Oxidation in fluoro alcohols: Mild and efficient preparation of disulfides from thiols

Article abstract of DOI:10.1055/s-2000-6262

Quantitative oxidative conversion of thiols to disulfides was effected by aqueous 30% H₂O₂ in trifluoroethanol at ambient temperature under neutral conditions.

Full text of DOI:10.1055/s-2000-6262

SHORT PAPER
223
Oxidation in Fluoro Alcohols: Mild and Efficient Preparation of Disulfides
from Thiols
Venkitasamy Kesavan, Danièle Bonnet-Delpon, Jean-Pierre Bégué*
Laboratoire BIOCIS associé au CNRS, Centre d’Etudes Pharmaceutiques, Rue J. B. Clément, 92296 Châtenay-Malabry, France
Fax +33(1)46835740; E-mail: jean-pierre.begue@cep.u-psud.fr
Received 2 September 1999; revised 16 October 1999
responding disulfides in quantitative yields (Table 1).
Benzenethiol (1a), 4-methylbenzenethiol (1b), 4-chlo-
robenzenethiol (1c) and 4-methoxybenzenethiol (1d) ex-
hibited a similar reactivity leading quickly to the
disulfides 2a,13 2b,14 2c15 and 2d4c respectively, in excel-
lent yields with no detectable influence of the substituent.
Under the same conditions, 2-aminobenzenethiol (1e) af-
forded the corresponding disulfide 2e15 in 96% yield,
whereas its oxidation with polyvinylpyridine/bromine
complex did not lead to the formation of the correspond-
ing disulfide.16
Abstract: Quantitative oxidative conversion of thiols to disulfides
was effected by aqueous 30% H2O2 in trifluoroethanol at ambient
temperature under neutral conditions.
Key words: thiols, disulfides, oxidative coupling, hydrogen perox-
ide, fluoro alcohols
Selective oxidative conversion of thiols to disulfides is of
interest from both a biological1 and a synthetic point of
view.2 It was found that under biological conditions this
reaction occurs in the presence of oxidants such as flavins,
cytochromes and dehydroascorbic acid.3 Thiols are
among functional groups which can be easily over oxi-
dized and therefore extensive studies have been carried
out for their controlled oxidation.4 Although hydrogen
peroxide is known to oxidize some thiols to disulfides,2a
this requires very long reaction times and proceeds only in
strong acidic or basic conditions. Reagents like iodine/hy-
drogen iodide,5 bromine-aqueous potassium-hydrogen-
carbonate,4c molecular bromine,6 Sm/BiCl3 in aqueous
medium,7 FeCl3/NaI2b and KMnO4−CuSO42c were report-
ed in the literature to effect oxidative coupling of thiols to
disulfides. Enzymatic8 and electrochemical9 methods are
also known to perform this oxidative transformation.
Most of the existing methods involve the use of metal cat-
alysts or reagents like halogens and always suffer with ef-
fluents due to these reagents. So there is a need to develop
a clean, mild and efficient methodology to synthesize ali-
phatic, aromatic and heteroaromatic disulfides.
30% H2O2 (1.1 equiv)
RS
2a-p
R
SH
SR
HFIP, 10 min
92-99%
1a-p
a
b
c
d
e
R= C6H5
j R= n-butyl
f
R= furfuryl
R= p-Me-C6H4
R= p-Cl-C6H4
R= p-OMe-C6H4
R= o-NO2-C6H5
k R= n-pentyl
l R= HOCH2CH2
m R= allyl
g
h
i
R= 2-pyridyl
R= 2-pyrimidyl
R= C6H5CH2
n R= tert-butyl
Scheme 1
The facile conversion of heteroaromatic thiols was dem-
onstrated by the oxidation of furfurylthiol (1f), 2-pyridi-
nethiol (1g), and 2-pyrimidinethiol (1h) (Table 1). Thus,
furfurylthiol (1f) underwent oxidation with hydrogen per-
Table 1 Oxidation of Thiols 1 in Hexafluoroisopropanol (HFIP) us-
ing 30% H2O2
The use of a fluorous medium has recently been proven to
present several advantages in organic synthesis.10 The in-
creasing demand for environment conscious chemical
processes has impelled organic chemists to explore truly
efficient oxidation methods using aqueous 30% hydrogen
peroxide as an oxidant since water is the sole side prod-
uct.11 In the course of our studies on the oxidation of or-
ganic sulfur compounds in fluorous medium12 we
explored the oxidation of thiols with aqueous hydrogen
peroxide in fluorinated alcohols.
Substrate
Producta
Yield (%)b
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
99
97
99
98
96
98
92
96
98
98
99
95
94
98
Hexafluoroisopropanol (HFIP) was first chosen as the sol-
vent since it has been proven to provide specific selectiv-
ities in oxidation reactions.12 The reactions were
performed with various thiols 1 at room temperature, us-
ing 1.1 equivalent of 30% hydrogen peroxide (Scheme 1).
The solvent was recovered during the work-up by distilla-
tion as an azeotrope and can be recycled. Aromatic thiols
could be selectively oxidized within 10 minutes to the cor-
a Reaction time: 10 min.
bAll yields are isolated yields.
Synthesis 2000, No. 2, 223–225 ISSN 0039-7881 © Thieme Stuttgart · New York

224
V. Kesavan et al.
SHORT PAPER
oxide in HFIP to afford difurfuryl disulfide17 2f in 98%
yield. 2,2’-Dipyridine disulfide18 (2g), which is a very
useful reagent in peptide chemistry,19 and 2,2’-dipyrim-
idyl disulfide18 (2h) were also obtained in very good
yields.
Table 2 Oxidation of Thiols 1 in Trifluoroethanol using 30% H2O2
Substrate
Product
Reaction time (h)
Yield (%)a
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4
5
4.5
3
2
3
1
0.5
1
1
4
6
3
1.5
8
100
98
96
97
94
96
97
94
99
95
93
96
94
92
54b
30b
Benzylthiol (1i) and aliphatic thiols 1(j-l) underwent oxi-
dation with hydrogen peroxide in HFIP to afford the cor-
responding disulfides 2i,4c 2j,20 2k2c and 2l4c in 1f
1g
1h
1i
1j
1k
1l
quantitative yields within very short times. These mild
conditions without any catalysts allow the selective oxida-
tion of allylthiol 1m to afford diallyl disulfide21 2m in
94% yield without affecting the double bond. This is a
great advantage compared to other processes such as the
use of halogens4c,5,6 that can easily add to the double bond 1m
1n
1o
1p
to give rise to mixture of products. Steric bulkiness at the
α-position does not affect the rate of the reaction as dem-
onstrated by the facile oxidation of tert-butanethiol (1n) to
6
the corresponding disulfide 2n22 in 98% yield. However,
thiosalicylic acid 1o and L-cysteine 1p under similar reac-
tion conditions gave rise to only 62% and 32% of the di-
sulfide 2o23and L-cystine 2p24 respectively, and remaining
starting material was recovered (Scheme 2). These low
yields can be attributed to the lack of solubility of thiosal-
icylic acid 1o and of L-cystine 1p in the reaction medium.
Despite the low yield in L-cystine, the reaction is selective
and no over oxidation into cysteic acid occurred unlike
other described processes such as the combination of bro-
aAll yields are isolated yields.
bStarting material was recovered.
anol was used as the solvent, the conversion was good af-
ter 24 hours, but it failed to oxidize aliphatic thiols. This
shows that a fluorous medium facilitates the oxidation
much faster.
mine and aqueous potassium hydrogen carbonate which Thus we have demonstrated a mild, efficient, and selec-
yields cysteic acid instead of cystine.4c
tive oxidation of thiols to disulfides in fluorous medium
under neutral conditions in very good yields using 30%
aqueous H2O2. No metal catalyst or reagents were used in
this methodology, which is environmentally friendly
since water is the sole byproduct. Moreover, since there is
a possibility to recover and reuse the solvent, this might be
useful in large-scale syntheses.
COOH
SH
30% H2O2 (1.1 equiv)
S
S
HFIP
62%
COOH
1o
NH2
HOOC
2o
OH
30% H2O2 (1.1 equiv)
Thiols were obtained from Aldrich Chemical Company and used
without further purification. Products were characterized by com-
parison of their physical data with those of known samples. All
yields refer to isolated products. IR spectra were recorded on a Per-
L-Cystine
HFIP
32%
SH
1p
O
2p
1
kin Elmer 1420 spectrometer. H NMR spectra were done at 200
Scheme 2
MHz in CDCl3 on a Bruker AC 200 spectrometer. TLC was per-
formed on 0.25 mm Merck precoated silica plates (60F254). Com-
pounds 2a,13 2b,14 2c15, 2d4c, 2e15, 2f17, 2g18, 2h18, 2i4c, 2j20, 2k2c,
Although HFIP could be recovered, the cost of the solvent 2l4c, 2m21, 2n22, 2o23 and 2p24 are known.
prompted us to explore the use of other less expensive flu-
orinated solvents. We found that HFIP could be suitably
Diphenyl Disulfide (2a); Typical Procedure
A round bottom flask was charged with fluorinated solvent (1 mL)
replaced by trifluoroethanol (TFE). All thiols 1(a-p) could
be selectively oxidized to the corresponding disulfides
2(a-p) in excellent yields at ambient temperature with 1.1
equivalent of aqueous 30% hydrogen peroxide in TFE.
However, the reaction times (0.5−8 hours) are longer than
in HFIP (Table 2). This difference seems to indicate the
importance of the acidity of the solvent in this reaction ef-
fectively.
and benzenethiol (1a) (0.110g, 1 mmol). To the solution, 30% aq
hydrogen peroxide (125 µL, 1.1 mmol) was added with constant
stirring. The completion of the reaction was ascertained by TLC or
GC. The solvent was distilled as an azeotrope, and can be recycled,
after destroying hydrogen peroxide with sodium sulfite (0.2 mmol).
The residue was washed with Et2O (3 x 10 mL). The ethereal solu-
tion was dried (MgSO4) and concentrated under vacuum to afford
diphenyl disulfide (2a) as the only product (0.109 g) in quantitative
yield without any purification.
When oxidation of benzenethiol (1a) was performed in
iso-propanol by 30% aqueous hydrogen peroxide, even
after 24 h only 30% conversion was observed. When eth-
Mp: 58−60 °C (lit.13 60 °C)
IR (KBr): ν = 3050, 1572, 1474, 1435, 734, 687, 470, 459 cm-1
1H NMR: δ = 7.63−7.49 (m, 4H), 7.42−7.20 (m, 6H).
Synthesis 2000, No. 2, 223–225 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Oxidation in Fluoro Alcohols: Mild and Efficient Preparation of Disulfides from Thiols
225
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We thank CEFIPRA for the financial support and a research asso-
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Synthesis 2000, No. 2, 223–225 ISSN 0039-7881 © Thieme Stuttgart · New York