96 RESEARCH PAPER
FEBRUARY, 96–97
JOURNAL OF CHEMICAL RESEARCH 2014
Simple conversion of thiols to disulfides in EtOH under ambient aerobic
conditions without using any catalyst or additive
Hang Wanga, Guojun Huanga, Yang Sunb and Yunyun Liua*
aState Key Laboratory of Functional Small Organic Molecules, Ministry of Education, and College of Chemistry and Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P.R. China
bDepartment of Anesthesiology, General Hospital of Benxi Steel and Iron Company, Benxi 117000, P.R. China
EtOH was found to be an excellent medium for the aerobic S–S coupling reactions of various alkyl and aryl thiols. A series
of useful disulfides RSSR have been synthesised in good to excellent yields without using any additional catalyst, oxidant
or additive. Moreover, most products could be obtained by simply removing the solvent after completion of the reaction.
Satisfactory results were obtained for both mg- and g-scale reactions.
Keywords: catalyst-free, aerobic, thiol coupling, disulfides, scale-up synthesis
Table 1 Optimisation of reaction conditions for the conversion of
thiophenol 1a to diphenyl disulfide 2a (Scheme 1; R=H)a
The chemistry of disulfides is a topic of high interest owing
to their usefulness in the chemical industry as well as for
laboratory synthesis. The most notable application of disulfides
is acting as operationally friendly thiolating reagents as well
precursors for sulfones/sulfoxides synthesis. Although the
synthesis of disulfides using oxidative coupling of thiols has
been known as a classical protocol, the development of cleaner,
simpler and scalable catalytic methods to synthesise these
products is still of great interest.
We have very recently reported the successful autoxidation of
thiols RSH to disulfides RSSR using ethyl lactate as a solvent
without the addition of catalyst or any additive.1 We have now
found that the reaction can be carried out more efficiently and
in good to excellent yields in the simple solvent, ethanol, again
without the addition of catalyst or any additive. Moreover, the
isolation of products merely requires evaporation of this low-
boiling solvent. We here describe our results which include the
conversion of aryl, heteroaryl and alkyl thiols to disulfides on
both the milligram and gram scale (Scheme 1).
Entry
T/oC
t/h
Yield/%b
1
2
3
4
5
6
7
8
9c
60
45
25
25
25
25
25
25
25
12
12
12
10
8
6
4
2
4
4
77
76
78
75
79
80
83
62
84
10d
25
71
aReaction conditions: 1a (1 mmol) in EtOH (1 mL) was stirred at room
temperature in the air.
bYield of isolated product 2a.
cEtOH was 1.0 mL; dEtOH was 0.5 mL.
(entries 2–10, Table 2), so the method shows wide applicability.
Only the naphth-2-yl and pyridine-2-yl thiols gave slightly lower
yields in the range 75–78% (entries 11 and 12, Table 2). All the
products are known and have been confirmed by comparing
their 1H NMR spectra as well as melting points (for solids) with
literature results.
S
R
EtOH
R
SH
R
S
2
1
We also investigated whether the method could be scaled
up 10-fold. We chose three thiophenols for experiments on the
10 mM scale. By simply stirring each of the compounds in the
open air in EtOH (10 mL) for 6 h, the conversion of thiophenol
1a, 4-methylthiophenol 1b and 4-bromothiophenol 1d to the
Scheme 1
Results and discussion
When thiophenol 1a (1 mM) was dissolved in EtOH (2 mL)
at 60 °C and stirred for 12 h without using any additional
reagent, diphenyl disulfide 2a was obtained in 77% yield. This
interesting result prompted us to further optimise the reaction
conditions and the results are shown in Table 1. Performing the
reaction at 45 °C or at room temperature gave similar yields of
product (entries 1–3, Table 1; TLC analysis was used to monitor
the reactions). Shortening the reaction times from 12 to 10, 8,
6, 4 and 2 h revealed that 4 h was optimal by giving a yield
of 83% (entries 4–8, Table 1). When the amount of EtOH was
reduced from 2 mL to 1.0 mL, the yield was similar, but the
yield dropped off when the volume was reduced to 0.5 mL
(entries 9–10, Table 1).
Table 2 EtOH-mediated catalyst- and additive-free conversion of thiols 1
to disulfides 2 (Scheme 1)a
Entry
1
2
3
4
5
6
7
8
R
Product
Yield/%b
M.p./°C)[lit.]
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
84
86
81
94
90
92
83
85
82
83
78
75
59–60 [58–60]1
Pale yellow liquid2
Pale yellow liquid3
91–92 [94–96]1
Pale yellow liquid4
61–62 [63–65]1
Colourless liquid5
Yellow liquid6
4-MeC6H4
4-FC6H4
4-BrC6H4
4-i-PrC6H4
Benzyl
Octyl
2-MeC6H4
3-MeC6H4
2-ClC6H4
Napth-2-yl
Pyridin-2-yl
Using the optimised conditions of stirring a solution of thiols
1 (1 mM) in EtOH (1 mL) for 4 h, a series of aryl, heteroaryl
and alkyl thiols were investigated and the results are shown in
Table 2. As can be seen, the yields of the dialkyl and diaryl
disulfides are all in the good to excellent range of 81–94%
9
Yellow liquid7
10c
11c
12c
2j
2k
2l
82–84 [85–87]1
135–136 [355–137]1
Yellow liquid2
aGeneral conditions: 1a (1 mmol) in alcohol (1 mL), was stirred at room
temperature in the air for 4 h.
bYield of isolated product.
* Correspondent. E-mail: chemliuyunyun@jxnu.edu.cn
cThe products were purified by silica gel column chromatography.
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Wang, Hang
