Molecular Iodine Catalyzed Hydroxysulfenylation of Alkenes with Disulfides in Aerobic Conditions

Article abstract of DOI:10.1055/s-0039-1690163

An environmentally friendly and efficient strategy has been developed for preparing β-hydroxy sulfides by a molecular-iodine-catalyzed radical reaction. This reaction involves hydroxysulfenylation of alkenes with disulfides in aqueous solution. Air is use

Full text of DOI:10.1055/s-0039-1690163

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
B.-q. Ni et al.
Letter
Synlett
Molecular Iodine Catalyzed Hydroxysulfenylation of Alkenes with
Disulfides in Aerobic Conditions
R3
Bang-qing Ni*
Yunpeng He
Xuejiao Rong
Teng-fei Niu*
Air, I2
R3
OH
R2
S
R1
Ar
60 °C
MeCN/H2O
ArS-SAr
+
R2
R1
metal-free catalysis
air as oxidant
0
0
0
0-0
0
0
2-6
0
8
0-2
6
6
8
both aryl and aliphatic alkenes
24 examples
up to 86% isolated yield
School of Chemical and Material Engineering, Jiangnan Univer-
sity, Wuxi 214122, Jiangsu Province, P. R. of China
byron_ni@yeah.net
niutf@jiangnan.edu.cn
Received: 09.06.2019
Accepted after revision: 31.07.2019
Published online: 09.08.2019
ported a Zn/AlCl3-catalyzed one-pot synthesis of -hydroxy
sulfides from various styrenes and disulfides (Scheme 1a).
Yadav and co-workers8 disclosed a metal-free radical path-
way to afford -hydroxy sulfides by using Rongalite
(HOCH2SO2Na·2H2O) as a promoter under aerobic condi-
tions (Scheme 1b). Recently, Yan and co-workers9 reported
a HBr/H2O2-mediated sulfidation of styrenes, leading to -
hydroxy sulfides (Scheme 1c). Although these methods pro-
vide efficient routes to -hydroxy sulfides, most of them
have drawbacks, such as the use of toxic catalysts or exces-
sive use of promoters or oxidants. Furthermore, these
methods are generally focused exclusively on terminal aryl
alkenes, whereas aliphatic alkenes are inert toward these
transformations. Therefore, an environmentally friendly
and efficient process for preparing such motifs remains
highly desirable.
DOI: 10.1055/s-0039-1690163; Art ID: st-2019-u0306-l
Abstract An environmentally friendly and efficient strategy has been
developed for preparing -hydroxy sulfides by a molecular-iodine-cata-
lyzed radical reaction. This reaction involves hydroxysulfenylation of
alkenes with disulfides in aqueous solution. Air is used as the oxidant
without any additives. Control experiments indicated that the oxygen
atom of products might come from O2. Both aryl alkenes and aliphatic
alkenes were well tolerated in this transformation and afforded the cor-
responding products in moderate to high yields.
Key words hydroxysulfenylation, hydroxy sulfides, iodine catalysis,
green chemistry
-Hydroxy sulfides have found widespread use as con-
venient intermediates for the construction of biologically
active heterocycles,1 pharmaceuticals,2 and natural prod-
ucts.3 Consequently, numerous synthetic methods have
been reported for the preparation of these compounds. The
classical approaches for accessing these compounds in-
volves the ring opening of epoxides with thiols.4 Alterna-
tively, the thiol–oxygen co-oxidation reaction of alkenes is
another useful method.5 Despite their great success, these
methods involve the use of large excesses of fetid, sensitive,
and toxic thiols, possibly hindering their widespread appli-
cation. Thus, an efficient way for building these useful
structures without generating obnoxious odors remains an
attractive prospect.
In the past decade, methods for the use of disulfides in-
stead of thiols have been developed for the preparation of
-hydroxy sulfides.6 Among these, the oxidative sulfidation
of alkenes with disulfides has attracted considerable atten-
tion. Alkene dihydroxysulfenylation can efficiently intro-
duce a C–O bond and a C–S bond in one step from simple
starting materials. For example, Movassagh and Navidi7 re-
previous works:
OH
Zn/AlCl3, O2
(a)
Ar'
Ar'
ArS-SAr
ArS-SAr
S
+
+
Ar
Ar'
80 °C
MeCN/H2O
K2CO3
HOCH2SO2Na⋅2H2O
OH
Ar'
(b)
(c)
S
Ar
air, rt
MeCN/H2O
OH
Ar'
H2O2
Ar'
ArSSO Na
+
S
3
Ar
MeCN, HBr
only aryl alkenes
this work:
R3
R3
(d)
air, I2 (0.2 equiv)
OH
R2
R1
S
ArS-SAr
+
R2
Ar
60 °C
MeCN/H2O
R1
both aryl and aliphatic alkenes
Scheme 1 Methods for the synthesis of -hydroxy sulfides
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
B.-q. Ni et al.
Letter
Synlett
As a classical nonmetallic-element-catalyzed process,
molecular-iodine-catalyzed oxidation represents a recent
advance in terms of environmental sustainability and cost
effectiveness.10 The Peddinti group11 recently developed a
regioselective synthesis of -hydroxy sulfides from termi-
nal styrenes and thiophenols by using iodine; however,
DMSO was used as the oxidant in this reaction. As an ideal
oxidant, molecular oxygen is clean, nontoxic, and environ-
mentally sustainable. In this context, we describe the devel-
opment of an environmentally friendly and efficient meth-
od for an aerobic molecular-iodine-catalyzed hydroxysulfe-
nylation of both aryl and aliphatic alkenes with disulfides
to generate -hydroxy sulfides (Scheme 1d).
In our initial study, we chose bis(4-chlorophenyl) disul-
fide (1a) and styrene (2a) as our model substrates. To our
delight, we obtained a 62% yield of the desired product 3a
in the presence of I2 in MeCN–H2O (3:1, v/v) at 40 °C under
air after two hours (Table 1, entry 1). To obtain an optimum
yield, we screened a wide variety of oxidants. O2 gave a low
yield of the desired product; instead, more than 50% of di-
phenyl disulfide was obtained (entry 2). H2O2 and K2S2O8 as
oxidants also showed negative effects, giving only trace
amounts of the desired product (entries 3 and 4). Conse-
quently, the reaction was carried out on the open air. A
study of the reaction temperature showed that 60 °C was
the best choice, and the yield of the corresponding product
3a increased to 82% (entry 6). The choice of solvent had a
significant impact on the reaction: MeOH–H2O (3:1, v/v)
and DMSO–H2O (3:1, v/v) afforded lower yields (entries 8
and 9).When the ratio of MeCN to H2O was 1:1, a similar
yield was obtained to that under the model condition (entry
10). However, only trace amount of the desired product was
obtained in water (entry 11). Finally, the effect of the
amount of the catalyst was also checked. Increasing the
amount of I2 to 30 mol% led to a similar yield (entry 12),
whereas decreasing the amount of I2 resulted in a signifi-
cantly lower yield (entry 13). Thus, the optimal experimen-
tal conditions were established as follows: disulfide 1 (1
equiv), alkene 2 (2.0 equiv), and I2 (20 mol%) as catalyst in a
1:1 (v/v) mixture of MeCN and H2O (2 mL) under ambient
conditions.
With the optimal condition in hand, we examined the
scope and generality of the present method.13 As shown in
Scheme 2, diverse aryl alkenes 2 bearing a variety of sub-
stituents were employed to react with diaryl disulfides 1
under the optimized reaction conditions to give the corre-
sponding products 3a–k smoothly in moderate to high
yields (52–86%). The electronic properties of substituents
on the aryl rings of alkene had a slight influence on the re-
action, but both electron-donating and electron-withdraw-
ing substituents gave satisfactory results (3g–j). Steric hin-
drance in the alkene had a significant effect, and aryl
alkenes with para-, meta-, or ortho-chloro substituents
were successfully converted into the corresponding prod-
ucts 3d–f in yields of 80, 72, and 51%, respectively. Note
that, ,-disubstituted alkenes 2l–n were suitable for this
protocol. The ,-substituted alkenes 2o and 2p also partic-
ipated in this reaction, but gave only moderate yields, prob-
ably due to steric hindrance. Furthermore, aliphatic alkenes
such as cyclohexene (2q), 4-methylpent-1-ene (2r), and 4-
bromobut-1-ene (2s) also showed good tolerance in this re-
action and afforded the corresponding -hydroxy sulfides
3q–s in moderate yields. In addition, the regioselectivity to-
ward the cyclohexene product 3q was examined; a NOESY
NMR showed that the regioisomer of the products is trans,
and the relative configuration of 3q is shown in Scheme 2.
The scope of the diaryl disulfide was also investigated.
Diaryl disulfides 2t–x with substituents such as fluoro,
chloro, methyl, or bromo were suitable for the present reac-
tion conditions, affording the desired products 3t–x in
moderate to good yields. The electronic effect of the substit-
uents had a significant influence on the reaction, and bis(4-
fluorophenyl) disulfide gave a relatively low yield (52%) of
3w, whereas bis(4-cyanophenyl) disulfide (1y) was inert
toward this transformation. Diethyl disulfide (1z) was not
suitable for this transformation.
Table 1 Optimization of the Reaction Conditionsa
Cl
OH
Ph
oxidant, I2
solvent
S
S
S
Ph
+
Cl
Cl
3a
2a
1a
Entry Catalyst
(mol%)
Oxidant
Temp (°C) Solvent
Yieldb (%)
1
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (30)
I2 (10)
air
O2
40
40
40
40
r.t.
60
80
60
60
60
60
60
60
MeCN–H2O
62
2
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeCN–H2O
MeOH–H2O
DMSO–H2O
MeCN–H2Od
H2O
32
c
3
H2O2
trace
trace
40
c
4
K2S2O8
air
5
6
air
82
7
air
74
8
air
55
9
air
25
10
11
12
13
air
82
air
trace
80
air
MeOH–H2O
MeOH–H2O
air
43
To gain insight into the mechanism, we performed sev-
eral control experiments. First, a radical trapping experi-
ment was conducted by employing (2,2,6,6-tetrameth-
ylpiperidin-1-yl)oxyl (TEMPO), and only an 11% yield of the
desired product was obtained (Scheme 3a), indicating that
a Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), solvent/H2O = 3:1 (2
mL), 2 h.
b Yield of isolated product.
c Two equivalents.
d MeCN/H2O = 1:1.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
B.-q. Ni et al.
Letter
Synlett
R3
air, I2
OH
R4
R1
R3
S
S
S
R2
60 °C
MeCN/H2O
R1
+
S
R1
R4
R2
2
3
1
OH
OH
OH
S
S
F
Cl
Cl
Cl
Cl
Br
Cl
Cl
Cl
3a,82%
OH
3b, 72%
OH
3c, 75%
Cl
OH
S
S
Cl
S
Cl
Cl
3d, 80%
3e, 51%
3f, 72%
OH
S
OH
S
OH
S
O2N
Cl
3g, 86%
3h, 73%
3i, 71%
OH
OH
S
OH
S
S
O
Cl
Cl
Cl
Cl
Cl
O
3j, 75%
3k, 72%
3l, 74%
Cl
OH
OH
OH
S
S
S
F
3m, 65%
3n, 76%
3o,66%
OH
H
S
H
OH
S
S
Cl
OH
Cl
Cl
3p, 58%
3q, 51%
OH
3r, 65%
OH
OH
S
S
S
Br
Cl
3s, 66%
3t, 76%
3u, 80%
F
OH
Br
OH
OH
S
S
S
3v, 78%
3w, 52%
3x, 74%
CN
S
S
S
S
NC
1z, NR
1y, NR
Scheme 2 Substrate scope of the reaction. Reagents and conditions: 1 (0.5 mmol), 2 (1 mmol), I2 (20 mol%), 1:1 MeCN–H2O (2 mL), under open air, 2 h,
60 °C. Isolated yields are reported. NR = no reaction.
the reaction might involve a radical pathway. Next, when
the reaction carried out without O2, only a trace amount of
3a was obtained (Scheme 3b), The reaction was completely
inhibited when the reaction was carried out in the absence
of H2O (Scheme 3c). Furthermore, when H2O was replaced
by H218O under the standard conditions, product 3a with no
18O label was detected (Scheme 3d). These results suggested
that the oxygen atom in the product does not originate
from H2O, but probably comes from O2.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
B.-q. Ni et al.
Letter
Synlett
tuted aryl alkenes, ,- substituted aryl alkenes, and ali-
phatic alkenes are tolerated well in this transformation to
give the corresponding products in moderate to high yields,
thereby providing a potential route for both academic and
industrial applications.
OH
Ph
Cl
+
S
standard conditions
TEMPO
S
S
(a)
Cl
S
S
Ph
Cl
11% yield
Cl
OH
S
N2, I2
60 °C
Ph
(b)
Cl
Ph
+
Cl
MeCN/H2O
Funding Information
trace
The authors gratefully acknowledge the National Natural Science
Foundation of China (no. 21808085), the China Postdoctoral Science
Foundation (2018M630519), and the Natural Science Foundation of
Cl
Cl
OH
Ph
air, I2
S
(c)
Cl
S
S
S
S
Ph
Ph
+
+
60 °C
dry MeCN
Cl
Jiangsu Province, China (BK20160164).
N
aturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
J
i
a
n
gsuPro
v
i
n
c
e
(B
K
2
0
1
6
0
1
6
4)C
h
i
n
a
P
ostd
o
ctoralS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(2
0
1
8
M
6
3
0
5
1
9)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
8
0
8
0
8
5)
trace
O18
H
Supporting Information
air, I2
S
Ph
(d)
Cl
60 °C
MeCN/H218O
Supporting information for this article is available online at
Cl
not detected
https://doi.org/10.1055/s-0039-1690163.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
Scheme 3 Control experiments
References and Notes
On the basis of these control experiments and previous
reports,8,9 we propose the plausible mechanism for the
present reaction shown in Scheme 4. Initially, I2 active the
disulfide ArSSAr 1 to give the intermediate ArS–I (I).11 This
liberates radical ArS∙ (II) and an iodine free radical.11 Subse-
quent addition of II to alkene 2 generates radical III, which
reacts with molecular oxygen to give the peroxy radical
IV.5h Reaction between intermediates III and IV then affords
radical V,12 which reacts with the iodine free radical and
abstracts one hydrogen atom from H2O to form the desired
product 3 and the catalyst I2.
(1) (a) Mitsudome, T.; Takahashi, Y.; Mizugaki, T.; Jitsukawa, K.;
Kaneda, K. Angew. Chem. Int. Ed. 2014, 53, 8348. (b) Sahu, D.;
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Chem. 2006, 8, 330.
OH
ArS-SAr
1
S
Ar
R
O
I2
3
H2O + I
ArS I
I
S
Ar
R
V
(5) (a) Singh, A. K.; Chawla, R.; Keshari, T.; Yadav, V. K.; Yadav, L. D.
S. Org. Biomol. Chem. 2014, 12, 8550. (b) Lanke, S. R.; Bhanage, B.
M. Catal. Commun. 2013, 41, 29. (c) Wang, H.; Lu, Q.; Liu, L.; Liu,
C.; Kai, C.; Lei, A. Angew. Chem. Int. Ed. 2016, 55, 1094. (d) Xi, H.;
Deng, B.; Zong, Z.; Lu, S.; Li, Z. Org. Lett. 2015, 17, 1180. (e) Zhou,
S.-F.; Pan, X.-Q.; Zhou, Z.-H.; Shoberu, A.; Zhou, J.-P. J. Org.
Chem. 2015, 80, 3682. (f) Wang, Y.; Jiang, W.; Huo, C. J. Org.
Chem. 2017, 82, 10628. (g) Huo, C.; Wang, Y.; Yuan, Y.; Chen, F.;
Tang, J. Chem. Commun. 2016, 52, 7233. (h) Zhang, B.; Liu, T.;
Bian, Y.; Lu, T.; Feng, J. ACS Sustainable Chem. Eng. 2017, 6, 2651.
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J. Org. Chem. 2002, 67, 9417. (b) Yoon, N. M.; Choi, J.; Ahn, J. H.
J. Org. Chem. 1994, 59, 3490. (c) Dowsland, J.; McKerlie, F.;
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2015, 56, 2892.
O
R
I
III
O
ArS
II
S
Ar
IV
R
S
2
Ar
R
III
O2
Scheme 4 The proposed mechanism
In summary, we have developed an environmentally
friendly and effective molecular-iodine-catalyzed reaction
for the preparation of -hydroxy sulfides in aqueous solu-
tion.13 This reaction uses disulfides instead of fetid, sensi-
tive, and toxic thiols. Importantly, air is used as the oxidant
without any additive. Furthermore, H218O isotope experi-
ment indicated that the oxygen atom of the products comes
from O2. Moreover, both terminal aryl alkenes, ,-substi-
(9) Zhang, R.; Jin, S.; Wan, Y.; Lin, S.; Yan, S. Tetrahedron Lett. 2018,
59, 841.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

E
B.-q. Ni et al.
Letter
Synlett
(10) (a) Liu, D.; Lei, A. Chem. Asian J. 2015, 10, 806. (b) Parvatkar, P.
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2062.
the mixture was stirred under air at 60 °C for 2 h. Surplus I2 was
quenched with sat. aq Na2S2O3, and the mixture was extracted
with EtOAc (3 × 10 mL). The organic phases were combined,
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude product was purified by column chromatogra-
phy [silica gel, hexanes–EtOAc (4:1)].
2-[(4-Chlorophenyl)thio]-1-(4-fluorophenyl)ethanol (3b)
Colorless oil; yield: 101.5 mg (72%); 1H NMR (400 MHz,
CDCl3):  = 7.51–7.16 (m, 6 H), 7.10–7.04 (m, 2 H), 4.86–4.71
(m, 1 H), 3.50–3.09 (m, 2 H), 2.81–2.53 (m, 1 H). 13C NMR (101
MHz, CDCl3):  = 163.7, 161.3, 137.7, 133.4, 133.1, 131.7, 129.3,
127.53, 115.5, 71.2, 44.3. 19F NMR (376 MHz, CDCl3):  = –114.0.
ESI-MS: m/z = 283 [M + 1]+. Anal. Calcd for C14H12ClFOS: C,
59.47; H, 4.28. Found: C, 59.30; H, 4.39.
(12) da Silva, G.; Hamdan, M. R.; Bozzelli, J. W. J. Chem. Theory
Comput. 2009, 5, 3185.
(13) -Hydroxy Sulfides 3; General Procedure
A 20 mL reaction vessel equipped with a magnetic stirring bar
was charged with the appropriate disulfide 1 (0.5 mmol),
alkyne 2 (1 mmol), I2 (20 mol%), and 1:1 MeCN–H2O (2 mL), and
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E