Ligand-Free CuI-Catalyzed Chemoselective S-Arylation of 2-Mercaptobenzimidazole with Aryl Iodides

Article abstract of DOI:10.1055/s-0037-1610655

A practical and efficient strategy for the chemoselective C-S cross-coupling of 2-mercaptobenzimidazole derivatives with a range of substituted aryl iodides is described. Under the optimized conditions of 5 mol% CuI and 100 °C, a variety of S-arylated products were obtained in good to excellent yields (up to 92 %) without the need for assisting ligands.

Full text of DOI:10.1055/s-0037-1610655

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
Ligand-Free CuI-Catalyzed Chemoselective S-Arylation of 2-Mer-
captobenzimidazole with Aryl Iodides
Bryan Yong-Hao Tan
CuI (5 mol%)
K3PO4 (1.5 equiv)
H
N
H
N
R2
Yong-Chua Teo*
R2
+
I
R1
R1
SH
S
DMSO (0.2 mL)
100 °C, 24 h
N
N
Natural Sciences and Science Education, National Institute
of Education, Nanyang Technological University, 1 Nanyang
Walk, Singapore 637616, Singapore
R1 = NH2, NO2,
OMe, OEt etc.
R2 = F, Cl, Br,
OMe, CF3, NO2,
acetyl etc.
32 examples
up to 92% yield
yongchua.teo@nie.edu.sg
Received: 25.04.2018
Accepted after revision: 16.07.2018
Published online: 27.08.2018
this core structure is synthesized through the reaction of
diphenyl sulfide and benzimidazoles.25 However, this reac-
tion has limited synthetic utility due to the low efficiency
and limited substrate scope. In this context, the Ullmann-
type cross-coupling provides a facile route for the synthesis
of S-aryl mercaptobenzimidazole derivatives.26,27 This route
is advantageous due to its high catalytic efficiency, while
the low cost and toxicity of the Cu catalyst further enhance
the attractiveness of the method.28–31
DOI: 10.1055/s-0037-1610655; Art ID: st-2018-u0259-l
Abstract A practical and efficient strategy for the chemoselective C–S
cross-coupling of 2-mercaptobenzimidazole derivatives with a range of
substituted aryl iodides is described. Under the optimized conditions of
5 mol% CuI and 100 °C, a variety of S-arylated products were obtained
in good to excellent yields (up to 92 %) without the need for assisting
ligands.
While substantial development has been observed in
the Ullmann-type C–S bond-formation reactions, examples
which used mercaptoazoles as the S-nucleophile are still
few and far between. Sambandam and co-workers em-
ployed a CuI/1,10-phenanthroline catalytic system for the
cross-coupling of iodobenzene and 2-mercaptobenzimidaz-
ole.32 While generally effective, substrate scope was limited
to stabilized mercaptobenzimidazole with strong electron-
donating substituents. The necessity for 1,10-phenanthro-
line-assisting ligand entails extra cost to the synthetic
method. Braga and co-workers demonstrated the C–S cross-
coupling reaction between benzenethiol and aryl iodides
through the use of ionic liquid and CuO nanopowder.
During his attempt to expand the generality of the reaction,
he successfully coupled 2-mercaptobenzimidazole and io-
dobenzene to afford the intended product at a good yield of
80%. However, the use of nanoparticle and ionic liquid com-
plicates the reaction which has very limited mercaptoazole
scope. Notably, we have recently established a Cu0-cata-
lyzed ligand-free C–S arylation of mercaptoazole with iodo-
benzene, which afforded excellent yields of up to 90%.33
Drawing inspiration from our preceding experience in
the development of sustainable and practical copper-cata-
lyzed, ligand-free carbon-heteroatom cross-coupling reac-
tions,34–37 we envision the application of a ligand-free Ull-
mann-type cross- coupling reaction for the chemoselective
C–S bond formation in 2-mercaptobenzimidazole. Hence-
Key words 2-mercaptobenzimidazole, ligand-free, S-arylation, cop-
per(I) iodide, chemoselective
Transition-metal-catalyzed cross-coupling reaction has
recently emerged as a powerful tool for the assembly of C–S
bonds. This class of reaction had been less extensively ex-
plored relative to the C–N and C–O counterparts, mainly
because of two reasons; the ability of sulfur-containing or-
ganic compounds to poison catalysts due to the sulfur’s
metal binding properties,1–3 and the affinity of sulfur to
form disulfide bonds.4 Nonetheless, considerable progress
has been attained ever since the first S-arylation was
achieved using Pd catalyst in 1980.5 Thereafter, various re-
search groups have reported different methodologies to
achieve S-arylation by using transition metals like Ni,6–8
Pd,2,3,9 and Cu6,10–15 as catalysts. However, the above-men-
tioned reactions are generally applied to benzenethiol and
derivatives as substrates, with little emphasis on other class
of S-containing compounds. Mercaptoazoles, which are
commonly found in bioactive molecules, are one of these
compounds that have not been studied comprehensively.
The S-aryl mercaptobenzimidazole functional groups
have been highlighted increasingly in pharmaceuticals and
bioactive molecules. This core structure is frequently asso-
ciated with anti-inflammatory,16,17 antiviral,18–20 antitu-
mor,21,22 and antibacterial23,24 characteristics. Classically,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
forth, a ligand-free chemoselective S-arylation of 2-mer-
captobenzimidazole is disclosed. Catalyzed by CuI salt, this
reaction proceeds efficiently at relatively mild temperature
of 100 °C to afford good to excellent yields of up to 92%
products.
Table 1 Optimization Studies on the Cu-Catalyzed C–S Cross-Coupling
of 2-Mercaptobenzimidazole and Iodobenzenea
[Cu] (10 mol%)
base (1.5 equiv)
H
N
H
N
S
+
I
SH
solvent (0.2 mL)
130 °C, 24 h
N
The optimization studies began with the use of iodo-
benzene and 2-mercaptobenzimidazole as model sub-
strates. Based on our precedent reaction,33 Cu0 and Cs2-
CO3were added to the reaction system, albeit at a higher re-
action temperature and catalyst loading of 130 °C and 10
mol%, respectively. An encouraging yield of 60% of S-aryl
mercaptobenzimidazole was obtained under this initial ex-
periment (Table 1, entry 1). This was followed up with a
brief study of several commercially available Cu salts as
possible catalyst (Table 1, entries 2–6). The Cu halide salts
were deemed to be the best catalysts for the reaction, with
a slight advantage in efficiency observed for CuI. CuII salts
also had potential catalytic properties for this protocol,
where a moderate yield of 49% was obtained through the
use of CuO. Next, a survey into the effect of different sol-
vents had on the protocol was carried out through the use
of commercially available solvents (Table 1, entries 7–11).
DMSO was the best solvent, affording excellent yield of 90%.
Significant decrease in product yield was observed when
toluene and water was applied. The effects of base on reac-
tion efficiency appeared to be inconsequential. This was ap-
parent as excellent yields of 80–90% were observed during
the screening reactions (Table 1, entries 12–15). K3PO4 was
selected as the ideal base for its slightly higher yield, as well
as intangibles like commercial availability and ease of han-
dling. Negative results were detected for control reactions
carried out in the absence of Cu catalyst and base, outlining
their critical role in the reaction (Table 1, entries 16 and
17). To conclude the optimization studies, attempts to re-
duce catalyst loadings and reaction temperature were both
successful, where no compensation was observed at half
the initial catalyst loading and lower operating temperature
of 100 °C (Table 1, entries 18 and 19). Based on these re-
sults, the optimized conditions were determined as fol-
lows: anhydrous K3PO4as base, DMSO as the solvent in the
presence of 5 mol% CuI catalyst.
N
Entry
Catalyst
Base
Cs2CO3
Solvent
Yield (%)b
1
2
Cu
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
60
90
86
84
79
49
86
75
67
38
39
83
90
80
80
0
CuI
CuBr
CuCl
Cu2O
CuO
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
KOH
3
4
5
6
7
8
THF
9
t-BuOH
toluene
water
10
11
12
13
14
15
16
17
18
19
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CsOAc
K3PO4
–
CuI
CuI
CuI
0
K3PO4
K3PO4
90c
90c,d
a Reaction conditions: Cu catalyst (10 mol%), base (0.75 mmol), 2-mercap-
tobenzimidazole (0.50 mmol), solvent (0.2 ml), iodobenzene (0.75 mmol),
130 °C for 24 h in air.
b Isolated yield.
c 5 mol% CuI used.
d Reaction carried out at 100 °C.
iodides, with naphthalene iodides also producing excellent
yields of the desired products (Table 2, entries 25 and 26).
However, this protocol does not apply to bromobenzene,
where only trace product was obtained when applied as
the aryl halide (Table 2, entry 27).
The substrate scope was studied through the applica-
tion of a wide range of substituted iodobenzenes. Under op-
timized reaction conditions, moderate to high yields of up
to 92% of the intended S-arylated compounds were ob-
tained, as shown in Table 2. In general, this reaction was
unaffected by the position and electronic nature of the sub-
stituents. Remarkably, unlike many Ullmann-type coupling
reactions which gave poor results with sterically hindered
ortho-substituted aryl halides,38,39 this protocol was able to
produce good results with these challenging substrates (Ta-
ble 2, entries 2–6). Excellent yields were also observed for
meta- and para-substituted iodobenzenes (Table 2, entries
7–24). Furthermore, the reaction was not limited to phenyl
In our endeavor to expand the scope of the newly estab-
lished protocol, several mercaptobenzazoles and differently
substituted mercaptobenzimidazoles were applied to the
catalytic system (Table 3). While 2-mercaptobenzothiazole
was successfully coupled to iodobenzene, forming the S-
aryl product in an excellent yield of 87% (Table 3, product
3a), only trace products were detected when 2-mercapto-
benzoxazole was utilized as the S-nucleophile (Table 3,
product 3b). This can be attributed to the basic property of
the oxygen atom which can coordinate to the Cu catalyst
and deactivate its catalytic activity. 2-Mercaptobenzimid-
azoles with substituents of either electron-donating or
electron-withdrawing effect were well-tolerated to form
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
B. Y.-H. Tan, Y.-C. Teo
Letter
Yield (%)b
84
Synlett
the corresponding products in good to excellent yields of up
to 85% (Table 3, products 3b–g). The cross-coupling of N-
protected 2-mercaptobenzimidazole was also complete,
where an excellent yield of 87% was observed (Table 3,
product 3h). This evidence supports the fact that arylation
indeed is favored at the sulfur atom rather than the nitro-
gen atom.
Entry ArX
Product
I
I
I
I
Cl
H
N
8
S
S
S
N
Cl
2ah
2h
Br
H
N
Table 2 Chemoselective S-Arylation of 2-Mercaptobenzimidazole
9
85
84
with Various Substituted Aryl Halidesa
N
Br
2ai
2i
H
N
SH
OMe
H
N
N
Cu (5 mol%)
H
10
1a
N
K3PO4 (1.5 equiv)
R
N
S
+
OMe
DMSO (0.2 mL)
100 °C, 24 h
N
2aj
R
2j
2aa–az
X
2a–z
O
H
N
11
92
S
S
Entry ArX
Product
Yield (%)b
N
O
2ak
2al
2k
I
H
N
I
I
S
1
90
H
N
N
12
87
83
83
85
2aa
2a
N
2l
I
F
H
N
F
2
86
88
83
84
82
S
S
NO2
H
N
N
13
2ab
2ac
2ad
2ae
S
S
S
2b
N
NO2
I
2am
2an
2ao
Cl
2m
H
N
Cl
3
I
CN
H
N
N
2c
14
N
CN
I
MeO
H
N
2n
OMe
4
S
I
CF3
N
H
N
2d
15
N
CF3
I
H
N
2o
5
S
N
H
N
I
F
2e
S
S
S
F
16
92
85
83
N
2p
I
I
O2N
S
2ap
2aq
2ar
H
N
NO2
6
H
N
N
I
Cl
Cl
Br
17
2af
2f
N
2q
F
H
N
H
N
7
86
S
I
Br
18
N
F
N
2ag
2r
2g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
Table 2 (continued)
Entry ArX
catalyst without the need for expensive ligands or stringent
inert conditions makes it a feasible alternative to estab-
lished C–S cross-coupling methodologies.
Product
Yield (%)b
84
H
N
I
OMe
S
S
S
S
S
S
OMe
Table 3 Chemoselective S-Arylation of 2-Mercaptobenzimidazole
19
Derivatives with Iodobenzenea
N
2s
2as
2at
Cu (5 mol%)
K3PO4 (1.5 equiv)
R
H
N
R
Y
N
Y
I
S
+ I
SH
20
90
86
72
71
86
O
N
N
DMSO (0.2 mL)
100 °C, 24 h
O
2t
Y = NH, S, O
H
N
S
N
O
I
21
S
S
N
N
2u
2au
2av
2aw
2ax
3a, 87% yield
3b, trace
H
N
H
N
H
N
I
NO2
NO2
22
S
S
S
N
N
N
H2N
2v
MeO
3c, 82% yield
3d, 66% yield
H
N
H
N
H
N
I
CN
CN
23
F
S
N
2w
N
N
O2N
EtO
3f, 84% yield
3e, 77% yield
H
N
H
N
I
CF3
Cl
CF3
24
N
N
S
S
2x
N
Cl
N
3h, 87% yield
3g, 85% yield
I
a Isolated yields for reactions carried out with Cu (5 mol%), K3PO4 (0.75
mmol), 2-mercaptoimidazole derivatives (0.50 mmol), DMSO (0.2 ml),
iodobenzene (0.75 mmol), 100 °C for 24 h in air.
H
N
25
90
S
S
N
2y
2ay
2az
H
N
Funding Information
I
26
92
We would like to thank Nanyang Technological University (RP 5/13
N
2z
TYC) for funding this work.
N
a
n
y
a
n
g
Tech
n
o
lgcai
l
Unvieytrsi
R(P
5
1/
3
T
Y
C)
Br
H
N
Acknowledgment
S
27
trace
N
We would like to thank the National Institute of Education, Singapore
for supporting this work.
2aa
2a’
a Reactions were carried out with CuI (5 mol%), K3PO4 (0.75 mmol), 2-mer-
captobenzimidzole (0.50 mmol), DMSO (0.2 ml), substituted iodobenzene
(0.75 mmol), 100 °C for 24 h in air.
Supporting Information
b Isolated yield.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610655.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In conclusion, an efficient ligand-free CuI catalytic sys-
tem for the Ullmann-type S-arylation of 2-mercaptobenz-
imidazoles40 is described. A good range of mercaptobenz-
azole and substituted mercaptobenzimidazole were found
to react with iodobenzene in the presence of 5 mol% CuI in
DMSO. The corresponding S-arylated products were ob-
tained in up to 92% yield. This protocol is general and mild,
and the use of inexpensive and commercially available CuI
References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

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B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
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(40) General Procedure for S-Arylation of 2-Mercaptobenzimid-
azoles
A mixture of CuI (Sigma-Aldrich, 0.025 mmol, 5 mol%), anhy-
drous K3PO4 (0.65 mmol), 2-mercaptobenzimidazole (0.5
mmol), DMSO (0.2 mL), and aryl halide (0.75 mmol) were added
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dichloromethane and was purified by silica gel column chroma-
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2-(Phenylthio)-1H-benzo[d]imidazole (2aa)
101 mg (90% yield) of the coupled product was obtained as an
off-white solid. 1H NMR (400 MHz, DMSO-d): δ = 12.50 (br s, 1
H), 7.62 (dd, J = 25.6, 7.6 Hz, 2 H), 7.42–7.31 (m, 7 H). 13C NMR
(100 MHz, DMSO-d): δ = 147.6, 135.4, 131.3, 130.1, 129.6,
122.8, 118.7, 110.4. HRMS: m/z calcd [M+]: 227.0641; found:
227.0644.
2-[(2-Fluorophenyl)thio]-1H-benzo[d]imidazole (2ab)
105 mg (86% yield) of the coupled product was obtained as an
off-white solid.
1H NMR (400 MHz, DMSO-d): δ = 12.77 (br s, 1 H), 7.58–7.48 (m,
3 H), 7.42–7.35 (m, 2 H), 7.28 (t, J = 5.6 Hz, 1 H), 7.16 (m, 2 H).
13C NMR (100 MHz, DMSO-d): δ = 160.8 (d, J = 240.0 Hz), 144.7
(d, J = 220.0 Hz), 134.7, 131.4 (d, J = 3.0 Hz), 125.5 (d, J = 3.0 Hz),
122.4, 119.8 (d, J = 340.0 Hz), 116.4, 116.2, 110.9. HRMS: m/z
calcd [M+]: 245.0546; found: 245.0547.
2-[(2-Chlorophenyl)thio]-1H-benzo[d]imidazole (2ac)
114 mg (88% yield) of the coupled product was obtained as an
off-white solid. 1H NMR (400 MHz, DMSO-d): δ = 12.96 (br s, 1
H), 7.60 (dd, J = 7.6, 1.6 Hz, 3 H), 7.40–7.29 (m, 3 H), 7.21 (s, 2
H). 13C NMR (100 MHz, DMSO-d): δ = 144.4, 133.1, 131.9, 131.3,
130.0, 129.4, 128.2, 122.7, 118.5, 111.3. HRMS: m/z calcd [M+]:
261.0251; found: 261.0249.
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2-[(2-Methoxyphenyl)thio]-1H-benzo[d]imidazole (2ad)
106 mg (83% yield) of the coupled product was obtained as an
off-white solid. 1H NMR (400 MHz, DMSO-d): δ = 12.64 (br s,
1 H), 7.49 (s, 2 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.24–7.11 (m, 3 H),
6.96 (t, J = 7.6 Hz, 1 H), 3.82 (s, 3 H). 13C NMR (100 MHz, DMSO-
d): δ = 157.1, 146.3, 131.8, 129.7, 121.9, 121.3, 119.3, 111.9,
106.1, 56.0. HRMS: m/z calcd [M+]: 257.0746; found: 257.0743.
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hedron Lett. 2011, 52, 3347.
(33) Tan, B. Y.-H.; Teo, Y.-C. Tetrahedron 2016, 72, 6646.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E