Deep eutectic mixture catalysed the synthesis of disulfides using Bunte salts as thiol surrogates

Article abstract of DOI:10.3184/174751915X14323930440061

Bunte salts, easily prepared from odourless sodium thiosulfates and various alkyl and aryl halides, acted as thiol surrogates for preparation of disulfides in the presence of hydrogen peroxide and a Bronsted-acidic deep eutectic mixture. The reaction proceeded smoothly to give the corresponding disulfide products in moderate to good yields, leaving odourless sodium bisulfite and water as the by-products. Moreover, this catalytic system could be readily recovered and reused several times without significant loss in activity.

Full text of DOI:10.3184/174751915X14323930440061

332 RESEARCH PAPER
VOL. 39 JUNE, 332–335
JOURNAL OF CHEMICAL RESEARCH 2015
Deep eutectic mixture catalysed the synthesis of disulfides using Bunte salts
as thiol surrogates
Yongsheng Zhou
School of Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China
Bunte salts, easily prepared from odourless sodium thiosulfates and various alkyl and aryl halides, acted as thiol surrogates for preparation
of disulfides in the presence of hydrogen peroxide and a Brønsted-acidic deep eutectic mixture. The reaction proceeded smoothly to
give the corresponding disulfide products in moderate to good yields, leaving odourless sodium bisulfite and water as the by-products.
Moreover, this catalytic system could be readily recovered and reused several times without significant loss in activity.
Keywords: deep eutectic mixture, dialkyl disulfides, diaryl disulfides, Bunte salts, thiol surrogates, hydrogen peroxide
Application of a deep eutectic mixture as a “green” solvent or
catalyst has invoked enormous interest in organic chemistry
and other fields.1 This kind of mixture exhibits similar
properties to those of ionic liquids such as low vapour pressure,
low flammability, biodegradability, ready availability and
reusability. Compared to the preparation of ionic liquids, the
preparation of a deep eutectic mixture is much easier. Generally,
they are prepared by combining a cationic salt with a hydrogen-
bond donor such as urea, a carboxylic acid, a sugar and an amide
without further purification. The low cost and low toxicity
make them alternatives to traditional organic solvents and
ionic liquids. Subsequently, their ability to serve as catalysts as
well as solvents has also been explored in the field of synthetic
organic chemistry for C–C coupling reactions,2,3 halogenation,4
alkylation,5 epoxide hydrolysis,6 nitroaldol reactions,7 multi-
component reactions,8 oxidative hydroxylation9 as well as other
useful transformations.10,11
On the other hand, organic disulfides play important roles
in both biological and chemical processes.12,13 Disulfides are
also valuable organic intermediates for the preparation of
sulfenyls,14 sulfinyls15 and thioethers by radical pathways.16
Disulfides are generally prepared from thiols, and various
reagents and oxidants have been employed including the
halogens and their derivatives,17,18 transition metal salts19,20
and peroxides.21,22 Despite considerable progress in this field,
the use of malodourous and air-sensitive thiols, excess and/
or expensive reagents, and hazardous solvents and oxidants,
together with over oxidation and tedious work-up procedures
are still issues to be addressed.
and trisulfides respectively. However, previous studies in this
field only focused on alkyl Bunte salts. Recently, Reeves et al.
reported25 the the synthesis of sulfides by reaction of Grignard
reagents with Bunte salts. The Bunte salts were readily
prepared from alkyl, aryl or vinyl halides with odourless and
inexpensive sodium thiosulfate. Jiang et al. also reported26,27
one-pot synthesis of sulfides using Na2S2O3 as a sulfurating
reagent. Notably, all these procedures avoided the use of thiols
or thiol-derived reagents, leaving odourless sulfites as the by-
products. Thus, the importance of Bunte salts prompted us to
explore other uses in organic synthesis. We now report a facile
procedure for the synthesis of disulfides from Bunte salts
catalysed by a recyclable Brønsted-acidic deep eutectic mixture
in water (Scheme 1).
Results and discussion
Initially, sodium benzyl thiosulfate (1a) was selected as the
model substrate to optimise the reaction conditions (Table 1).
It was observed that no reaction took place in the absence of
any catalyst. Different choline chloride (ChCl)-based eutectic
mixtures such as choline chloride–urea, choline chloride–
malonic acid, and choline chloride–glycerol did not promote
the reaction. When the more acidic deep eutectic mixture
ChCl/p-TsOH was employed, the corresponding product 2a
was obtained in 38% yield (Table 1, entry 5). However, when
p-toluenesulfonic acid was used alone, 29% yield of product
was obtained. The concentration of ChCl/p-TsOH was then
examined. The results suggested 20% (v/v) of ChCl/p-TsOH
in water was the best choice, providing 2a in 55% yield. Since
substrate 1a was only soluble in a polar solvent, other solvents
including methanol and ethanol were also checked, but only
lower yields were obtained.
S-alkyl thiosulfates (Bunte salts) can be hydrolysed under
acidic conditions to generate thiols. Other nucleophiles such as
thiols23 and Na2S24 also react with Bunte salts to give disulfides
O
RS S ONa
O
ChCl/ -TsOH
p
+
RS SR
NaHSO4
+ H
2O2
60 oC
H
2O,
N
O
Cl
HO S
O
OH
ChCl/ -TsOH
p
Scheme 1 Synthesis of disulfides catalysed by acidic deep eutectic mixture.
* Correspondent. E-mail: yszhou@126.com

JOURNAL OF CHEMICAL RESEARCH 2015 333
Table 1 Optimisation of reaction conditionsa
S
S
a
N
SO3
+
H
2O2
S
a
1
a
2
Entry
Catalyst/%
Solvent
H2O2/equiv.
Temperature/oC
Yield/%b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
1
1
1
1
1
1
1
1
1
1
2
3
4
3
3
3
3
30
30
30
30
30
30
30
30
30
30
30
30
30
50
60
80
60
0
0
0
0
ChCl/urea (10)
ChCl/malonic acid (10)
ChCl/glycerol (10)
ChCl/p-TsOH (10)
p-TsOH (10)
ChCl/p-TsOH (20)
ChCl/p-TsOH (25)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
ChCl/p-TsOH (20)
p-TsOH (20)
38
29
55
56
37
39
60
67
62
78
85
84
76
a Reaction conditions: Bunte salt 1a (2 mmol), solvent (10 mL), deep eutectic mixture (%, v/v), 6 h. For entry 6 and 17, catalyst amount is based on mol%.
b Isolated yield.
Table 2 Synthesis of disulfides from Bunte salts
O
S S O
O
- s
H
O
h l
C C /
T
p
+
R R
S S
a
N
H
2O2
R
H2 60 o 6h
O
,
C
,
1
2
M.p./oClit
.
Entry
1
2
3
4
5
6
7
8
Product
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
R
Yield/%b
85
87
92
90
95
84
83
86
82
83
90
91
88
87
85
91
PhCH2
69–70(69–71)29
59–61(58–60)30
61–62(62.0–63.7)31
124–125(126.5)32
146–147(147.5)33
40–41(40–42)34
75–77(76–80)32
Oil33
4-ClC6H4CH2
4-FC6H4CH2
4-NO2C6H4CH2
4-CNC6H4CH2
4-MeC6H4CH2
4-MeOC6H4CH2
n-C3H7
n-C8H17
cyclohexyl
Ph
4-MeC6H4
3-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
9
Oil30
Oil33
10
11
12
13
14
15
16
17
18
19
20
60–61(59–62)29
45–46(44–46)29
Oil32
40–42(41–43)35
114–116(118–119)35
72–73(72–74)35
89–90(90–92)29
Oil29
168–170(172–173)20
128–129(130–131)32
4-BrC6H4
4-FC6H4
4-CNC6H4
2-naphthyl
90
93
92
88
2s
2t
a Reaction conditions: Bunte salt 1 (2 mmol), H2O (10 mL), deep eutectic mixture (20%, v/v), 30% H2O2 (3equiv.), 60 oC, 6 h.
Next, we investigated the concentration of the hydrogen peroxide.
It was found that the yield increased along with the concentration
of H2O2 and a 69% yield was obtained when 3 equiv. of H2O2 are
used. Further addition of H2O2 led to lower product yields. Finally,
variation of the reaction temperature clearly showed that 60 oC was
optimum, affording the product in 85% yield. Again, we checked
the activity of p-toluenesulfonic acid on its own; a relatively lower
yield (76%) was obtained (Table 1, entry 17).
To evaluate the scope and limitations of the current procedure,
a series of Bunte salts was tested under the optimised reaction
conditions (Table 1, entry 15). The results are summarised in
Table 2.

334 JOURNAL OF CHEMICAL RESEARCH 2015
(CDCl3) and D2O using TMS as an internal standard. High-resolution
mass spectrometry (HRMS) was performed on an Agilant 6540
Q-TOF instrument with an ESI source.
Since S-alkyl Bunte salts could be readily prepared from the
corresponding alkyl halides and sodium thiosulfate, a series
of S-alkyl Bunte salts was then subjected to the optimum
reaction conditions. All the reactions proceeded smoothly to
give the disulfides in good to excellent yields (2a–j, 82–95%).
For the benzyl-substituted Bunte salts, those bearing electron-
withdrawing substituents afforded the corresponding products
in excellent yields. S-Aryl Bunte salts, prepared by coupling of
aryl halides with sodium thiosulfate using a copper catalyst,
showed good reactivity. S-Aryl Bunte salts with either electron-
withdrawing or electron-donating substituents such as halide,
OCH3 or CN underwent the reaction in good to excellent yields
(85–93%). The steric effect of an ortho –OCH3 group was also
negligible, with the product 2o being obtained in 85% yield.
The reusability of the catalytic system was also an advantage
of this protocol. For most of the reactions, the disulfide products
precipitated out from the reaction mixture and were isolated by
filtration. The filtrate containing the ChCl/p-TsOH, could be
easily recovered and reused directly by the addition of a new
substrate and oxidant. For the liquid disulfide products, the
reaction mixture was extracted with ethyl acetate, followed by
evaporation of the solvent to give the crude disulfide, which was
further purified by column chromatography on silica gel using
petroleum ether/EtOAc as eluent. As above the aqueous system
containing ChCl/p-TsOH could be reused directly for the next
run. Using substrate 1a as an example, it was found that the
catalytic system could be readily recovered and reused without
substantial loss in activity in six consecutive runs (85%, 85%,
84%, 82%, 80%, and 77% yield respectively, see Fig. 1).
Synthesis of deep eutectic mixture
The deep eutectic mixture was readily prepared according to
the literature28 by mixing the choline chloride (0.1 mol) with
p-toluenesulfonic acid (0.1 mol) at 100 oC until a clear solution
was obtained (40 min) which was used for reactions without any
purification or waste products.
Synthesis of Bunte salts
The Bunte salts were prepared according to the literature.25 For the
S-alkyl Bunte salts, the reaction of alkyl bromides (20 mmol, 1.0
equiv.) and sodium thiosulfate pentahydrate (24 mmol, 1.2 equiv.)
o
in water (10 mL) and MeOH (20 mL) for 3–24 h at 65 C provided
the corresponding salts as white solids. For the S-aryl Bunte salts,
a 100 mL flask was charged with aryl iodides (10 mmol, 1.0 equiv.),
anhydrous sodium thiosulfate (15 mmol, 1.5 equiv.) and CuI (1 mmol,
0.10 equiv.). The flask was sealed with a septum, evacuated and filled
with nitrogen. DMSO (10 mL) was charged using a syringe followed by
N,N’-dimethylethylenediamine (DMEDA, 2 mmol, 0.20 equiv.). The
mixture was stirred for 5 min at rt and then heated at 80 oC for 4–12 h.
The reaction mixture was cooled to room temperature. Then saturated
aqueous NaCl (30 mL) was added and the resultant slurry was stirred
vigorously at rt for 1 h. The mixture was filtered and the solid was
washed successively with saturated aqueous NaCl and hexanes. The
o
solid was dried under reduced pressureat 50 C for 6 h to provide the
corresponding salts.
Melting points ranges are not provided for the Bunte salts, since they
contain variable amounts of residual NaCl and also because the salts,
even in the absence of residual NaCl, did not display a melting point but
rather decomposition. For new Bunte salts, NMR spectra and HRMS
data are provided.
Sodium S-(m-tolyl) sulfurothioate (1m): White solid. 1H NMR (400
MHz, D2O): δ 7.53–7.50 (m, 2 H), 7.14 (d, J = 7.6 Hz, 1 H), 7.01–6.97
(m, 1 H), 2.31 (s, 3 H); 13C NMR (100 MHz, D2O) δ 140.8, 134.9, 132.4,
130.5, 130.1, 129.7, 21.2. HRMS-ESI: calcd for C7H8NaO3S2 [M+H]+:
226.9807; found: 226.9819.
Sodium S-(4-methoxyphenyl) sulfurothioate (1n): Tan solid.
1H NMR (400 MHz, D2O): δ 7.56 (d, J = 8.9 Hz, 2H), 6.68 (d, J = 8.9
Hz, 2H), 3.78 (s, 3H); 13C NMR (100 MHz, D2O) δ 158.5, 135.9, 123.1,
116.5, 56.1. HRMS-ESI: calcd for C7H8NaO4S2 [M+H]+: 242.9756;
found: 242.9748.
Sodium S-(2-methoxyphenyl) sulfurothioate (1o): Tan solid.
1H NMR (400 MHz, D2O): δ 7.77 (dd, J = 7.7, 1.3 Hz, 1H), 7.33–7.29
(m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.75–6.69 (m, 1H), 3.88 (s, 3H);
13C NMR (100 MHz, D2O) δ 160.9, 134.6, 128.3, 127.5, 124.4, 118.6,
56.8. HRMS-ESI: calcd for C7H8NaO4S2 [M+H]+: 242.9756; found:
242.9762.
Conclusion
In summary, a facile procedure for the synthesis of disulfides has
been developed. S-Alkyl and S-aryl Bunte salts are employed as
thiol surrogates and hydrogen peroxide is used as the oxidant,
leaving only sodium bisulfite and water as the by-products. The
workup procedure is simple and the products can be isolated by
filtration. Moreover, the remaining aqueous system containing
the deep eutectic mixture can be reused directly without further
purification.
Experimental
All reagents were obtained from local commercial suppliers and used
without further purification. Melting points were determined with
1
a WRS-1B apparatus and were uncorrected. H and 13C NMR spectra
were recorded on a Bruker Advance 400 analyser in chloroform-d
Sodium S-(4-bromophenyl) sulfurothioate (1q): Tan solid. 1H NMR
(400 MHz, D2O): δ 7.54 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H);
13C NMR (100 MHz, D2O) δ 134.2, 133.9, 133.1, 121.3. HRMS-ESI:
calcd for C6H5BrNaO3S2 [M+H]+: 290.8756; found: 290.8767.
1
Sodium S-(4-fluorophenyl) sulfurothioate (1r). Tan solid. H NMR
(400 MHz, D2O): δ 7.64-7.61 (m, 2H), 6.86-6.81 (m, 2H); 13C NMR
(125 MHz, D2O) δ 162.7 (d, J = 245.8 Hz), 138.9 (d, J = 7.7 Hz), 126.8,
117.7 (d, J = 22.0 Hz). HRMS-ESI: calcd for C6H5FNaO3S2 [M+H]+:
230.9556; found: 230.9570.
1
Sodium S-(4-cyanophenyl) sulfurothioate (1s): Tan solid. H NMR
(400 MHz, D2O): δ 7.85–7.82 (m, 2H), 7.36 (d, J = 8.3 Hz, 2H);
13C NMR (100 MHz, D2O) δ 137.3, 135.0, 129.7, 118.9, 110.0. HRMS-
ESI: calcd for C7H5NNaO3S2 [M+H]+: 237.9603; found: 237.9620.
Synthesis of disulfides; general procedure
The Bunte salt (2 mmol) was dissolved in water (10 mL) in a 25 mL
round bottom flask. To this mixture, the deep eutectic mixture (2 mL)
was added, followed by slow addition of 30% H2O2 (3 equiv.). The
o
Fig. 1 Recycle study.
mixture was then stirred at 60 C for 6 h. After completion of the

JOURNAL OF CHEMICAL RESEARCH 2015 335
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could be reused directly for the next run. All the disulfides are known
compounds and were identified by comparison of their physical and
spectroscopic data with those reported in the literature.
4
5
6
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9
1,2-Di(n-propyl) disulfide (2h):33 Colourless oil; 1H NMR (400
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1,2-Di(n-octyl) disulfide (2i):30 Colourless oil; H NMR (400 MHz,
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1,2-Dicyclohexyl disulfide (2j):33 Colourless oil; 1H NMR (400 MHz,
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1,2-Di(3-tolyl) disulfide (2m):32 Colourless oil; 1H NMR (400 MHz,
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1,2-Di(4-fluorophenyl) disulfide (2r):29 Colourless oil; 1H NMR (400
MHz, CDCl3) δ 7.56–7.43 (m, 4H), 7.10–6.96 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 163.0 (d, J = 245.7 Hz), 133.2 (d, J = 8.4 Hz), 131.2 (d, J
= 8.3 Hz), 116.2 (d, J = 23.3 Hz).
Electronic Supplementary Information
References for the known Bunte salts and NMR spectra of the
novel ones have been deposited in the ESI available through stl.
publisher.ingentaconnect.com/content/stl/jcr/supp-data.
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Received 30 January 2015; accepted 21 May 2015
Paper 1503176 doi: 10.3184/174751915X14323930440061
Published online: 4 June 2015
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