Mild ligand-free Cu0-catalyzed chemoselective S-arylation of 2-mercaptoimidazole at low catalyst loading

Article abstract of DOI:10.1016/j.tet.2016.08.085

A mild method for the Cu⁰-catalyzed chemoselective C[sbnd]S cross-coupling of 2-mercaptoimidazole derivatives with a series of with differently substituted iodobenzenes and iodothiophenes at 100 °C is described. This method proceeds efficiently without ligands and at low catalyst loading (3 mol %), without the need for stringent inert conditions. Under optimized conditions, the S-arylated products were obtained in good yields of up to 90%.

Full text of DOI:10.1016/j.tet.2016.08.085

Accepted Manuscript
0
Mild ligand-free Cu -catalyzed chemoselective S-arylation of 2-mercaptoimidazole at
low catalyst loading
Bryan Yong-Hao Tan, Yong-Chua Teo
PII:
S0040-4020(16)30880-8
10.1016/j.tet.2016.08.085
TET 28066
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 April 2016
Revised Date: 17 August 2016
Accepted Date: 30 August 2016
0
Please cite this article as: Tan BY-H, Teo Y-C, Mild ligand-free Cu -catalyzed chemoselective
S-arylation of 2-mercaptoimidazole at low catalyst loading, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.08.085.
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Graphical Abstract
Mild Ligand-free Cu0-Catalyzed
Chemoselective S-Arylation of 2-
Leave this area blank for abstract info.
Mercaptoimidazole at Low Catalyst Loading
Bryan Yong-Hao Tan and Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1
Nanyang Walk, Singapore 637616

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Mild ligand-free Cu0-catalyzed chemoselective S-arylation of 2-
mercaptoimidazole at low catalyst loading
Bryan Yong-Hao Tan and Yong-Chua Teo
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616,
Singapore
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
mild method for the Cu0-catalyzed chemoselective C-S cross-coupling of 2-
mercaptoimidazole derivatives with a series of with differently substituted iodobenzenes and
iodothiophenes at 100 ºC is described. This method proceeds efficiently without ligands and at
low catalyst loading (3 mol%), without the need for stringent inert conditions. Under optimized
conditions, the S-arylated products were obtained in good yields of up to 90%.
Available online
Keywords:
2-mercaptoimidazole
ligand-free
2009 Elsevier Ltd. All rights reserved
.
chemoselective
S-arylation
Copper
as well as low cost26,27 compared to the palladium-16,17,28 and
nickel-catalyzed29-31 variants.
1. Introduction
The S-arylmercaptoimidazole motif has been highlighted
increasingly in medicinal chemistry literature, and can be
predominantly found in compounds with antiviral,1-3 anti-
inflammatory,4,5 antibacterial6,7 and antitumor8,9 properties.
Among the few reported protocols, diphenyl sulfide10,11 and aryl
halides with the strong electron-withdrawing –NO2 group12,13 are
typically used for their preparation. These reactions are not facile
and require harsh conditions like the use of sodium hydride as
base. Moreover, the presence of nucleophilic nitrogen in 2-
mercaptoimidazole entails additional challenge in the synthesis.
Therefore, an efficient method for the direct S-arylation of 2-
mercaptoimidazole to access this important motif and its analogs
will represent a significant advance to the synthetic community.
In spite of all these recent developments, catalytic
methodologies for the S-arylation of 2-mercaptoimidazole remain
elusive, with no successful C-S cross-coupling of 2-
mercaptoimidazole and aryl halides being reported. Sambandam
and co-workers demonstrated the cross-coupling between
iodobenzene and 2-mercaptobenzimidazole through the use of
CuI and 1,10-phenanthroline as assisting ligand.32 However, this
method lacks substrate scope and only worked with stabilized
mercaptobenzimidazole substrates having strong electon-
donating substitutents. The use of assisting ligand also adds
additional cost to the methodology. Moreover, there are only
three other reports that demonstrated cross-coupling reactions
between sulfur-containing azoles with aryl halides.33-35 In all
instances, emphasis was conversely placed on the formation of
more established diarylsulfides, with no examples of reaction
between functionalized aryl halides and 2-mercaptoimidazole
being described.
The transition metal-catalyzed C-S cross-coupling reaction
has recently emerged as a powerful instrument for organic
synthesis. Although challenges associated with the formation of
disulfide bonds14 and more crucially, the metal binding properties
of organic sulfur compounds which in turn lead to catalyst
poisoning,15-17 have led to this class of reaction being less studied
compared to its C-N and C-O counterparts, there has been
considerable progress ever since the first S-arylation was
achieved using a palladium catalyst in 1980.18 In particular,
copper-catalyzed Ullmann-type S-arylation reactions19-25 caught
our interest due to their relatively low toxicity, ease of handling
Therefore, we were motivated to channel our endeavor
towards a facile and practical strategy for the synthesis of the
above-mentioned S-arylmercaptoimidazole. However, the
exsistence of thioketo and thiol tautomers in 2-
mercaptoimidazole36,37 will pose a potential challenge as both S-
and N-arylation may take place. Given our prior experience in
the development of practical and sustainable copper-catalyzed
———
Corresponding author. Tel.: +65 6790 3846; fax: +65 6896 9414; e-mail address: yongchua.teo@nie.edu.sg (Y.-C. Teo).

2
Tetrahedron
ACCEPTED MANUSCRIPT
eReaction carried out at 90 ºC.
carbon-heteroatom cross-coupling reactions,38-41 we envisage
the application of such catalytic systems for this challenging
transformation. We report herein the first Cu0-catalyzed
chemoselective S-arylation of 2-mercaptoimidazole with aryl and
heteroaryl iodides. This mild ligand-free system affords excellent
yields of the S-arylated derivatives (up to 90%) at low catalyst
loadings (3 mol%), while the exclusion of stringent inert
conditions exemplifies the simplicity and practicality of the
protocol.
ions carried out in the absence of Cu and base respectively
illustrated that both are essential for the success of the protocol,
with no intended product observed in either experiments (entries
11 & 12). The impact which different bases have on the reaction
efficiency was subsequently investigated (entries 13–17).
Although the use of different bases did not alter
chemoselectivity, lower yield was detected. To improve atom
efficiency and practicality, catalyst loading and reaction
temperature were consequently lowered (entries 18–20). We are
pleased to report that there was no reduction in yield when the
catalyst loading was lowered to a mere 3 mol% (entry 18). In
2. Results/Discussion
summary,
the
chemoselective
S-arylation
of
2-
As an initial probe into the viability of such a chemoselective
S-arylation reaction, 2-mercaptoimidazole and iodobenzene were
used as model substrates. These two coupling partners were
reacted in water at 100 ºC in the presence of 5 mol% CuI and 1.5
equivalents of anhydrous K3PO4, affording a yield of 20% even
in ligand-free conditions (Table 1, entry 1). With this preliminary
finding, we proceeded with our optimization stage with the
screening of different bench-top organic solvents (entries 1–6).
To our delight, good yields were obtained when polar aprotic
solvents like DMF and DMSO were used as solvents respectively
(entries 2 & 3). Next, the efficacy of different copper salts on the
cross-coupling reaction was investigated. While CuCl, CuBr and
Cu2O have similar catalytic ability (entries 7–9), Cu0 proved to
be the best catalyst, affording the S-arylated product in an
excellent yield of 84%, with no trace of regioisomers or
polyarylated products being observed (entry 10). Control react-
mercaptoimidazole in DMSO was accomplished through a
combination of Cu0 (3 mol%) and anhydrous K3PO4 (1.5 equiv),
stirring the mixture under air at 100 ºC for 24 h.
With the optimal conditions in hand, we demonstrated the
generality of the protocol through the coupling of 2-
mercaptoimidazole with a variety of electron-rich and electron-
poor aryl iodides (Table 2, entries 1–22). In general, good to
excellent yields (60–89%) were observed, and we are pleased to
disclose that most of the desired products obtained in this table
are new, with no prior synthesis recorded by other protocols.
Despite the possible hindrance to the reaction due to steric
repulsion, a common phenomenon seen in our previously
reported cross-coupling reactions,42,40,43,44 good to excellent
yields (up to 82%) were still achieved for ortho-substituted aryl
iodides (entries 2–5). This is likely due to the bigger size of the
sulfur atom compared to nitrogen, hence able to better tolerate
the steric hindrance.45 In addition, 2-mercaptoimidazole reacted
readily with various meta- and para-substituted iodobenzenes,
regardless of the electronic nature, to give the corresponding
products 2af–av in good to excellent yields (entries 6–22).
Table 1. Optimization studies on the Cu-catalyzed cross-
coupling of 2-mercaptoimidazole and iodobenzene.a
Notably,
a
representative base-sensitive enolizable ketone
substituent was well-tolerated by the protocol affording the
product in a good yield of 84% (entry 11). However, reactions
did not proceed when iodobenzene with strongly basic and acidic
substituents were employed. This is a common phenomenon
observed in many Ullmann-type carbon-heteroatom bond
formation reactions.46-49 Another potential drawback of the
protocol is the low reactivity when bromobenzene was used as
the electrophile, affording a low yield of 20% (entry 23).
Entry
1
2
3
4
5
6
7
8
Catalyst
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cu2O
Cu
-
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Base
Solvent
water
DMF
DMSO
Dioxane
THF
Yield (%)b
20
81
84
12
10
0
79
80
82
84
0
0
73
78
80
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
-
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Table 2. Chemoselective S-arylation of 2-mercaptoimidazole
with various substituted aryl halides.a
9
10
11
12
13
14
15
16
17
18
19
20
K2CO3
KOH
Cs2CO3
CsOAc
KOtBu
K3PO4
K3PO4
K3PO4
Entry
1
ArX
Product
Yield (%)b
84
70
45
84c
40d
70c,e
Cu
Cu
2aa
2a
2b
2c
aReaction conditions: Cu catalyst (5 mol%), base (0.75 mmol), 2-
mercaptoimidazole (0.50 mmol), solvent (0.2 mL), iodobenzene (0.75 mmol),
100 ºC for 24 h in air.
2
3
71
76
2ab
2ac
bIsolated yield.
c3 mol% Cu used.
d1 mol% Cu used.

3
Table 2. (continued)
ACCEPTED MANUSCRIPT
Yield (%)b
23
20
Entry
ArX
Product
2aa
2w
aReactions were carried out with Cu (3 mol%), K3PO4 (0.75 mmol), 2-
mercaptoimidzole (0.50 mmol), DMSO (0.2 mL), substituted iodobenzene
(0.75 mmol), 100 ºC for 24 h in air.
4
82
60
80
80
80
2ad
2d
2e
2f
bIsolated yield.
5
6
7
8
2ae
2af
2ag
2ah
Motivated by the positive results above, we proceeded to
explore the possible chemoselective cross-coupling of heteroaryl
halides with 2-mercaptoimidazole, as shown in Table 3. Indeed,
S-arylation for a range of iodothiophenes afforded good to
excellent yields of up to 85% (Table 3, entries 1–4). Regrettably,
similar to our observations with bromobenzene (Table 2, entry
23), both 2- and 3-bromothiophene were not reactive enough for
successful heteroarylation (entries 5 & 6). Furthermore, attempts
with various iodopyridines as the coupling partner were not
conclusive as the products obtained from the reactions could not
be adequately characterized.
2g
2h
9
82
81
84
2ai
2aj
Table 3. Chemoselective S-arylation of 2-mercaptoimidazole
2i
2j
with substituted iodoheterocycles.a
10
11
2ak
2al
2k
2l
Entry
1
Het-X
Product
3aa
Yield (%)b
60
12
13
81
80
3a
2
3
85
62
3b
3c
3ab
2m
2n
2am
2an
2ao
2ap
2aq
2ar
2as
2at
14
15
16
17
18
19
20
83
89
84
82
81
88
85
3ac
3ad
3aa
3ab
4
5
6
70
15
17
2o
2p
2q
2r
2s
2t
3d
3e
3f
aReactions were carried out with Cu (3 mol%), K3PO4 (0.75 mmol), 2-
mercaptoimidzole (0.50 mmol), DMSO (0.2 mL), substituted heterocycles
(0.75 mmol), 100 ºC for 24 h in air.
bIsolated yield.
Next, we focused our attention on broadening the scope of the
methodology by applying it on a series of mercaptoazoles. The
results are summarized in Table 4, where moderate to excellent
yields of up to 95% were obtained. Particularly, we were able to
obtain a good yield of 73% of 4aa, formed by the cross-coupling
of iodobenzene and 2-mercapto-1-methylimidazole. This
reaction, achieved using the N-methyl derivative of 2-
mercaptoimidazole.
21
22
70
80
2u
2v
2au
2av

4
Tetrahedron
ACCEPTED MANUSCRIPT
properties to give us access to a large number of new compounds
that were not previously synthesized. The experimental
simplicity of this catalytic system, which does not require the
addition of assisting ligands and inert conditions, is expected to
be particularly useful in industrial applications and the
development of therapeutics.
Table 4. Chemoselective S-arylation of sulfur-containing
azoles with iodobenzene.a
4. Experimental section
4.1. General Methods
Chemicals and solvents were either purchased from
commercial suppliers or purified by standard techniques.
Analytical thin layer chromatography (TLC) was performed
using Merck 60 F254 precoated silica gel plate (0.2 mm
thickness). Subsequent to elution, plates were visualized using
UV radiation (254 nm) on Spectroline Model ENF-24061/F 254
nm. Flash chromatography was performed using Merck silica gel
60 with AR grade solvents. Proton nuclear magnetic resonance
spectra (1H NMR) were recorded on a Bruker Avance DPX 400
1
spectrophotometer (CDCl3 as solvent). Chemical shifts for H
NMR spectra are reported as δ in units of parts per million (ppm)
downfield from SiMe4 (δ 0.0) and relative to the signal of
DMSO-d6 (δ 2.500, quintet). Carbon nuclear magnetic resonance
spectra (13C NMR) are reported as δ in units of parts per million
(ppm) downfield from SiMe4 (δ 0.0) and relative to the signal
of DMSO-d6 (δ 39.51, septet). Mass spectroscopy was
performed using Agilent 1100 series LC/MSD.
aIsolated yields for reactions carried out with Cu (3 mol%), K3PO4 (0.75
mmol), azoles (0.50 mmol), DMSO (0.2 mL), iodobenzene (0.75 mmol), 100
ºC for 24 h in air.
While the mechanism of copper-catalyzed cross-coupling
reactions has not been fully determined, based on the reported
literature,50,51 as well as observations made throughout our study;
firstly, all Cu salts screened were efficient catalysts for the
reaction (Table 1, entries 1, 7–9), and secondly, solid Cu0 was not
observed at the end of every reaction, we postulate that the
mechanism involves three elementary steps. The first step begins
with the coordination of 2-mercaptoimidazole to the CuI metal
center, formed through the oxidation of Cu0 by DMSO, a well-
known oxidant.52-54 Next, an oxidative addition of the
iodobenzene to the catalyst, and lastly, the regeneration of the Cu
catalyst after a reductive elimination of the S-arylated product.
All reagents were purchased from commercial supplier and
were used without any purification. Copper powder was
purchased from Sigma Aldrich.
4.2. General procedure for S-aryl/heteroarylation of 2-
mercaptoimidazole/Sulfur-containing azoles.
A mixture of Cu0 powder (Sigma-Aldrich, <425 ꢀm, 99.5%
trace metals basis, 0.095 mg, 0.015 mmol, 3-mol%), anhydrous
K3PO4 (0.75 mmol), 2-mercaptoimidazole/sulfur-containing
azoles (0.5 mmol), DMSO (0.2 mL) and aryl halide (0.75 mmol)
were added to a reaction vial and a screw cap was fitted to it. The
reaction mixture was stirred under air in a closed system at 100
ºC for 24 h. The heterogeneous mixture was subsequently cooled
to room temperature and diluted with 4.0 mL dichloromethane.
The combined organic extracts were dried with anhydrous
Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude product was loaded onto the column using
minimal amounts of dichloromethane and was purified by silica-
gel column chromatography to afford the S-arylated product. The
Scheme 1. Proposed mechanism for the selective S-arylation
of 2-mercaptoimidazole with iodobenzene.
1
identity and purity of products was confirmed by H and 13C
NMR spectroscopic analysis.
4.3. NMR Data for Products
2-(phenylthio)-1H-imidazole (2aa) Following the general
procedure using 2-mercaptoimidazole (0.501 g, 0.50 mmol) and
iodobenzene (0.084 mL, 0.75 mmol), 74 mg (84% yield) of the
coupled product was obtained as an off-white solid after
purification by flash chromatography (hexane/ethyl acetate,
3. Conclusions
60:40). m.p. 102-104 ºC. Rf = 0.46 (50% hexane/EtOAc). νmax
=
In summary, a mild protocol which requires only a low 3
mol% of Cu0 catalyst is developed for the chemoselective S-
arylation of 2-mercaptoimidazole with differently substituted
iodobenzenes and iodothiophenes. This method has shown good
efficiency, tolerating aryl iodides of various electronic and steric
3047, 3001, 2700, 2542, 1860, 1550, 1310, 1211, 1087, 1020 cm-
1
1. H NMR (400 MHz, DMSO-d6): δ = 12.74 (bs, 1H, NH), 7.31
(t, J = 7.6 Hz, 2H, Ph), 7.23-7.18 (m, 3H, Ph), 7.12 (d, J = 8.1
Hz, 2H, CHCH). 13C NMR (100 MHz, DMSO-d6): δ = 135.9,

5
134.5, 129.3, 127.3, 125.6, 125.4. HRMS (EI): Calcd [M+]:
177.0484. [C9H9N2S]+ Found: 177.0474.
(100 MHz, DMSO-d6): δ = 203.9, 163.5, 161.1, 136.2 (d, J =
ACCEPTED MANUSCRIPT
133.4 Hz), 131.1 (d, J = 8.4 Hz), 122.8 (d, J = 3.0 Hz), 113.4 (d,
J = 23.6 Hz), 113.1 (d, J = 21.3 Hz). HRMS (EI): Calcd [M+]:
195.0390. [C9H8N2SF]+ Found: 195.0387.
2-((2-fluorophenyl)thio)-1H-imidazole (2ab) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 2-fluoroiodobenzene (0.087 mL, 0.75 mmol), 69 mg
(71% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 123-125 ºC. Rf = 0.38 (50% hexane/EtOAc).
2-((3-chlorophenyl)thio)-1H-imidazole (2ag) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-chloroiodobenzene (0.093 mL, 0.75 mmol), 84 mg
(80% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 120-122 ºC. Rf = 0.37 (50% hexane/EtOAc).
νmax = 3055, 2991, 2882, 2737, 2575, 1860, 1619, 1565, 1460,
ν
max = 3091, 3004, 2747, 2547, 1865, 1547, 1473, 1329, 1229,
1101, 1028 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.84 (bs,
1H, NH), 7.30-7.23-7.11 (m, 5H, Ph, CHCH), 6.90 (td, J = 8.3
Hz, 1.5 Hz, 1H, Ph). 13C NMR (100 MHz, DMSO-d6): δ = 158.5
(d, J = 242.3 Hz), 132.8, 129.7 (d, J = 2.2 Hz), 128.7 (d, J = 7.6
Hz), 125.3 (d, J = 3.0 Hz), 122.6 (d, J = 17.5 Hz), 115.8, 115.6.
HRMS (EI): Calcd [M+]: 195.0390. [C9H8N2SF]+ Found:
195.0378.
1
1327, 1164, 1099, 1070 cm-1. H NMR (400 MHz, DMSO-d6): δ
1
= 12.90 (bs, 1H, NH), 7.36-7.26 (m, 4H, Ph, CHCH), 7.10-7.07
(m, 2H, Ph). 13C NMR (100 MHz, DMSO-d6): δ = 138.5, 135.2,
133.8, 133.4, 130.9, 126.2, 126.1, 125.5. HRMS (EI): Calcd
[M+]: 211.0094. [C9H8N2SCl]+ Found: 211.0090.
2-((2-chlorophenyl)thio)-1H-imidazole (2ac) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 2-chloroiodobenzene (0.091 mL, 0.75 mmol), 80 mg
(76% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 139-141 ºC. Rf = 0.36 (50% hexane/EtOAc).
νmax = 3098, 2902, 2771, 2640, 2548, 1755, 1454, 1327, 1255,
2-((3-bromophenyl)thio)-1H-imidazole (2ah) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-bromoiodobenzene (0.096 mL, 0.75 mmol), 102 mg
(80% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 129-131 ºC. Rf = 0.45 (50% hexane/EtOAc).
νmax = 3129, 3049, 2989, 2737, 2619, 1864, 1619, 1560, 1458,
1
1
1100, 1030 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.97 (bs,
1327, 1164, 1100, 1065 cm-1. H NMR (400 MHz, DMSO-d6): δ
1H, NH), 7.48-7.18 (m, 5H, Ph, CHCH), 6.58 (d, J = 9.1 Hz, 1H,
Ph). 13C NMR (100 MHz, DMSO-d6): δ = 203.9, 136.0, 132.3,
129.6, 129.2, 128.0, 127.3, 127.0. HRMS (EI): Calcd [M+]:
211.0094. [C9H8N2SCl]+ Found: 211.0090.
= 12.89 (bs, 1H, NH), 7.41 (d, J = 7.6 Hz, 2H, Ph), 7.29-7.24 (m,
2H, CHCH), 7.12 (d, J = 8.1 Hz, 2H, Ph). 13C NMR (100 MHz,
DMSO-d6): δ = 203.9, 138.7, 133.4, 131.2, 129.1, 128.9, 125.5,
122.2. HRMS (EI): Calcd [M+]: 254.9589. [C9H8N2SBr]+ Found:
254.9588.
2-(o-tolylthio)-1H-imidazole (2ad) Following the general
procedure using 2-mercaptoimidazole (0.501 g, 0.50 mmol) and
2-iodotoluene (0.096 mL, 0.75 mmol), 78 mg (82% yield) of the
coupled product was obtained as an pale brown solid after
purification by flash chromatography (hexane/ethyl acetate,
2-((3-(trifluoromethyl)phenyl)thio)-1H-imidazole
(2ai)
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 3-iodobenzotrifluoride (0.108 mL, 0.75
mmol), 100 mg (82% yield) of the coupled product was obtained
as an off-white solid after purification by flash chromatography
(hexane/ethyl acetate, 60:40). m.p. 136-137 ºC. Rf = 0.36 (50%
hexane/EtOAc). νmax = 3141, 3003, 2772, 2630, 1870, 1555,
60:40). m.p. 115-116 ºC. Rf = 0.42 (50% hexane/EtOAc). νmax
=
3134, 3015, 2895, 2628, 2554, 1915, 1545, 1454, 1426, 1329,
1
1253, 1104, 1041 cm-1. H NMR (400 MHz, DMSO-d6): δ =
1
12.72 (bs, 1H, NH), 7.23-7.20 (m, 3H, Ph), 7.14-7.07 (m, 2H,
CHCH), 6.78-6.75 (m, 1H, Ph), 2.33 (s, 3H, CH3). 13C NMR (100
MHz, DMSO-d6): δ = 203.90, 135.5, 135.1, 134.4, 130.3, 127.7,
126.7, 126.4, 19.6. HRMS (EI): Calcd [M+]: 191.0641.
[C10H11N2S]+ Found: 190.0646.
1478, 1424, 1322, 1273, 1168, 1102, 1072 cm-1. H NMR (400
MHz, DMSO-d6): δ = 12.93 (bs, 1H, NH), 7.58-7.53 (m, 2H,
CHCH), 7.40 (s, 2H, Ph), 7.29 (s, 2H, Ph). 13C NMR (100 MHz,
DMSO-d6): δ = 203.9, 138.0, 130.8, 130.3, 130.1, 129.8, 125.1,
123.0 (qn, J = 4.5 Hz), 122.3. HRMS (EI): Calcd [M+]: 245.0358.
[C10H8N2SF3]+ Found: 245.0360.
2-((2,6-dimethylphenyl)thio)-1H-imidazole (2ae) Following
the general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 2-iodo-1,3-dimethylbenzene (0.108 mL, 0.75 mmol),
61 mg (60% yield) of the coupled product was obtained as an off-
white solid after purification by flash chromatography
(hexane/ethyl acetate, 60:40). m.p. 192-194 ºC. Rf = 0.54 (50%
hexane/EtOAc). νmax = 3434, 3146, 3025, 2692, 2641, 1931,
2-((3-methoxyphenyl)thio)-1H-imidazole (2aj) Following
the general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-iodoanisole (0.089 mL, 0.75 mmol), 83 mg (81%
yield) of the coupled product was obtained as an off white solid
after purification by flash chromatography (hexane/ethyl acetate,
50:50). m.p. 109-110 ºC. Rf = 0.38 (50% hexane/EtOAc). νmax
=
1
1661, 1556, 1460, 1331, 1254, 1093 cm-1. H NMR (400 MHz,
3135, 2960, 2892, 2829, 2734, 2488, 1866, 1589, 1483, 1419,
1
DMSO-d6): δ = 12.13 (bs, 1H, NH), 7.21-6.85 (m, 5H, Ph,
CHCH), 2.41 (s, 6H, CH3). 13C NMR (100 MHz, DMSO-d6): δ =
164.0, 142.2, 137.9, 130.5, 128.9, 128.3, 21.7. HRMS (EI): Calcd
[M+]: 205.0797. [C11H14N2S]+ Found: 205.0796.
1327, 1247, 1105, 1029 cm-1. H NMR (400 MHz, DMSO-d6): δ
= 12.8 (bs, 1H, NH), 7.24-7.20 (m, 3H, Ph), 6.80-6.77 (m, 1H,
Ph), 6.67-6.65 (m, 2H, CHCH), 3.69 (s, 3H). 13C NMR (100
MHz, DMSO-d6): δ = 203.9, 159.7, 137.2, 134.3, 130.2, 119.2,
112.7, 111.8, 55.1. HRMS (EI): Calcd [M+]: 207.0590.
[C10H11N2SO]+ Found: 207.0588.
2-((3-fluorophenyl)thio)-1H-imidazole (2af) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-fluoroiodobenzene (0.088 mL, 0.75 mmol), 78 mg
(80% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 71-73 ºC. Rf = 0.38 (50% hexane/EtOAc).
νmax = 3068, 2996, 2752, 2630, 1862, 1599, 1473, 1416, 1327,
1-(3-((1H-imidazol-2-yl)thio)phenyl)ethanone
(2ak)
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 3`-iodoacetophenone (0.136 mL, 0.75
mmol), 92 mg (84% yield) of the coupled product was obtained
as an brown solid after purification by flash chromatography
(hexane/ethyl acetate, 40:60). m.p. 113-115 ºC. Rf = 0.35 (50%
hexane/EtOAc). νmax = 3359, 3135, 3062, 2998, 2576, 2521,
1
1263, 1097, 1062 cm-1. H NMR (400 MHz, DMSO-d6): δ =
12.89 (bs, 1H, NH), 7.38-7.20 (m, 3H, Ph, CHCH), 7.04 (td, J =
8.6 Hz, 2.5 Hz, 1H, Ph), 6.91 (t, J = 8.5 Hz, 2H, Ph). 13C NMR
1864, 1690, 1563, 1422, 1249, 1160, 1100 cm-1. H NMR (400
1

6
Tetrahedron
ACCEPTED MANUSCRIPT
MHz, DMSO-d6): δ = 12.90 (bs, 1H, NH), 7.80 (d, J = 7.6 Hz,
1418, 1328, 1103, 1085, 1006 cm-1. 1H NMR (400 MHz, DMSO-
1H, Ph), 7.67 (s, 1H, Ph), 7.47 (t, J = 7.6 Hz, 1H, Ph), 7.36 (d, J
= 8.1 Hz, 1H, Ph), 7.27 (s, 2H, CHCH), 2.53 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ = 197.3, 137.6, 136.9, 131.6,
129.0, 129.7, 126.4, 126.3, 125.9, 26.7. HRMS (EI): Calcd [M+]:
219.0590. [C11H11N2SO]+ Found: 219.0592.
d6): δ = 12.83 (bs, 1H, NH), 7.50 (d, J = 8.6 Hz, 2H, Ph), 7.24 (s,
2H, CHCH), 7.06 (d, J = 8.6 Hz, 2H, Ph). 13C NMR (100 MHz,
DMSO-d6): δ = 202.0, 135.5, 133.9, 132.1, 129.1, 119.3. HRMS
(EI): Calcd [M+]: 254.9589. [C9H8N2SBr]+ Found: 254.9590.
2-((4-(trifluoromethyl)phenyl)thio)-1H-imidazole
(2aq)
2-(m-tolylthio)-1H-imidazole (2al) Following the general
procedure using 2-mercaptoimidazole (0.501 g, 0.50 mmol) and
3-iodotoluene (0.102 mL, 0.75 mmol), 77 mg (81% yield) of the
coupled product was obtained as an pale yellow solid after
purification by flash chromatography (hexane/ethyl acetate,
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 4-iodobenzotrifluoride (0.110 mL, 0.75
mmol), 100 mg (82% yield) of the coupled product was obtained
as an off white solid after purification by flash chromatography
(hexane/ethyl acetate, 60:40). m.p. 145-147 ºC. Rf = 0.36 (50%
hexane/EtOAc). νmax = 3097, 2997, 2889, 2821, 2633, 2548,
50:50). m.p. 105-107 ºC. Rf = 0.48 (50% hexane/EtOAc). νmax
=
1
2996, 2889, 2744, 2581, 1866, 1591, 1474, 1421, 1330, 1101,
1080 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 12.75 (bs, 1H,
NH), 7.22-7.17 (m, 3H, Ph), 7.02 (d, J = 8.1 Hz, 1H, CHCH),
6.96 (s, 1H, Ph), 6.90 (d, J = 7.1 Hz, 1H, CHCH), 2.23 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ = 139.5, 137.6, 136.4,
135.5, 130.0, 128.7, 128.0, 125.4, 21.8. HRMS (EI): Calcd [M+]:
191.0641. [C10H11N2S]+ Found: 191.0640.
1869, 1607, 1420, 1404, 1330, 1161, 1087, 1012 cm-1. H NMR
(400 MHz, DMSO-d6): δ = 12.92 (bs, 1H, NH), 7.66 (d, J = 8.6
Hz, 2H, Ph), 7.31 (s, 2H, CHCH), 7.24 (d, J = 8.6 Hz, 2H, Ph).
13C NMR (100 MHz, DMSO-d6): δ = 142.3, 132.8, 126.6, 126.3,
126.0 (qn, J = 3.8 Hz), 125.5, 122.8. HRMS (EI): Calcd [M+]:
245.0358. [C10H8N2SF3]+ Found: 245.0359.
2-((4-methoxyphenyl)thio)-1H-imidazole (2ar) Following
the general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 4-iodoanisole (0.176 g, 0.75 mmol), 83 mg (81%
yield) of the coupled product was obtained as a grey solid after
purification by flash chromatography (hexane/ethyl acetate,
2-((3,5-dimethylphenyl)thio)-1H-imidazole
(2am)
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 1-iodo-3,5-dimethylbenzene (0.108
mL, 0.75 mmol), 82 mg (80 % yield) of the coupled product was
obtained as an off-white solid after purification by flash
chromatography (hexane/ethyl acetate, 60:40). m.p. 171-173 ºC.
Rf = 0.48 (50% hexane/EtOAc). νmax = 3109, 3001, 2912, 2488,
50:50). m.p. 153-155 ºC. Rf = 0.42 (50% hexane/EtOAc). νmax
=
3067, 3003, 2886, 2735, 2621, 1865, 1645, 1596, 1495, 1326,
1
1255, 1170, 1094, 1023 cm-1. H NMR (400 MHz, DMSO-d6): δ
1
1866, 1599, 1580, 1449, 1419, 1328, 1167, 1099, 1038 cm-1. H
= 12.60 (bs, 1H, NH), 7.24 (d, J = 8.6 Hz, 2H, Ph), 7.14 (s, 2H,
CHCH), 6.91 (d, J = 8.6 Hz, 2H, Ph), 3.72 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ = 194.6, 159.6, 136.6, 132.1,
125.8, 115.8, 55.3. HRMS (EI): Calcd [M+]: 207.0590.
[C10H11N2SO]+ Found: 207.0588.
NMR (400 MHz, DMSO-d6): δ = 12.70 (bs, 1H, NH), 7.20 (s,
2H, CHCH), 6.84 (s, 1H, Ph), 6.75 (s, 2H, Ph), 2.19 (s, 6H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 189.118, 138.4, 135.2,
134.8, 128.1, 125.1, 20.8. HRMS (EI): Calcd [M+]: 205.0797.
[C11H14N2S]+ Found: 205.0799.
1-(4-((1H-imidazol-2-yl)thio)phenyl)ethanone
(2as)
2-((4-fluorophenyl)thio)-1H-imidazole (2an) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 4-fluoroiodobenzene (0.087 mL, 0.75 mmol), 81 mg
(83% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 55:45). m.p. 133-134 ºC. Rf = 0.40 (50% hexane/EtOAc).
νmax = 3146, 3094, 2629, 2544, 1856, 1587, 1489, 1418, 1326,
1220, 1103 cm-1.1H NMR (400 MHz, DMSO-d6): δ = 12.75 (bs,
1H, NH), 7.26-7.16 (m, 6H, Ph, CHCH). 13C NMR (100 MHz,
DMSO-d6): δ = 203.9, 162.3, 147.5 (d, J = 24.2 Hz), 130.8 (d, J
= 4.0 Hz), 123.3 (d, J = 21.3 Hz), 123.3 (d, J = 24.2 Hz). HRMS
(EI): Calcd [M+]: 195.0390. [C9H8N2SF]+ Found: 195.0391.
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 4`-iodoacetophenone (0.185 g, 0.75
mmol), 96 mg (88% yield) of the coupled product was obtained
as a brown solid after purification by flash chromatography
(hexane/ethyl acetate, 40:60). m.p. 120-122 ºC. Rf = 0.38 (50%
hexane/EtOAc). νmax = 3103, 3003, 2770, 2642, 1873, 1676,
1590, 1333, 1264, 1106, 1009 cm-1. 1H NMR (400 MHz, DMSO-
d6): δ = 12.96 (bs, 1H, NH), 7.87 (d, J = 8.0 Hz, 2H, Ph), 7.31 (s,
2H, CHCH), 7.14 (d, J = 8.0 Hz, 2H, Ph), 2.52 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ = 196.9, 143.1, 137.6, 134.4,
132.8, 129.0, 125.9, 26.6. HRMS (EI): Calcd [M+]: 219.0590.
[C11H11N2SO]+ Found: 219.0593.
2-((4-chlorophenyl)thio)-1H-imidazole (2ao) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 4-chloroiodobenzene (0.179 g, 0.75 mmol), 93 mg
(89% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 139-141 ºC. Rf = 0.41 (50% hexane/EtOAc).
νmax = 3097, 2994, 2880, 2817, 2756, 2629, 1831, 1620, 1546,
2-(p-tolylthio)-1H-imidazole (2at) Following the general
procedure using 2-mercaptoimidazole (0.501 g, 0.50 mmol) and
4-iodotoluene (0.164 g, 0.75 mmol), 81 mg (85% yield) of the
coupled product was obtained as an off-white solid after
purification by flash chromatography (hexane/ethyl acetate,
50:50). m.p. 129-131 ºC. Rf = 0.48 (50% hexane/EtOAc). νmax
=
3145, 3096, 2993, 2746, 2630, 1849, 1547, 1492, 1416, 1326,
1103, 1096, 1017 cm-1. 1H NMR (400 MHz, DMSO-d6): δ =
12.68 (bs, 1H, NH), 7.18 (s, 2H, CHCH), 7.13 (d, J = 8.1 Hz, 2H,
Ph), 7.07 (d, J = 8.6, 2H, Ph), 2.24 (s, 3H). 13C NMR (100 MHz,
DMSO-d6): δ = 136.1, 135.3, 131.9, 129.8, 128.0, 126.7, 20.5.
HRMS (EI): Calcd [M+]: 191.0641. [C10H11N2S]+ Found:
191.0644.
1
1476, 1416, 1325, 1089 cm-1. H NMR (400 MHz, DMSO-d6): δ
= 12.81 (bs, 1H, NH), 7.39-7.37 (m, 2H, Ph), 7.24 (s, 2H, Ph),
7.14-7.12 (m, 2H, CHCH). 13C NMR (100 MHz, DMSO-d6): δ =
134.9, 134.1, 131.1, 129.2, 129.1, 48.6. HRMS (EI): Calcd [M+]:
211.0094. [C9H8N2SCl]+ Found: 211.0094.
2-((4-bromophenyl)thio)-1H-imidazole (2ap) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 4-bromoiodobenzene (0.212 g, 0.75 mmol), 107 mg
(84% yield) of the coupled product was obtained as an brown-
yellow solid after purification by flash chromatography
(hexane/ethyl acetate, 60:40). m.p. 169-171 ºC. Rf = 0.41 (50%
hexane/EtOAc). νmax = 2996, 2824, 2487, 1864, 1611, 1472,
2-(naphthalen-1-ylthio)-1H-imidazole (2au) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 1-iodonaphthalene (0.110 mL, 0.75 mmol), 79 mg
(70% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 191-193 ºC. Rf = 0.62 (50% hexane/EtOAc).

7
νmax = 2994, 2539, 1866, 1619, 1551, 1419, 1329, 1255, 1100,
0.75 mmol), 69 mg (62% yield) of the coupled product was
ACCEPTED MANUSCRIPT
1
1064 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.75 (bs, 1H,
obtained as an brownish-yellow solid after purification by flash
chromatography (hexane/ethyl acetate, 30:70). m.p. 144-146 ºC.
Rf = 0.34 (50% hexane/EtOAc). νmax = 3146, 3090, 2920, 1654,
NH), 8.31 (d, J = 7.6 Hz, 1H，Ph), 7.97 (d, J = 8.1 Hz, 1H，Ph),
7.86 (d, J = 8.6 Hz, 1H，Ph), 7.65-7.57 (m, 2H， CHCH), 7.64
(t, J = 8.1 Hz, 1H，Ph), 7.25-7.21 (m, 3H，Ph). 13C NMR (100
MHz, DMSO-d6): δ = 135.2, 134.7, 133.5, 132.1, 131.0, 128.6,
127.6, 127.5, 126.9, 126.5, 125.9, 124.0. HRMS (EI): Calcd
[M+]: 227.0641. [C13H11N2S]+ Found: 227.0640.
1520, 1413, 1273, 1120, 1104, 1014 cm-1. H NMR (400 MHz,
1
DMSO-d): δ = 12.89 (bs, 1H，NH), 7.79 (d, J = 4.0 Hz, 1H，
heteroaryl), 7.22-7.19 (m, 3H, heteroaryl, CHCH), 2.50 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d): δ = 206.3, 190.0, 149.8,
144.9, 143.9, 134.2, 130.2, 26.3. HRMS (EI): Calcd [M+]:
225.0154. [C9H9N2S2O]+ Found: 225.0155.
2-(naphthalen-2-ylthio)-1H-imidazole (2av) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-fluoroiodobenzene (0.191 g, 0.75 mmol), 90 mg
(80% yield) of the coupled product was obtained as an off white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 152-154 ºC. Rf = 0.62 (50% hexane/EtOAc).
2-(benzo[b]thiophen-2-ylthio)-1H-imidazole
(3ad)
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 2-iodobenzothiophene (0.195 mL, 0.75
mmol), 81 mg (70% yield) of the coupled product was obtained
as an yellowish solid after purification by flash chromatography
(hexane/ethyl acetate, 60:40). m.p. 186-188 ºC. Rf = 0.46 (50%
hexane/EtOAc). νmax = 3433, 2992, 2579, 1861, 1618, 1497,
1419, 1326, 1245, 1127, 1101 cm-1. 1H NMR (400 MHz, DMSO-
d6): δ = 12.84 (bs, 1H, NH), 7.87 (d, J = 7.6 Hz, 1H, heteroaryl),
7.79 (d, J = 7.6 Hz, 1H, heteroaryl), 7.53 (s, 1H, heteroaryl),
7.38-7.31 (m, 2H, CHCH), 7.18 (s, 2H, heteroaryl). 13C NMR
(100 MHz, DMSO-d6): δ = 203.9, 140.7, 139.3, 134.4, 128.6,
128.1, 127.2, 124.7, 123.4, 122.1. HRMS (EI): Calcd [M+]:
233.0205. [C11H9N2S2]+ Found: 233.0205.
ν
max = 3055, 2629, 1859, 1621, 1499, 1416, 1325, 1268, 1131,
1102, 1017 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.83 (bs,
1H，NH), 7.87 (d, J = 8.6 Hz, 2H，Ph), 7.78 (d, J = 8.6 Hz,
1H，Ph), 7.96 (s, 1H，Ph), 7.52-7.46 (m, 2H，CHCH), 7.26-
7.23 (m, 3H，Ph). 13C NMR (100 MHz, DMSO-d6): δ = 196.4,
134.7, 133.2, 133.1, 131.4, 130.4, 128.8, 127.7, 127.0, 126.9,
126.1, 125.6. HRMS (EI): Calcd [M+]: 227.0641. [C13H11N2S]+
Found: 227.0638.
1
2-(phenylthio)-1H-imidazole (2aa) Following the general
procedure using 2-mercaptoimidazole (0.501 g, 0.50 mmol) and
bromobenzene (0.079 mL, 0.75 mmol), 18 mg (20% yield) of the
coupled product was obtained as an off-white solid after
purification by flash chromatography (hexane/ethyl acetate,
2-(thiophen-2-ylthio)-1H-imidazole (3aa) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 2-bromothiophene (0.073 mL, 0.75 mmol), 14 mg
(15% yield) of the coupled product was obtained as a yellow
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 148-150 ºC. Rf = 0.36 (50% hexane/EtOAc).
νmax = 3085, 2993, 2812, 2744, 2621, 1804, 1542, 1415, 1323,
60:40). m.p. 102-104 ºC. Rf = 0.46 (50% hexane/EtOAc). νmax
=
3047, 3001, 2700, 2542, 1860, 1550, 1310, 1211, 1087, 1020 cm-
1
1. H NMR (400 MHz, DMSO-d6): δ = 12.74 (bs, 1H, NH), 7.31
(t, J = 7.6 Hz, 2H, Ph), 7.23-7.18 (m, 3H, Ph), 7.12 (d, J = 8.1
Hz, 2H, CHCH). 13C NMR (100 MHz, DMSO-d6): δ = 135.9,
134.5, 129.3, 127.3, 125.6, 125.4. HRMS (EI): Calcd [M+]:
177.0484. [C9H9N2S]+ Found: 177.0474.
1216, 1096 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.61 (bs,
1
1H, NH), 7.64 (dd, J = 6.7 Hz, 1.0 Hz, 1H, CHCH), 7.28 (dd, J =
6.7 Hz, 1.0 Hz, 1H, CHCH), 7.10-7.03 (m, 3H, heteroaryl). 13C
NMR (100 MHz, DMSO-d6): δ = 136.9, 135.6, 133.4, 130.8,
127.9, 125.1. HRMS (EI): Calcd [M+]: 183.0048. [C7H7N2S2]+
Found: 183.0050.
2-(thiophen-2-ylthio)-1H-imidazole (3aa) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 2-iodothiophene (0.083 mL, 0.75 mmol), 55 mg (60%
yield) of the coupled product was obtained as a yellow solid after
purification by flash chromatography (hexane/ethyl acetate,
2-(thiophen-3-ylthio)-1H-imidazole (3ab) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-bromothiophene (0.070 mL, 0.75 mmol), 16 mg
(17% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 60:40). m.p. 145-147 ºC. Rf = 0.35 (50% hexane/EtOAc).
νmax = 3105, 2993, 2884, 2816, 2741, 2621, 1860, 1614, 1547,
60:40). m.p. 148-150 ºC. Rf = 0.36 (50% hexane/EtOAc). νmax
=
3085, 2993, 2812, 2744, 2621, 1804, 1542, 1415, 1323, 1216,
1
1096 cm-1. H NMR (400 MHz, DMSO-d6): δ = 12.61 (bs, 1H,
NH), 7.64 (dd, J = 6.7 Hz, 1.0 Hz, 1H, CHCH), 7.28 (dd, J = 6.7
Hz, 1.0 Hz, 1H, CHCH), 7.10-7.03 (m, 3H, heteroaryl). 13C NMR
(100 MHz, DMSO-d6): δ = 136.9, 135.6, 133.4, 130.8, 127.9,
125.1. HRMS (EI): Calcd [M+]: 183.0048. [C7H7N2S2]+ Found:
183.0050.
1419, 1326, 1195, 1098 cm-1. H NMR (400 MHz, DMSO-d6): δ
1
= 12.54 (bs, 1H, NH), 7.60-7.58 (m, 1H, heteroaryl), 7.44-7.43
(m, 1H，heteroaryl), 7.14 (s, 2H，CHCH), 6.98 (dd, J = 5.0 Hz,
1.5 Hz, 1H，heteroaryl). 13C NMR (100 MHz, DMSO-d6): δ =
137.2, 129.9, 129.8, 128.4, 125.8, 125.3. HRMS (EI): Calcd
[M+]: 183.0048. [C7H7N2S2]+ Found: 183.0050.
2-(thiophen-3-ylthio)-1H-imidazole (3ab) Following the
general procedure using 2-mercaptoimidazole (0.501 g, 0.50
mmol) and 3-iodothiophene (0.076 mL, 0.75 mmol), 77 mg (85%
yield) of the coupled product was obtained as an off-white solid
after purification by flash chromatography (hexane/ethyl acetate,
1-methyl-2-(phenylthio)-1H-imidazole (4aa)34 Following the
general procedure using 2-mercapto-1-methylimidazole (0.057 g,
0.50 mmol) and iodobenzene (0.084 mL, 0.75 mmol), 69 mg
(73% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 80:20). m.p. 94-96 ºC. Rf = 0.34 (50% hexane/EtOAc).
νmax = 3040, 3003, 2715, 2541, 1863, 1554, 1311, 1230, 1089,
1021 cm-1. 1H NMR (400 MHz, DMSO-d6): δ = 7.46 (s, 1H, Ph),
7.31 (t, J = 7.1 Hz, 2H, Ph), 7.21 (t, J = 8.1 Hz, 1H, Ph), 7.11 (s,
1H, Ph), 7.06 (d, J = 7.6 Hz, 2H, CHCH), 3.61 (s, 3H, CH3). 13C
NMR (100 MHz, DMSO-d6): δ = 136.0, 135.0, 129.6, 129.4,
127.0, 126.4, 125.0, 33.4. HRMS (EI): Calcd [M+]: 191.0641.
[C10H11N2S]+ Found: 191.0642.
60:40). m.p. 145-147 ºC. Rf = 0.35 (50% hexane/EtOAc). νmax
=
3105, 2993, 2884, 2816, 2741, 2621, 1860, 1614, 1547, 1419,
1326, 1195, 1098 cm-1. 1H NMR (400 MHz, DMSO-d6): δ =
12.54 (bs, 1H, NH), 7.60-7.58 (m, 1H, heteroaryl), 7.44-7.43 (m,
1H，heteroaryl), 7.14 (s, 2H，CHCH), 6.98 (dd, J = 5.0 Hz, 1.5
Hz, 1H ，heteroaryl). 13C NMR (100 MHz, DMSO-d6): δ =
137.2, 129.9, 129.8, 128.4, 125.8, 125.3. HRMS (EI): Calcd
[M+]: 183.0048. [C7H7N2S2]+ Found: 183.0050.
1-(5-((1H-imidazol-2-yl)thio)thiophen-2-yl)ethanone (3ac)
Following the general procedure using 2-mercaptoimidazole
(0.501 g, 0.50 mmol) and 2-acetyl-5-iodothiophene (0.189 g,

8
Tetrahedron
ACCEPTED MANUSCRIPT
4-methyl-3-(phenylthio)-4H-1,2,4-triazole (4ba) Following
the general procedure using 4-methyl-4H-1,2,4-triazole-3-thiol
(0.058 g, 0.50 mmol) and iodobenzene (0.084 mL, 0.75 mmol),
91 mg (95% yield) of the coupled product was obtained as a
yellow solid after purification by flash chromatography
(dichloromethane/methanol, 95:5). m.p. 71-73 ºC. Rf = 0.54 (50%
hexane/EtOAc). νmax = 3410 bs, 3096, 2995, 1958, 1751, 1645,
Acknowledgments
We would like to thank the National Institute of Education and
Nanyang Technological University (RP 5/13 TYC) for funding
this work.
1582, 1505, 1481, 1330, 1205, 1082, 1018 cm-1. H NMR (400
1
MHz, DMSO-d6): δ = 8.73 (s, 1H, CH), 7.37 (t, J = 6.6 Hz, 2H,
Ph), 7.31-7.28 (m, 1H, Ph), 7.25-7.23 (m, 2H, Ph), 3.57 (s, 3H,
CH3). 13C NMR (100 MHz, DMSO-d6): δ = 203.9, 147.4, 132.0,
129.7, 128.6, 127.5, 31.31. HRMS (EI): Calcd [M+]: 192.0593.
[C9H10N3S]+ Found: 192.0594.
References and notes
1. Chimirri, A.; Grasso, S.; Molica, C.; Monforte, A.; Monforte, P.;
Zappalà, M.; Bruno, G.; Nicolò, F.; Witvrouw, M.; Jonckeere, H.
Antivir. Chem. Chemoth. 1997, 8, 363-370.
2. Buckheit, R. W.; Hollingshead, M. G.; Germany-Decker, J.;
White, E. L.; McMahon, J. B.; Allen, L. B.; Ross, L. J.; Decker,
W. D.; Westbrook, L.; Shannon, W. M. Antivir. Res. 1993, 21,
247-265.
3. De Palma, A. M.; Heggermont, W.; Lanke, K.; Coutard, B.;
Bergmann, M.; Monforte, A.-M.; Canard, B.; De Clercq, E.;
Chimirri, A.; Pürstinger, G. J. Virol. 2008, 82, 4720-4730.
4. Ferrini, P. G.; Goschke, R. U.S. Patent No. 4632930. 1984.
5. Gilman, N. W.; Chen, W. Y. U.S. Patent No. 4973599, 1990.
6. Carcanague, D.; Shue, Y.-K.; Wuonola, M. A.; Uria-Nickelsen,
M.; Joubran, C.; Abedi, J. K.; Jones, J.; Kühler, T. C. J. Med.
Chem. 2002, 45, 4300-4309.
3-(phenylthio)-1H-1,2,4-triazole (4ca) Following the general
procedure using 1H-1,2,4-triazole-3-thiol (0.051 g, 0.50 mmol)
and iodobenzene (0.084 mL, 0.75 mmol), 35 mg (40% yield) of
the coupled product was obtained as a yellow oil after
purification by flash chromatography (hexane/ethyl acetate,
65:35). Rf = 0.26 (50% hexane/EtOAc). νmax = 3055, 2992, 1970,
1
1655, 1643, 1588, 1500, 1400, 1332, 1247, 1082, 1018 cm-1. H
NMR (400 MHz, DMSO-d6): δ = 14.34 (bs, 1H, NH), 8.66 (s,
1H, CH), 7.37-7.28 (m, 5H, Ph). 13C NMR (100 MHz, DMSO-
d6): δ = 145.4, 142.2, 132.9, 129.9, 129.1, 127.2. HRMS (EI):
Calcd [M+]: 178.0437. [C8H8N3S]+ Found: 178.0440.
7. de Assis, J. V.; Couri, M. R. C.; Porto, R. S.; de Almeida, W. B.;
dos Santos, L. H. R.; Diniz, R.; de Almeida, M. V. J. Heterocycl.
Chem. 2013, 50, E142-E147.
8. Bennamane, N.; Zaïoua, K.; Akacem, Y.; Kaoua, R.; Bentarzi, Y.;
Bakhta, S.; Nedjar-Kolli, B.; Ouhab, L. Org. Comm. 2009, 2.
1-methyl-5-(phenylthio)-1H-tetrazole (4da)35 Following the
general procedure using 5-mercapto-1-methyltetrazole (0.058 g,
0.50 mmol) and iodobenzene (0.084 mL, 0.75 mmol), 81 mg
(84% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 85:15). m.p. 76-78 ºC. Rf = 0.51 (50% hexane/EtOAc).
νmax = 3010, 2992, 1766, 1752, 1642, 1555, 1500, 1400, 1321,
9.
Jung, E. J.; Hur, M.; Kim, Y. L.; Lee, G. H.; Kim, J.;
Kim, I.; Lee, M.; Han, H.-K.; Kim, M.-S.; Hwang, S. J.
Pharmacol. Exp. Ther. 2009, 331, 1005-1013.
10. Barrish, J. C.; Spergel, S. H.; World Patent No. 1999009845,
1999.
11. Alvarez, C. S.; Baldwin, J. J.; Bishop, R. W.; Cooper, A. B.;
Desai, J. A.; Doll, R. J.; Girijavallabhan, V. M.; Guzi, T.; Huang,
C. Y.; James, R. A.; World Patent No. 1998011092, 2002.
12. Vecchia, L. D.; Dellureficio, J.; Kisis, B.; Vlattas, I. J. Heterocycl.
Chem. 1983, 20, 1287-1294.
13. Vlattas, I.; U.S. Patent No. 4391808, 1983.
14. Schwab, R. S.; Singh, D.; Alberto, E. E.; Piquini, P.; Rodrigues,
O. E.; Braga, A. L. Catal. Sci. Tech. 2011, 1, 569-573.
15. Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205-3220.
16. Fernández-Rodríguez, M. A.; Hartwig, J. F. Chemistry 2010, 16,
2355-2359.
17. Fernández-Rodríguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 2180-2181.
18. Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-1389.
19. Carril, M.; SanMartin, R.; Domínguez, E.; Tellitu, I. Chem. Eur. J.
2007, 13, 5100-5105.
20. Feng, Y.; Wang, H.; Sun, F.; Li, Y.; Fu, X.; Jin, K. Tetrahedron
2009, 65, 9737-9741.
21. Herrero, M. T.; SanMartin, R.; Domínguez, E. Tetrahedron 2009,
65, 1500-1503.
1
1208, 1018 cm-1. H NMR (400 MHz, DMSO-d6): δ = 7.53-7.51
(m, 2H, Ph), 7.45-7.43 (m, 3H, Ph), 4.01 (s, 3H, CH3). 13C NMR
(100 MHz, DMSO-d6): δ = 151.9, 131.8, 129.9, 129.1, 128.5,
34.2. HRMS (EI): Calcd [M+]: 193.0546. [C8H9N4S]+ Found:
193.0544.
4-phenyl-2-(phenylthio)-1H-imidazole (4ea) Following the
general procedure using 4-phenylimidazole-2-thiol (0.088 g, 0.50
mmol) and iodobenzene (0.084 mL, 0.75 mmol), 98 mg (78%
yield) of the coupled product was obtained as a yellow solid after
purification by flash chromatography (hexane/ethyl acetate,
85:15). m.p. 122-124 ºC. Rf = 0.51 (50% hexane/EtOAc). νmax
=
3066, 2996, 2766, 2441, 1866, 1652, 1555, 1522, 1341, 1210,
1
1201, 1033, 1014 cm-1. H NMR (400 MHz, DMSO-d6): δ =
12.98 (bs, 1H, NH), 7.80 (d, J = 7.6 Hz, 3H, Ph), 7.39-7.30 (m,
4H, Ph, CH), 7.24-7.21 (m, 4H, Ph). 13C NMR (100 MHz,
DMSO-d6): δ = 203.5, 135.6, 135.5, 133.0, 129.3, 128.6, 127.4,
126.7, 126.5, 124.3, 54.9. HRMS (EI): Calcd [M+]: 253.0797.
[C15H13N2S]+ Found: 253.0799.
22. Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.;
Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org. Chem. 2009, 74,
1971-1976.
4,5-diphenyl-2-(phenylthio)-1H-imidazole (4fa)33 Following
the general procedure using 4,5-diphenyl-2-imidazolethiol (0.126
g, 0.50 mmol) and iodobenzene (0.084 mL, 0.75 mmol), 128 mg
(78% yield) of the coupled product was obtained as an off-white
solid after purification by flash chromatography (hexane/ethyl
acetate, 85:15). m.p. 148-149 ºC. Rf = 0.63 (50% hexane/EtOAc).
23. Li, Y.; Li, X.; Wang, H.; Chen, T.; Xie, Y. Synthesis 2010, 3602-
3608.
24. Xu, H.-J.; Zhao, X.-Y.; Deng, J.; Fu, Y.; Feng, Y.-S. Tetrahedron
Lett. 2009, 50, 434-437.
25. Zhang, X.-Y.; Zhang, X.-Y.; Guo, S.-R. J. of Sulfur Chem. 2011,
32, 23 - 35.
26. Rao, H.; Fu, H. Synlett 2011, 745-769.
27. Li, C.-J.; Trost, B. M. Proc. Nat. Acad. Sci. 2008, 105, 13197-
13202.
28. Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D.;
Volante, R. P. J. Org. Chem. 1998, 63, 9606-9607.
29. Jammi, S.; Barua, P.; Rout, L.; Saha, P.; Punniyamurthy, T.
Tetrahedron Lett. 2008, 49, 1484-1487.
30. Xu, X.-B.; Liu, J.; Zhang, J.-J.; Wang, Y.-W.; Peng, Y. Org. Lett.
2013, 15, 550-553.
ν
max = 3055, 2978, 2762, 2400, 1861, 1612, 1542, 1501, 1304,
1
1214, 1043, 1007 cm-1. H NMR (400 MHz, DMSO-d6): δ =
13.15 (bs, 1H, NH), 7.48-7.25 (m, 15H, Ph). 13C NMR (100
MHz, DMSO-d6): δ = 203.9, 135.5, 135.2, 129.4, 128.7, 128.3,
128.1, 127.9, 127.1, 126.8, 126.6. HRMS (EI): Calcd [M+]:
329.1110. [C21H17N2S]+ Found: 329.1111.
31. Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9, 3495-
3498.

9
32. Sekar, R.; Srinivasan, M.; Marcelis, A. T.; Sambandam, A.
46. Xu, H. J.; Zheng, F. Y.; Liang, Y. F.; Cai, Z. Y.; Feng, Y. S.;
Che, D. Q. Tetrahedron Lett. 2010, 51, 669-671.
47. Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org.
Chem. 2008, 640-643.
ACCEPTED MANUSCRIPT
Tetrahedron Lett. 2011, 52, 3347-3352.
33. Correa, A.; Carril, M.; Bolm, C. Angew. Chem. Int. Ed. 2008, 47,
2880-2883.
34. Kao, H.-L.; Chen, C.-K.; Wang, Y.-J.; Lee, C.-F. Eur. J. Org.
Chem. 2011, 2011, 1776-1781.
48. Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-X. Tetrahedron
Lett. 2005, 46, 7295-7298.
35. Niu, L.-F.; Cai, Y.; Liang, C.; Hui, X.-P.; Xu, P.-F. Tetrahedron
2011, 67, 2878-2881.
49. Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248,
2337-2364.
36. Zhu, H.-J.; Ren, Y.; Ren, J.; Chu, S.-Y. J. Mol. Struct. 2005, 730,
199-205.
50. Sperotto, E.; van Klink, G. P.; van Koten, G.; de Vries, J. G.
Dalton Trans. 2010, 39, 10338-10351.
37. Perez-Peña, J.; Gonzalez-Davila, M.; Suarez-Tangil, M.;
Hernandez-Brito, J. Collect. Czech. Chem. Commun. 1989, 54,
2045-2053.
38. Yong, F.-F.; Teo, Y.-C.; Chua, G.-L.; Lim, G. S.; Lin, Y.
Tetrahedron Lett. 2011, 52, 1169-1172.
39. Yong, F.-F.; Teo, Y.-C. Synlett 2010, 3068-3072.
40. Tan, B. Y.-H.; Teo, Y.-C.; Seow, A.-H. Eur. J. Org. Chem. 2013,
7, 1541-1546
51. Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954-
6971.
52. Zou, J.-F.; Huang, W.-S.; Li, L.; Xu, Z.; Zheng, Z.-J.; Yang, K.-
F.; Xu, L.-W. RSC Adv. 2015, 5, 30389-30393.
53. Song, J. H.; Sailor, M. J. Inorg. Chem. 1998, 37, 3355-3360.
54. Epstein, W. W.; Sweat, F. W. Chem. Rev. 1967, 67, 247-260.
41. Yong, F.-F.; Teo, Y.-C.; Yan, Y.-K.; Chua, G.-L. Synlett 2012,
101-106.
42. Tan, Y. H.; Teo, Y. C. Org. Biomol. Chem. 2014, 12, 7478-7481
43. Tan, B. Y.-H.; Teo, Y.-C. Synlett 2015, 1697-1701.
44. Yong, F.-F.; Teo, Y.-C.; Tay, S.-H.; Tan, B. Y.-H.; Lim, K.-H.
Tetrahedron Lett. 2011, 52, 1161-1164.
Supplementary Material
NMR spectra of new compounds related to this article can be
found at http://dx.doi.org/
45. Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8,
5613-5616.