Tetrabutylammonium peroxydisulfate in organic synthesis. XII. A convenient and practical procedure for the selective oxidation of thiols to disulfides with tetrabutylammonium peroxydisulfate under solvent-free conditions

Article abstract of DOI:10.1081/SCC-120014782

An efficient method for the oxidative coupling of thiols to their corresponding disulfide by (n-Bu₄N₂)S₂O₈ in high yields under solvent-free conditions is described. The reaction was applicable to a variety of thiols with high chemoselectivity.

Full text of DOI:10.1081/SCC-120014782

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TETRABUTYLAMMONIUM PEROXYDISULFATE IN ORGANIC
SYNTHESIS. XII. A CONVENIENT AND PRACTICAL
PROCEDURE FOR THE SELECTIVE OXIDATION OF
THIOLS TO DISULFIDES WITH TETRABUTYLAMMONIUM
PEROXYDISULFATE UNDER SOLVENT-FREE CONDITIONS
Fen-Er Chen a , Yun-Wen Lu a , Yan-Ping He a , You-Fu Luo a & Ming-Guo Yan a
a Department of Chemistry, Fudan University, Shanghai, 200433, P.R. China
Published online: 22 May 2009.
To cite this article: Fen-Er Chen , Yun-Wen Lu , Yan-Ping He , You-Fu Luo & Ming-Guo Yan (2002): TETRABUTYLAMMONIUM
PEROXYDISULFATE IN ORGANIC SYNTHESIS. XII. A CONVENIENT AND PRACTICAL PROCEDURE FOR THE SELECTIVE OXIDATION
OF THIOLS TO DISULFIDES WITH TETRABUTYLAMMONIUM PEROXYDISULFATE UNDER SOLVENT-FREE CONDITIONS, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:22, 3487-3492
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 22, pp. 3487–3492, 2002
TETRABUTYLAMMONIUM
PEROXYDISULFATE IN ORGANIC
SYNTHESIS. XII.[1] A CONVENIENT AND
PRACTICAL PROCEDURE FOR THE
SELECTIVE OXIDATION OF THIOLS
TO DISULFIDES WITH
TETRABUTYLAMMONIUM
PEROXYDISULFATE UNDER
SOLVENT-FREE CONDITIONS
*
Fen-Er Chen, Yun-Wen Lu,Yan-Ping He,
You-Fu Luo,and Ming-Guo Yan
Department of Chemistry, Fudan University,
Shanghai 200433, P.R. China
ABSTRACT
An efficient method for the oxidative coupling of thiols to their
corresponding disulfide by (n-Bu4N2)S2O8 in high yields
under solvent-free conditions is described. The reaction was
applicable to a variety of thiols with high chemoselectivity.
*Corresponding author. Fax: þ86-21-65642021; E-mail: rfchen@fudan.edu.cn
3487
DOI: 10.1081/SCC-120014782
Copyright & 2002 by Marcel Dekker, Inc.
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3488
CHEN ET AL.
Selective oxidation of thiols to disulfides is of practical importance
both in biochemistry[2] and in synthetic chemistry.[3] Disulfides are also
important intermediates with a lot of applications in organic synthesis.
For example, they serve as precursors for the synthesis of dithiin
derivatives,[4] 4H-1,4-benzothiazines[5] and thiocarbonyl compounds[6] etc.
Since thiols are among functional groups which can be easily over-
oxidized, a variety of chemical oxidation (O2,[7] Br2/KHCO3,[8] I2/HI,[9]
FeCl3/Bu3SnOMe,[10] FeCl3/NaI,[11] KMnO4/CuSO4,[12] H2O2/HFIP,[13]
Ca(OCl2)2,[14] Sm/BiC13,[15] TTCPP,[16] Zn(BiO3)2,[17] Cu(NO3)2,[18] bis
[benzyltriethyl] ammonium dichromate[19] and benzyltriphenyl phospho-
nium dichromate,[20] etc), electrochemical oxidation[21] and enzymatic
(horseradish peroxidase or mushroom tyrosinase[22] and Baker’s yeast[23]
)
methods have been developed for the controlled oxidative coupling of thiols
to disulfides. However, most of the existing methods use toxic metal ions
and solvents which are detrimental to the environment, lack the general
applicability to thiol substrates bearing alkyl, aryl, and heterocyclic
moieties, isolation and form over oxidation products leading to lower
yield. As a result, there is still a need for the development of general,
efficient, and eco-friendly methodology to synthesize aliphatic, aromatic,
and heterocyclic disulfides from the corresponding thiols under mild reac-
tion conditions. In recent years, the use of solvent-free synthesis has been
proven to present many advantages over conventional solution procedures
in organic synthesis.[24] In the light of ever increasing environmental concern
about today’s chemical research, attempts are on to perform the organic
reaction in the solid state. During the course of our systematic study on
oxidation of organic compounds with tetrabutylammonium peroxydisulfate
[(n-Bu4N2)S2O8],[25] we report here a facile and selective oxidation of thiols
to disulfide using [(n-Bu4N2)S2O8] under solvent-free conditions as displayed
in Sch. 1.
The feasibility of the present oxidation of thiols was first examined
using benzenethiol 1a as a model substrate. Thus, 1a was thoroughly mixed
with 1.1 equivalents of (n-Bu4N)2S2O8 in a mortar with a pestle and in an
ambient air environment at room temperature and the desirable coupling
product 2a was obtained in 87% yield within 5 min (Entry 1). It is
noteworthy that the oxidation did not proceed to completion even after
prolonged hours of reaction (1.5 h) when less than 1.1 equivalents of the
oxidant was used.
With the first successful result in hand, oxidative coupling reactions of
other thiols (1b–r) with (n-Bu4N)2S2O8 were carried out under similar reac-
tion conditions. The results obtained are presented in Table 1. As shown in
the Table 1, aliphatic, aromatic, and the heterocyclic thiols were oxidized to
the corresponding disulfides in substantially quantitative yields with very

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TETRABUTYLAMMONIUM PEROXYDISULFATE. XII
3489
Scheme 1.
short times (4–6 min). Electronic and/or steric variation of the thiols has no
effect on the efficiency of either the oxidation reaction rate or yields of the
reaction. Other oxidizable functional groups such as amino (Entry 5),
hydroxy (Entry 13), and C, C double bonds (Entry 11) present in some of
the substrates tested were found to be tolerated under the present protocol.
It should also be noted was that under the present reaction conditions,
purity of the product was >99% in all cases and no other over-oxidized
byproducts were detected on GC and by 1H NMR spectroscopy, even when
the reactions were carried out with an excess of the oxidant.
In conclusion, the oxidation of thiols using (n-Bu4N)2S2O8 under
solvent-free conditions provides a very rapid, general, and environmentally
benign procedure for the high-yielding preparation of a variety of disulfides
that may find useful, practical applications in organic synthesis.
EXPERIMENTAL
All melting points were determined on a WRS-1 digital melting point
apparatus, and are uncorrected. IR spectra were recorded on a Nicolet FI-
1
IR 360 spectrometer. H NMR spectra were measured on a Brucker AC-80
or DPX 300 spectrometer using CDCl3 as solvent and TMS as an internal
standard. TLC was performed on Silica Gel 60 F254 purchased from Qing
Dao Marine Chemical Company (China). The purity determination of
products was accomplished by GC on a Shimadzu GC-14Ainstrument.

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3490
CHEN ET AL.
Table 1. Oxidation of Thiols 1a–r to Disulfides 2a–r with (n-Bu4N)2S2O8 Under
Solvent-Free Conditions
M.P. (ꢁ) or B.P. (ꢁ)/Torr
Reaction Time
(min)
Yieldb
(%)
Entry Thiol
Producta
Found
61–62
45–47
44–45
73–74
79–81
288–290
184–185
113–115/18
111–114/15
90–92/1
137–198/760
140–141
140–141/1
120–121/1
56–58
Reported
1
2
3
4
5
1a
1b
1c
1d
1e
1f
5
6
5
5
6
5
5
6
5
5
5
4
6
6
5
5
5
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
87
88
86
82
88
90
88
88
86
86
90
87
88
86
85
83
86
87
58–60[13]
45–46[11]
42–44[8]
72–73[19]
80[20]
6
286[20]
7
8
9
1g
1h
1i
184–186[20]
115/17[26]
197–200[20]
89–91/1[27]
139/760[28]
139–141[8]
150–152/0.01[8]
118–120/0.8[20]
54–57[17]
10
11
12
13
14
15
16
17
18
1j
1k
1l
2j
2k
2l
1m
1n
1o
1p
1q
1r
2m
2n
2o
2p
2q
2r
144–146
199–201
181–182
141–145[17]
200–201[20]
183–184[11]
aAll products were characterized by IR, 1H NMR, MS, and comparison of the TLC,
m.p. with those of authentic samples.
bYields of isolated pure product.
Mass spectra were measured on HP-5989Aspectrometer by direct inlet at
70 eV. Thiols were obtained from Joint Venture Zhejiang Shou & Fu
Chemical Company (China) or Aldrich Chemical Company and are used
without further purification. (n-Bu4N)2S2O8 was prepared according the
literature procedure.[29]
Typical procedure for the oxidation of thiols benzenethiol (1a) to
diphenyl disulfide (2a): Amixture of benzenethiol ( 1a) (10 mmol, 1.1 g) and
(n-Bu4N)2S2O8 (5.5 mmol, 3.73 g) was ground thoroughly in a mortar and
pestle in for 5 min at room temperature until the reaction was complete
by GC monitoring. The product was extracted with Et2O (4 ꢀ 35 mL).
The combined Et2O layers were washed with brine (315 mL), dried
(Na2SO4) and the solvent was evaporated under reduced pressure to
give crude product, which was recrystallized from EtOH to give pure 2a
(1.6 g, 87%) as colorless crystals; m.p. 61–62ꢁC (lit.[13] 58–60ꢁC),

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TETRABUTYLAMMONIUM PEROXYDISULFATE. XII
3491
IR (KBr): ꢀ ¼ 3048, 1570, 1473, 1435, 685, 469 cmꢂ1
ꢁ ¼ 7.45–7.50 (m, 4H), 7.22–7.39 (m, 6H).
.
1H NMR:
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Received in Japan September 17, 2001