Diacetoxyiodobenzene mediated oxidative transformation of thione to disulfides

Article abstract of DOI:10.1016/j.tetlet.2016.11.091

We have developed an efficient oxidative transformation of thione to disulfides using diacetoxyiodobenzene (DIB) in acetonitrile at room temperature. This strategy is suited for oxidation of thiols to disulfide also. The present oxidation protocol is mild reaction condition, column free, and a new route for disulfide formation.

Full text of DOI:10.1016/j.tetlet.2016.11.091

Tetrahedron Letters 57 (2016) 5941–5943
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journal homepage: www.elsevier.com/locate/tetlet
Diacetoxyiodobenzene mediated oxidative transformation of thione to
disulfides
b,
Sarangthem Joychandra Singh a, , Nepram Sushuma Devi
⇑
⇑
a Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
b Department of Chemistry, Manipur University, Canchipur 795003, Manipur, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient oxidative transformation of thione to disulfides using diacetoxyiodoben-
zene (DIB) in acetonitrile at room temperature. This strategy is suited for oxidation of thiols to disulfide
also. The present oxidation protocol is mild reaction condition, column free, and a new route for disulfide
formation.
Received 28 September 2016
Revised 20 November 2016
Accepted 21 November 2016
Available online 23 November 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
DIB
Thiosemicarbazone
Disulfide
Thiols
Introduction
transformations.26 In particular, diacetoxyiodobenzene (DIB) is
one of the most extensively used reagent for carrying out reactions
The reactions for the construction of disulfides (SAS bonds)
have emerged as an important research area due to their valuable
role in biological1 and chemical processes.2 Disulfides are essential
for DNA-cleavage and stabilization of peptide in protein. They are
also used as protecting groups in organic synthesis, vulcanizing
agents for rubber, sulphenylation of enolates and other anions.
Various methods have been reported for oxidative coupling of thi-
ols to disulfides. Metallic reagents such as Fe(III),3 permanganate,4
manganese dioxide,5 2,6-dicarboxypyridinium chlorochromate,6
cetyltrimethylammonium dichromate,7 sodium iodate,8 potassium
phosphate,9 molybdate sulfuric acid,10 tungstophosphoric acid,11
caesium fluoride,12 bismuth (III) Nitrate13 and Co(II) phthalocyani-
nes14 have been used for effective transformation of thiols to
disulfides. Moreover, some of the non-metallic reagents such as
benzyltriphenylphosphonium peroxymonosulfate,15 DMSO,16
trichloronitromethane,17 hydrogen peroxide,18 molecular Br2,19
and sulfuryl chloride20 NO2 gas,21 activated carbon,22 and DDQ23
were well documented in the literature to effect oxidative coupling
of thiols to disulfides. In addition, air oxidation24 and photocat-
alytic method25 are also known. However, the oxidative coupling
of thiocarbonyl to disulfide was seldom studied.21,22
with compounds containing heteroatom such as nitrogen, sulfur
and oxygen.27 Recently, Singh et al. reported the synthesis of N-
acylated ureas from acyclic 1,3-disubstituted thiourea using
DIB.28 Very recently, Bhong’s group reported diacetoxyiodoben-
zene (DIB) mediated oxidative desulfurization of 3,4-dihydropy-
rimidin-2(1H)-thione, a structural analog of cyclic thiourea.29
Base on these reported method,28,29 we expected the reaction of
thiosemicarbazone with diacetoxyiodobenzene (DIB) may provide
N-acylated ureas or oxidative desulfurization product.
Results and discussion
Keeping this knowledge in mind, a trial reaction was conducted
by treating thiosemicarbazone (1a) with diacetoxyiodobenzene
(DIB) in acetonitrile at room temperature. After 15 min stirring, a
product was detected (monitored by TLC). The product was iso-
lated (80%) and spectroscopic analysis (1H NMR, 13C NMR, HRMS)
determined its structure to be 2-benzylidene-N-phenylhy-
drazinecarbimidic dithioperoxyanhydride. Instead of expected
result, dimerization of thiosemicarbazone takes place through
SAS bond formation (Scheme 1). To the best of our knowledge,
disulfide bond formation has never been realized from thiosemi-
carbazone using diacetoxyiodobenzene (DIB).
In recent year, the applications of hypervalent iodine reagents
have been well developed for carrying out a number of oxidative
To optimize reaction condition, various solvents such as
ethanol, THF, 1,4-dioxane and toluene were tested instead of ace-
tonitrile. However, no further improvement of the yield was
⇑
Corresponding authors.
E-mail addresses: joysarang@iitg.ernet.in (S.J. Singh), nsushuma@gmail.com
(N.S. Devi).
http://dx.doi.org/10.1016/j.tetlet.2016.11.091
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

5942
S.J. Singh, N.S. Devi / Tetrahedron Letters 57 (2016) 5941–5943
Table 2
Ar2
Ar2
Ar1
Ar2
Substrate scope of disulfides.a
N
HN
N
HN
N
NH
DIB (0.5 equiv)
Ar2
Ar1
Ar2
Ar2
CH3CN, r.t,
15 min
S
S
S
N
N
HN
N
Ar1
NH
N
Ar1
DIB (0.5 equiv)
CH3CN, r.t,
N
HN
NH
N
S
S
S
Ar1
NH
(1a-l)
Ar1
Scheme 1. Dimerization of thiosemicarbazone.
N
(2a-l)
Entry
Ar1
Ar2
Product
Yield (%)b
observed. Subsequently, a series of non-metallic oxidants such as
hydrogen peroxide, tert-butyl hydrogen peroxide (TBHP), iodine
(I2), and bis(trifluoroacetoxy)iodobenzene (PIFA) were investi-
gated. The result shows that the diacetoxyiodobenzene (DIB) sys-
tem gave the desired product (2a) in highest yield (80%). The
increase of DIB could not reduce the reaction time, however, a
slightly increase in the yield. The use of base or acid medium gave
no beneficial effect in the yield of the product (Table 1, entries 13–
14).
Optimized reaction conditions were applied to a broad range of
thiosemicarbazone (1). As shown in Table 2, the disulfide products
(2) were obtained in good to high yield. When phenyl was fixed on
aryl ring (Ar1) of thiosemicarbazone, other aryl ring (Ar2) with sub-
stituents such as electronic neutral H, 4-OCH3, 4-Cl, and 4-Br, all
reacted smoothly, affording the disulfide (2a–d) in good to high
yields. Introduction of 4-Br and 4-F substituent on aryl ring (Ar1)
while other aryl ring (Ar2) with phenyl, react to give the desired
disulfide (2e) and (2f) in moderate yield. Among the 4-CH3 substi-
tuted on aryl ring (Ar1) of thiosemicarbazones, 4-Br (1h) substi-
tuted on aryl ring (Ar2) gave the higher yield than their
corresponding substrate (1g) and (1i). Highest yield (90%) was
obtained when 3,4-diCH3 (1j) was substituted on aryl ring (Ar1)
of thiosemicarbazone. Substitution on aryl ring (Ar1) with 2-CH3
could react well to afford (2k) in 73% yield. The substrate possess-
ing 2-Cl on aryl ring (Ar1) of thiosemicarbazone and 2,6-diCl on
other aryl ring (Ar2) also gave the product (2l) in moderate yield.
The structures of all the products were characterized by 1H NMR,
13C NMR, and mass spectrometry (see ESI).
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
4-BrC6H4
4-FC6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
3,4-diCH3C6H3
2-CH3C6H4
2-ClC6H4
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
80
70
82
85
65
60
68
75
72
90
73
62
4-OCH3C6H4
4-ClC6H4
4-BrC6H4
C6H5
C6H5
4-CH3C6H4
4-BrC6H4
C6H5
C6H5
C6H5
9
10
11
12
2j
2k
2l
2,6-diClC6H4
a
Reaction conditions: (1a–l) (1.0 mmol), DIB (0.5 mmol), and solvent (2 mL) at
room temperature for 15 min.
b
Isolated yield.
Encouraged by the success of disulfide synthesis from thione,
we now further extend the scope of this synthetic method for
the oxidative coupling of thiols to disulfides (Table 3). The synthe-
sis of disulfides was carried out by treating thiols with diace-
toxyiodobenzene (DIB) in acetonitrile at room temperature for
30 min. Thiophenols having electron rich and electron deficient
substituents at para position were able to give their corresponding
products (2m–2p) in excellent yield. The sterically hindered thio-
phenols bearing 2-CH3 (2q) and 2,6-diCH3 (2r) gave the desired
disulfide in low yield.25 Additionally, thiophenols bearing electron
withdrawing group at ortho, 2-Cl (2s) and meta position, 3-Cl (2t)
can successfully transform in their corresponding product. This
synthetic protocol is also applicable for alkyl thiols such as ben-
zylthiol and cyclohexylthiol respectively. However, thiophenols
having nitro and amine functional groups were failed to give
desired disulfide.
Table 1
Optimization of reaction conditions.a
Based on literature reports,28,29 the plausible mechanism for
this reaction is proposed as shown in Scheme 2. The thiocarbonyl
N
N
HN
N
[oxidant]
[solvent]
HN
NH
1a
NH
N
S
S
S
)
Table 3
N
Coupling of thiol.a,b
2a
(
DIB
(
)
R-S-S-R
R-SH
CH3CN
Entry
Oxidant
Solvent
Yield (%)b
(2m-x)
(1m-x)
1
2
3
4
5
6
7
8
DIB
DIB
DIB
DIB
DIB
DIB
PIFA
I2
CH3CN
C2H5OH
THF
1,4-Dioxane
Toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
80
75
72
51
65
67
78
75
00
00
00
81
80
75
Entry
R
Disulfidec
Yield (%)
m.p (°C)
Lit. m.p (°C)
1
2
3
4
5
6
7
8
C6H5
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
92
95
97
90
87
80
63
68
92
93
00
00
58–59
48–49
41–42
72–73
35–36
57–58
Oil
79–82
70–71
Oil
57–5925
47–4925
41–4325
72–7425
35–3925
57–5824
Oil23
4-CH3C6H4
4-OCH3C6H4
4-ClC6H4
2-CH3C6H4
2,6-diCH3C6H3
2-ClC6H4
3-ClC6H4
C6H5CH2
9
H2O2
79–8230
70–7130
Oil30
–
–
10
11
12
13
14
TBHP (in dec)
DDQ
9
CH3CN
CH3CN
CH3CN
CH3COOH
DIBc
10
11
12
C6H11
4-NO2C6H4
2-NH2C6H4
DIBd
–
–
DIB
a
a
Reaction conditions: (1m–x) (1.0 mmol), oxidant (0.5 mmol), and CH3CN (2 mL)
Reaction conditions: (1a) (1.0 mmol), oxidant (0.5 mmol), and solvent (2 mL) at
at room temperature for 30 min.
room temperature for 15 min.
b
b
Isolated yield.
Isolated yield.
0.75 mmol of DIB was used.
DIB in presence of triethylamine (1 mmol).
c
c
All products were identified by comparison with those of the reported
d
compounds.

S.J. Singh, N.S. Devi / Tetrahedron Letters 57 (2016) 5941–5943
5943
A. Supplementary data
N
NH
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.11.
091.
N
S
HN
N
HN
PhI(OAc)2
-AcOH
N
H
S
S
I
OAc
NH
Ph
-AcOH
-PhI
1a
(
)
A
(
)
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Acknowledgements
S.J.S acknowledge the Department of Science and Technology
(DST), New Delhi, India, for generous grant support (SB/FT/CS-
006/2014), and Central Instruments Facility (CIF), IIT Guwahati
for spectral recording.