Oxidation of disulfides with Selectfluor: Concise syntheses of thiosulfonates and sulfonyl fluorides

Article abstract of DOI:10.1016/j.tetlet.2011.03.132

The reaction of aromatic or benzylic disulfides with 2.5 equiv of Selectfluor in acetonitrile/water (10:1) at room temperature efficiently produced the corresponding thiosulfonates. On the other hand, the reaction of disulfides with 6.5 equiv of Selectfluor in refluxing acetonitrile/water (10:1) provided sulfonyl fluoride in high yields.

Full text of DOI:10.1016/j.tetlet.2011.03.132

Tetrahedron Letters 52 (2011) 3086–3089
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidation of disulfides with Selectfluor™: concise syntheses of
thiosulfonates and sulfonyl fluorides
⇑
Masayuki Kirihara , Sayuri Naito, Yuki Ishizuka, Honoka Hanai, Takuya Noguchi
Department of Materials and Life Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi, Shizuoka 437-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of aromatic or benzylic disulfides with 2.5 equiv of Selectfluor™ in acetonitrile/water (10:1)
at room temperature efficiently produced the corresponding thiosulfonates. On the other hand, the reac-
tion of disulfides with 6.5 equiv of Selectfluor™ in refluxing acetonitrile/water (10:1) provided sulfonyl
fluoride in high yields.
Received 11 March 2011
Accepted 28 March 2011
Available online 3 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidation
Selectfluor™
Disulfide
Thiosulfonate
Sulfonyl fluoride
Thiosulfonates, which are stable compounds, can be used as
strong electrophilic sulfenylating agents in organic synthesis. Sul-
sulfenyl halide
(unstable)
thiosulfonate
(stable)
1
fenyl halides also act as electrophilic sulfenylating agents and have
been widely used for this purpose. However, they are unstable, dif-
ficult to handle, and have to be prepared before use (Scheme 1). In
O
R
S
X
R
S
Nu
R
S
S R
2
O
spite of the synthetic importance of thiosulfonates, they have been
:Nu
:Nu
3
seldom used as sulfenylating agents, because there had not been
very many methods of synthesizing them.4 Therefore, several
groups recently have developed new practical syntheses of
Scheme 1.
4
thiosulfonates.
Sulfonyl fluorides have been seldom used in organic syntheses,
however, some, for example phenyl methyl sulfonyl fluoride
O
O
S
S
F
F
(
PMSF) and 4-(2-aminomethyl)benzensulfonyl fluoride hydrochlo-
O
O
ride (AEBSF), are strong protease inhibitors, and are frequently uti-
ClH N
3
5
lized in biochemistry (Scheme 2).
AEBSF
PMSF
For such sulfonyl fluorides, there have been only a few prepara-
tive methods. The traditional method to prepare sulfonyl fluorides
6
Scheme 2.
is the nucleophilic substitution of sulfonyl chlorides by the fluoride
ion. This method requires strictly anhydrous conditions, otherwise
hydrolyzed compounds (sulfonic acids) are obtained as the major
In this Letter, the reaction of disulfides (1) with Selectfluor™ is
reported to effectively provide thiosulfonate (2) or sulfonyl fluo-
ride (3) (Scheme 3).
During the course of our study of the synthesis of organofluo-
rine compounds, we examined the reaction of diphenyl disulfide
(1a) with 2.5 equiv of Selectfluor™ to prepare di(p-fluorophenyl)
disulfides (4a). Unexpectedly, 4a was not obtained at all, and phe-
nyl benzensulfonthiolate (thiosulfonate) (2a) was produced in high
yield accompanied by a small amount of phenyl sulfonyl fluoride
6
a,b
products.
Recently, Liskamp reported that the reaction of so-
dium sulfonates with diethylaminosulfer trifluoride (DAST) effi-
ciently produces the corresponding sulfonyl fluoride.6 However,
this method also required anhydrous conditions, because DAST is
sensitive to water. Therefore, a concise method for the preparation
of sulfonyl fluoride has been desired.
c
(3a) (Scheme 4)
⇑
Corresponding author. Tel.: +81 538 45 0166; fax: +81 538 45 0110.
E-mail address: kirihara@ms.sist.ac.jp (M. Kirihara).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.132

M. Kirihara et al. / Tetrahedron Letters 52 (2011) 3086–3089
3087
SelectfluorTM(2.5 eq.)
Table 2
SelectfluorTM
2.5 eq.)
Cl
N
O
S
O
S
(
BF -
R
S
S
R
R
F
R
S
R +
2
N
4
CH CN-H O
O
S
1
3
2
O
O
3
F
(10:1), rt
2
R
S
R
CH CN-H O (10:1), rt
3
2
O
2
(R= aromatic or benzylic)
Entry
R
Time (min)
Yielda (%)
R
S S R
1
SelectfluorTM (6.5 eq.)
CH CN-H O (10:1), reflux
O
S
1
2
3
2
R
F
1
2
3
4
5
6
Ph
p-Tol
p-MeOC
Bn
p-ClC
2
2
1
2
20
20
0
0
0
0
3
84
93
51
82
72
2
3
2
O
Trace
8
10
10
26
3
6
H
5
Scheme 3.
6
H
5
b
b
b
3
CH (CH
2
)
9
26
36
a
Isolated yield except for entry 6.
Based on GC–MS analysis.
b
SelectfluorTM
S
S
F
S
S
F
CH CN, H O
3
2
1
a
4a
(
3) in the cases of disulfides having aromatic or benzylic substitu-
ents. The reaction proceeded very quickly in most cases (entries 1–
). In the case of a disulfide bearing a relatively electron-deficient
aromatic substituent, the reaction proceeded more slowly (entry
). In the case of an aliphatic disulfide, the reaction rate was slow
SelectfluorTM (2.5 eq.)
4
CH CN, H O, rt, 2 min
3
2
5
O
S
O
S
9
and produced an inseparable mixture of 2 and 3 (entry 6). This
reaction is a useful method to prepare aromatic or benzylic thiosul-
fonates from the corresponding disulfides, because the reaction
conditions are mild and the experimental procedure is quite simple
and easy without requiring anhydrous conditions.
S
+
F
O
O
2
a (84%)
3a (2%)
Scheme 4.
A plausible reaction mechanism of this disulfide oxidation by
Selectfluor™ is depicted in Scheme 5. One of the sulfur atoms of
Selectfluor™ has been usually used as an electrophilic fluorinat-
1
is fluorinated by Selectfluor™ to form a sulfonium compound
7
8
ing reagent ; however, it is also a strong oxidizing agent. These
compounds (2a, 3a) must be produced from the Selectfluor™-de-
rived oxidation of 1a and this reaction must be one-step syntheses
of thiosulfonates.
Initially, di-p-toluyl disulfide (1b) was treated with 2.5 equiv of
Selectfluor™ at room temperature to investigate any solvent effect
Table 1). With acetonitrile, the amount of water is crucial to
obtaining the thiosulfonate (2b) (runs 1–3), and acetonitrile/water
10:1) is an ideal solvent system to prepare 2b (run 2). An aqueous
methanol or aqueous dimethylformamide solution did not afford
satisfactory results (runs 4 and 5).
The reaction of several disulfides (1) with 2.5 equiv of Selectflu-
or™ was examined in acetonitrile/water (10:1) at room tempera-
ture to prepare the corresponding thiosulfonates (2) (Table 2).
The desired thiosulfonates (2) were obtained in moderate to high
yields accompanied by small amounts of the sulfonyl fluorides
(A), and the successive substitution of the fluorine atom by an oxy-
gen atom of water affords a thiosulfinate (B). Thiosulfinate (B) is
further oxidized by a similar mechanism to produce an unstable
10
disulfoxide (C) which rearranges to a stable thiosulfonate (2).
According to the reaction mechanism, hydrogen fluoride must be
produced and trapped by the amine produced from the consumed
Selectfluor™ to provide the corresponding ammonium fluorides.
Actually, ammonium fluorides were detected in the resulting reac-
(
(
19
tion mixture by F NMR analysis (À155.7 and À189.1 ppm).
The synthesis of sulfonyl fluorides (3) using Selectfluor™ was
then examined. It was surmised that the sulfonyl fluorides (3) ob-
tained as byproducts of the reaction of the disulfides with Select-
fluor™ were produced by the further reaction of thiosulfonates
with Selectfluor™ and water. In fact, the reaction of thiosulfonate
(
(
2b) with Selectfluor™ (4.5 equiv) in refluxing acetonitrile/water
10:1) produced the corresponding sulfonyl fluoride (3b) in high
yield (Scheme 6).
The reaction of p-ditoluyl disulfide (1b) or p-toluylthiol (5b)
with Selectfluor™ in refluxing acetonitrile/water (10:1) also effi-
ciently provided 3b (Scheme 7).
It is interesting that the corresponding sulfonic acid was not ob-
tained even in the presence of water. This phenomenon strongly
Table 1
SelectfluorTM (2.5 eq.)
p-Tol
S
S
p-Tol
solvent, rt
1b
O
O
S
p-Tol
S
S
p-Tol
p-Tol
F
O
:F
O
Cl
2
b
3b
N
H
R
H
2
N
BF4-
F
S
Ratioa (%)
H
H
Run
Solvent
Time
O
S
O
F
R
S
R
R
S
R
1
b
2b
3b
R
S
S
1
A
1
2
3
4
5
CH
3
CH
3
CH
3
CH
3
CN
CN/H
CN/H
1 h
52
0
11
94
4
26
97
87
5
22
3
2
1
37
2
O (10:1)
O (5:1)
2 min
24 h
1 h
O
S
O
O O
S
2
+
-
H , -HF
R
R
OH/H
2
O (10:1)
S
R
R
S
R
S
DMF/H
2
O (10:1)
1 h
59
R
S
2
B
C
O
a
Determined by 1H NMR (methyl protons). No products other than the thio-
sulfonate (2b) and the sulfonyl fluoride (3b) were detected in all cases.
Scheme 5.

3
088
M. Kirihara et al. / Tetrahedron Letters 52 (2011) 3086–3089
SelectfluorTM
oxidized by Selectfluor™ and water to produce the disulfone (F).
The radical or electrophilic reaction of F with Selectfluor™ affords
the sulfonyl fluoride (3).
In conclusion, the oxidation of disulfides (1) with Selectfluor™
in the presence of water produces the corresponding thiosulfo-
nates (2), which further reacts with Selectfluor™ and water to pro-
vide the corresponding sulfonyl fluorides.
O
S
O
S
(4.5 eq.)
2
p-Tol
F
p-Tol
S
p-Tol
CH CN-H O
3
2
O
O
2
(
1
10:1), reflux,
h
b
3b (97%)
Scheme 6.
SelectfluorTM
O
A representative experimental procedure to prepare
thiosulfonates from disulfides
(
6.5 eq.)
p-Tol
S
S p-Tol
2
p-Tol
S
F
CH CN-H O
3
2
O
(
10:1), reflux
1
b
3b (86%)
To a stirred solution of p-tolyl disulfide (246.3 mg, 1.0 mmol) in
acetonitrile (2.0 ml) and water (0.2 ml) was added Selectfluor™
(885.5 mg, 2.5 mmol) at room temperature for 20 min, and the
resulting mixture was stirred. The reaction was monitored by thin
layer chromatography (TLC). After the disulfide disappeared from
the TLC, water (5 ml) was added and the resulting mixture was ex-
tracted with ethyl acetate (15 ml  3). The extract was washed
with brine, dried over anhydrous magnesium sulfate, and evapo-
rated. Chromatography on silica gel gave thiosulfonate (259.3 mg,
SelectfluorTM
O
(
7.5 eq.)
p-Tol SH
p-Tol
S
O
F
CH CN-H O
3
2
5b
(10:1), reflux
3
b (70%)
Scheme 7.
Table 3
9
3%) as colorless crystals.
SelectfluorTM (6.5 eq.)
O
R
S
S
R
2 R
S
F
A representative experimental procedure to prepare sulfonyl
fluorides from disulfides
CH CN-H O (10:1), reflux
1
3
2
O
3
Entry
R
Time (h)
Yielda (%)
To a stirred solution of p-tolyl disulfide (246.3 mg, 1.0 mmol) in
acetonitrile (10.0 ml) and water (1.0 ml) was added Selectfluor™
(2306.2 mg, 6.5 mmol) and the resulting mixture was heated under
reflux for 1.5 h. The reaction was monitored by thin layer chroma-
tography (TLC). After the disulfide and the corresponding thiosulf-
onate disappeared from the TLC, water (10 ml) was added and the
resulting mixture was extracted with ethyl acetate (20 ml  3). The
extract was washed with brine, dried over anhydrous magnesium
sulfate, and evaporated. Chromatography on silica gel gave the sul-
fonyl fluoride (299.0 mg, 86%) as colorless crystals.
1
2
3
4
5
6
7
Ph
2.0
1.5
1.0
1.5
3.0
1.0
1.0
69
86
77
88
96
60
91
p-Tol
p-MeOC
Bn
p-ClC
Cyclohexyl
CH (CH
6
H
5
6 5
H
3
2 9
)
a
Isolated yield.
suggests that the fluorine–sulfur bond is constructed via a radical
or electrophilic mechanism.
References and notes
The reaction of several disulfides (1) with 6.5 equiv of Selectflu-
or™ was examined in refluxing acetonitrile/water (10:1) (Table 3).
The corresponding sulfonyl fluorides (3) were produced in moder-
ate to high yields in all cases. This method must be superior to the
previous methods to prepare sulfonic fluorides,6 because the
experimental procedure is quite simple and does not require strict
anhydrous conditions.
1
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nates (2) with Selectfluor™ is shown below (Scheme 8). A sulfur
atom of 2 is fluorinated by Selectfluor™ and the resulting
sulfonium ion (D) is attacked by water to form E, and E is further
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Cl
H
N
2BF4-
O
N
H
O
O
O O
S
R
F
S
R
R
S
R
S
5.
2
F
D
Cl
N
2BF4-
N
O
O
O O
S
O
O
S
R
F
R
R
S
R
S
S
2
R
F
Electrophilic or
Radical Reaction
O
O O
3
E
F
Scheme 8.

M. Kirihara et al. / Tetrahedron Letters 52 (2011) 3086–3089
3089
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