Hexamethyldisilazane (HMDS) promotes highly efficient oxidative coupling of thiols by DMSO under nearly neutral reaction conditions

Article abstract of DOI:10.1055/s-2002-19764

A variety of thiols were efficiently converted to their disulfides using DMSO in the presence of hexamethyldisilazane (HMDS) under almost neutral reaction conditions. Due to the neutrality of the reaction medium in this protocol, acid sensitive functional groups survived intact.

Full text of DOI:10.1055/s-2002-19764

346
LETTER
Hexamethyldisilazane (HMDS) Promotes Highly Efficient Oxidative Coupling
of Thiols by DMSO Under Nearly Neutral Reaction Conditions
O
xidative Coupli
a
ng of
T
hiol
b
s
Using D
M
a
S
k Karimi,* Daryoush Zareyee
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P. O. Box 45195-159, Gava Zang, Zanjan, Iran
Fax +98(241)4249023; E-mail: karimi@iasbs.ac.ir
Received 24 October 2001
perature the reaction was very sluggish and no detectable
Abstract: A variety of thiols were efficiently converted to their dis-
product was formed even after 12 hours. Once again, we
attempted a similar reaction in the presence of HMDS (1.2
ulfides using DMSO in the presence of hexamethyldisilazane
(HMDS) under almost neutral reaction conditions. Due to the neu-
equiv). Interestingly, in this case the reaction proceeded
smoothly to afford almost quantitative yield of the corre-
sponding disulfides (Table, entry 1).8 Among the various
solvents such as CH3CN, THF, and CH2Cl2, CH3CN
turned out to be a suitable solvent for this transformation.
It is worth mentioning that at least 1.2 equivalents of
HMDS were required to obtain good results. Similarly,
different types of aromatic thiols were efficiently convert-
ed to the corresponding disulfides in excellent yields un-
der similar reaction conditions (Table, entry 2–4). By this
method including acyclic, benzylic and cyclic mercap-
tanes were effectively oxidized to afford the correspond-
ing disulfides in good to excellent yields (Table, entries 5–
9). In order to show the neutrality of the reaction, we used
2-(1-phenylpropxy)-tetrahydropyran as a model for THP
ethers under the reaction conditions described above. In-
terestingly, we observed that the THP group survived in-
tact even after 24 hours. Furthermore, due to the neutrality
and mildness, this method tolerates a range of functional
groups such as organic sulfides, aromatic ethers, THP
ethers, furan rings and hydroxy groups of alcohols. In
sharp contrast to the Swern oxidation, the HMDS/DMSO
protocol only protects hydroxy functions in alcohols. To
the best of our knowledge this method can be considered
as the first example of the oxidative coupling of thiols us-
ing DMSO under nearly neutral reaction conditions.
trality of the reaction medium in this protocol, acid sensitive func-
tional groups survived intact.
Key words: oxidation, oxidative coupling, thiols, disulfides, hex-
amethyldisilizane, DMSO
Oxidative conversion of thiols to disulfides is of impor-
tance from both biological1 and synthetic point of view,2
as shown by a plethora of procedures and methods that
have been devised for this transformation.2,3 Among this,
it has been shown, that DMSO in combination with a va-
riety of acidic co-reagents can be used for this purpose.4
However, many of these protocols suffers from draw-
backs such as long reaction times, use of acidic catalysts,
and in certain cases, moderate to low yields of the desired
disulfides. Consequently, it seems that the development of
new improved protocols for high yielding oxidative cou-
pling of thiols to disulfides using inexpensive reagents are
being pursued. Application of DMSO in organic transfor-
mations is of interest because of its stability, ease of han-
dling, none corrosive and safe nature and
inexpensiveness. However, the major limitation of the use
of DMSO is its low oxidizing power. This problem can be
circumvented by prior treatment of DMSO with a variety
of oxophilic co-reagents under acidic conditions as shown
by the pioneer work of Swern et al.5 1,1,1,3,3,3-hexame-
thyldisilazane (HMDS) is a stable, weak oxophilic, com-
mercially available and cheap reagent that has generally
been used for trimethylsilylation of hydrogen labile sub-
strates,6 and giving ammonia as the only byproduct. On
the other hand, reactions using this silazane-type reagent
are nearly neutral and do not need special precaution. In
development of new methods for functional group trans-
formation, we especially interested in exploring the poten-
tial use of various types of neutral or nearly neutral
catalysts.6d,7 With this strategy in mind, we hypothesized
that HMDS might increase the reactivity of DMSO to a
reasonable level to carry out the oxidation of thiols under
nearly neutral reaction conditions. We first examined the
oxidative coupling of thiophenol using DMSO (3 equiv)
in CH2Cl2 in the absence of any additives. At room tem-
The actual mechanism of the protocol and the precise role
of HMDS are not clear at this stage. However, it is plausi-
ble that at the first stage HMDS reacts with the first mol-
ecule of thiol in the presence of DMSO to produce a
reactive species 1 and trimethylsilyl amine. Intermediate
1 in turn reacts with the second molecule of thiol in the
presence of trimethylsilylamine with concomitant release
of NH3 to afford the corresponding oxonium intermediate
2. The rapid collapse of intermediate 2 then results the for-
mation of the corresponding disulfide along with the evo-
lution of dimethylsulfide and hexamethyldisiloxane as
by-products (Scheme).
Further applications of this reagent for functional group
transformations are currently ongoing in our laboratories.
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0346,0348,ftx,en;G31301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Oxidative Coupling of Thiols Using DMSO/HMDS
347
Table Oxidative Coupling of Thiols to Disulfides Using HMDS/DMSO in CH3CN Under Nearly Neutral Conditions
Entry
1
Substrate
Product
T (min)
45
Yielda,b (%)
96
2
3
80
80
98
90
4
225
76c
5
6
250
50
82
86
7
70
90
8
9
90
95
97
96
a Yields refer to isolated pure products.
b The ratios of thiol:DMSO:HMDS were 1:3:1.2, respectively and all reactions were performed in CH3CN (5 mL per mmol of substrate).
c Reaction was performed under reflux.
Scheme
1587. (c) Firouzabadi, H.; Abbassi, M.; Karimi, B. Synth.
Commun. 1999, 29, 2527. (d) Kesavan, V.; Bonnet-Delpon,
D.; Begue, J. P. Synthesis 2000, 223. (e) Fujihara, H.;
Akashi, R.; Furukawa, N. Bull. Chem. Soc. Jpn. 1989, 62,
616. (f) Meshram, H. M.; Kache, R. Synth. Commun. 1997,
27, 2403. (g) Lu, G.; Zhang, Y. Synth. Commun. 1998, 28,
4479. (h) Mckillop, A.; Koyuneu, D. Tetrahedron Lett.
1990, 31, 5007. (i) Salehi, P.; Farrokhi, A.; Gholizadeh, M.
Synth. Commun. 2001, 31, 2777. (j) Zhonh, P.; Guo, M. P.
Synth. Commun. 2001, 31, 1825. (k) Raghavan, S.;
Ragender, A.; Joseph, S. C.; Rasheed, M. A. Synth.
Commun. 2001, 31, 1477. (l) Varma, R. S.; Meshram, H.
M.; Dahiya, R. Synth. Commun. 2000, 30, 1249.
Acknowledgement
The authors appreciate Institute for Advanced Studies in Basic Sci-
ences (IASBS) Research Council for support of this work.
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Synlett 2002, No. 2, 346–348 ISSN 0936-5214 © Thieme Stuttgart · New York

348
B. Karimi, D. Zareyee
LETTER
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(8) General Procedure for Oxidative Coupling of Thiols to
Disulfides: To a solution of thiol (3 mmol) and DMSO (9
mmol) in anhyd acetonitrile (5 mL), HMDS (3.6 mmol) was
added and the resulting solution was magnetically stirred at
r.t. The progress of the reaction was monitored by TLC.
After completion of the reaction, the mixture was poured
into 10% aq NaOH solution. The organic layer was
separated and the aq phase was extracted with ether (3 50
mL). The organic extracts were combined together and was
washed successively with 10% NaOH (25 mL) and water
(2 50 mL) and dried over anhyd Na2SO4. Evaporation of
the solvent under reduced pressure gave the almost pure
disulfide. Further purification of the product was achieved
by re-crystallization or column chromatography through a
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