Unexpectedly ligand-free copper-catalyzed C-S cross-coupling of benzothiazole with aryl iodides in aqueous solution

Article abstract of DOI:10.1016/j.tetlet.2012.04.004

A novel synthetic protocol for 2-aminophenyl sulfide derivatives via the reactions of benzothiazole with aryl iodides was reported for the first time. The reactions were catalyzed by CuCl with tetrabutylammonium hydroxide as the base and water as the solvent without ligand at 50°C or room temperature. A variety of aryl iodides underwent the C-S cross-coupling reaction with benzothiazole to afford smoothly the corresponding products in excellent yield.

Full text of DOI:10.1016/j.tetlet.2012.04.004

Tetrahedron Letters 53 (2012) 2914–2917
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpectedly ligand-free copper-catalyzed C–S cross-coupling of benzothiazole
with aryl iodides in aqueous solution
Yi-Si Feng a, Hong-Xia Qi a, Wei-Cheng Wang b, Yu-Feng Liang a, Hua-Jian Xu b,
⇑
a School of Chemical Engineering, Hefei University of Technology, Hefei 230009, PR China
b School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic protocol for 2-aminophenyl sulfide derivatives via the reactions of benzothiazole with
aryl iodides was reported for the first time. The reactions were catalyzed by CuCl with tetrabutylammo-
nium hydroxide as the base and water as the solvent without ligand at 50 °C or room temperature. A vari-
ety of aryl iodides underwent the C–S cross-coupling reaction with benzothiazole to afford smoothly the
corresponding products in excellent yield.
Received 12 January 2012
Revised 29 March 2012
Accepted 1 April 2012
Available online 5 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Copper
2-Aminophenyl sulfides
C–S cross-coupling
Aqueous solution
Since Migita and coworkers firstly reported palladium-catalyzed
C–S cross-coupling reaction, much attention had been focused on
the carbon–sulfur bonds forming reaction.1 Amine-substituted aryl
sulfides are important intermediates in biological, pharmaceutical,
and material aspects. For example, various sorts of amine-substi-
tuted aryl sulfides are used in different kinds of pharmaceutical
compounds which have anti-inflammatory, antitumor, antiproto-
zoal, antipsychotic, and antidepressant properties.2 The classic
methods preparing 2-aminophenyl sulfides included the direct
reaction of aryl halides with thiols (Scheme 1, Eq. 1),3 synthesis of
nitroaryl sulfides and subsequent reduction of the nitro group
(Scheme 1, Eq. 2),4 and the reaction of phenyl azide with sulfides
(Scheme 1, Eq. 3).5 In 2009, Luo and coworkers reported cross-cou-
pling of 1,2-diaryldisulfides with aryltrimethoxysilane to obtain
objective products (Scheme 1, Eq. 4).6 Later, a protocol for copper-
catalyzed synthesis of thioethers that employed tris(fluorinated
phenyl)boroxins and disulfides were described, which used CuI as
the catalyst and 1,10-phenanthroline as ligand in DMSO/H2O at
90 °C under O2 atmosphere (Scheme 1, Eq. 5).7 Duan disclosed a
simple one-pot procedure in situ reduction of nitro group to
produce amine-substituted aryl sulfides (Scheme 1, Eq. 6).8
Recently, Prasad and Sekar described an efficient Cu-catalyzed
one-pot approach for the synthesis of unsymmetrical diaryl thio-
ethers using potassium ethyl xanthogenate as a thiol surrogate
(Scheme 1, Eq. 7),9 and Fang developed FeF3/I2-catalyzed synthesis
of chalcogen-substituted arylamines by direct thiolation of an
arylamines C–H bond (Scheme 1, Eq. 8).10 These methods have
become common and reliable methods in application, but the
design of a ‘green’ chemical protocol for 2-aminophenyl sulfides
remains a challenge for this field.
In the past few decades the environmentally-benign and eco-
nomic chemical processes have attracted broad attention.
Water has many advantages such as non-toxicity, low cost, and
availability compared with organic solvents.11 So the development
of
a ligand-free, environment-friendly, and efficient catalyst
system is still attractive. Herein, we reported an unprecedented
copper-catalyzed reaction of benzothiazole with aryl iodides to
form 2-aminoaryl sulfides in water without ligand.
This new reaction was unprecedentedly found during the
course of our recent research on Cu-mediated arylation of a hetero-
cycle C–H bond in aqueous solution. Upon treatment of benzothi-
azole with iodobenzene, CuCl, (5 mol %) and nBu4NOH (aq, 3 equiv/
1 mL) at room temperature for 12 h, we surprisingly found that
only 1a was formed in 81% yield instead of 1b (Scheme 2). This
result showed that benzothiazole was used as a thiol surrogate
in C–S bond formation. Benzothiazole has been widely used in
organic synthesis,12 but has never been used as a reagent reacting
with aryl halides to generate 2-aminophenyl sulfide. Considering
our group’s experience in the copper-catalyzed S-arylation of thiols
with aryl halides,3f,3g,13a and selective synthesis of phenols, ani-
lines, and thiophenols from aryl halides in water,13b we decided
to explore the novel reaction using benzothiazole as a thiol surro-
gate to further develop aqueous catalysis.
⇑
Corresponding author.
E-mail address: hjxu@hfut.edu.cn (H.-J. Xu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.004

Y.-S. Feng et al. / Tetrahedron Letters 53 (2012) 2914–2917
2915
Table 1
Prior Work
Optimization of the reaction conditionsa
M
Ar1X
S
+
Ar2SH
M
eq 1
eq 2
Ar1
Ar2
X=Br, I
I
S
Y
S
N
cat.,
base
S
S
+
Ar'SH
Ar'
Ar'
H2O, Ar
H2N
O2N
+
NH2
O2N
Ar'SSAr'
Y=Cl
S
N3
S
TFA, TFSA
R
S
+
eq 3
eq 4
R
R'
Entry
Cat. (mol %)
Base
T (°C)
Yield b(%)
NH2
1
2
3
4
5
6
7
8
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuBr (5)
CuI (5)
nBu4NOH
nBu4NOH
NaOtBu
KOH
Cs2CO3
K2CO3
K3PO4
nBu4POH
Et4NOH
Me4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
nBu4NOH
rt
81
98
nr
nr
nr
nr
nr
91
80
93
97
98
95
97
94
95
Trace
Trace
nr
nr
84
Trace
89
80
Ph
+
S
Si(OMe)3
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
M
S
R
R
NH2
NH2
Ar
B
M
S
+
eq 5
eq 6
RS-SR
O
B
O
B
R
Ar
Ar
O
Ar
9
Z
S
10
11
12
13
14
15
16
17
18
19
20
21c
22d
23e
24
PEG-600
R
R
SH
+
H2N
O2N
Z=Cl, F
Cu2O (5)
Cu(OAc)2ꢀH2O (5)
I
S
S
M
Ar
CuBr2 (5)
R
+
+
R
eq 7
eq 8
EtO
SK
R2
KOH, Ar-X
CuSO4 (5)
FeCl3(5)
Co(OAc)2ꢀ4H2O
Ni(OAc)2ꢀ4H2O
Pd(OAc)2
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (2)
H
S
M
R2
R2
S
R1HN
R1HN
S
This Work
I
CuCl (5 mol%)
S
S
nBu4NOH (40% aq., 1 mL)
+
R'
R'
N
50 °C, Ar, 12 h
NH2
a
Reaction conditions: Benzothiazole (0.5 mmol), iodobenzene (1.2 mmol), base
Scheme 1. Synthetic protocols of 2-aminophenyl sulfides.
(3.0 equiv), H2O (1.0 mL) under Ar for 12 h.
b
Determined by GC. rt = room temperature. nr = no reaction.
The reaction was carried out in air.
The reaction was carried out in O2.
c
d
S
e
6 h.
CuCl (5 mol%)
%
1
I
NH2
1a
nBu4NOH
8
S
N
(40% aq., 1 mL)
+
to 89% (Table 1, entries 23) when the reaction time was decreased
to 6 h. Optimization of the amount of CuCl showed that 5 mol %
CuCl was necessary to achieve high yield(Table 1, entry 24).
To examine the scope of the catalytic system, the reactions of
benzothiazole with various aryl iodides were carried out under
the optimized conditions (5 mol % CuCl, 3 equiv of nBu4NOH (40%
aq 1 mL), 50 oC), and the results were provided in Table 2. Both
electron-donating methyl or methoxy substituents and electron-
withdrawing chloro, bromo, or fluoro substituents on the phenyl
rings of aryl iodides all gave 2-aminophenyl sulfide derivatives in
excellent yields. Even sterically hindered substrates such as 1-
iodo-2-methylbenzene, 2-iodo-1,3,5-trimethylbenzene, 1-chloro-
2-iodobenzene, 1-bromo-2-iodobenzene, 1-fluoro-2-iodobenzene
were also proved to be excellent substrates. Besides, excellent
yields were obtained by the reactions of heteroaryl iodides with
benzothiazole which gave the corresponding 2-aminophenyl
heteroaromatic sulfides. 4-Iodo-1,2-dimethylbenzene, 4-fluoroiod-
o-benzene, 4-iodobiphenyl, and 1-iodonaphthalene could react
with benzothiazole even at room temperature. The reaction
time of 2-(4-methoxyphenylthio)-aniline, 2-(4-chlorophenylthio)
aniline, and 2-(pyridin-3-ylthio)aniline only needs 6 h. The reaction
between 1,4-diiodobenzene and benzothiazole could also proceed
smoothly to produce 2,20-(1, 4-phenylenebis(sulfanediyl))-diani-
line in 96% yield. Unfortunately, ArBr, ArCl, and ArF could not react
with benzothiazole in spite of making many attempts. Only poor
amounts of the products were obtained for aryl bromides with elec-
tron-withdrawing substituents. Both 1-methyl-1H-benzo[d]-imid-
azole and benzo[d]oxazole could not react with aryl iodides in
this catalyst system.
rt, Ar, 12 h
S
N
1b
Scheme 2. Formation of 2-aminophenyl sulfide via the reaction of iodobenzene
with benzothiazole.
We first investigated the C–S cross-coupling of benzothiazole
with iodobenzene in the presence of 5 mol % CuCl using
aq nBu4NOH as base and solvent at room temperature for 12 h.
The corresponding product was obtained in 81% yield. A screening
of the temperature showed that when the temperature was
elevated to 50 oC, the yield increased to 98% (Table 1, entries 2).
The reaction could not proceed when the reaction used traditional
inorganic bases, such as NaOtBu, KOH, Cs2CO3, K2CO3, and K3PO4,
and other organic ionic bases such as nBu4POH, Me4NOH, and
Et4NOH were observed to be inferior to nBu4NOH (Table 1, entries
3–10). No significant differences of the yield of the desired product
1a was observed when other copper salts were used as the catalyst,
.
such as CuCl, CuBr, CuI, Cu2O, Cu(OAc)2 H2O, CuBr2 and CuSO4, so
we chose the cheaper CuCl (Table 1, entries 2 and 11–16) for the fol-
lowing research. When FeCl3 and Co(OAc)2ꢀ4H2O were used as the
catalysts, trace products were obtained. No product was obtained
with Ni(OAc)2ꢀ4H2O and Pd(OAc)2 as catalysts (Table 1, entries
17–20). The reaction could also provide moderate yield of product
under air atmosphere, but only trace product was obtained under
O2 atmosphere (Table 1, entries 21–22). The yield was decreased

2916
Y.-S. Feng et al. / Tetrahedron Letters 53 (2012) 2914–2917
CuI
Table 2
S
Ar
CuCl catalyzed C–S cross-coupling of aryl iodides with benzothiazolea
Ar
I
I
NH2
CuCl (5 mol%)
nBu4NOH (40% aq.,1 mL)
50°C, Ar,12 h
S
S
N
R'
+
R'
NH2
CuIII
CuIII
I
Ar
S
Ar
D
S
S
NH2
S
E
NH2
97%
NH2
98%, 79%b
S
NH2
94%
Cl
-S
H2N
NH2
S
S
I-
C
NH2
O
NH2
97%
nBu4N+HCOO-
H2O
96%
S
96%, 80%c
S
C
N
Br
S
N
S
N
S
N
OH-
S
:
S-
NH2
Cl
NH2
Br
B
NH2
87%
A'
A
99%, 84%c
S
98%
Scheme 3. Possible mechanism of the reactions of benzothiazole with aryl iodides.
Cl
S
Br
S
NH2
Cl
85%
S
NH2
NH2
F
Acknowledgments
98%, 83%b
S
93%
F
S
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 20802015, 21072040,
21071040) and the Program for New Century Excellent Talents in
University of the Chinese Ministry of Education (NCET-11-0627).
We thank Wen-Long Qiao in this group for reproducing the results
of some products in Table 2.
NH2
F
NH2
N
NH2
99%, 86%c
S
85%
89%
S
S
NH2
NH2
NH2
NH2
Supplementary data
S
92%
97%, 80%b
83%
Supplementary data (experimental procedure, 1H and 13C NMR
spectra and spectral data for all compounds) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.04.004. These data include MOL files and
InChiKeys of the most important compounds described in this
article.
H2N
S
S
H2N
S
NH2
99%, 84%b
96%d
aCuCl (5 mol %), benzothiazole (0.5 mmol), Ar-I (0.6 mmol), 40% nBu4NOH aq
(1.0 mL/3.0 equiv) at 50 °C under Ar for 12 h; isolated yield.
References and notes
bAt rt.
c6 h.
dCuCl (5 mol %), benzothiazole (1.0 mmol), Ar-I (0.6 mmol), 40% nBu4NOH aq
(1.0 mL/3.0 equiv) at 50 °C under Ar for 12 h.
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enters the catalytic cycle. Cu(I) undergoes oxidative addition with
the aryl iodides in the usual way to provide intermediate D,
which subsequently reacts with C to form a Cu(III) species E.
Reductive elimination ensues to form the products and regener-
ate Cu(I) species.
In summary, we reported a novel copper-catalyzed reaction of
benzothiazole with aryl iodides producing 2-aminophenyl sulfides
under mild conditions for the first time. A number of aryl iodides
could undergo the transformation and afford smoothly the corre-
sponding products in excellent yields. This catalytic system used
only 5 mol % amount of simple copper salt as catalyst and water
as solvent, which makes this protocol for a potential alternative
on scale-production.

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