337 [M+H] ;
+
HRMS calcd.for C19
H
14ClN
2
S 337.0561; Found: 337.0567.
+
[M + H] .
f
o
1
ASSOCIATED CONTENT
Supporting Information
9
3
1H), 8.16 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 9.0 Hz, 1H), 7.29 (t,
J = 8.0 Hz, 1H), 7.19 (t, J = 7.5 Hz, 2H), 7.12-7.10 (m, 1H),
Copies of H NMR and 13C NMR of all the synthesized
1
6
7
.99 (d, J = 7.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.82 (t, J =
compounds, GCMS spectra of intermediates A and B, and
plausible reaction mechanism has been provided. The material
is available free of charge on the ACS Publications website.
.0 Hz, 1H), 4.05 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H);
1
3
1
C{ H} NMR(125 MHz, CDCl
3
) : δ 159.4, 151.4, 147.1,
1
1
35.4, 129.7, 129.4, 126.6, 126.0, 125.8, 125.5, 124.4, 117.4,
14.4, 112.9, 105.2, 63.4, 14.9; MS (ESI) m/z 347 [M+H] ;
Corresponding Author
+
+
*E-mail: njain@chemistry.iitd.ac.in
ACKNOWLEDGMENT
HRMS calcd.for C21
H
19
N
2
OS 347.1213; Found: 347.1220. [M
+
+
H] .
-(4-fluorophenyl)-6-methyl-3-(phenylthio)imidazo[1,2-
a]pyridine (7f):
2
P.S. thanks MHRD for her graduate fellowship. The authors
thank DST for project DST/INT/Hun/P-11/2016, and DST-
FIST for funding the ESI-HRMS facility at IIT Delhi.
7
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S.; Singh, V. K.; Maiti, D. Copper-Mediated Thiolation
Page 8 of 9
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