A novel rapid sulfoxidation of sulfides with cyclohexylidenebishydroperoxide

Article abstract of DOI:10.1016/j.tetlet.2008.03.122

Cyclohexylidenebishydroperoxide was successfully used as the oxygen source for the oxidation of sulfides to sulfoxides for the first time. The sulfoxides were obtained in good to high yields without any detectable over-oxidation to sulfones under normal conditions.

Full text of DOI:10.1016/j.tetlet.2008.03.122

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3463–3465
A novel rapid sulfoxidation of sulfides
with cyclohexylidenebishydroperoxide
J. Jon Paul Selvam, V. Suresh, K. Rajesh, D. Chanti Babu, N. Suryakiran, Y. Venkateswarlu *
Natural Products Laboratory, Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 29 November 2007; revised 17 March 2008; accepted 21 March 2008
Available online 28 March 2008
Abstract
Cyclohexylidenebishydroperoxide was successfully used as the oxygen source for the oxidation of sulfides to sulfoxides for the first
time. The sulfoxides were obtained in good to high yields without any detectable over-oxidation to sulfones under normal conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Oxidation; Peroxides; Sulfides; Sulfoxides; Cyclohexylidenebishydroperoxide
1. Introduction
perature and the relative amount of oxidants have to be
controlled to avoid the formation of side product.
Increasing interest and applications of sulfoxides have
stimulated investigations on new methods of sulfoxide syn-
thesis. Organic sulfoxides are useful synthetic intermediates
for the construction of various chemically and biologically
active molecules. These often play an important role as
therapeutic agents such as antiulcer (proton pump inhibi-
tor),1–3 antibacterial, antifungal, antiatherosclerotic,4–6
anthelmintic,7 antihypertensive,8 and cardiotonic agents,9
as well as psycotonics10,11 and vasodilators.12
The oxidation of sulfides is the most straightforward
method for the synthesis of sulfoxides. Racemic sulfoxida-
tion has been studied in solution and on solid phase using
several types of oxidizing agents. For example, in solution,
H2O2 is one of the most used,13 but classical oxygen trans-
fer reagents, such as m-CPBA,14 or ozone15 have also been
examined. On solid phase, there are some references to sul-
fide oxidation using H2O2 with a catalytic amount of
AcOH,16 or Sc(OTf)3,17 TBHP with p-TSA18 as catalyst
or using 4,8-dihydro-3H-[1,2]oxazineno-[3,2-a]isoquino-
line.19 Many of these reagents will result in over-oxidation
to sulfones. Therefore, the reaction conditions time, tem-
Recently, Iskra and co-workers reported a novel method
for the preparation of gem-dihydroperoxides from ketones
and H2O2 under iodine catalysis.20 This method uses read-
ily available starting materials and is easy to operate, which
paves the way for the synthetic applications of these inter-
esting peroxides as stoichiometric oxidants. As a result of
our continued interest in the development of new method-
ologies,21–25 we became interested in using these peroxides
as potential oxidizing agents for sulfoxidation. Herein, we
report the application of cyclohexylidenebishydroperoxide,
which was prepared following the reported procedure in a
high yield (Scheme 1), in the sulfoxidation of sulfides.
Initially, we used methyltolyl sulfide (Table 1, entry 2) as
the model compound for the sulfoxidation using cyclo-
hexylidenebishydroperoxide in dichloromethane as the sol-
vent at room temperature (Scheme 2). The reaction was
O
HOO
OOH
I2
+
H2O2
CH3CN
93%
*
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
Scheme 1. Preparation of cyclohexylidenebishydroperoxide.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.122

3464
J. Jon Paul Selvam et al. / Tetrahedron Letters 49 (2008) 3463–3465
Table 1
Sulfoxidation of various sulfides using cyclohexylidenebishydroperoxide (1)
Entry
Substrate
Product
Time (min)
30
Yielda (%)
O
S
S
1
89
O
S
S
2
30
92
O
S
S
3
4
50
50
90
87
O
S
S
O
S
S
5
6
7
8
60
120
120
120
91
93
92
81
MeO
MeO
O
S
S
S
O
S
OH
O
O
S
OH
O
S
S
O
S
O
O
9
120
83
79
OTBDMS
OTBDMS
OH
OH
O
S
S
10
60
a
Isolated yields after chromatographic purification.
complete in 30 min to give the corresponding sulfoxide in
good yield. To understand the scope of this reaction, we
studied the reaction of various sulfides under optimized
conditions (room temperature) and the results are summa-
rized in Table 1. The formation of products was established
from downfield chemical shift of the vicinal protons of the
sulfoxide compared to the sulfide in the H NMR spectra.
For example, the methyl group attached to sulfoxide
appeared at d 2.61 (s, 3H) (Table 1, entry 1), as compared
to the sulfide methyl at d 2.46 (s, 3H) in the 1H NMR spec-
1

J. Jon Paul Selvam et al. / Tetrahedron Letters 49 (2008) 3463–3465
3465
completion of the reaction as monitored by TLC, the sol-
vent was removed under reduced pressure and pure prod-
ucts were obtained after silica gel column chromatography.
HOO
OOH
O
S
S
Acknowledgements
DCM, RT
The authors thank the CSIR, MoES and DBT, New
Delhi, India, respectively, for the financial support and
the Director of the Indian Institute of Chemical Technol-
ogy, for his encouragement.
92%
Scheme 2. Preparation of sulfoxides using cyclohexylidenebishydro-
peroxide.
References and notes
trum of the starting material. Further, the downfield chem-
ical shift of the aromatic ortho protons of the sulfoxide
from d 7.27 to 7.62 in the H NMR spectra of sulfoxides
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1
was further proof of successful oxidation. It is evident from
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In contrast to other oxidizing reagents, cyclo-
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2. Procedure for the preparation of
cyclohexylidenebishydroperoxide 1
To a solution of I2 (25.4 mg, 0.1 mmol) in CH3CN
(10 mL) were added cyclohexanone (98 mg, 1 mmol) and
30% aq H2O2 (0.45 mL, 4 mmol), and the reaction mixture
was stirred at room temperature for 24 h. After completion
of the reaction as monitored by TLC, the solvent was
removed under reduced pressure, water (10 mL) was added
and the product was extracted into dichloromethane
(3 Â 10 mL). The combined organic layer was dried over
anhydrous sodium sulfate and evaporated under reduced
pressure. The crude product was purified through a small
column of silica gel using ethyl acetate/hexane (1:9) as elu-
ent to give pure cyclohexylidenebishydroperoxide 1, in 93%
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3. General experimental procedure for the preparation of
sulfoxides
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To a solution of sulfide (1 mmol) in DCM (10 mL) was
added cyclohexylidenebishydroperoxide (1 mmol) and the
reaction mixture was allowed to stir for the appropriate
amount of time (see Table 1) at room temperature. After