Oxidative coupling of thiols to disulfides using a solid anhydrous potassium phosphate catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.03.040

Thiols are oxidized to the corresponding disulfides with a mild base, anhydrous potassium phosphate, under ambient conditions in the presence of air.

Full text of DOI:10.1016/j.tetlet.2005.03.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3583–3585
Oxidative coupling of thiols to disulfides using a solid
anhydrous potassium phosphate catalyst
Ashutosh V. Joshi,a Sudhakar Bhusare,b Mubeen Baidossi,a
Nida Qafisheha and Yoel Sassona,*
aCasali Institute of Applied Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
bDepartment of Medicinal Chemistry, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
Received 8 January2005; revised 19 February2005; accepted 8 March 2005
Available online 2 April 2005
Abstract—Thiols are oxidized to the corresponding disulfides with a mild base, anhydrous potassium phosphate, under ambient
conditions in the presence of air.
Ó 2005 Elsevier Ltd. All rights reserved.
Applications in biochemical and industrial processes
render oxidation of thiols to disulfides as an important
reaction class.1 Moreover thiols can be conveniently
protected as disulfides and be regenerated bycleavage
of the S–S bond.2 Thus, oxidation of thiols to disulfides
is one of the widelystudied transformations. Thiols are
susceptible to over oxidation and hence there are reports
on their controlled oxidation.3 Oxidative couplings of
thiols to disulfides have been reported in the presence
of dimethyl sulfoxide,4 halogens or variants,5 nitric
oxide,6 sodium perborate,7 calcium hypochlorite and sil-
ica gel,8 phase transfer catalysts,9 hydrogen peroxide in
fluoro alcohols10 and even with superoxide ions.11 En-
zymes12 and electrochemical techniques13 have also been
utilized for this purpose. Nevertheless, it is desirable to
achieve this transformation using a clean and effective
reagent viz. air or oxygen. Oxidation of thiols depends
upon their acidities and hence theycan be subjected to
base catalysis.14 Consequently, oxidation of thiols with
air or oxygen in the presence of basic alumina,15 alkali
we considered it worthwhile to explore its efficacyin oxi-
dation of thiols to disulfides. K3PO4 has also been uti-
lized for reactions such as nitroladol,22a Knoevenagel
condensation22b and dithiocarbamates,22c whereas
hydrated K3PO4 has frequentlybeen used in transition
metal catalyzed cross coupling reactions.22d
In this communication we report an efficient and simple
method for oxidative coupling of alkyl or aryl thiols to
the corresponding disulfides in the presence of the weak
solid base, potassium phosphate (Scheme 1).
In a typical reaction, a mixture of 1 g (9.1 mmol) of thio-
phenol, 994 mg (4.55 mmol) anhydrous K3PO4 and
20 mL of acetonitrile were stirred at 25 °C in a round
bottom flask equipped with an air bubbler. GC analysis
of the reaction mixture revealed complete conversion to
the disulfide after 1 h of reaction. Similarlyother sub-
strates were subjected to the above reaction conditions
giving the corresponding disulfides. The results are listed
in Table 1.
18
base,16 CsF-Celite,17 a weaklybasic mineral support
and hydrotalcite clay19 have also been studied. Oxid-
ation of thiols with O2, catalyzed by Co(II) phthalocya-
nines has been studied in ionic liquids.20
21
Our earlier studies established that K3PO4 was basic
enough to deprotonate a substrate with a pKa as high
In our laboratorywe have studied alkylations of differ-
ent carbon acids using solid K3PO4 as a base.21 Thus
K3PO4, 25-37 ºC
2RSH + 1/2O2(air)
RSSR + H2O
acetonitrile, 1-2 h
1
2
Where: R=Ph, 4-ClC6H4, 4-tert-butyl-C6H4, PhCH2,
cyclohexyl, n-C5H11, 2-pyridyl
Keywords: Disulfides; Autoxidation; Mild base.
*
Corresponding author. Tel.: +972 26584530; fax: +972 25667064;
e-mail: ysasson@huji.ac.il
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.040

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A. V. Joshi et al. / Tetrahedron Letters 46 (2005) 3583–3585
Table 1. Oxidative coupling of thiols 1 to the corresponding disulfides
2a
yields and purity under simple and mild reaction
conditions.
c
EntryReactant
Yield of disulfide (%)
Procedure for the preparation of diphenyl disulfide: Thio-
phenol 9.1 mmol (1.0 g), anhydrous 97% K3PO4
4.55 mmol (994 mg) and acetonitrile 20 mL were stirred
together in a glass reactor equipped with an air purge
at 25 °C. Air was purged at a rate of 25–50 cm3/min.
The progress of the reaction was monitored byGC. After
completion of the reaction (1 h) the organic layer was
decanted, and the solid was washed twice with 10 mL
of acetonitrile and filtered. The combined organic layer
was concentrated under reduced pressure to give a solid,
then dried under vacuum. The weight of diphenyl disul-
fide was 904 mg (91% of theoretical yield). The identity
of the product was confirmed byGC–MS and NMR
analysis.
1
2
3
4
5
6
7
Thiophenol
91
88
85
85
89
92
89
Benzyl mercaptan
4-tert-Butylbenzenethiol
4-Chlorobenzenethiol
Cyclohexanethiol
Pyridine-2-thiol
Pentane-1-thiolb
a Reaction conditions: substrate, 1 g; anhydrous K3PO4, 50 mol % of
the substrate; acetonitrile, 20 mL; air, 25–50 cm3/min; temp, 25 °C;
time, 1–2 h.
b Temp, 37 °C; 12 h.
c Isolated yield (purity and identity of the products was confirmed by
NMR, GC and GC–MS).
as 21, consequentlywe expected that active substrates
such as thiols with pKa values in the range of 7–11 could
be easilyconverted to their conjugated base in the pres-
ence of K3PO4 (Table 1). In fact the oxidation reaction
was efficient with alkyl, cycloalkyl, aryl and benzyl
thiols. Heteroaromatic thiols were also effectively
transformed to their corresponding disulfides.
Acknowledgements
We thank Mrs. Marcela Haimberg and Mr. Michael
Mogilnitskyfrom the MS laboratoryat Makhteshim
Chemical Works, Beer Sheva, for GCMS analysis and
interpretation of several products in this study.
The reusabilityof K PO4 was verified in a thiophenol
3
oxidation reaction. The amount of base employed was
half the mole quantityof the substrate. The base could
be reclaimed and reused in a subsequent reaction after
filtration and drying.
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