Synthesis of Vinyl Sulfones via I2-mediated Alkene Sulfonylations with Thiosulfonates

Article abstract of DOI:10.1002/bkcs.11426

A simple sulfonylation strategy involving I₂ and thiosulfonates, as sulfonyl-group precursors, is reported for the synthesis of vinyl sulfones. Sulfonyl radicals are presumed to be generated from thiosulfonates, which subsequently react with st

Full text of DOI:10.1002/bkcs.11426

Article
DOI: 10.1002/bkcs.11426
BULLETIN OF THE
S. Hwang et al.
KOREAN CHEMICAL SOCIETY
Synthesis of Vinyl Sulfones via I2-mediated Alkene Sulfonylations
with Thiosulfonates
*
Sang Joon Hwang, Pranab K. Shyam, and Hye-Young Jang
Division of Energy Systems Research, Ajou University, Suwon 16499, South Korea.
*E-mail: hyjang2@ajou.ac.kr
Received December 27, 2017, Accepted February 1, 2018
A simple sulfonylation strategy involving I2 and thiosulfonates, as sulfonyl-group precursors, is reported
for the synthesis of vinyl sulfones. Sulfonyl radicals are presumed to be generated from thiosulfonates,
which subsequently react with styrene or cinnamic acid derivatives to afford a variety of vinyl sulfones
under the described reaction conditions. Detailed conditions, the substrate scope, and mechanistic studies
are discussed.
Keywords: Vinyl sulfone, Iodine, Thiosulfonate, Sulfonylation, Alkene
Introduction
Experimental
Vinyl sulfones have unique chemical and physical proper-
ties that make them attractive to the pharmaceutical indus-
try as well as for use in organic synthesis. These features
have led to the development of efficient, economical, and
environmentally benign methods for the synthesis of vinyl
sulfones.1,2 From early traditional methods that employed
olefination, β-elimination of sulfonyl derivatives, or the oxi-
dation of sulfides to recent direct-coupling procedures using
sulfonyl precursors,3–5 numerous methods and reagents
have been reported for the formation of vinyl sulfones.
Sodium sulfinates or thiosulfonates are often employed to
deliver the sulfonyl group in direct-coupling reactions
involving alkenes, where I2, (diacetoxyiodo)benzene/KI, or
General Procedure for the Synthesis of Vinylsulfones
from Styrene Derivatives. A mixture of S-phenyl benze-
nethiosulfate (63 mg, 0.25 mmol), Cs2CO3 (163 mg,
0.5 mmol), and I2 (127 mg, 0.5 mmol) in MeOH (0.5 mL)
was taken in a seal tube. Styrene (57.5 μL, 0.5 mmol) was
added to this reaction mixture. The reaction was stirred at
50 ꢀC for 16 h. After cooling down the mixture, it was trea-
ted with aqueous sodium thiosulfate solution, and extracted
with dichloromethane (3 x 30 mL). The organic layer was
dried over Na2SO4 and isolated by flash column chroma-
tography to afford 1 as a white solid in 80% yield.
General Procedure for the Synthesis of Vinylsulfones
from Cinnamic Acid Derivatives. A mixture of S-phenyl
benzenethiosulfate (63 mg, 0.25 mmol), cinnamic acid
(76 mg, 0.5 mmol), Cs2CO3 (163 mg, 0.5 mmol), and I2
(127 mg, 0.5 mmol) in DCE/H2O (9:1, 0.5 mL) was taken
CuI/KI were used to induce sulfonylation (Scheme 1).
Although thiosulfonates were reported almost 30 years
ꢀ
in a seal tube. The reaction was stirred at 80 C for 16 h.
ago, studies into their use have not been actively
conducted.6–8 Recently, our research group successfully
synthesized thiosulfonates through catalytic methods and
explored their uses as sulfonylation reagents in organic
reactions.4d,8,9 While we studied the reactions of thiosulfo-
nates, we noticed that thiosulfonates were converted into
sulfonyl radicals under oxidative conditions; hence, we
expected that iodine (I2) itself, in the absence of any other
oxidant or transition-metal catalyst would generate sulfonyl
radicals that then react with olefins or carboxylated olefins.
Gratifyingly, I2 promoted the desired coupling of thiosulfo-
nates and olefins/carboxylated olefins to give the desired
vinyl sulfones in good yields. In this study, we present
detailed synthetic conditions for a range of substrates along
with mechanistic considerations.
After cooling down the mixture, it was treated with aque-
ous sodium thiosulfate solution, and extracted with dichlor-
omethane (3 x 30 mL). The combined organic layer was
dried over Na2SO4 and isolated by flash column chroma-
tography to afford 1 as a white solid in 78% yield.
Results and Discussion
The reaction of S-phenyl benzenethiosulfonate with styrene
was examined under the conditions listed in Table 1. A
mixture of the thiosulfonate (1 equiv), styrene (2 equiv),
ꢀ
Cs2CO3 (1 equiv), and I2 (2 equiv) was stirred at 50 C.
First, the effect of solvents was examined (entries 1–4);
desired vinyl sulfone 1 was formed in 13% yield (toluene),
49% (CH3CN), 65% (EtOH), and 72% (MeOH), respec-
tively. The yield of 1 was subsequently increased to 80%
by increasing the amounts of Cs2CO3 to 2 equiv (entry 5).
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Table 2. Coupling reactions of thiosulfonates and styrene
derivatives.a
Entry
R1
R2
Yield
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
H
pF
pCl
pCH3
mNO2
H
H
H
pF
pF
pF
pCl
pCl
pCl
pCH3
pCH3
pCH3
mNO2
mNO2
mNO2
80% (1)
77% (2)
71% (3)
85% (4)
64% (5)
78% (6)
71% (7)
51% (8)
79% (9)
73% (10)
62% (11)
77% (12)
49% (13)
51% (14)
84% (15)
70% (16)
59% (17)
78% (18)
63% (19)
51% (20)
C6H5
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
a
Scheme 1. Synthesis of vinyl sulfones.
Table 1. Optimizing the coupling of S-phenyl
benzenethiosulfonate with styrene.a
Reaction conditions: Thiosulfonates (0.25 mmol) and styrene
derivatives (0.5 mmol) were subjected to the indicated conditions.
(entries 8 and 9). In addition, the desired reaction did not
proceed in the absence of a base (entry 10).
Entry
Base (equiv)
Additive (equiv)
Solvent
Yield (1)
With the optimized conditions described in Table 1 in
mind, various thiosulfonates and styrene derivatives were
examined (Table 2). First, reactions of S-phenyl benze-
nethiosulfonate with styrene derivatives were explored
(entries 1–5); results showed slightly lower yields for the
halogen- and nitro-substituted styrenes (entries 2, 3, and 5).
For the reactions of thiosulfonate derivatives with styrene
(entries 6–8), the electron-rich p-methyl substituted thiosul-
fonate afforded the desired product in diminished yield
compared to the p-halo substituted thiosulfonates. Lower
yields were consistently observed for S-(p-methyl phenyl)
p-methylbenzenethiosulfonate in reactions with F-, Cl-,
Me-, and NO2-substituted styrene derivatives (entries 8, 11,
14, 17, and 20). As an example of aliphatic thiosulfonate,
the octyl-substituted thiosulfonate did not afford the desired
product. Overall, this coupling reaction appears to favor
electron-deficient thiosulfonates and electron-rich styrene
derivatives.
1
2
3
4
5
6
7
8
9
10
a
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (1)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
K2CO3 (2)
DIPEA(2)
—
l2(2)
l2(2)
l2(2)
l2(2)
l2(2)
—
Toluene
CH3CN
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
13%
49%
65%
72%
80%
0%
43%
70%
40%
0%
NIS (2)
l2(2)
l2(2)
l2(2)
Reaction conditions: S-Phenyl benzenethiosulfate (0.25 mmol) and
styrene (0.5 mmol) were subjected to the indicated conditions.
To examine the effect of iodine, the reaction was carried
out in the absence of I2, which resulted in a lack of the
product (entry 6). In addition to I2, N-iodosuccinimide
(NIS) was used; this reagent resulted in diminished yield
(entry 7). Other bases, namely K2CO3 and diisopropylethy-
lamine (DIPEA), were also used to afford 1 in lower yields
We next explored the reaction of S-phenyl benzenethio-
sulfonate with cinnamic acid (Table 3). The optimized
conditions used for coupling the phenyl thiosulfonate and
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Table 3. Optimizing the coupling of S-phenyl benzenethiosulfonate
with cinnamic acid.a
Entry
Solvent
Temp (ꢀc)
Yield %
1
2
3
4
5
6
a
MeOH
DCE
DCE/H2O (4:1)
DCE/H2O (4:1)
DCE/H2O (9:1)
DCE/H2O (9:1)
50
50
50
80
80
100
18
31
54
72
78
82
Scheme 2. Control experiments in the presence of TEMPO.
of water is presumed to increase the solubility of cinnamic
acid. As was observed for the reaction of S-phenyl benze-
nethiosulfonate with styrene (Table 1, entries 6 and 10), no
vinyl sulfone 1 was obtained in the absence of Cs2CO3 or I2.
With the optimized conditions described in Table 3 in
mind, reactions involving a variety of thiosulfonates and
cinnamic acid derivatives were explored (Table 4). Interest-
ingly, reactions involving electron-deficient cinnamic acid
derivatives and the phenyl thiosulfonate mostly exhibited
higher yields (entries 1–5). p-Nitro cinnamic acid reacted
with S-phenyl benzenethiosulfonate to form vinyl sulfone
50 in 90% yield (entry 5), but the reaction of p-methyl cin-
namic acid afforded vinyl sulfone 4 in only 72% yield
(entry 4). The effect of the thiosulfonate substituent is simi-
lar to that observed in Tables 1 and 2; decreased yields are
observed in the reactions of the p-methyl substituted thio-
sulfonate with the cinnamic acid derivatives (entries 8, 11,
14, 17, and 20). The methyl groups on thiosulfonates may
affect the reactivities toward I2 during the generation of sul-
fonyl radicals, as well as stabilities of the radicals formed,
although it has been reported that the electronic nature of a
sulfonyl radical is not affected by the substituents on the
sulfonyl group due to localization of the unpaired electron
on the sulfonyl group.10 Consistent with this electron-
donating group effect, the electron-rich octyl-thiosulfonate
participated in this reaction to afford product 21 in only
10% yield.
To gain insight into the reaction mechanism, the reaction
of the S-phenyl benzenethiosulfonate with either styrene or
cinnamic acid was conducted under standard conditions in
the presence of TEMPO (2,2,6,6-tetramethylpiperidine-1-
oxyl), a radical scavenger (Scheme 2). Vinyl sulfone 1 was
formed in 4% yield from styrene and was not observed in
the reaction with cinnamic acid. The suppressed yields
observed in the presence of TEMPO suggest that these
reactions involve radical intermediates.
In previously reported sulfonylation reactions using
I2,4b,5d sulfonyl iodides were proposed to be formed as key
intermediates. In the current work, the desired product was
obtained when independently prepared PhSO2I was sub-
jected to our reaction conditions (Scheme 3).5d The reactions
Reaction conditions: S-phenyl benzenethiosulfate (0.25 mmol) and
cinnamic acid (0.5 mmol) were subjected to the indicated reaction
conditions.
Table 4. Coupling reactions of thiosulfonates and cinnamic acid
derivatives.a
Entry R1
R2
Yield
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
H
F
CI
78% (1)
81% (2)
77% (3)
CH3 72% (4)
NO2 90% (50)
C6H5
pF-C6H4
pCI-C6H4
pMe-C6H4
pF-C6H4
pCI-C6H4
pMe-C6H4
pF-C6H4
pCI-C6H4
pMe-C6H4 CI
pF-C6H4
pCI-C6H4
pMe-C6H4 CH3 65% (17)
H
H
H
F
F
F
80% (6)
78% (7)
70% (8)
83% (9)
75% (10)
76% (11)
76% (12)
70% (13)
75% (14)
9
10
11
12
13
14
15
16
17
18
19
20
a
CI
CI
CH3 78% (15)
CH3 76% (16)
pF-C6H4
pCI-C6H4
pMe-C6H4 NO2 55% (200)
NO2 67% (180)
NO2 62% (190)
Reaction conditions: Thiosulfonates (0.25 mmol) and cinnamic acid
derivatives (0.5 mmol) were subjected to the indicated reaction
conditions.
styrene (Table 1) were disappointing (entry 1). The desired
coupling product 1 was obtained in good yield by changing
the solvent and increasing the reaction temperature; the role
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acid derivatives) with concomitant decarboxylation.
Depending on the thiosulfonate substituent, interesting
electronic effects are observed in these reactions. Thiosulfo-
nates and cinnamic acid derivatives bearing electron-
withdrawing groups afford products in higher yields, while
styrene derivatives bearing electron-donating substituents
are converted to vinyl sulfones in higher yields. The pro-
posed reaction mechanisms are supported by control experi-
ments using TEMPO and PhSO2I.
Acknowledgments. This study was supported by the
Human Resources Development of the KETEP grant
(No. 20154010200820) from the Korea Government and
the Ajou University Research Fund (S2017G000100012)
Scheme 3. Reactions using PhSO2I.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
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