Oxidation of thiols to the corresponding symmetric disulfides with benzyltriphenylphosphonium peroxodisulfate (BTPPD) under nonaqueous conditions

Article abstract of DOI:10.1080/10426500307894

This article describes the preparation of benzyltriphenylphosphonium peroxodisulfate (BTPPD), an efficient and mild reagent for oxidation of a variety of aromatic and aliphatic thiols to the corresponding disulfides in refluxing acetonitrile. The experimental procedure is simple and the products are easily isolated in excellent yields.

Full text of DOI:10.1080/10426500307894

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Phosphorus, Sulfur, and Silicon and the Related
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Oxidation of Thiols to the Corresponding Symmetric
Disulfides with Benzyltriphenylphosphonium
Peroxodisulfate (BTPPD) Under Nonaqueous Conditions
a b
a
Abdol R. Hajipour
& Arnold E. Ruoho
a
Medical School, University of Wisconsin, Madison, Wisconsin, USA
Isfahan University of Technology, Isfahan, Iran
b
Available online: 27 Oct 2010
To cite this article: Abdol R. Hajipour & Arnold E. Ruoho (2003): Oxidation of Thiols to the Corresponding Symmetric
Disulfides with Benzyltriphenylphosphonium Peroxodisulfate (BTPPD) Under Nonaqueous Conditions, Phosphorus, Sulfur, and
Silicon and the Related Elements, 178:6, 1277-1281
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Phosphorus, Sulfur, and Silicon, 178:1277–1281, 2003
Copyright �C Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200567
OXIDATION OF THIOLS TO THE CORRESPONDING
SYMMETRIC DISULFIDES WITH
BENZYLTRIPHENYLPHOSPHONIUM
PEROXODISULFATE (BTPPD) UNDER
NONAQUEOUS CONDITIONS
Abdol R. Hajipoura,b and Arnold E. Ruohoa
University of Wisconsin, Medical School, Madison, Wisconsin,
a
b
USA; and Isfahan University of Technology, Isfahan Iran
(Received October 29, 2002; accepted November 18, 2002)
This article describes the preparation of benzyltriphenylphosphonium
peroxodisulfate (BTPPD), an efficient and mild reagent for oxidation
of a variety of aromatic and aliphatic thiols to the corresponding disul-
fides in refluxing acetonitrile. The experimental procedure is simple and
the products are easily isolated in excellent yields.
Keywords: Disulfides; oxidation; peroxodisulfate; thiols
Selective oxidative coupling of thiols to disulfides is of interest from
both a biological and a synthetic point of view.1 Since thiols are among
functional groups, which can be over oxidized, extensive research has
–3
4
–9
been performed to control their oxidation. Most of the existing meth-
ods involve the use of metal catalysts or reagents like halogens and
always suffer from metal ions and solvents that are toxic in nature.
The oxidation of thiols 2 to disulfides 3 is a characteristic reaction,
and further oxidation to disulfide S-oxides (thiosulfinates), 1,1-dioxides
(
thiosulfonates), and sulfonic acids are possible. Weak S S bonds in
1
0
these compounds impart high reactivity and in natural products these
moieties and related cyclic analogues are associated with interesting
biological activity and DNA-cleaving properties.1
1–12
We gratefully acknowledge the funding support received for this project from the
Isfahan University of Technology (IUT), IR Iran (A.R.H.) and Grant GM 33138 (A.E.R.)
from the National Institutes of Health, USA.
Address correspondence to Abdol R. Hajipour, Department of Pharmacology, Univer-
sity of Wisconsin, Medical School, 1300 University Ave., Madison, WI 53706-1532. E-mail:
haji@cc.iut.ac.ir
1
277

1
278
A. R. Hajipour and A. E. Ruoho
RESULTS AND DISCUSSION
In connection with our ongoing program to introduce new reagents for
oxidation of organic compounds under mild conditions,1
3–14
we report
on the preparation of benzyltriphenylphosphonium peroxodisulfate 1
and the application of this inexpensive and mild reagent for oxidative
coupling of a variety of aliphatic and aromatic thiols and aliphatic dithi-
ols to their corresponding acyclic and cyclic disulfides. This reagent is
prepared readily by the dropwise addition of Na2S2O8 to an aqueous
solution of benzyltriphenylphosphonium chloride at room temperature.
Filtration and drying of the precipitate produced a white powder which
could be stored for months without losing its oxidizing ability.This
reagent is quite soluble in methylene chloride, chloroform, acetone,
THF, DMF, DMSO, and acetonitrile and insoluble in non-polar solvents,
such as carbon tetrachloride, n-hexane, and diethyl ether (Scheme 1).
H
O/RT
+
�
2
+
2�
2
PhCH P Ph CI + Na S O ������→ (PhCH P Ph ) S O +2NaCI
2
3
2
2
8
2
3
2
2
8
20 min
1
SCHEME 1
This method is a remarkably effective methodology for oxidizing
aliphatic and aromatic thiols to disulfides. This reagent also exhibits
a synthetically valuable method for producing cyclic disulfides from
dithiols. The oxidation of dithiols results in the formation of cyclic
and/or polymers disulfides. The polymers result from intermolecular
oxidation, while the cyclic disulfides arise from intramolecular ox-
idative coupling of dithiols. For example, oxidative coupling of 1,4-
benzenedimethanethiol gives only polymeric product (Table I), while
1
,3-dithiol gives 70% cyclic disulfides and 30% polymeric products. The
butane 1,4-dithiol gives only cyclic disulfides in 98% yields. It was found
that further oxidation producing disulfide to S-oxides, 1,1-dioxides, and
sulfonic acid did not occur. A series of thiols was oxidized to disulfides
rapidly by this reagent (Table I). Primary alcohol, amine, carboxylic
acid, ester, and methoxy functional groups were unaffected during the
oxidation of the thiols. The dithiols were oxidizing to the corresponding
cyclic disulfides in good yields (Scheme 2 and Table I).
The reactions are relatively clean with no tar formation and no over
oxidation to the corresponding disulfide S-oxides, 1,1-dioxides, and sul-
fonic acids was observed and isolation of products are straightforward.
In conclusion, in this study we have introduced a new and mild
reagent for oxidation of thiols to the corresponding disulfide The sta-
bility, ease of preparation of reagent, straightforward work-up, mild

1279

1
280
A. R. Hajipour and A. E. Ruoho
SCHEME 2
reaction conditions, high yields of the products, and reaction under non-
aqueous conditions make this method a useful one for oxidation of thiols
and dithiols to disulfides.
EXPERIMENTAL
General
All yields refer to isolated products. Products were characterized by
1
comparison with authentic samples (IR and H-NMR spectrum, melting
5
,15–20
1
and boiling point, TLC).
All H-NMR spectra were recorded at
3
00 MHz in CDCl3 and CCl4 relative to TMS (0.00 ppm).
Preparation of Benzyltriphenylphosphonium
Peroxodisulfate (BTPPD) 1
A solution of benzyltriphenylphosphonium chloride (8.63 g, 22 mmol)
in 75 ml of water was prepared, and then Na2S2O8 (3 g, 11 mmol) H2O
(
50 mL) was added dropwise to the above solution and the mixture
stirred for 20 min at room temperature. The resulting white precipi-
tate was removed by filtration and washed with cooled distilled water
(
2 � 50 mL), and dried in a desiccator under vacuum over calcium chlo-
ride to afford a white powder (9.5 g, 96% yield), which decomposed at
�
1
1
2
1
80–182 C to a dark-brown material. H-NMR (CD3CN) � 6.80-790 (m,
1
3
0 H), 4.7 (d, J = 25.6 Hz, 2 H, CH2-P), C � 134.5, 133.5, 130.2, 129.6,
29.4, 128.1, 127.7, 127.2, 117.3 (d, J = 85.7 Hz, 2 H, P-CH2). Anal calcd
for C50H44O8P2S2: C, 66.70; H, 4.90; S, 7.35%. Found: C, 66.80; H, 4.90;
S, 7.13%.
General Procedure
Oxidation of Thiols with BTPPD 1
The thiol (1 mmol) was added to a stirred solution of BTPPD (0.90 g,
mmol) in acetonitrile (5 mL). The reaction mixture was heated at
1
reflux until TLC (eluent: cyclohexane/EtOAc: 8:2) showed complete

Oxidation of Thiols to the Corresponding Symmetric Disulfides
1281
disappearance of starting material. The reaction mixture was then
cooled to room temperature and the mixture solid separated through
a short pad of silica gel and washed with acetonitrile (15 mL). The fil-
trate was evaporated and the resulting crude material was dissolved
in CH2Cl2 and washed with 5% NaOH solution. The organic layer was
dried (MgSO4) and then evaporated to dryness. The crude product was
purified by column chromatography on silica gel using a mixture of
ethyl acetate and hexane as eluent (10:90) to give disulfides in 70–98%
yields (Table I).
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