Disulfides as efficient thiolating reagents enabling selective bis-sulfenylation of aryl dihalides under mild copper-catalyzed conditions

Article abstract of DOI:10.1039/c4ra02935f

Selective bis-sulfenylation reactions of aryl dihalides have been achieved by copper-catalyzed C-S coupling reactions under mild conditions of refluxing EtOH (80 °C). Employment of disulfides as thiolating reagents enables the production of various bis(phenylthio)benzenes with excellent selectivity, and no products from mono C-S coupling are isolated. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02935f

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Disulfides as efficient thiolating reagents enabling
selective bis-sulfenylation of aryl dihalides under
mild copper-catalyzed conditions†
Cite this: RSC Adv., 2014, 4, 19472
a
a
b
a
b
Received 27th February 2014
Accepted 15th April 2014
*
*
Yunyun Liu, Hang Wang, Jida Zhang, Jie-Ping Wan and Chengping Wen
DOI: 10.1039/c4ra02935f
www.rsc.org/advances
Selective bis-sulfenylation reactions of aryl dihalides have been ach-
ieved by copper-catalyzed C–S coupling reactions under mild
conditions of refluxing EtOH (80 ꢀC). Employment of disulfides as
thiolating reagents enables the production of various bis(phenylthio)
benzenes with excellent selectivity, and no products from mono C–S
coupling are isolated.
Introduction
Scheme 1 Tunable mono- and bis-sulfenylation of dihaloaryls.
The formation of C–S bonds is one of the fundamental trans-
formations of organic synthesis. Owing to the prevalent pres-
ence of the C–S bond in biologically relevant compounds,
natural products, argrochemicals and organic materials, the
research on the construction of C–S bonds, especially sp2 C–S
bonds that involving the transformation of inactive sp2 C–X (X
¼ halide, H, etc.) bonds has become an issue of widespread
interest.1–7 Presently, transition metal-catalyzed C–S coupling
reactions between thiol nucleophiles and aryl/vinyl halides are
amongst the most practical approach for the generation of sp2
C–S bonds.8,9 Originally, this kind of reaction has been domi-
nantly performed in the presence of a transition metal catalyst
and high temperature in polar solvents such as DMSO, DMF or
NMP.10–12 Among the different transition metal species which
have been used in the C–S cross-coupling reactions, copper
catalysts have attracted tremendous attention because of their
low cost as well as low toxicity.13–30
few attentions have been paid to the chemo-selective C–S
coupling reactions of dihalide substrates. These kind of selec-
tive reactions providing mono- and bis-sulfenylated aryls,
however, are crucial in expanding the application scope of C–S
coupling chemistry by affording structurally diverse S-contain-
ing products. In 2011, Mao and coworkers reported the
ligand-free bis-sulfenylation of diiodoaryls using thiols as
S-nucleophiles in the presence of iron–copper mixed catalysts at
140 ꢀC.31 In addition, Bagley and coworkers reported the
microwave irradiated, copper-catalyzed protocol which has also
been found selectively promote the bis-sulfenylation of dihalo-
benzenes.26 While these methods rely on the tough reaction
conditions to achieve bis-sulfenylation, developing new meth-
odologies enabling selective bis-sulfenylation reactions under
milder conditions is highly demanding.
While spectacular progress has been witnessed in the eld of
C–S coupling chemistry during the past decade, interestingly,
Following our previous work on copper-catalyzed selective
mono-sulfenylation (Scheme 1)32 as well as other related copper-
catalyzed coupling chemistry,33–37 we report herein the copper-
catalyzed selective bis-sulfenylation of dihaloaryls under mild
and clean conditions by using disuldes as bis-thiolating
agents38 (Scheme 1).
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education, College
of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang
330022, P. R China. E-mail: chemliuyunyun@gmail.com; Fax: +86 791 8812 0380;
Tel: +86 791 8812 0380
bCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou
310053, P. R China. E-mail: cpwen.zcmu@yahoo.com; Fax: +86 571 86633131; Tel:
+86 571 86633131
Results and discussion
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data of all products, 1H and 13C NMR spectra of all products. See
DOI: 10.1039/c4ra02935f
Since we previously discovered that using thiols in the coupling
reactions with diiodobenzenes led to selective mono-
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Table 1 Experiments on optimizing reaction conditionsa
sulfenylation,32 in order to achieve the tunable selective bis-
sulfenylation, we tentatively chosen disuldes as thiolating
reagents in the reactions. Firstly, a class of aryl and alkyl
disuldes were synthesized following a simple and clean
method developed in our lab.39 The reaction of 1,2-diiodo-
benzene 1a and phenyl disulde 2a was then employed as
model reaction for optimizing investigation. In the presence of
CuI, Cs2CO3 at 120 ꢀC in DMSO, a series of different ligands
were rstly screened. It was found that the bis-sulfenylation
could be achieved in the presence of CuI and different types of
ligands. Among the examined ligands, including 1,10-phenan-
throline (L1), 8-hydroxylquinoline (L2), L-proline (L3), D-glucose
(L4) and two enaminone-based ligands (L5 and L6), 2-hydrox-
ylphenyl functionalized enaminone ligand L5 (ref. 40) displayed
the best effect in assisting the bis-sulfenylation reaction with
93% yield of product 3a (Fig. 1).
Subsequently, other parameters of the model reaction were
investigated. The experiments employing different copper
catalysts, including cupric, cuprous salts and copper dust,
suggested that CuI was the most efficient catalyst (entries 1–6,
Table 1). Examination on the effect of different organic and
inorganic bases found no better alternative to Cs2CO3 (entries
7–10, Table 1). Experiments in different solvents implied that
DMF, toluene or dioxane were not able to provide improved
yield over DMSO, however, it has been found that ethanol as the
solvent allowed smooth bis-sulfenylation reaction with excellent
yield of 3a at reux and open air conditions (entries 11–14,
Entry
Cat.
Base
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl2$2H2O
CuBr
CuBr2
CuO
Cu (dust)
Cu(OAc)2$H2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaOH
Et3N
t-BuOK
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Toluene
Dioxane
Ethanol
MeCN
Ethanol
Ethanol
120
120
120
120
120
120
120
120
120
120
120
Reux
Reux
Reux
Reux
90
64
79
67
59
76
62
36
67
Trace
87
89
69
59
95
46
95
59
9
10
11
12
13
14
15
16c
17d
90
a
General conditions: 1a (0.15 mmol), 2a (0.15 mmol), Cu cat. (20 mol
%), L5 (20 mol%) and base (0.3 mmol) in solvent (1 mL), stirred for
b
c
d
15 h (TLC). Yield of isolated product. CuI in 10 mol%. CuI in 5
mol%.
Table 1). Other low boiling point solvent such as acetonitrile
was not able to mediate the reaction effectively (entry 15, Table
1), demonstrating the unique advantage of ethanol in this
selective bis-sulfenylation process. Finally, reducing the
amount of CuI to 10 mol% loading gave 3a with equally excel-
lent yield (entry 16, Table 1). Further decreasing the catalyst
loading, however, was not favored (entry 17, Table 1).
Under the optimal conditions, the application scope of this
catalytic method has been investigated by subjecting different
diiodoaryls and disuldes. As outlined in Table 2, this method
has been found with excellent applicability for the synthesis of
various bis(phenylthio)benzenes. 4-Substituted phenyl disul-
des such as alkyl, halide substituted phenyl disuldes reacted
with different diiodobenzenes 2a–c with generally excellent
yields (3a–f, 3n–r and 3u–y, Table 2). Similarly, 2- and 3-
substituted phenyl disuldes also displayed excellent tolerance
to this synthetic method by providing corresponding products
with satisfactory yields (3g–i, 3s–t and 3z, Table 2). More
importantly, other aryl disuldes such as naphthyl disulde
and heteroaryl disuldes also acted as double thiolating
reagents to yield structurally divergent bis-thiolated benzenes
3j–l (Table 2).
Finally, it is noteworthy that alkyl disulde was also able to
incorporate diiodobenzene to give corresponding bis(alkylthio)
benzene 3m, albeit with lower yield than equivalent entries
using aryl disuldes. Further attempts on running the bis-sul-
fenylation with amino and nitro functionalized phenyl disul-
des revealed the intolerance of these groups to the present
protocol (Table 2).
Based on the known conditions for bis-sulfenylation, the
cross bis-sulfenylation using two different disuldes to incor-
porate 1,2-diiodobenzene was attempted. As outlined in
Scheme 2, the reaction employing simultaneously tolyldisulde
Fig.
1 Different ligands for bis-sulfenylation of 1,2-diiodobenze;
conditions: 1a (0.15 mmol), 2a (0.15 mmol), Cs2CO3 (0.30 mmol), CuI
(0.03 mmol) and ligand (0.03 mmol) in DMSO (1 mL), 120 ꢀC, 15 h
(TLC).
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Table 2 Application scope of the copper-catalyzed, EtOH mediated
bis-sulfenylation of diiodoarylsa
Scheme 3 Bis-sulfenylation reactions of 1,2-dibromobenzene.
Following the good results provided the reactions of diio-
dobenzenes, the entries using 1,2-dibromobenzene have also
been investigated. However, the expect products could only be
obtained with low to fair yields from these experiments,
although harsher conditions (sealed tube, 110 ꢀC) were
employed (Scheme 3).
R
Diiodobenzene
Product
Yieldb (%)
Ph
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
2c
—
—
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
94
91
86
86
85
79
82
83
94
92
84
81
72
91
85
82
82
86
81
83
92
94
86
87
87
91
—
—
4-CH3C6H4
4-i-PrC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-ClC6H4
2-CH3C6H4
3-CH3C6H4
Naphth-2-yl
Pyridine-2-yl
Benzothiazol-2-yl
sec-Butyl
Conclusions
The selective bis-sulfenylation reactions of aryl dihalides have
been achieved with excellent efficiency by employing the
disuldes as double thiolating reagent. The present method
provided a highly useful methodology for the synthesis of
bis(phenylthio)benzenes of type 3. This method also possessed
notable advantages such as green reaction medium, mild
conditions and full utility of thiolating reagents.
Ph
4-CH3C6H4
4-i-PrC6H4
4-FC6H4
4-ClC6H4
2-CH3C6H4
2-ClC6H4
Ph
4-CH3C6H4
4-i-PrC6H4
4-FC6H4
4-ClC6H4
3-CH3C6H4
2-NH2C6H4
2-NO2C6H4
Acknowledgements
3s
3t
This work is nancially supported by NSFC of China (no.
21202064), a research project of the Jiangxi Provincial Depart-
ment of Education (no. GJJ12211), a Sponsored Program for
Cultivating Youths of Outstanding Ability in Jiangxi Normal
University (Y. Liu), a program Sponsored by Zhejiang Provincial
Program for the Cultivation of High-level Innovative Health
talents (C. Wen) as well as a program of Graduate Student
Innovative Research from Jiangxi Province (no. YC2013-S104).
3u
3v
3w
3x
3y
3z
—
—
a
General conditions: 1 (0.5 mmol), 2 (0.5 mmol), CuI (0.05 mmol), L5
(0.1 mmol) and Cs2CO3 (1.0 mmol) in alcohol (2 mL), reux for 15 h.
b
Yield of isolated product.
Notes and references
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