A concise synthetic strategy to alkynyl sulfides via transition-metal-free catalyzed C-S coupling of 1,1-dibromo-1-alkenes with thiophenols

Article abstract of DOI:10.1016/j.tetlet.2012.05.072

A novel synthetic strategy to alkynyl sulfides via transition-metal-free catalyzed C-S coupling of 1,1-dibromo-1-alkenes with thiophenols has been developed. The new strategy which avoided the transition-metal toxicities is environmental friendly and very

Full text of DOI:10.1016/j.tetlet.2012.05.072

Tetrahedron Letters 53 (2012) 3907–3910
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A concise synthetic strategy to alkynyl sulfides via transition-metal-free
catalyzed C–S coupling of 1,1-dibromo-1-alkenes with thiophenols
⇑
Zhangqin Ni, Sichang Wang, Hui Mao, Yuanjiang Pan
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 March 2012
Revised 7 May 2012
Accepted 15 May 2012
Available online 19 May 2012
A novel synthetic strategy to alkynyl sulfides via transition-metal-free catalyzed C–S coupling of
1,1-dibromo-1-alkenes with thiophenols has been developed. The new strategy which avoided the tran-
sition-metal toxicities is environmental friendly and very important for alkynyl sulfides synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Transition-metal-free
C–S cross-coupling
Alkynyl sulfides
The development of transition-metal-catalyzed cross-coupling
reactions is one of the most significant advances in modern organic
synthesis and has received much attention due to their efficient
construction of C–C bond and C–X bond.1 Alkynyl sulfides are very
important intermediates in organic synthesis and can be used as
versatile building blocks for a variety of chemical purposes, such
as cycloaddition2 and cross-coupling reactions.3 Generally, the most
precedent methodologies are based on the use of transition-metal
catalysts (Scheme 1). A report by Braga et al. in 1993 described
the synthesis of alkynyl sulfides by reacting alkynyl bromides with
disulfides in the presence of CuI (Eq. 1).4 Later, they also developed
an alternative preparation by employing terminal alkynes with
thiophenols (Eq. 2).5 Recently, copper and rhodium reagents were,
respectively, used by the groups of Bieber6 and Yamaguchi7 to cat-
alyze the C–S coupling of 1-alkynes with disulfides (Eq. 3).
K2CO3 (4 equiv) (Table 1, entry 1). The reaction was completely
ineffective in this condition. The desired product still could not
be obtained adopting other similar ligands (Table 1, entries 2–4).
It was interesting to find that the reaction could occur in the
absence of CuI and ligand, and gave the product (phenyleth-
ynyl)(phenyl)sulfide (3a) with 39% yield (Table 1, entry 5). Inspired
by this result, we further investigated this transformation under
different conditions. Various bases were evaluated in this reaction
and Cs2CO3 was proved to be most effective (Table 1, entries 5–10).
Further optimization was focused on reaction temperature and
solvent effect. The reaction got lower yield in 90 °C or 110 °C com-
pared with that in 100 °C (Table 1, entries 6, 11, 12). It was turned
out that the solvent is an important factor of the reaction. The non-
polar solvents such as dioxane and toluene could not afford the
desired product. The reaction could happen in polar solvents, but
the yield in DMF was lower than that in DMSO (Table 1, entries
6, 13–15). Finally, it was realized that the optimum condition to
To our knowledge, few studies8 are focused on the formation of
alkynyl sulfides without transition metal reagents. These methods
suffer from strict conditions and limited scopes. On the basis of the
promising potentialities of alkynyl sulfides, it would be desired to
develop a general method for the synthesis without any transition-
metals. Drawing from recent experiences in the field of construc-
tion of C–X bond, vinyl dibromides were used to construct alkynes
by the groups of Evano,9 Rao,10 and Hayes.11 Herein, we report the
first example for the synthesis of alkynyl sulfides from vinyl dibro-
mides without any transition-metals (Eq. 4).
Cu cat
R1
R1
SR2
SR2
R1
R1
Br
H
R2SSR2
R2SBr
(1)
(2)
Cu cat
Cu cat
or Rh cat
TMF
R1
R1
SR2
SR2
R1
H
R2SSR2
R2SH
(3)
(4)
We initiated our studies by examining the reaction of thiophe-
nol (2a) with 1.2 equiv of (2,2-dibromovinyl)benzene12 (1a) in
DMSO in the presence of CuI (10 mol %), DMEDA (10 mol %), and
Br
Br
R1
TMF = Transition-Metal-Free
⇑
Corresponding author.
E-mail address: cheyjpan@zju.edu.cn (Y. Pan).
Scheme 1. The synthetic methodologies of alkynyl sulfides.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.072

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Z. Ni et al. / Tetrahedron Letters 53 (2012) 3907–3910
Table 1
Table 2
Screening of reaction conditions for synthesis of alkynyl sulfidesa
Transition-metal-free coupling of (2,2-dibromovinyl)benzene with various thi
ophenols a
Br
Br
Br
Ph
SPh
S
SH
SH
Cs2CO3
Ph
Br
R
R
Ph
Ph
1a
2a
Base
DMSO, 100 °C
3a
2
3
1
Entry
Additive
Temp (°C)
Solvent
Yieldb (%)
Entry
1
Thiophenol
Product
Yieldb (%)
55
1
2
3
4
5
6
7
8
CuI/L1
CuI/L2
CuI/L3
CuI/L4
No
No
No
No
No
No
No
No
No
No
No
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
Na2CO3
Et3N
t-BuONa
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
100
100
100
100
100
100
100
100
100
100
90
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
N.Rc
N.R
N.R
N.R
39
55
50
30
N.R
N.R
45
34
48
SH
S
3a
Ph
SH
SH
3b
S
S
2
3
58
43
Ph
3c
9
10
11
12
13
14
15
Ph
SH
3d
S
110
100
100
100
4
40
Ph
1,4-Dioxane
Toluene
N.R
N.R
t-Bu
t-Bu
S
SH
SH
3e
Ph
3f
5
6
7
48
37
40
N
PPh3
L4
F
F
N
F
N
N
N
N
F
S
L1
L2
L3
Ph
a
All the reactions were conducted with (2,2-dibromovinyl)benzene (1.2 equiv,
0.75 mmol), thiophenol (1 equiv, 0.5 mmol), and base (4 equiv, 2 mmol) in 3 mL
of solvent under nitrogen atmosphere, 10 h.
Isolated yield.
Pure product was not obtained.
SH
3g
S
b
c
Ph
Cl
Cl
SH
Cl
S
3h
Ph
8
38
obtain high coupling yield was Cs2CO3 (4 equiv) in DMSO at 100 °C
(Table 1, entry 6). The product of the reaction was fully character-
ized by 1H and 13C NMR and mass spectroscopic data.
Cl
SH
SH
3i
Ph
3j
Ph
S
S
9
10
11
43
34
38
With the optimized condition in hand, we investigated the
scope and limitation of this coupling with various thiophenols.
As shown in Table 2, thiophenols bearing electron-donating
or -withdrawing groups on the aromatic ring could react with
(2,2-dibromovinyl)benzene smoothly to afford the corresponding
products in moderate yields (Table 2, entries 2–11). The presence
of electron-withdrawing groups on the aromatic ring decreased
the nucleophilicity of thiophenols and the products were obtained
in lower yields (Table 2, entries 5–11). Moreover, the homo-cou-
pling product was not isolated in these reactions.
To further explore the utility of the reaction, different 1,1-dibro-
mo-1-alkenes were subjected to the reaction. The substrates pre-
pared for examining the scope of this synthesis were readily
synthesized. It was pleased to find that 1,1-dibromo-1-alkenes
with electron-donating or -withdrawing groups on the aromatic
ring could react with thiophenol to get the desired product with
acceptable yields (Table 3, entries 1–7). The presence of electron-
donating groups decreased the efficiency of the reaction and the
products were obtained in lower yields (Table 3, entry 2). In turn,
the derivates having electron-withdrawing groups got higher
yields (Table 3, entries 3–5). Furthermore, 1,1-dibromo-1-alkenes
with heteroaromatic ring were found to be good partners in this
reaction (Table 3, entries 6 and 7).
Br
Br
Br
Br
SH
S
3k
Ph
F3C
F3C
a
All the reactions were conducted with 1,1-dibromo-1-alkenes (1.2 equiv,
0.75 mmol), thiophenols (1 equiv, 0.5 mmol), and Cs2CO3 (4 equiv, 2.0 mmol) in
3 mL of DMSO at 100 °C in nitrogen atmosphere.
b
Isolated yield.
In order to confirm which could be the proposed mechanism, we
designed such experiment. (2,2-Dibromovinyl)benzene and ben-
zenethiol were stirred in standard condition for 4 h. Then the ex-
tract was analyzed by GC–MS (see Supplementary data). There
were three main peaks. The peak retention time at 4.2 min corre-
sponded to alkynyl sulfide and the molecular weight was 210. The
peak retention time at 4.4 min might correspond to (1-bromo-2-
phenylvinyl)(phenyl)sulfane. The molecular weight was 290 and
the peak ratio was 1:1. From the peak ratio, we could confirm there
was one bromine atom in the compound. Thus, we felt that the path
B (Scheme 2) is more favorable for the present conversion.
In conclusion, a novel synthetic strategy to alkynyl sulfides via
transition-metal-free catalyzed C–S coupling of 1,1-dibromo-1-al-
kenes with thiophenols has been developed. Through this efficient
and general protocol, a series of alkynyl sulfides have been
prepared from readily available starting material. This method pro-
vided a facile and useful supplement for those already established
routes. Further studies on the C–S coupling are underway in our
laboratory.
Based on these results, the mechanism of the reaction can be
proposed as shown in Scheme 2. There may be two possible
pathways for the thiol to form the corresponding alkynyl sulfides.
Path A: 1,1-dibromo-1-alkene was dehydrobrominated firstly and
the resulted alkynyl bromide could convert to the corresponding
product by treating with thiol anion. Path B: thiol anion attacked
1,1-dibromo-1-alkene. Then the resulted (1-bromo-2-phenylvi-
nyl)(phenyl)sulfane could be dehydrobrominated to form alkynyl
sulfide.

Z. Ni et al. / Tetrahedron Letters 53 (2012) 3907–3910
3909
Table 3
Transition-metal-free coupling of thiophenol with various 1,1-dibromo-1-alkenesa
Br
Br
SH
Cs2CO3
S
Ar
DMSO, 100 °C
Ar
1
2
3
Entry
1
Ar
Sulfide
Yieldb (%)
58
Br
Br
3l
S
Br
Br
3m
3n
S
2
3
42
70
Br
Br
S
Br
Cl
Br
Cl
Br
S
3o
Br
4
5
65
76
Br
3p
S
Br
Cl
Cl
3q
S
Br
6
7
80
40
Br
Br
3r
S
S
Br
S
a
All the reactions were conducted with 1,1-dibromo-1-alkenes (1.2 equiv, 0.75 mmol), thiophenols
(1 equiv, 0.5 mmol), and Cs2CO3 (4 equiv, 2.0 mmol) in 3 mL of DMSO at 100 °C in nitrogen atmosphere.
b
Isolated yield.
Br
Base
SH
S
R
Br
Base
Path A
Br
Path B
S
R
R
Br
Ph
Base
R
S
Base
SH
S
Scheme 2. Proposed mechanism.
Acknowledgments
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.
072.

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