Efficient C-S cross coupling catalyzed by Cu2O

Article abstract of DOI:10.1016/j.tetlet.2008.11.029

A protocol for the copper-catalyzed C-S bond formation between aryl, alkyl, or heteroaryl thiols and aryl or heteroaryl halides is reported. The reaction is catalyzed by Cu₂O which shows the highest catalytic activity with ethyl 2-oxocyclohexanecarboxylate ligand in DMSO at 80 °C. The corresponding coupling products are obtained with good to excellent yields under relatively mild reaction conditions with good chemoselectivity and functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2008.11.029

Tetrahedron Letters 50 (2009) 434–437
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient C–S cross coupling catalyzed by Cu2O
a,
Hua-Jian Xu a, Xiao-Yang Zhao a, Jin Deng b, Yao Fu b, , Yi-Si Feng
*
*
a School of Chemical Engineering, Hefei University of Technology, Hefei 230009, China
b Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2008
Revised 2 November 2008
Accepted 11 November 2008
Available online 14 November 2008
A protocol for the copper-catalyzed C–S bond formation between aryl, alkyl, or heteroaryl thiols and aryl
or heteroaryl halides is reported. The reaction is catalyzed by Cu2O which shows the highest catalytic
activity with ethyl 2-oxocyclohexanecarboxylate ligand in DMSO at 80 °C. The corresponding coupling
products are obtained with good to excellent yields under relatively mild reaction conditions with good
chemoselectivity and functional group tolerance.
Ó 2008 Published by Elsevier Ltd.
The formation of the C–S bond is indispensable in synthetic
chemistry. Their importance stems from the prevalence of this
bond in many pharmaceutical compounds and from the utility of
aryl sulfides as intermediates in organic synthesis.1 Traditional
methods for the formation of C–S bond involved condensation of
aryl halides with thiols requiring strongly basic and harsh reaction
conditions.2 To overcome these difficulties, considerable attention
has been focused on the development of transition metal-catalyzed
coupling of thiols with aryl halides. Palladium-,3 copper-,4 nickel-,5
cobalt-,6 and iron-based7 catalytic systems have been reported for
this purpose. The high cost and air sensitivity of Pd catalyst sys-
tems and tedious procedures for the preparation of ligands restrict
their applications in large-scale processes. On the other hand, Cu-
mediated coupling reactions sometimes require some expensive
Cu salts and the water-free conditions. Hence, there is a need for
improved procedures for this important reaction in organic chem-
istry. As an ongoing research of exploring the less expensive Cu
salts for this coupling reaction,4h we reported here that cheap
and readily available Cu2O catalyzes efficiently the C–S cross-cou-
pling of aryl, alkyl, and heteroaryl thiols with aryl and heteroaryl
halides in excellent yields. During the preparation of this article,
Bao and co-workers8 had reported that the system Cu2O/ethyl 2-
oxocyclohexanecarboxylate can catalyze Ullmann-type reaction
of vinyl bromides and chlorides with imidazole and benzimidazole.
In the first stage of the study, we tried to seek the optimal li-
gand from compounds 1–8 for the reaction of the model substrate
p-methyl benzenethiol with iodobenzene with Cu2O as the cata-
lyst. The reactions promoted by N,N-type ligands 7 and 8 gave
low yields, although 7 was often used as an excellent ligand for
the C–N coupling.9 O,O-type ligands 3, 4, 5, and 6 were also tested,
and moderate results were achieved. Interestingly, the reactions
gave different results when ligands 1 and 2 were used, where only
ethyl group of 1 was changed into methyl group of 2. Finally, a con-
trol experiment without any ligand was carried out, and low yield
was obtained under the similar condition. From the above descrip-
tions, ligand 1 was chosen for further investigation.
A brief search of other reaction conditions was carried out after
finding the best ligand. The reaction with Cs2CO3 was superior to
that using KOH, K2CO3, and K3PO4. Then, the effect of solvent
was evaluated. Dioxane and toluene were not suitable as solvents.
DMSO performed as the best solvent. DMF gave fair results, but
was not as good as DMSO. The copper sources were also found to
have remarkable effects on the reaction. CuO and Cu(OAc)2 were
not suitable as copper sources. CuI, CuBr, CuCl, CuSO4, and CuBr2
were found to be inferior to Cu2O as catalysts for the C–S coupling
reaction. No reaction was observed without any copper source. The
100
90
80
70
60
50
40
30
20
10
0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
volume of H2O
* Corresponding authors. Tel./fax: +86 551 3607476 (Y.F.).
E-mail address: fuyao@ustc.edu.cn (Y. Fu).
Figure 1. Effect of H2O on the cross-coupling reaction of PhI and p-Me-C6H4SH. The
volume sum of H2O and DMSO is equal to 1 ml.
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.11.029

H.-J. Xu et al. / Tetrahedron Letters 50 (2009) 434–437
435
Table 1
Table 2
Copper-catalyzed coupling of p-methyl benzenethiol with iodobenzenea
The C–S cross-coupling reaction of aryl iodides with thiolsa
Cu2O, ligand 1
Cu source (5 mol%)
ligand (10 mol%)
S
R1I
+
R2SH
R1
R2
Cs CO , DMSO, Ar, 80
˚C
2
3
I
HS
S
base, solvent
Entry Aryl iodides
Thiols
Product
Isolated
yield (%)
O
O
O
O
O
O
O
O
O
O
O
OMe
1
86
95
93
96
OEt
H2N
SH
I
H2N
S
MeO
EtO
OMe
OEt
O
O
2
3
4
1
2
3
4
I
I
I
MeO
SH MeO
S
O
N(Me)2
N(Me)2
NHMe
NHMe
OH
OH
SH
S
5
6
7
8
Yieldb (%)
SH
S
Entry
Cu source
Ligand
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24c
25d
26e
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
1
2
3
4
5
6
7
8
—
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Dioxane
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
98
85
76
76
78
63
53
33
54
75
84
76
85
42
22
66
39
50
18
65
86
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
5
6
7
8
9
90
95
93
51
92
F
SH
I
I
I
I
I
F
S
Cl
SH
Cl
Br
S
Br
SH
S
K3PO4
KOH
O2N
SH O2N
S
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeO
S
OMe
SH
CuBr
CuCl
Cu(OAc)2
CuSO4
CuBr2
CuO
10
11
12
13
14
15
16
17
18
19
20
21
90
81
93
90
76
89
82
73
71
70
91
92
I
I
I
I
I
I
I
I
I
I
SH
S
H2N
S
NH2
SH
—
0
Cu2O
Cu2O
Cu2O
25
98
90
MeO
OMe
S
S
SH
a
General reaction conditions: iodobenzene (1.0 mmol), p-methyl benzenethiol
(1.1 mmol), Cu catalyst (0.05 mmol), ligand (0.1 mmol), and Cs2CO3 (2 mmol) in
indicated solvent (1.0 ml) at 80 °C under Ar for 20 h.
SH
SH
b
GC yield.
c
The reaction was carried out at 60 °C.
The reaction was carried out at 100 °C.
The reaction was carried out in air.
d
S
S
e
N
N
CH2SH
yield of product drastically decreased when reducing the reaction
temperature, while the yield of product remain the same with
higher reaction temperatures. In addition, the yield of product re-
duced only slightly even when the reaction was carried out in air.
Therefore, the optimized conditions employed 5 mol % of Cu2O,
10 mol % of ligand 1, and 2 equiv of Cs2CO3 in DMSO at 80 °C under
argon.
Next, in order to further simplify the procedure, we explored
the effect of water on the reaction under the optimized conditions
as shown in Figure 1. Small amount of water had no impact on the
reaction (volume of H2O = 0.1 ml). However, the yield of product
decreased when more water was added. No reaction was observed
in water.
According to these findings, all materials used in the experi-
ments need not be dry and can be used directly, which can drasti-
cally reduce the cost and time of the reaction. This is important for
application to large-scale processes (see Table 1).
After the best reaction condition was set, we firstly screened a
range of commercially available aryl and heteroaryl iodides and
aryl, alkyl, and heteroaryl thiols to explore the scope of the C–S
SH
S
S
S
S
SH
SH
6
6
SH
SH
SH
10
10
I
S
MeO
I
MeO
S

436
H.-J. Xu et al. / Tetrahedron Letters 50 (2009) 434–437
Table 2 (continued)
Table 3
The C–S cross-coupling reaction of aryl halides with thiophenola
Entry
Aryl iodides
Thiols
Product
Isolated
yield (%)
Cu2O, ligand 1
S
+
PhSH
RX
R
Ph
Cs CO , DMSO, Ar, 80
˚C
2
3
22
90
87
93
91
95
96
86
X= Br, Cl
Cl
I
I
SH
SH
SH
SH
SH
SH
SH
Cl
S
S
Entry
1
Aryl halides
Thiols
Product
Isolated
yield (%)
23
24
25
26
27
28
Br
O
Br
O
O
O
61
67
90b
85
85
52
SH
Br
Br
S
I
S
2
3
4
5
6
NC
SH
SH
SH
SH
SH
NC
S
NC
I
NC
S
O2N
Br
O2N
F3C
S
O2N
F3C
I
O2N
F3C
S
F3C
Br
S
Br
S
I
S
N
O
N
O
Cl
S
I
S
7
8
9
53
82
71
77
NC
Cl
SH
SH
SH
SH
NC
S
S
S
OMe
I
OMe
S
29
30
83
90
SH
SH
O2N
F3C
Cl
O2N
F3C
CN
I
CN
S
Cl
I
Cl
S
S
10
31
32
93
SH
N
N
a
Reaction conditions: arylhalide (1 mmol), thiol (1.1 mmol), Cu2O (0.05 mmol,
ligand 1 (0.1 mmol), and Cs2CO3 (2 mmol) in DMSO (1 ml) at 80 °C under Ar for
24 h.
I
S
S
91
90
SH
SH
N
b
N
S
Only 8% yield of the corresponding product was obtained without Cu2O and
ligand 1 under the similar reaction condition.
33
I
S
moderate yields. 3-Bromopyridene and 3-chloropyridene also
could be applied to this coupling reaction and satisfactory yields
were obtained. The results are summarized in Table 3.
On the basis of these observations and by reference to the liter-
ature,11 we propose that these reactions proceed by oxidative addi-
tion followed by reductive elimination. The results from the
a
Reaction conditions: aryl iodide (1 mmol), thiol (1.1 mmol), Cu2O (0.05 mmol),
ligand 1 (0.1 mmol), and Cs2CO3 (2 mmol) in DMSO (1 ml) at 80 °C under Ar for
20 h.
coupling reaction. As shown in Table 2,10 the coupling of different
thiols with aryl and heteroaryl iodide moieties was successful,
leading to the desired products in excellent yields. The protocol
is tolerant to electron-withdrawing and -donating functional
groups and also to the presence of a functional group in the
ortho-position of the aryl iodide or thiol (entries 9–11 and 28–
30). Heteroaryl iodides (entries 32 and 33) and heteroaryl thiols
(entry 14) were also applied to this coupling reaction. The coupling
reaction is also very chemoselective. Aryl iodides coupled with thi-
ols without affecting fluoro, chloro and bromo groups present in
the aryl ring (entries 5–7, 22 and 23). Moreover, the reaction
showed interesting chemoselectivity for the thiol. For instance, in
entries 1 and 11 C–S coupling was preferred in the presence of
an –NH2 group.
HSR + Base
X
OEt
O
O
X
OEt
(III)
Cu
Ar
O
O
(III)
Ar
Cu
SR
OEt
ArX
Next, we investigated the reactivities of diverse aryl (or hetero-
aryl) bromides and chlorides. Both aryl bromides and chlorides
with electron-donating groups or without any substituents could
not react with thiophenol, while aryl bromides and chlorides with
electron-withdrawing groups could react with thiophenol to give
ArSR
O
O
(I)Cu
Scheme 1.

H.-J. Xu et al. / Tetrahedron Letters 50 (2009) 434–437
437
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coordinated Cu(III) intermediate is involved (see Scheme 1).
According to the mechanism, the role of the ethyl 2-oxocyclohex-
anecarboxylate ligand in the reaction is either to promote the oxi-
dative addition of ArX to the Cu(I) species or to stabilize the Cu(III)
intermediate.
In conclusion, we have described an efficient modified protocol
for C–S cross-coupling of aryl, alkyl, and heteroaryl thiols with aryl
and heteroaryl iodides, bromides, and chlorides using cheap and
available Cu2O as the catalyst. This catalytic procedure offers gen-
eral applicability and simplicity, avoiding the use of expensive Cu
salts and the use of dry starting materials. Because of these inter-
esting features, we believe that the newly developed protocol
can be applied to large-scale synthesis of aromatic thioethers.
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10. General experimental procedure. All reagents and solvents were pure
analytical grade materials purchased from commercial sources and were
used without further purification. The 1H and 13C NMR spectra were recorded
in CDCl3 on a 300 MHz instrument with TMS as internal standard. High-
resolution mass spectra (HRMS) were determined on a Micromass GCT-MS
mass spectrometer. TLC was carried out with 0.2 mm thick silica gel plates
(GF254). The columns were hand packed with silica gel 60 (200-300). All
reactions were carried out in a Schlenk tube equipped with a magnetic stir bar
under Ar atmosphere. A Schlenk tube was charged with Cu salt (0.05 mmol),
inorganic base (2 mmol), and solid substrate, if present. Then liquid reagents
(aryl or heteroaryl halide, 1 mmol; thiol, 1.1 mmol), ligand (0.1 mmol), and
solvent (1 ml) were added under Ar. The reaction vessel was closed and placed
under stirring in a preheated oil bath at 80 °C. The reaction mixture was stirred
for the time listed in Tables 1–3. The resulting suspension was cooled to room
temperature and filtered through a pad of filter paper with the help of 10 ml of
ethyl acetate. The filtrate was concentrated and the residue was purifiled by
silica gel chromatography.
Acknowledgments
This research was financially supported by the National Natural
Science Foundation of China (Nos. 20802015 and 20602034) and
the Doctoral Special Fund of Hefei University of Technology (No.
2007GDBJ021).
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