Air-Induced Disulfenylation of Alkenes: Facile Synthesis of Vicinal Dithioethers

Article abstract of DOI:10.1055/s-0039-1691493

A novel disulfenylation of alkenes with thiophenols and their corresponding disulfides by using air as the oxidant has been achieved. This transformation provides a facile and practical protocol for the synthesis of vicinal dithioethers under mild conditions.

Full text of DOI:10.1055/s-0039-1691493

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
G. Yu et al.
Letter
Synlett
Air-Induced Disulfenylation of Alkenes: Facile Synthesis of Vicinal
Dithioethers
Guodian Yu
Yingcong Ou
Danyao Chen
Yuanting Huang
Yan Yan
ArSH (0.2 equiv)
trace O2
SAr
+
ArS SAr
R
SAr
CH2Cl2, rt
R
R = aryl, alkyl
24 examples
39–80% yield
• air as green oxidant • neutral conditions • room temperature
Qian Chen*
0
0
0
0-0
0
0
2-
0
8
1
8-6
0
2
8
School of Chemical Engineering and Light Industry,
Guangdong University of Technology, Guangzhou
510006, P. R. of China
qianchen@gdut.edu.cn
Received: 10.09.2019
Accepted after revision: 05.11.2019
Published online: 19.11.2019
fur bonds.8 Notably, thiyl radicals can be easily generated
by the autoxidation of thiols in the presence of oxygen.8c,9 In
addition, we have also recently developed a variety of met-
al-free methods for the construction of carbon–sulfur,
phosphorus–sulfur, sulfone–sulfur, and sulfur–oxygen
bonds by pathways involving thiyl radicals.10 On this basis,
we surmised that vicinal dithioethers might be formed by
disulfenylation of alkenes with thiols and disulfides in the
presence of air (oxygen). As shown in Scheme 1, under an
air atmosphere, the autoxidation of thiol 2 generates a thiyl
radical that can undergo subsequent homocoupling to pro-
duce the corresponding disulfide 3.9 The thiyl radical can
also add across alkene 1 with anti-Markovnikov selectivity
to form a carbon-centered radical.7b This radical can then
react with disulfide 3 to produce the desired vicinal dithio-
ether 4 through radical propagation, with regeneration of
the thiyl radical.11 Moreover, additional reaction pathways
would be competitive and would give the corresponding
byproducts. Thus, the carbon-centered radical could ab-
stract a hydrogen atom from another molecule of thiol 2 to
give the hydrothiolated product 512 or it might react with
oxygen to form a peroxy radical that might afford the -
keto sulfide 613 or -hydroxy sulfide 7.14 Here, we report
DOI: 10.1055/s-0039-1691493; Art ID: st-2019-u0480-l
Abstract A novel disulfenylation of alkenes with thiophenols and their
corresponding disulfides by using air as the oxidant has been achieved.
This transformation provides a facile and practical protocol for the syn-
thesis of vicinal dithioethers under mild conditions.
Key words disulfenylation, alkenes, thioethers, aerial oxidation
Organosulfur compounds bearing carbon–sulfur bonds
are of great importance in organic synthesis and biological
chemistry.1,2 As a result, the development of novel methods
for the construction of carbon–sulfur bonds under mild
conditions has attracted enormous attention.3 Among these
methods, the disulfenylation of carbon–carbon unsaturated
bonds is a facile and practical protocol for the preparation
of vicinal dithioethers,4 which have been widely used as
bidentate ligands and in pharmaceutical chemistry as syn-
thetic intermediates.5 Previous disulfenylations of alkenes
with disulfides typically require a Lewis acid (e.g., GaCl3 or
FeCl3)4a,4b or molecular iodine4f as a catalyst. In particular, Li
and Chen reported an NH4I-promoted bismethylthiolation
of terminal alkenes by using dimethyl sulfoxide (DMSO) as
the thioetherification reagent.4h Our group recently devel-
oped a catalyst-free direct C(sp3)–H sulfenylation of xan-
thenes by using air as the oxidant.6 Consequently, we be-
came interested in studying an air-induced disulfenylation
of alkenes for the synthesis of vicinal dithioethers under
mild conditions.
O2
ArSH
ArS
ArS SAr
ArS
2
3
SAr
SAr
R
R
SAr
this work
R
1
2
4
O2
ref. 12
SAr
R
5
Thiyl radicals are known to add efficiently to a wide
range of unsaturated compounds such as alkenes, alkynes,
or isonitriles.7 The most useful synthetic applications of thi-
yl radicals are based on their ability to add to carbon–car-
bon unsaturated bonds for the construction of carbon–sul-
O
OH
O
ref. 14
ref. 13
O
SAr
SAr
SAr
R
R
R
7
6
Scheme 1 Additions of thiyl radicals to alkenes
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
G. Yu et al.
Letter
Synlett
that air can efficiently induce the addition of thiols and di-
sulfides to alkenes and provide good yields of vicinal dithio-
ethers through a radical pathway under neutral conditions.
The reaction conditions were tested by using a model
reaction of styrene (1a) with 4-methylbenzenethiol (2a)
and bis(4-methylphenyl) disulfide (3a) under air (Table 1).
First, we carried out the reaction of 1a with 2a (0.5 equiv)
and 3a (3 equiv) in CH3CN at room temperature under air
for 24 hours (Table1, entry 1). To our delight, the reaction
afforded the desired vicinal dithioether 4a in 52% yield, to-
gether with -keto sulfide 6a and -hydroxy sulfide 7a in
yields of 17 and 24%, respectively. A screening of solvents
(entries 2–8) showed that CH2Cl2 is the optimal solvent,
leading to the formation of 4a in 59% yield (entry 8). When
two equivalents of disulfide 3a were employed, 4a was still
obtained in the same yield (entry 9), whereas the use of one
equivalent of 3a significantly decreased the product yield
(entry 10). When a catalytic amounts of thiol 2a (0.2 equiv)
was used, the yield of 4a remained unchanged (entry 11),
suggesting that the propagation of thiyl radicals might be
involved in the reaction. In an attempt to prevent the for-
mation of byproducts 6a and 7a, we carried out the reac-
tion under various air–N2 atmospheres (entries 12–15).
Pleasingly, when the amount of oxygen in the reaction at-
mosphere was about 5%, the reaction proceeded smoothly
to afford 4a in 76% yield (entry 13), and the formation of
byproducts was significantly reduced by the use of the low-
er concentration of oxygen. In addition, a further decrease
in the amount of thiol 2a led to a poor yield of 4a, probably
due to the difficulty in the formation of thiyl radicals in the
presence of catalytic amounts of both the thiol and oxygen
(entries 16 and 17). Finally, we concluded that the optimal
conditions for the disulfenylation of alkenes involve the use
0.2 equivalents of the thiol and two equivalents of the disulfide
as a sulfur source with a trace amount of oxygen as the oxidant
and CH2Cl2 as the solvent at room temperature (entry 13).
We then set out to explore the generality of the disulfe-
nylation of alkenes.15 We first applied the optimized condi-
tions to the reaction of styrene (1a) with a variety of thiols
2 and their corresponding disulfides 3 (Table 2). Thiophe-
nols and disulfides substrates bearing various substituents
such as electron-donating groups (Me or OMe) or weakly
electron-withdrawing groups (Br, Cl, or F) on the para- or
meta-positions of the aromatic rings were all well tolerated,
and the corresponding vicinal dithioethers 4a–j were iso-
lated in good yields (60–80%). Unfortunately, the disulfe-
nylation of 1a with (2-methylphenyl)thiol and the corre-
sponding disulfide failed to give the desired product 4k,
probably due to the steric hindrance by the ortho-substitu-
ent. We then turned our attention to aliphatic thiols.
Phenylmethanethiol and its corresponding disulfide did not
afford the dithioether 4l, possibly because aliphatic thiols
fail to generate thiyl radicals under air.6 In addition, a
Table 1 Optimization of Reaction Conditionsa,b
STol-p
STol-p
air
+ p-TolSH + (p-TolS)2
+ 6a/7a
Ph
1a
solvent, rt
Ph
2a
3a
4a
Entry 2a
3a
Solvent
Yieldb (%) Yieldb (%) Yieldb
of 4a
(equiv) (equiv)
of 6a
(%) of 7a
1
2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.2
0.2
0.2
0.2
0.15
0.1
3
3
3
3
3
3
3
3
2
1
2
2
2
2
2
2
2
CH3CN
THF
52
22
17
24
24
35
3
1,4-dioxane
DMF
trace
trace
trace
65
4
trace
trace
22
trace
trace
trace
trace
15
5
EtOH
trace
trace
27
6
DCE
7
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
trace
59
8
19
9
59
15
20
10
11
12c
13d
14e
15f
16d
17d
43
24
30
59
15
19
68
10
14
76
trace
trace
trace
trace
trace
9
70
11
52
trace
trace
trace
42
trace
a Reaction conditions: a 25 mL vial was charged with 1a (0.2 mmol), 2a,
and 3a in the appropriate solvent (2 mL) and sealed under an air atmo-
sphere (1 atm). The mixture was stirred at rt for 24 h.
b Yield based on 1a as determined by 1H NMR analysis of the crude product
using an internal standard.
c Air (9 mL) was introduced into the sealed vial under N2.
d Air (7 mL) was introduced into the sealed vial under N2.
e Air (5 mL) was introduced into the sealed vial under N2.
f Air (3 mL) was introduced into the sealed vial under N2.
scaled-up reaction was attempted and, when we increased
the scale of the reaction of 1a with 2a and 3a from 0.2 to
7 mmol, we obtained 4a in 65% yield (1.6 g).
To further define the scope of our protocol, the sub-
strate scope was extended to various alkenes 1 under the
optimized conditions (Table 3). Terminal aromatic alkenes
with various groups (Me, Br, Cl and F) in the para-, meta-, or
ortho-position of aromatic rings underwent the reaction,
delivering the desired products 4m–w in good yields. Sig-
nificantly, the disulfenylation of terminal aliphatic alkenes
gave 4x and 4y in yields of 39 and 67%, respectively. Fur-
thermore, cyclohexene, an internal aliphatic alkene, stereose-
lectively afforded the trans-vicinal dithioether 4z in 45% yield.
To gain more insight into the mechanism of the reac-
tion, we conducted a series of control experiments (Scheme
2). The disulfenylation of styrene (1a) with disulfide 3a
failed to give the desired 4a in the absence of thiol 2a under
otherwise standard conditions (Scheme 2a), suggesting
that the reaction is initiated by thiol 2a. When the reaction
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
G. Yu et al.
Letter
Synlett
Table 2 Scope of Thiols and Disulfidesa,b
Table 3 Scope of Alkenesa,b
RSH (2) (0.2 equiv)
ArSH (2) (0.2 equiv)
SR
SAr
trace O2
trace O2
RS SR
+
+
ArS SAr
Ph
R
SR
SAr
CH2Cl2, rt
CH2Cl2, rt
Ph
R
1a
3
1
3
4
4
SPh
SPh
SPh
STol-p
STol-p
Me
OMe
SPh
S
S
S
4m, 73%
4n, 66%
4o, 72%
Me
Cl
Cl
S
S
S
Ph
Ph
Ph
Cl
4a, 71% (65%)c
4b, 70%
4c, 80%
Me
OMe
SPh
SPh
STol-p
STol-p
S
Cl
F
Br
S
4p, 67%
4q, 70%
F
F
S
S
S
4r, 65%
F
Cl
S
S
S
Ph
Ph
Ph
Ph
Ph
SPh
STol-p
STol-p Br
SPh
4e, 70%
4f, 73%
4d, 71%
Cl
SPh Cl
SPh
Cl
F
Br
4s, 62%
SPh
4t, 68%
STol-p
STol-p
4u, 66%
STol-p
STol-p
Cl
Cl
S
Me
S
Br
S
Cl
SPh
S
Me
S
Br
S
Cl
Me
Ph
4v, 70%
STol-p
STol-p
4w, 65%
SPh
4x, 39%
4g, 70%
4h, 60%
4i, 62%
Me
Me
Me
SPh
PhO
S
S
Me
SBn
4z, 45%
4y, 67%
S
Me
Me
S
SBn
Ph
Ph
Ph
a Reaction conditions: a 25 mL vial was charged with 1a (0.2 mmol), 2 (0.04
mmol), and 3 (0.4 mmol) in CH2Cl2 (2 mL) and sealed under an air–N2 at-
mosphere (~5% O2). The mixture was stirred at rt for 24 h.
b Isolated yields based on 1 are reported.
4j, 75%
4k, 0%
4l, 0%
a Reaction conditions: a 25 mL vial was charged with 1a (0.2 mmol), 2 (0.04
mmol), and 3 (0.4 mmol) in CH2Cl2 (2 mL) and sealed under an air–N2 at-
mosphere (~5% O2). The mixture was stirred at rt for 24 h.
b The isolated yields based on 1a are reported.
c Scaled-up reaction (7 mmol).
pletely inhibited, and the TEMPO adduct 8 was detected by
LC-MS (Scheme 2d), indicating that this reaction might in-
volve an addition of a thiyl radical to the alkene. Overall, the
results of these control experiments are in good agreement
with the mechanism proposed in Scheme 1.
In summary, we have developed a green and efficient
disulfenylation of alkenes with thiophenols and their corre-
sponding disulfides induced by a trace amount of oxygen,
thereby providing a facile and practical protocol for the
synthesis of vicinal dithioethers. The good yields and mild
reaction conditions showcase the potential of this approach
in chemical synthesis.
was carried out under N2, 4a was not detected (Scheme 2b),
suggesting that an aerobic oxidation might be involved in
the reaction. The yield of 4a remained unchanged when the
reaction was performed in the dark (Scheme 2c), suggesting
that visible light is unnecessary for this transformation.
When the radical scavenger TEMPO (2,2,6,6-tetrameth-
ylpiperidine N-oxyl) was employed under the standard con-
ditions, the desired reaction of 1a with 2a and 3a was com-
standard conditions
STol-p
STol-p
(a)
+
(p-TolS)2
Ph
1a
1a
Funding Information
without p-TolSH (2a)
Ph
1a
3a
4a
N2 atmosphere
This research was supported by the Science and Technology Planning
Project of Guangdong Province (No. 2017A010103044), the Natural
Science Foundation of Guangdong Province (No. 2017A030313071),
the National Undergraduate Training Program for Innovation and En-
trepreneurship (No. 201911845133), and the 100 Young Talents Pro-
0%
(b)
(c)
+
2a
+
3a
3a
4a
CH2Cl2, rt
0%
standard conditions
in the dark
+
+
2a
2a
+
+
4a
70%
Me
Me
gram of Guangdong University of Technology (No. 220413506).
N
atura
l
S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
G
u
a
n
g
d
o
n
g
Pro
v
i
n
c
e
(2
0
1
7
A
0
3
0
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1
3
0
7
1)S
c
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n
d
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o
g
y
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2
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4
1
3
5
0
6)
standard conditions
TEMPO (2 equiv)
1a
3a
4a
0%
+
S
N
(d)
O
Me
Me
Acknowledgment
Me
8, detected by LC-MS
We thank the Guangdong University of Technology Analysis and Test
Center for providing characterization data for all compounds.
Scheme 2 Mechanistic studies
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
G. Yu et al.
Letter
Synlett
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.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691493.
S
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(15) 1,1′-[(1-phenylethane-1,2-diyl)di(sulfanediyl)]bis(4-methyl-
benzene) (4a): Typical Procedure
A 25 mL vial was charged with styrene (1a) (21 mg, 0.2 mmol),
thiol 2a (5 mg, 0.04 mmol), and disulfide 3a (99 mg, 0.4 mmol)
in CH2Cl2 (2 mL), then sealed under a N2 atmosphere. Air (7 mL)
was introduced into the sealed vial and the mixture was stirred
at rt for 24 h. After removal of the solvent, the residue was puri-
fied by flash column chromatography (silica gel, PE) to give a
white solid; yield: 50 mg (71%); mp 67.2–68.5 °C.
1H NMR (400 MHz, CDCl3):  = 7.29–7.17 (m, 5 H), 7.14 (d,
J = 8.0 Hz, 2 H), 7.07–6.97 (m, 6 H), 4.15 (dd, J = 10.1, 4.9 Hz, 1
H), 3.42 (dd, J = 13.5, 4.9 Hz, 1 H), 3.27 (dd, J = 13.5, 10.2 Hz, 1
H), 2.29 (s, 3 H), 2.29 (s, 3 H). 13C NMR (100 MHz, CDCl3):
 = 140.0, 137.9, 136.6, 133.5, 131.9, 130.7, 130.5, 129.80,
129.77, 128.6, 128.2, 127.8, 52.7, 40.2, 21.3, 21.2.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D