Synthesis of disulfides and diselenides by copper-catalyzed coupling reactions in water

Article abstract of DOI:10.1039/c3ob40464a

A simple and efficient protocol for copper-catalyzed coupling reactions between aryl halides and elemental sulfur or selenium has been developed. A variety of disulfides and diselenides can be obtained in moderate to excellent yields up to 96%. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40464a

Organic &
Biomolecular Chemistry
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Synthesis of disulfides and diselenides by copper-
catalyzed coupling reactions in water†
Cite this: Org. Biomol. Chem., 2013, 11,
2943
Zhengkai Li,a Fang Ke,*a Hang Deng,a Hualong Xu,a Haifeng Xianga and
Xiangge Zhou*a,b
Received 6th March 2013,
Accepted 20th March 2013
DOI: 10.1039/c3ob40464a
www.rsc.org/obc
A simple and efficient protocol for copper-catalyzed coupling reac- CuCl2 as a catalyst, Cs2CO3 as a base, and (nBu)4NF as a phase
tions between aryl halides and elemental sulfur or selenium has transfer reagent, and water as a reaction medium at 100 °C.
been developed. A variety of disulfides and diselenides can be The desired product was obtained in only 10% yield (Table 1,
obtained in moderate to excellent yields up to 96%.
Recently, there has been an increasing demand for efficient
Table 1 Optimization of reaction conditions of the copper-catalyzed reactions
between iodobenzene and sulphur in watera
methods to synthesize disulfides and diselenides owing to
their important roles as structural motifs in a wide range of
biologically and pharmaceutically active compounds.1 Tran-
sition metal-catalyzed reactions have made a great contri-
bution to the preparation of them. For example, the coupling
of thiol and selenol with aryl halide by using copper or cobalt
catalysts under basic conditions has been reported to result in
corresponding disulfides and diselenides.2 However, some dis-
advantages such as long reaction time, difficulty in workup,
and the use of expensive reagents limited their applications.3
Although copper-catalyzed syntheses of organo-sulfur and
organo-selenium compounds have been well studied, the cata-
lysis by using aryl halide and elemental chalcogen substrate
has seldom been explored to date.4,5 The polymeric structures
of elemental chalcogens (S, Se) which possess chalcogen–
chalcogen bonds might also result in mixture products.6
On the other hand, water has attracted much attention as a
reaction medium because of its low cost, availability, safety
and environmental-friendliness.7,8 In continuation of our
efforts in aqueous catalysis,9 herein is disclosed an environ-
mentally-friendly protocol of dichalcogenation of aryl halides
with elemental S or Se catalyzed by copper(II) catalysts in
water.
Entry [Cu] Source Ligand Base
t [h] T [°C] Yieldb [%]
1
CuCl2
CuCl2
—
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOH
24
24
24
24
24
24
24
24
24
24
24
24
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
10
16
12
92
33
5
44
23
70
20
16
83
47
39
60
18
85
92
85
92
40
2
3
4
5
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
6
7
8
9
Cu(OAc)2
CuSO4
CuI
10
11
12
13
14
15
16
17
18
19
20
21c
CuO
Cu2O
CuCl2
Na2CO3 24
KOH
Initially, our studies began with the reaction between iodo-
benzene and elemental sulphur powder in the presence of
24
24
24
20
28
24
24
24
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
aInstitute of Homogeneous Catalysis, College of Chemistry, Sichuan University,
Chengdu 610064, China. E-mail: zhouxiangge@scu.edu.cn; Fax: +86-28-85412026;
Tel: +86-28-85412026
110
100
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123,
China
a Reactions were carried out by using iodobenzene (1.0 mmol), sulphur
powder (3.0 mmol), Cu source (0.1 mmol), ligand (0.1 mmol), base
(1.0 mmol) and (nBu)4NF (0.1 mmol) in water (2 mL). b Determined by
GC with 1,4-dichlrobenzene as an internal standard. c Without the
addition of (nBu)4NF.
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40464a
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entry 1). Then, various copper sources and ligands were tested, highest yield of 92% (Table 1, entries 2–11). Probably, the stab-
and the results revealed that CuCl2 was better than other ility and solubility in water as well as proper steric hindrance
copper salts including Cu(OAc)2, CuSO4, CuI, CuO and Cu2O, might make the chelating ligand L3 superior to others.10
while 1,10-phenanthroline (L3) was more suitable for the reac- Furthermore, different bases were evaluated, and Cs2CO3
tion than other ligands such as picolinic acid, proline, tetra- exhibited the best efficiency (Table 1, entries 12–16). The
methylethylenediamine (TMEDA) and Schiff base to give the effects of reaction time and temperature were also studied;
24 h and 100 °C were optimal reaction conditions (Table 1,
Table 2 Screening of different substratesa
Table 3 The copper-catalyzed coupling of aryl halides and seleniuma
Entry
1
Aryl halide
Product
Yieldb (%)
90
Entry
1
Aryl halides
Product
Yieldb (%)
88
2
3
4
96 (X = I),
94 (X = Br)
1
2
90
82 (X = I),
76 (X = Br)
85 (X = I),
80 (X = Br)
3
84 (X = I),
80 (X = Br)
86 (X = I),
81 (X = Br)
4
5
79
83
5
6
79
89
6
92 (X = I),
89 (X = Br)
7
8
9
95 (X = I),
90 (X = Br)
7
8
78
88
80 (X = I),
75 (X = Br)
82 (X = I),
78 (X = Br)
9
88
10
11
86
10
87 (X = I),
85 (X = Br)
92 (X = I),
87 (X = Br)
11
85
12
90
a Reactions were carried out by using aryl halide (1.0 mmol), sulphur a Reactions were carried out by using aryl halide (1.0 mmol), Se
powder (3.0 mmol), CuCl2 (0.1 mmol), L3 (0.1 mmol), Cs2CO3 (3.0 mmol), CuCl2 (0.1 mmol), L3 (0.1 m mol), Cs2CO3 (1.0 mmol) and
(1.0 mmol) and (nBu)4NF (0.1 mmol) in water (2 mL) at 100 °C for (nBu)4NF (0.1 mmol) in water (2 mL) at 120 °C for 24 h. b Isolated
24 h. b Isolated yields after chromatography.
yields after chromatography.
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entries 17–20). Meanwhile, a phase transfer reagent seemed to 1,10-phenanthroline; water as a reaction medium instead of
be essential for the reaction, and only 40% yield was obtained the usually used organic solvents; the reactions can be carried
in the absence of (nBu)4NF (Table 1, entry 21). Thus, the opti- out in the air without inert gas. These results indicate great
mized reaction condition for the dichalcogenation of aryl potential of this protocol. Further applications to the synthesis
halides with elemental sulphur consists of CuCl2 (10 mol%), of biologically important molecules are in progress in this lab.
L3 (10 mol%), Cs2CO3 (1 equiv.) and (nBu)4NF (10 mol%) in
water at 100 °C for 24 h.
This project was supported by the Natural Science Foun-
dation of China (Nos. 21072132 and 21272161).
With the optimized reaction condition in hand, we then
examined a series of aryl halides to establish the scope of sub-
strates and find the limits of the catalytic system.
As summarized in Table 2, some functional groups such as
methyl, chloro, nitro, and methoxyl could be introduced into
aryl halides to generate the corresponding disulfides in good
to excellent yields ranging from 78% to 95%. In general, aryl
iodides gave slightly higher yields than their bromo analogs.
Moreover, electron donating substituents seemed to be bene-
ficial to the catalysis. For example, 94% yield was obtained
when 4-methylbromobenzene was used as the substrate, while
81% and 79% yields were obtained in the case of 4-nitro-
bromobenzene and 4-fluorobromobenzene, respectively
(Table 2, entries 2, 4 and 5). Steric hindrance, on the other
hand, has less effect on the results. Both 4-nitro and 2-nitro-
bromobenzene resulted in similar yields around 80% (Table 2,
entries 4 and 9). The highest yield of 96% was obtained in the
case of 4-methyliodobenzene (Table 2, entry 2). It is worthy to
note that heterocyclic halides such as 3-bromopyridine could
also afford the corresponding products in 87% yield (Table 2,
entry 11).
Furthermore, the above method could also be applied to
synthesize diaryl diselenides. As shown in Table 3, selenium is
in general less reactive than sulphur under the same reaction
conditions, and it would be better to increase the reaction
temperature to 120 °C in yields ranging from 75 to 92%
(Table 3).
To demonstrate the application of this method, we syn-
thesized cystine starting from aminoalcohol. As shown in
Scheme 1, the desired product could be obtained in a total
yield around 41%,11 which indicated the potential usage of
this protocol to construct S–S bond in organic compounds.
In conclusion, we have developed an efficient procedure for
the preparation of dichalcogenides from aryl halides and
sulphur or selenium in water. This protocol has several advan-
tages: an easily available catalyst formed in situ by CuCl2 and
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