Sodium Iodide Mediated Oxysulfenylation of Olefins with Thiosulfates: A Strategy for Constructing Sulfenylated 2,3-Dihydrobenzofurans and β-Acetoxy Sulfides

Article abstract of DOI:10.1055/s-0036-1591492

A strategy has been developed for constructing sulfenylated 2,3-dihydrobenzofurans and β-acetoxy sulfides through NaI/DMSO-mediated oxysulfenylation of alkenes with environmentally friendly thiosulfates. The reactions involve simple operations and give a series of sulfenylated 2,3-dihydrobenzofurans or β-acetoxy sulfides in moderate to good yields.

Full text of DOI:10.1055/s-0036-1591492

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
R. Zhang et al.
Letter
Synlett
Sodium Iodide Mediated Oxysulfenylation of Olefins with Thiosul-
fates: A Strategy for Constructing Sulfenylated 2,3-Dihydrobenzo-
furans and β-Acetoxy Sulfides
Rongxing Zhang
Nu
NaI, DMSO
R1SSO3Na
R2
Zhaohua Yan*
Sen Lin*
+
S
R2
R1
NuH
NuH = MeCOOH, ROH
18 examples
up to 92% yield
College of Chemistry, Nanchang University,
Nanchang, Jiangxi 330031, P. R. of China
senlin@ncu.edu.cn
yanzh@ncu.edu.cn
Received: 26.07.2017
Accepted after revision: 18.09.2017
Published online: 20.10.2017
Cu(II)-catalyzed synthesis of sulfenylated cyclic ethers
through the intramolecular cycloetherification of olefinic
alcohols with sodium sulfonates.
DOI: 10.1055/s-0036-1591492; Art ID: st-2017-w0582-l
Thiosulfates (also called Bunte salts) have received more
and more attention because they are readily synthesized by
the reaction of sodium thiosulfate with various halides.8
These compounds show potential value in C–S bond forma-
tion, because they are odorless, readily available, and envi-
ronmentally benign.9 Thiosulfates have been widely applied
in the construction of C–S bonds; for example, in 2016, Qiao
and Jiang reported a Pd-catalyzed synthesis of thio ethers
and thio esters from organosilicon compounds and thiosul-
fates.10 Subsequently, the groups of Luo11a and Ji11b devel-
oped syntheses of 3-thioindoles by using thiosulfates with
iodine as a catalyst and DMSO as both an oxidant and a sol-
vent.
Although several strategies have been reported for oxy-
sulfenylation of alkenes to construct sulfenylated 2,3-dihy-
drobenzofurans and β-acetoxy sulfides, these methods
have several disadvantages such as the use of thiolating re-
agents with unpleasant odors or which contain metals.
Consequently, environmentally friendly approaches to the
synthesis of sulfenylated cyclic ethers and β-acetoxy sul-
fides remain to be developed. We previously prepared β-ac-
etamido sulfides from thiosulfates,11c and consequently we
wish to synthesize various other thio ether compounds
from other nucleophiles and thiosulfates. Here, we reported
a novel NaI/DMSO-mediated oxysulfenylation of 2-allylphe-
nol or alkenes with environmentally friendly thiosulfates as
thiolating reagents, leading to the smooth formation of
sulfenylated 2,3-dihydrobenzofurans and β-acetoxy sul-
fides.
Abstract A strategy has been developed for constructing sulfenylated
2,3-dihydrobenzofurans and β-acetoxy sulfides through NaI/DMSO-
mediated oxysulfenylation of alkenes with environmentally friendly
thiosulfates. The reactions involve simple operations and give a series of
sulfenylated 2,3-dihydrobenzofurans or β-acetoxy sulfides in moderate
to good yields.
Key words oxysulfenylation, alkenes, thiosulfates, dihydrobenzo-
furans, acetoxy sulfides
The synthesis of organosulfur compounds has emerged
as a popular field in synthesis science1 because C–S bonds
are widely present in the drugs,2 materials,3 and natural
products.4 Sulfenylated cyclic ethers are useful sulfur-con-
taining compounds, and these special structures play vital
roles in natural products and medicinal molecules that
show a variety of biological activities;5 for example, some
thioglycosides have anticancer activities5a and a lactone de-
rived from thioglucose is an inhibitor of angiogenesis.5b β-
Acetoxy sulfides are also useful entities in medicinal chem-
istry, biochemistry, and other fields.6 Therefore, the synthe-
ses of sulfenylated 2,3-dihydrobenzofurans and β-acetoxy
sulfides have received considerable attention, resulting in
the development of new synthetic methods.7 Previously,
sulfenylated 2,3-dihydrobenzofuran and β-acetoxy sulfides
have been prepared by oxysulfenylation of alkenes with
several thiolating reagents, including sulfonyl hydrazides,7a
disulfides,7b and sodium sulfonates,7c among others.7d–h In
2015, Tian7a and Braga7b and their respective co-workers
described the oxysulfenylation of alkenes with sulfonyl hy-
drazides and disulfides to give β-alkoxy sulfides and β-acet-
oxy sulfides. In 2016, Jiang and co-workers7c reported a
We initially optimized the conditions for the reaction of
2-allylphenol (1a) with sodium S-benzyl thiosulfate (2a) in
the presence of various iodine salts, DMSO as oxidant, and
acetonitrile as solvent (Table 1). Various iodine catalysts
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
R. Zhang et al.
Letter
Synlett
were explored for the oxysulfenylation of 2-allylphenol (1a)
in acetonitrile at 50 °C for three hours, and these gave the
desired product 3a in 28 to 56% yield (Table 1, entries 1–4).
Among the catalysts, NaI produced the best results, giving
3a in 56% yield (entry 4). Subsequently, when we explored
the effects of temperature on the oxysulfenylation of 2-al-
lylphenol (1a) with sodium S-benzyl thiosulfate (2a) (en-
tries 5 and 6), we found that that 100 °C was optimal, giving
3a in 91% yield (entry 6). The yield of 3a did not increase
when tert-butyl hydroperoxide (TBHP), K2S2O8, DDQ, or
Cu(OAc)2 was employed as an oxidant (entries 7–10). The
yield of 3a fell on reducing the amount of NaI or DMSO (en-
tries 11 and 12). Therefore, the optimized conditions were
established as follows: 2-allylphenol (1a; 1.0 equiv), sodi-
um S-benzyl thiosulfate (2a; 1.2 equiv), NaI (20 mol%) as
catalyst, DMSO (2.0 equiv) as oxidant, and acetonitrile as
the solvent at 100 °C in a sealed tube.
nylation with 2-allyphenol (1a) to give products 3a–e in
moderate to excellent yields. When sodium S-butyl thiosul-
fate, sodium S-(4-chlorobenzyl) thiosulfate, or sodium S-(4-
methylbenzyl) thiosulfate was used as the substrate, the
corresponding products 3f, 3g, and 3h were obtained in 88,
56, and 92% yield, respectively. Notably, the corresponding
tetrahydrofuran 3i was similarly obtained in 65% yield by
the oxysulfenylation of pent-4-en-1-ol.
S
R1
NaI, DMSO
MeCN
+
R1SSO3Na
O
OH
1a
2
3
S
S
O
O
F
3a, 91%
3b, 83%
S
S
Table 1 Optimization of the Reaction Conditionsa
O
O
Cl
Br
3c, 64%
3d, 67%
OH
S
1a
catalyst (20 mol%)
S
S
+
O
DMSO (2.0 equiv)
MeCN (1.0 mL)
SSO3Na
O
3a
O
3f, 88%
3e, 87%
2a
Entry
Catalyst (mol%)
Oxidant (equiv)
Temp (°C) Yieldb
S
Cl
S
1
2
I2 (20)
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
DMSO (2.0)
TBHP (2.0)
K2S2O8 (2.0)
H2O2 (2.0)
50
50
50
O
O
3g, 56%
TBAI (20)
NH4I (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (10)
NaI (20)
NaI (20)
I2 (120)
28
3h, 92%
3
50
45
S
4
50
56
O
5
80
83
3ia, 65%
6
100
100
100
100
100
100
100
100
100
91
7
trace
35
Scheme 1 Reaction conditions: 1a (0.30 mmol), 2 (0.36 mmol), NaI (20
mol%), DMSO (0.60 mmol), MeCN (1.0 mL), 100 °C. Yields of the isolat-
ed products are reported.
8
9
NRc
NR
79
a Pent-4-en-1-ol was used.
10
11
12
13
14
Cu(OAc)2 (2.0)
DMSO (2.0)
DMSO (1.0)
DMSO (0)
Next, we investigate the synthesis of β-acetoxy sulfides
from various alkenes and thiosulfates as substrates (Scheme
2). Several para-substituted styrenes with electron-with-
drawing groups (F, Cl, or Br) reacted with sodium S-benzyl
thiosulfate (2a) to give the desired products 5a–d in moder-
ate yields. To our delight, cyclohexene, a nonaromatic
alkene, underwent acetoxysulfenylation with sodium S-
benzyl thiosulfate (2a) to give a moderate yield of product
5e. Similarly, sodium S-(4-methylbenzyl), sodium S-(4-
chlorobenzyl) thiosulfate, and sodium S-butyl thiosulfate
gave the corresponding products 5f, 5g, and 5h in 81, 65
and 60% yield, respectively. Fortunately, when pent-4-enoic
acid was used as a substrate, a 1:2 mixture of furanone 5i1
and pyranone 5i2 was obtained in 84% yield.
64
NR
81
DMSO (0)
a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), catalyst (20 mol%),
oxidant (2.0 equiv), MeCN (1 mL), 3 h, 100 °C.
b Yield of isolated product.
c NR = no reaction.
A series of thiosulfates were used to construct sulfe-
nylated cyclic ethers under the optimized reaction condi-
tions (Scheme 1). Various para-substituted sodium S-benz-
ylthiosulfates with electron-withdrawing groups (F, Cl, or
Br) or electron-donating group (Me) underwent oxysulfe-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
R. Zhang et al.
Letter
Synlett
.
control experiment in which hydrochloric acid was added
to the reaction of 2-allylphenol (1a) with dibenzyl sulfide
(6a) [Scheme 3(d)], and we found that the oxysulfenylation
worked well and gave the desired product 3a in good yield.
These control experiments showed that the disulfide prob-
ably serves as an intermediate and that the presence of an
acid plays a vital role in the reaction.
O
O
NaI, DMSO
R1SSO3Na
R2
MeCOOH
O
+
+
S
R2
R1
4
2
5
O
O
O
S
S
MeCN
PhCH2SSCH2Ph
PhCH2SSO3Na
(a)
F
6a, 92%
2a, 0.3 mmol
1a, 0.3 mmol
5a, 75%
5b, 56%
NaI, MeCN
O
6a, 0.2 mmol
6a, 0.2 mmol
3a, trace
5a, 73%
3a, 83%
O
+
+
(b)
(c)
(d)
DMSO (2 equiv)
NaI, DMSO
MeCOOH
O
O
S
4a, 0.3 mmol
1a, 0.3 mmol
S
Cl
NaI, MeCN
Br
6a, 0.2 mmol
+
HCl (2 equiv)
DMSO(2 equiv)
5c, 63%
5d, 71%
O
O
Scheme 3 Control experiments
O
O
S
S
On the basis of the experimental results described
above and previous reports,7a,7b,7f,11,12 we propose the reac-
tion pathway shown in Scheme 4. Initially, a bisulfate anion
and the thiol or thiol anion species B are formed in the re-
action system due to the ready hydrolysis of thiosulfate A
on heating in the presence of water.12a Thiosulfate A is then
attacked by the thiol or thiol anion B to generate disulfide C
and a sulfite anion.11b Next, the electrophilic species D is
formed through the reaction of disulfide C with iodine;11a
meanwhile, the sulfenyl iodide D attacks the double bond of
olefin E to give intermediate F.7a,12b Subsequently, the de-
sired compound G13 is formed and HI is released through at-
5e, 62%
5f, 81%
O
O
O
O
S
S
Cl
5g, 65%
5h, 60%
S
O
O
5i1a
S
R1SSO3Na
A
5i2a
5i1/5i2 = 1:2, 85%
O
O
H2O
R1SNa
R1SSR1
C
+
or
R1SSO3Na
R1SH
Scheme 2 Reaction conditions: 4 (0.30 mmol), 2 (0.36 mmol), NaI (20
mol%), DMSO (0.60 mmol), MeCOOH (1.0 mL), 100 °C. Yields of the iso-
lated products are reported.
A
B
NaI
HSO4
2
DMS+H2O
SO3
OH
a Pent-4-enoic acid was used.
DMSO
I2
S
HI
I
H
HI
To gain further insight into the reaction mechanism,
several control experiments were conducted and the re-
sults are shown in Scheme 3. First, dibenzyl sulfide (6a) was
isolated in 92% yield on stirring a solution of sodium S-ben-
zyl thiosulfate (2a) in MeCN [Scheme 3(a)]. None of the tar-
get product 3a was obtained when 2-allylphenol (1a) was
treated with dibenzyl disulfide (6a) under the optimized
conditions [Scheme 3(b)]. However, the oxysulfenylation of
styrene (4a) with dibenzyl sulfide (6a) proceeded smoothly
when acetic acid was used as the solvent [Scheme 3(c)]. On
the basis of previous experimental results, we conducted a
R1
I
R1SI
D
S
R2
F
NuH = -RCOOH, -ROH
R2
NuH
S
E
Nu
R2
R1
G
Scheme 4 A plausible reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
R. Zhang et al.
Letter
Synlett
tack on intermediate F by the nucleophilic species.7a,7b Fi-
nally, two equivalents of HI are oxidized by DMSO to give
iodine together with dimethyl sulfide and water.7f
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In summary, we have developed an iodine-catalyzed ox-
ysulfenylation of alkenes with various thiosulfates for the
efficient synthesis of sulfenylated 2,3-dihydrobenzofurans
and β-acetoxy sulfides, in which stable, odorless, and envi-
ronmentally friendly thiosulfates were employed as thiolat-
ing reagents, DMSO as a mild oxidant, and 2-allylphenol or
acetic acid as a nucleophile. A series of sulfenylated 2,3-di-
hydrobenzofurans and β-acetoxy sulfides were obtained in
moderate to good yields under simple and mild reaction
conditions.
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Funding Information
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (21302084).
)(
Supporting Information
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Synlett 2017, 28, 1195.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591492.
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(13) 2,3-Dihydro-1-benzofurans 3; General Procedure
NaI (0.06 mmol) and the appropriate thiosulfate 2 (0.36 mmol)
were added to a solution of 2-allylphenol (1a; 0.30 mmol) in
MeCN (1 mL). DMSO (0.60 mmol) was then added and the
mixture was stirred in a sealed tube at 100 °C for 3 h. When the
reaction was complete, the mixture was diluted with EtOAc
(3 × 5 mL) and the reaction was quenched with sat. aq Na2SO3.
The mixture was extracted with EtOAc (3 × 10 mL), and the
organic layers were combined, washed with H2O (10 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, PE).
2-[(Benzylthio)methyl]-2,3-dihydro-1-benzofuran (3a)
Yellow oil; yield: 76.9 mg (91%). 1H NMR (400 MHz, CDCl3):
δ = 7.34–7.25 (m, 5 H), 7.17–7.10 (m, 2 H), 6.87–6.79(m, 2 H),
4.92–4.85 (m, 1 H), 3.82 (s, 2 H), 3.33–3.27 (dd, J = 8, 16 Hz, 1 H),
3.05–2.99 (dd, J = 8, 16 Hz, 1 H), 2.84–2.79 (dd, J = 6, 14 Hz, 1 H),
2.72–2.67 (dd, J = 6, 14 Hz, 1 H). 13C NMR (100 MHz, CDCl3):
δ = 159.15, 138.17, 129.00, 128.57, 128.06, 127.13, 126.28,
124.99, 120.54, 109.41, 82.19, 36.81, 36.09, 34.97. HRMS (ESI):
m/z [M + Na]+ Calcd for C16H16NaOS: 279.0814; found: 279.0794.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D