A traceless, one-pot preparation of unsymmetric disulfides from symmetric disulfides through a repeated process involving sulfenic acid and thiosulfinate intermediates

Article abstract of DOI:10.1016/j.tetlet.2010.11.042

A variable group of unsymmetric disulfides was prepared under mild reaction conditions and in high yields through the reaction of symmetric disulfides with sulfuryl chloride followed by treatment with thiols in the presence of water.

Full text of DOI:10.1016/j.tetlet.2010.11.042

Tetrahedron Letters 52 (2011) 236–239
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A traceless, one-pot preparation of unsymmetric disulfides from
symmetric disulfides through a repeated process involving sulfenic acid
and thiosulfinate intermediates
⇑
Minsoo Han, Jong Tak Lee, Hoh-Gyu Hahn
Organic Chemistry Laboratory, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A variable group of unsymmetric disulfides was prepared under mild reaction conditions and in high
yields through the reaction of symmetric disulfides with sulfuryl chloride followed by treatment with thi-
ols in the presence of water.
Received 17 September 2010
Revised 19 October 2010
Accepted 4 November 2010
Available online 29 November 2010
Ó 2010 Published by Elsevier Ltd.
Keywords:
Unsymmetric disulfide
Thiosulfinate
Sulfenic acid
1. Introduction
approaches, a microwave assisted transformation was involved.19
The drawback of most of these reported synthetic methodologies
Disulfides are found in numerous natural products and biologi-
cally significant functional materials.1 Numerous disulfides occur
naturally, and the study of their biogenesis should lead to fascinat-
ing results. For example, diallyl disulfide is the active constituent of
garlic and the antibacterial disulfide monoxide (a thiosulfinate)
also present is allicin.2 Some disulfides express antitumor activity.3
Although symmetric disulfides can be prepared by the direct trans-
formation of thiols, through treatment with hydrogen peroxide, io-
dine, chromates, bromine or sulfuryl chloride, efficient synthetic
methods, for unsymmetric disulfides are still in need.4 The
synthetic methodologies of unsymmetric disulfides reported in lit-
eratures over the past three decades were classified into three cat-
egories: First, the thiolysis of reactive sulfenylating agents such as
sulfenyl chlorides,5 sulfenamides,6 sulfenimides,7 sulfenyl hydra-
zides,8 thiobenzotriazoles,9 thiotriphenylphosphonium salts,10
sulfenyl thiocarbonates,11 thionitriles12 and immobilized thiosul-
fonates13 through nucleophilic SN2 attack of thiol or thiolate anions
to yield unsymmetric disulfides (Eq. 1). In this method, the isola-
tion of the reactive sulfenylating agent intermediate should be
done in advance in most of the cases. Second, syntheses through
a thio-disulfide interchange reaction of symmetric disulfides, such
as bistetrazole disulfide,14 dithiobis(benzothiazole),15 N-alkylpyr-
idyl disulfide16 or dithiopyridine N-oxides17 (Eq. 2). Third, synthe-
ses using metal complex catalyst (Eq. 3).18 In a number of other
is the necessity of preparation of the reactive sulfenylating agents
or thio-disulfide interchangeable symmetric disulfides in advance.
In addition, the elimination of the leaving sulfenylating moiety (HL
or R3SH) or the symmetric disulfide, byproduct resulted from using
excess thiol, at the end of the reaction is another drawback of the
reported syntheses of unsymmetric disulfides.20
R1—SH þ R2—S—L ! R1—S—S—R2 þ HL
ð1Þ
ð2Þ
R4—SH
R5—SH
R3—S—S—R3
!
R4—S—S—R3
R —S—S—R
4
ƒƒƒ!
5
þ
þ
R3—SH
R3—SH
metal catalyst
ðR6—SÞ2 þ ðR7—SÞ2
R —S—S—R
6
ð3Þ
ƒƒƒƒƒƒƒ!
7
Herein, we report a simple and convenient preparation of
unsymmetric disulfides under mild reaction conditions and in high
yields from symmetric disufides through thiosulfinate intermedi-
ates. This is a practical synthesis of unsymmetric disulfides
through thiolysis using thiosulfinate as a reactive sulfenylating
agent. In addition, an important advance in this new methodology
is the traceless preparation of unsymmetric disulfides in a one-pot
reaction without separation of leaving sulfenylating moiety.
In the course of development of new herbicides, it was impor-
tant to synthesize a new triazolyl phenyl disulfide 1 as an interme-
diate. The retrosynthetic analysis of this intermediate is shown in
Scheme 1. According to this retrosynthetic analysis, a nucleophilic
attack by the sulfur atom of 3-mercapto-1,2,4-triazole 3 at the
⇑
Corresponding author. Tel.: +82 2 958 5139; fax: +82 2 958 5189.
E-mail address: hghahn@kist.re.kr (H.-G. Hahn).
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.11.042

M. Han et al. / Tetrahedron Letters 52 (2011) 236–239
237
reaction conditions. Although the mechanism of formation of
unsymmetric disulfide by nucleophilic displacement at sulfur of
thiosulfinate by thiol was previously proposed,24 no such examples
were reported. Recently, the transformation of thiosulfinate inter-
mediate produced by oxidation of diallyl disulfide by the action of
cytochrome P450 in allium tissues into unsymmetric disulfide was
proposed in living system, mediated by enzymatic metabolic trans-
N
N
N
N
NH
NH
HS
+
S
S
S
Cl
Et3N
2
3
1
SO2Cl2 or Cl2
formation.25 However,
a practical chemical synthesis of the
4
S
S
unsymmetric disulfide by the mechanism depicted in Scheme 2
has not been reported until now according to our knowledge.
Evidence in support of the proposed reaction mechanism in
Scheme 2 was that the thiosulfinate 12 prepared by the oxidation
of the diphenyl disulfide 4 with m-chloroperoxoybenzoic acid26
was found to react with triazolyl thiol 3 (2.0 M equiv) smoothly
under anhydrous conditions to afford the unsymmetric disulfide
1 in a high yield (90%) (Scheme 3, see experimental in Supplemen-
tary data).
It has been reported that sulfenyl halides react rapidly with
water to produce the corresponding sulfenic acids and thiosulfi-
nates, which are vulnerable to attack by nucleophiles.21 Therefore,
an immediate dropwise addition of a freshly prepared solution of
the sulfenyl chloride 7 in THF, prepared by chlorinolysis of sym-
metric disulfide, into a solution of the thiol 10, triethylamine and
water at the same solvent below room temperature is preferable
in order to obtain high product yield and to avoid formation of
byproducts.
Scheme 1. Retrosynthetic analysis for triazolyl phenyl disulfide 1.
sulfur atom of the benzenesulfenyl chloride 2, that is prepared
from diphenyldisulfide 4 in the presence of triethylamine, would
be expected to give the unsymmetric disulfide 1.
The benzenesulfenyl chloride intermediate 2 was prepared by
the reaction of diphenyldisulfide 4 with sulfuryl chloride in dried
benzene, and was then treated with 3-mercapto-1,2,4-triazole 3
in the presence of triethylamine under nitrogen atmosphere and
at room temperature to yield the target unsymmetric disulfide 1
(see Scheme 1). Under these reaction conditions, the yield was very
low and the starting disulfide 4 was recovered unchanged. Similar
results were obtained by repeating the reaction at ambient
temperature, and the yields were less than 40% in all these trials.
Prudent experiments with protection from moisture showed a ten-
dency towards lower yields of the product. Therefore, we tried to
repeat the reaction in moist tetrahydrofuran instead of dried ben-
zene as a solvent. Surprisingly, the reaction proceeded smoothly as
monitored by TLC. Thus, it is conceivable that the addition of water
would be a critical factor in obtaining high yields of the products.
Accordingly, the reaction was repeated for several times using dif-
ferent molar equivalents of water in order to determine the opti-
mum water equivalent for the highest yields. It was found that
the highest yields of product were obtained when 5–10 M equiv
of water were used.
A suggested mechanism of the reaction is shown in Scheme 2.
The sulfenyl chloride 7 was obtained from either treatment of 5
with sulfuryl chloride (1.65 M equiv) or chlorinolysis of the disul-
fide 6 by treatment with sulfuryl chloride (1.1 M equiv).5 In the
presence of water the sulfenyl chloride 7 initially reacts with water
to form the corresponding sulfenic acid 8, which dimerizes into
thiosulfinate 9 upon loss of water.21,22 The nucleophilic attack of
the sulfur atom of the thiol 10 (R2SH) at the sulfenyl sulfur of 9 re-
sults in the desired unsymmetric disulfide 11 with the regenera-
tion of the sulfenic acid 8.23 The generated sulfenic acid 8
dimerizes again to repeat the cycle. The net result is that the sym-
metric disulfide 6 was converted to the unsymmetric disulfide 11
in the presence of water and in high yield. On the basis that greater
than 50% isolated yield of the product was obtained and the ab-
sence of any thiosulfonate or thiosulfonate-derived products, we
concluded that disproportionation22 did not take place in these
For an extension of this new methodology for the preparation of
various unsymmetric disulfides, a group of variable symmetric
disulfides and thiols were used and the results are summarized
in Table 1.
The structures of the prepared unsymmetric disulfides were
confirmed by 1H NMR, 13C NMR, HRMS spectral data and X-crystal-
lographic analysis. The 1H NMR and 13C NMR spectra of the pre-
pared compounds were in agreement with the structures. The
molecular ions (M+ or MH+) of the prepared unsymmetric disul-
fides 11 were successfully obtained by using Direct Analysis in Real
Time ion source installed on a high-resolution time-of-flight mass
spectrometer.27 Further proof of the structure was established by
means of an X-ray crystallographic analysis (Fig. 1) for compound
11j.28 Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
CCDC-791710. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Since the symmetric disulfides could be prepared by oxidation of
the corresponding thiols and a lot of thiols are commercially avail-
able it is most likely that this new methodology would be very use-
ful for the preparation of unsymmetric disulfides.
In summary, we have prepared a variable group of unsymmetric
sulfides under mild reaction conditions and in high yield. Treat-
ment of symmetric disulfides with sulfuryl chloride followed by
the reaction with thiols in the presence of water without isolation
of sulfenic acid and thiosulfinate intermediates gave unsymmetric
disulfides. The reagents were used in equimolar ratios and the
reaction proceeded in a nearly quantitative yield. Little trace
R1 SH
5
SO2Cl2
(1.65 eq)
SO2Cl2
H2O
R1
S S R1
R1
S
Cl
R1
S
OH
R1
S
11
S R2
6
8
7
-H2O
N
dimerization
NH
HS
3
O
S
N
N
N
m-CPBA
R1 = phenyl
R2 = 1,2,4-triazol-3-yl
NH
Ph
S S Ph
O
S
Ph
S
Ph
Ph S S
R2 SH
CHCl3, 0oC
THF, r.t
R1
S R1
10
4
12
1
9
HPLC yield : 90%
Scheme 2. The proposed mechanism for the formation of the disulfide 11 through
the intermediates sulfenic acid 8 and thiosulfinate 9.
Scheme 3. The reaction of thiosulfinate intermediate 12 and triazolyl thiol 3.

238
M. Han et al. / Tetrahedron Letters 52 (2011) 236–239
Table 1
Physical properties and isolated yields of the prepared unsymmetric disulfides 11
SO2Cl2
(1.65 eq)
R1 SH
R2 SH
10
THF
, H2O, TEA
5
(5~10 eq)
or
R1
S
S
R2
R1
S Cl
SO2Cl2
(1.1 eq)
THF, 1~ 6h, r.t.
11
7
R1
S S R1
THF
6
Entry
Compounds
R1
R2
Mp (°C)
Yieldsa (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
11s
C6H4(4-Cl)
1,2,4-triazol-3-yl
C6H4(4-CH3)
88
95
63
90
Oil
Oil
Oil
Oil
91
71
87
81
78
81
63
86
76
57
47
84
92
65
71
96
91
46
83
72
C6H4(4-Cl)
C6H4(4-Cl)
Cyclohexyl
Cyclohexyl
Cyclohexyl
t-Butyl
t-Butyl
t-Butyl
t-Butyl
n-Propyl
n-Propyl
n-Propyl
n-Propyl
n-Propyl
C6H5
C6H5
C6H5
C6H5
Benzothiazol-2-yl
1,2,4-triazol-3-yl
C6H4(4-OCH3)
Benzothiazol-2-yl
C6H4(4-CH3)
C6H4(4-OCH3)
1,2,4-Triazol-3-yl
Benzothiazol-2-yl
C6H4(4-CH3)
C6H4(4-OCH3)
1,2,4-Triazol-3-yl
Benzothiazol-2-yl
C6H4(4-Cl)
1,2,4-Triazol-3-yl
C6H4(4-Cl)
82
Oil
Oil
Oil
Oil
Oil
109
Oil
Oil
Oil
C6H4(4-OCH3)
Benzothiazol-2-yl
a
Yields: either isolated yields (solid) by crystallization or isolated yields (oil) by flash chromatography.
Figure 1. ORTEP plots of prepared unsymmetric disulfide 11j.
byproducts were produced from the reaction through the cyclic
process involving the intermediates.
2.2. Step 2: The preparation of the unsymmetric disulfides 11
To solution of the thiol 10 (1.0 mmol), triethylamine
a
(2.2 mmol) and water (10 mmol) in THF (4.0 mL) at room temper-
ature was added the pre-prepared solution of sulfenyl chloride
(1.0 mmol) dissolved in THF while stirring. The reaction mixture
was stirred for 1–6 h at room temperature. The reaction progress
was monitored by TLC. The reaction mixture was diluted with
methylene chloride (20 mL), washed sequentially with aqueous
saturated NaHCO3 solution and water and then dried over anhy-
drous MgSO4. The solvent was removed by evaporation, and the
residue was purified by flash chromatography on silica gel to ob-
tain the corresponding unsymmetric disufide 11.
2. General procedure for the synthesis of unsymmetric
disulfides 11
2.1. Step 1: The preparation of the sulfenyl chloride 7
Method A: To a solution of the thiol 5 (1.0 mmol) in tetrahydro-
furan (THF) (5.0 mL) at 0 °C under ice-bath was added slowly
SO2Cl2 (1.65 mmol). The reaction mixture was stirred for 1 h at
the same temperature. This solution was used immediately in
the next step.
Method B: To a solution of the disulfides 6 (0.5 mmol) in THF
(5.0 mL) at 0 °C under ice-bath was added dropwise SO2Cl2
(0.55 mmol). The reaction mixture was stirred for 30 min at the
same temperature and the resulted solution was used immediately
in the next step.
Acknowledgements
We thank for Professor S. H. Cheon and Mr. I. M. El-Deeb for
assistance in preparation of the Letter.

M. Han et al. / Tetrahedron Letters 52 (2011) 236–239
239
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ꢀ
space group P1ð#2Þ; a = 5.9806(9), b = 9.526(2), c = 11.421(2) Å,
a = 83.223°,
b = 79.387°,
(Mo-K
c
= 77.541°, V = 622.4 Å3, Z = 2, Dc = 1.363 g/cm3, F(0 0 0) = 268.00,
l
a
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measurement on Rigaku RAXIS RAPID imaging plate area detector with
graphite monochromated Mo-K
a radiation. I >2r(I). Final indices: R1 = 0.049,
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